OA17263A

OA17263A - Glucosylceramide synthase inhibitors.

Info

Publication number: OA17263A
Application number: OA1201500080
Authority: OA
Inventors: Mario A. Cabrera-Salazar; Cassandra Celatka; Elyse Bourque; Seng H. Cheng; Bradford Hirth; Andrew Good; Katherine Jancsics; John Marshall; Markus; Metz; Ronald K. Scheule; Yibin Xiang; Elina Makino; Herve Husson; Oxana Beskrovnaya; Zhong Zhao; John Leonard; Thomas Natoli; Renato Skerlj
Original assignee: Genzyme Corporation
Priority date: 2012-09-11
Filing date: 2013-09-10
Publication date: 2016-04-20

Abstract

The invention relates to inhibitors of glucosylceramide synthase (GCS) useful for the treatment of metabolic diseases, such as lysosomal storage diseases, either alone or in combination with enzyme replacement therapy, cystic disease and for the treatment of cancer.

Description

Field of the Invention

The présent invention relates gcnerally to the field of thcrapcutics for cystic, cancer and metabolic diseases. More specifically, the invention relates to inhibitors of glucosylceramîde synthase (GCS) useful for the treatment of diseases, such as metabolic diseases, including lysosomal storage diseases, cithcr alone or in combination with enzyme replacement therapy, neuropathie disease, cystic disease, or for the treatment of cancer.

Summary of the Related Art

Glucosylceramîde synthase (GCS) is a pivotai enzyme which catalyzes the initial glycosylation step in the biosynthesis of glucosylccramide-base glycosphingolipids (GSLs) namcly via the pivotai transfer of glucose from UDP-glucose (UDP-GIc) to ceramide to form glucosylceramîde (See Fig. I ). GCS is a transmembranc, type III intégral protein localized in the cis/medial Golgi. Glycosphingolipids (GSLs) are believed to be intégral for the dynamics of many cell membrane events, including cellular interactions, signaling and trafficking. Synthesis of GSL structures has been shown (sec, Yamashita et al., Proc. Natl. Acad. Scî. USA 1999, 96(16), 9142-9147) to bc essential for cmbryonic development and for the différentiation of some tîssucs. Ccramîdc plays a central rôle in sphingolipid metabolism and down régulation of GCS activity has been shown to hâve marked effects on the sphingolipid pattern with diminished expression of glycosphingolipids, Sphingolipids (SLs) hâve a biomodulatory rôle in physiological as well as pathological cardiovascular conditions. In particular, sphingolipids and their regulating enzymes appear to play a rôle in adaptive responscs to chronic hypoxia in the néonatal rat heart (see, El Alwanit et al., Prostaglandins & Other Lipid Mediators 2005, 78(1-4), 249-263).

GCS inhibitors hâve been proposed for the treatment of a variety of diseases (see for exampie, W02005068426). Such treatments include treatment of glycolipid storage discases (e.g., Tay Sachs, Sandhoffs, GM2 Activator deficiency, GM1 gangliosidosis and Fabry diseases), diseases associated with glycolipid accumulation (e.g., Gaucher disease; Miglustat (Zavesca), a GCS inhibitor, has been approved for therapy in type 1 Gaucher disease patients, see, Treiber et al., Xenobiotica 2007,37(3), 298-314), diseases that cause rénal hypertrophy or hyperplasia such as diabctic nephropathy; discases that cause hypcrglycemia or hypcrinsulcmia; cancers in which glycolipid synthesis is abnormal, infectious diseases caused by organisms which use cell surface glycolipids as rcceptors, infcctious discases in which synthesis of glucosylceramidc is cssential or important, discases in which synthesis of glucosylceramidc is esscntial or important, diseases in which excessive glycolipid synthesis occurs (c,g., athcrosclerosis, polycystic kidney discase, and rcnal hypertrophy), neuronal disorders, neuronal injury, inflammatory discases or disorders associated with macrophage recruitmcnt and activation (e.g., rheumatoid arthritis, Crohn’s discasc, asthma and sepsis) and diabètes mcllitus and obesity(see, WO 2006053043).

In particuiar, it has been shown that overexpression of GCS is implicated in multidrug résistance and disrupts ceramide-induced apoptosis. For example, Turzanski et al., (Experimental Hematology 2005, 33 (1), 62-72 hâve shown that ccramide induccs apoptosis in acute myeloid leukemia (AML) colis and that P-glycoprotein (p-gp) confcrs résistance to ceramide-induced apoptosis, with modulation of the ceramideglucosylceramide pathway making a marked contribution to this résistance in TF-I colis. Thus, GCS inhibitors can be useful for treatment of proliférative disorders by inducing apoptosis in discased cells.

SUMMARY OF THE INVENTION

The présent invention refera to a compound represented by the following structural formula,

p

I or a pharmaceutically acceptable sait or prodrug thereof, wherein:

n is 1, 2 or 3; m is 0 or 1 ; p is 0 or 1 ; t is 0,1 or 2; y is 1 or 2; zis 0, 1 or 2; E is S, O, NH, NOH, NNO₂, NCN, NR, NOR or NSO₂R; X¹ is CR* when m is 1 or N when m is 0;

X² is O, -NH, -CH₂-, SO₂, NH-SO₂;CH(C|-C₆) alkyl or -NR² ;

X³ is a direct bond, O, -NH, -CH₂-, CO, - CH(Ci-Cû) alkyl, SO₂NH, -CO-NH- orNR³;

X⁴ is a direct bond, CR⁴R⁵, CH2 CR⁴R⁵ or CH2 -(Ci-C₆) alkyl-CR⁴R⁵;

X⁵ is a direct bond, O, S, SO2, CR⁴R⁵; (Ci-C6)alkyl, (Ci-C₆)alkyloxy, -O- (C_rCejalkyl, (Ci-Côjalkcnyl, (Cj-Cfijalkcnyloxy, - R⁷-(C3-Cio)cycloalkyl, (C3-C|o)cycloalkyl R⁷-,- R⁷- (Cs-Ci2)aryl, (Ce-Ci2)aryl - R⁷-, - R⁷- (C2-C<))hetcroaryl, (C₂-C9)heteroaryl- R⁷-, R⁷- (C2-Ct>)heterocycloalkyl, and (C2-Ci))hetcrocycloalkyl - R⁷-, wherein R⁷ is a direct bond, O, S, SO2, CR⁴R⁵; (Ci-C6)alkyl, (Ci-C6)alkyloxy, -O- (Ci-C6)alkyl, (Ci-C6)alkenyl, (Ci-Cû)alkcnyloxy; and further wherein when X⁵is defined as - R⁷-(C3-Cio)cycloalkyl, (C3Cio)cycloalkyl - R⁷-,- R⁷- (C6-Ci2)aryl, (C6-Ci₂)aryl - R⁷-, - R⁷- (C2-C9)hctcroaryl, (C2Cpjheteroaryl- R⁷-, - R⁷- (C2-C9)hetcrocycloalkyl, and (C₂-C9)hcterocycloalkyl-R7-, wherein the (C3-C[o)cycloalkyl, (C6-C|₂)aryl, (C₂-C9)hcteroaryl, (C₂-C9)heterocycloalkyl groups arc optionally substituted by one or more substituents selected from the group consisting of halo, (Ci-Ccjalkyl, (C|-C6)alkylenyl, amino, (Cj-Cg) alkylamino, (CjCejdialkylamino, (Ci-Cr.)alkoxy, O(C3-Cô cycloalkyl), (C3-C6) cycloalkoxy, nitro, CN, OH, (Ci-Cô)alkyloxy, (C3-C6) cycloalkyl, (Ci-Cû) alkoxycarbonyl, (Ci-Ce) alkylcarbonyl, (CiCe) haloalkyl, (C₂-C9)heterocycloalkyl, R^rR⁹N-CO- wherein R⁸ and R⁹ are each independentiy selected from the group consisting of hydrogen and (Ci-Cû)alkyl or R⁸ and R⁹ can be taken together with the nitrogen to which they arc attached to form a (C₂C9)hcterocycloalkyl or (C₂-C9)hctcrocycloalkyl group optionally substituted by one to three halo groups, (Ci-Cejalkylsulfonyl optionally substituted by one or two groups selected from (Ci-Cô)alkoxy and (C3-C]o)cycloalkyl;

(Ci-Csjalkyl substituted by one to four substituents selected from the group consisting of halo, hydroxy, cyano, (Cj-CôJalkoxy, (Ci-C6)alkoxy(Ci-C6)alkoxy, (C₂4

Cs)heterocycloalkyl, (C2-C9)hcteroaryl optionally substituted by (Ci-Cejalkoxy; or (C3Cio)cycloalkoxy optionally substituted by (Ci-Cû)alkoxy; and (Ci-Ce)alkyloxy substituted by one to four substituents selected from the group consisting of halo, hydroxy, cyano, (Ci-Cô)alkoxy, (Ci-CeJalkoxyfCj-Cejalkoxy, (C2C9)hcterocycloalkyl, (C2-C9)hctcroaryl optionally substituted by (Ci-Cû)alkoxy; or (C3Cio)cycloalkoxy optionally substituted by (Ci-Cc)alkoxy;

R is (C6-C[₂)aryl, (C₂-C9)hetcroaryl, (Ci-Ccjalkyl, (C₂-C9)hctcroaryl(Ci-Cû)alkyl;

R¹ is H, CN, (Ci-Cf,)alkylcarbonyl, or (Ci-Ce)alkyl;

R² and R³ arc cach independently -H, (Ci-Ce)alkyl optionally substituted by one or more substituents selected from the group consisting of halogen, (Ci-C(i)alkyl, (C6-Ci2)aryl, (C2-C9)heteroaryl, (Ci-C6)alkyl(C6-C|2)aryl, halo(C6-Ci2)aryl, and halo(C2-C())hetcroaryl, or optionally when X² is -NR² and X³ is -NR³, R² and R³ may bc taken together with the nitrogen atoms to which they arc attached form a non-aromatic hcterocyclic ring optionally substituted by with one or more substituents selected from halogen, (Ci-Ccjalkyl, (CeCnjaryl, (C2-Ci))hctcroaryl, (Cj-C6)alkyl(C6-Ci2)aryl, halo(Ce-Ci2)aryl, and halo(C2C9)hcteroaryl;

R⁴ and R^s arc independently selected from H, (Ci-Cejalkyl, or taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3C|o)cycloalkoxy ring;

R⁶ is -H, halogen, -CN, (C6-Cj2)aryl, (Cs-Cnjaryloxy, (Ci-Ce)alkyloxy;

(Ci -Cô)alkyl optionally substituted by one to four halo or (Ci-C6)alkyl;

A¹ is (C2-C₆)alkynyl; (C3-Cio)cycloalkyl, (Cg-C^jaryl, (C₂-C9)heteroaryl, (C₂C9)hetcrocycloalkyl or benzo(C2-C9)hctcrocycloalkyl optionally substituted with one or more substituents selected from the group consisting of halo, (Ci-Cgjalkyl optionally substituted by one to three halo; (Ci-Cc)alkenyl, amino, (Ci-Cejalkylamino, (CiCû)dialkylamino, (Cj-Cfjalkoxy, nitro, CN, -OH, (C]-C6)alkyloxy optionally substituted by one to three halo; (Ci-Cgjalkoxycarbonyl, and (Cj-Ce) alkylcarbonyl;

A² is H, (C₃-Cio)cycloalkyl, (C6-Ci2)aryl, (C2-C9)hetcroaryl, (C2C9)heterocyclo alkyl or benzo(C2-C9)heterocycloalkyl optionally substituted with one or more substituents selected from the group consisting of halo, (Ci-Ce)alkyl optionally substituted byonc to three halo; (C]-Ce)alkylenyl, amino, (Ci-Ce) alkylamino, (CiCejdialkylamino, (Ci-Côjalkoxy, O(C3-Ce cycloalkyl), (C3-C6) cycloalkoxy, nitro, CN, OH, (Ci-Ce)alkyloxy optionally substituted by one to three halo; (C₃-C₆) cycloalkyl, (Cj-Cô) alkoxycarbonyl, (Ci-Cg) alkylcarbonyl, (Cj-Cè) haloalkyl, (Cj-Csjheterocycloalkyl,

R⁸R⁹N-CO- wherein R⁸ and R⁹ arc each independently selected from the group consisting of hydrogen and (Ci-Cejalkyl or R⁸ and R⁹ can be taken together with the nitrogen to which they arc attached to form a (C2-C9)hctcrocycloalkyl or (C25 CçOhcterocycloalkyl group optionally substituted by one to three halo groups, (CiCe)alkylsulfonyl optionally substituted by one or two groups selected from (Ci-Câ)alkoxy and (C3-Cio)cycloalkyl;

(Ci-Ce)alkyl substituted by one to four substituents selected from the group consisting of hydroxy, cyano, (Ci-Ccjalkoxy, (Ci-Cû)alkoxy(Ci-C6)alkoxy, (C210 Cgjhctcrocycloalkyl, (C2-C<>)hctcroaryl optionally substituted by (Ci-Cc)alkoxy; or (C3Cio)cycloalkoxy optionally substituted by (Ci-Ce)alkoxy;

or (Cj-Côjalkyloxy substituted by one to four substituents selected from the group consisting of hydroxy, cyano, (Ci-Ccjalkoxy, (Ci-CcjalkoxyiCi-Cejalkoxy, (C2Cgjhctcrocycloalkyl, (C2-Cç>)heteroaryl optionally substituted by (Ci-Ce)alkoxy; or (C315 Cio)cycloalkoxy optionally substituted by (Ci-Ce)alkoxy;

with the proviso that tlie sum of n +1 + y + z is not greater than 6;

with the proviso that when p is 0; X² is NH-SO2 and X³ is NH;

A with the proviso that when n is l; t is 0; y is l ; z is l; X is NH; E is Ο; X is NH;

A e 1

A is H and X is a direct bond; A is not unsubstituted phenyl, halophcnyl or isopropenyl 20 phenyl;

with the proviso that when n is l; t is 0; y is l ; z is 1; X² is O; E is Ο; X³ is NH; A¹is (Cû-Ci2)aryl and X^s is a direct bond; A² is H and R⁴ is H then R⁵ is not cyclohexyl;

with the proviso that when n is 1 ; t is 0; y is 1 ; z is 1 ; X² is NH; E is Ο; X³ is CH2;

R⁴ and R^s are both hydrogen; A² is H and X⁵ is a direct bond; then A* is not unsubstituted 25 phenyl; and with the proviso that when X³ is O, -NH, -CH2-, CO, - CH(Ci-Cô) alkyl, SO2NH, CO-ΝΗ- or -NR³;and X⁴ is CR⁴R⁵, CH2 CR⁴R⁵ or CH2 -(Cj-Ce) alkyl-CR⁴R⁵; then A²must be (C3-Cio)cycloalkyl, (C6-Ci2)aryl, (Cî-Cgjhetcroaryl, (C2-C(>)heterocycloalkyl or benzo(C2-C<))hetcrocycloalkyl substituted with one or more substituents selected from tlie 30 group consisting of, (C2-Ci>)heterocycloalkyl, R⁸R⁹N-CO- wherein R⁸ and R⁹ are each independently selected from the group consisting of hydrogen and (C_rC6)alkyl or R⁸ and R⁹ can be taken together with the nitrogen to which they arc attached to form a (C2Cçfihctcro cycloalkyl or (Cz-C^Jhetcrocycloalkyl group optionally substituted by one to three halo groups, (Ci-C6)alkylsulfonyl optionally substituted by one or two groups selected from (Ci-Ce)alkoxy and (C3-Cio)cycloalkyl;

(Cj-Cû)alkyl substituted by one to four substituents selected from the group consisting of hydroxy, cyano, (Ci-Cejalkoxy, (C]-Cfi)alkoxy(Ci-C6)alkoxy, (CîCrjjhctcrocycloalkyl, (Cî-Cpjhetcroaryl option“Ily substituted by (Ci-Cejalkoxy; or (C3Cio)cycloalkoxy optionally substituted by (Ci-Cfi)alkoxy;

or (Ci-Cfijalkyloxy substituted by one to four substituents selected from the group consisting of hydroxy, cyano, (Cj-CeJalkoxy, (C|-C6)alkoxy(Ci-Câ)alkoxy, (C2Cç>)hctcrocycloalkyl, (Cî-C^hctcroaryl optionally substituted by (Ci-Ce)alkoxy; or (C3Cio)cycloalkoxy optionally substituted by (Ci-Cû)alkoxy.

Certain aspects of the invention include administering the foregoing compound to a patient as part of combination therapy that includes an enzyme replacement therapy (ERT) and small molécule therapy (SMT) to reduce the amount of and/or inhibit substratc accumulation in a patient diagnoscd with a lysosomal storage disease.

The présent invention further relates to the compound of Formula I, wherein n is 1; t is 0; y is 1 andzis 1.

The présent invention further relates to the compound of Formula I, wherein n is 1; t is 1; y is 1 and z is 1.

The présent invention further relates to the compound of Formula I, wherein n is 2; tis 0; y is 1 and z is 1.

The présent invention further relates to the compound of Formula I, wherein n is 2; t is 1; y is 1 and z is 1.

The présent invention further relates to the compound of Formula I, wherein n is 3; t is 0; y is 1 and z is 1.

The présent invention further relates to the compound of Formula I, wherein n is 1; tis 2; y is 1 and z is 1.

The présent invention further relates to the compound of Formula I, wherein n is 1; t is 0; y is 1 and z is 0.

The présent invention fùrthcr relates to the compound of Formula 1, wherein n is 1; t is 1; y is 1 andzisO.

The présent invention further relates to the compound of Formula I, wherein n is 2; t is 0; y is 1 and z is 0.

The présent invention further relates to the compound of Formula I, wherein n is 2; t is l; y is l and z is 0.

The présent invention further relates to the compound of Formula I, wherein n is 3; t is 0; y is 1 and z is 0.

The présent invention further relates to the compound of Formula I, wherein n is 1; t is 2; y is 1 andz is 0.

The présent invention further relates to the compound of Formula I, wherein n is 1 ; t is 1 ; y is 2 and z is 0.

The présent invention further relates to the compound of Formula I, wherein n is 2; t is 0; y is 2 and z is 0.

The présent invention further relates to the compound of Formula I, wherein m is 1 andX¹ is CR¹.

The présent invention further relates to the compound of Formula I, wherein m is 0 and X* isN.

The présent invention further relates to the compound of Formula I, wherein m is l;Eis Ο; X² isOand X³ is NH.

The présent invention further relates to the compound of Formula I, wherein m is 1 ; E is Ο; X² is NH and X³ is NH.

The présent invention further relates to the compound of Formula I, wherein m is 1 ; E is Ο; X² is CH² and X³ is NH.

The présent invention further relates to the compound of Formula I, wherein m is 1 ; E is Ο; X² is NH and X³ is CH².

The présent invention further relates to the compound of Formula 1, wherein m is 1 ; E is S; X² is NH and X³ is NH.

The présent invention further relates to the compound of Formula I, wherein m is 0; E is Ο; X¹ is NH and X³ is NH.

The présent invention further relates to the compound of Formula I, wherein m is 1 ; E is Ο; X² is NH and X³ is CO-NH.

The présent invention further relates to the compound of Formula I, wherein m is 1 ; p is 0; X² is NH-SO; and X³ is NH.

The présent invention further relates to the compound of Formula I, wherein R⁴and R^s arc each (Ci-Ce)alkyl or taken together with the carbon to which they are attached to form a spiro (Cj-Ciojcyclo- alkyl ring or a spiro (C3-Cjo)cycloalkoxy ring.

The présent invention further relates to the compound of Formula I, wherein R⁴and R⁵ arc each methyi.

The présent invention further relates to the compound of Formula I, wherein R⁴and R⁵ arc taken together with the carbon to which they arc attached to form a spiro (C3Cio)cycloalkyl ring.

The présent invention further relates to the compound of Formula 1, wherein R⁴and R⁵ arc taken together with the carbon to which they arc attached to form a spiro cyclopropyl ring.

The présent invention further relates to the compound of Formula I, wherein R⁴and R⁵ arc taken together with the carbon to which they arc attached to form a spiro (C3Cio)cycloalkoxy ring.

The présent invention further relates to the compound of Formula 1, wherein A¹ is (Cî-Cejalkynyl or (C6-Ci2)aryl.

The présent invention further relates to the compound of Formula I, wherein A¹ is (C2-C9) hetero aryl.

The présent invention further relates to the compound of Formula I, wherein A¹ is thiophenc, thiazole, isothiazole, furanc, oxazole, isoxazole, pyrrole, imidazole, pyrazole, triazole, pyridine, pymiridine, pyridazinc, indole, bcnzotiazolc, benzo isoxazole, benzopyrazole, benzoimidazolc, benzofuran, benzooxazole or benzoisoxazole.

The présent invention further relates to the compound of Formula I, wherein A¹ is (C2-C9)hetcrocycloalky 1.

The présent invention further relates to the compound of Formula I, wherein A¹ is pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, azetidinyl, oxiranyl, methylcncdioxyl, chromenyl, barbituryl, isoxazolidinyl,

1.3- oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, l,2-pyrazolidin-2-yl, 1,3pyrazolidin-1-yl, pipcridinyl, thiomorpholinyl, l,2-tctrahydrothiazin-2-yl, 1,3tctrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, l,2-tctrahydrodiazin-2-yl,

1.3- tctrahydrodiazin-l-yl, tetrahydroazcpinyl, piperazinyl, pipcrizin-2-onyl, piperizin-3onyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyi, imidazolidinyl, 2-imidazolidinyl, 1,4dioxanyl, 8-azabicyc!o[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 3,8diazabicyclo[3.2.1 joctanyl, 2,5-diazabicyclo[2.2.1 Jhcptanyl, 2,5diazabicyclo[2.2.2]octanyl, octahydro-2H-pyrido[l ,2-a]pyrazînyl, 3azabicyclo[4.1 .OJheptanyl, 3-azabicyclo[3,l.0]hexanyl 2-azaspiro[4.4]nonanyl, 7-oxa-laza-spiro[4.4]nonanyl, 7-azabicyclo[2.2.2]heptanyl, octahydro-lH-indolyl, 2,6 diazaspiro[3.3]hcptane, 2-azaspiro[3.3]heptane, 2,7-diazaspiro[4.4]nonane, azcpane, l,4diazepanc, 3,6-diazabicyclo[3.1.l]heptane, 2-azabicyclo[2.2.1]heptane, 7azabicyclo[2.2.2]octane, 3-azabicyclo[3.1.1Jheptane or 6-azabicyclo[3.1.1 Jheptane.

The présent invention further relates to the compound of Formula I, wherein A¹ is benzo(C2-C<))hetcrocycloalkyl.

The présent invention further relates to the compound of Formula I, wherein A¹ is

2,3-dihydrobcnzo[b][l,4J dioxine or 2,2-difluorobenzo[d][l,3]dioxolc.

The présent invention further relates to the compound of Formula 1, wherein R⁶ is H.

The présent invention further relates to the compound of Formula I, X^s is a direct bond.

The présent invention further relates to the compound of Formula I, X⁵ is a CR⁴R⁵.

The présent invention further relates to the compound of Formula I, wherein R⁴and R⁵ are each methyl.

The présent invention further relates to the compound of Formula I, wherein R⁴and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3Cio)cycloalkyl ring.

The présent invention further relates to the compound of Formula I, wherein R⁴and R⁵ arc taken together with the carbon to which they arc attached to form a spiro cyclopropyl ring.

The présent invention further relates to the compound of Formula I, wherein R⁴and R⁵ arc taken together with the carbon to which they are attached to form a spiro (C3Cio)cycloalkoxy ring.

The présent invention further relates to the compound of Formula I, wherein A² is (C6-C]₂)aryl.

The présent invention further relates to the compound of Formula 1, wherein A² is (Cî-Cpjheteroaryl.

The présent invention further relates to the compound of Formula I, wherein A² is pyridine.

The présent invention further relates to the compound of Formula 1, wherein A² is (C2-C9)heterocycloalkyl.

The présent invention further relates to the compound of Formula 1, wherein A² is pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tctrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, azctidinyl, oxirartyl, mcthylencdioxyl, chromcnyl, barbituryl, isoxazolidinyl, l,3-oxazolidin-3-yl, isothiazolidinyl, l,3-thiazolidin-3-yl, l,2-pyrazolidin-2-yl, l,3pyrazolidin-l-yl, pipcridinyl, thiomorpholinyl, l,2-tctrahydrothiazin-2-yl, l,3tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, l ,2-tctrahydrodiazin-2-yl,

1,3-tctrahydrodiazin-l-yl, tetrahydroazepinyl, pipcrazinyl, pipcrizin-2-onyl, pipcrizin-3onyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyl, imidazolidinyl, 2-imidazolidinyl, 1,4dioxanyl, 8-azabicycIo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 3,8diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]hcptanyl, 2,5diazabicyclo[2.2.2]octanyl, octahydro-2H-pyrido[l,2-a]pyrazinyl, 310 azabicyclo[4.1.0]heptanyl, 3-azabicyclo[3.1.0]hcxanyl 2-azaspiro[4.4]nonanyl, 7-oxa-laza-spiro[4.4]nonanyl, 7-azabicyclo[2.2.2]hcptanyl or octahydro-lH-indoIyl.

The présent invention further relates to the compound of Formula 1, wherein A² is benzo(C2-C9)hctcrocycloalkyl.

The présent invention further relates to the compound of Formula I, where R¹ is hydrogen or methyl.

The présent further relates to the compound of Formula I, wherein n is I; 2 or 3; t is 0,1 or 2; y is 0 or 1; z is 0,1 or 2; X¹ is CR¹; m is 1; p is 1; E is Ο; X² is Ο; X³ is NH; R¹ is H; R⁴ and R⁵ arc taken together with the carbon to which they arc attached to form a spiro (Cj-CioJcycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Ce-CuJaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (Ce-Cnjaryl.

The présent invention further relates to the compound of Formula 1, wherein n is 1; 2 or 3; t is 0,1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; p is 1; E is Ο; X² is O; X³ is NH; R¹ is H; R⁴ and R^s arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Ce-Ci2)aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (Cô-Ci2)aryl.

The présent invention further relates to the compound of Formula 1, wherein n is 1; 2or3;tis0, 1 or 2; yisOor l;zis0, 1 or2;X’ isCR’;mis 1; p is 1; E is Ο; X² isO; X³ is NH; R¹ is H; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a 30 hydrogen or methyl; A¹ is (Ce-C^Jaryl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C2C^hctcroaryl.

The présent invention further relates to the compound of Formula I, wherein n is ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; p is 1 ; E is Ο; X² is O;

X³ is NH; R¹ is H; R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Cc-Ci2)aryl; X^s is a direct bond, O or CR⁴R⁵and A² is (C₂-C9)heteroaryl.

The présent invention further relates to the compound of Formula 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; zis 0, 1 or 2; X¹ is CR¹; m is 1; p is 1; E is Ο; X² is O; X³ is NH; R¹ is H; R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (C3-Cjo)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C<j)hcteroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C6-Ci₂)aryl.

The présent invention further relates to the compound of Formula 1, wherein n is 1; 2 or 3; tis 0,1 or 2; y is Oor 1; z is 0, 1 or2;X' isCR’imis 1; p is l;EisO; X² is O; X³ is NH; R* is H; R⁴ and R^s arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heteroaryl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C6-C]2)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0,1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² isNH; X³ is NH; R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Cc-Ci2)ary 1 ; X⁵ is a direct bond, O or CR⁴R^S and A² is (C6-Ci2)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2or3;tis0, 1 or 2; yisOor l;zis 0, 1 or 2; X¹ is CR*;m is 1; E is O; X²isNH;X³is NH; R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C6-Ci2)aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C6-Ci2)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is NH; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A* is (C6-Ci₂)aryl; X⁵ is a direct bond, O or CR⁴R⁵and A² is (Ci-Cpjheteroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; tis 0,1 or 2; yisOor l;zis 0, 1 or 2; X¹ is CR¹; mis l;Eis Ο; X² isNH;X³ is NH; R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Cf,-Ci2)aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2-Ci))hcteroaryL

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is NH; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (Cj-C]o)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C₂-C9)heteroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (Cô-Cnjaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1 ; 2 or 3; t is 0,1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is Ο; X² is NH; X³ is NH; R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2Co)hctcroaryl; X⁵ is a direct bond, O or CR⁴R⁵and A² is (C6-C|2)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0,1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is CH2; R⁴ and R^s are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (Qj-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Ce-C^aryl; X^s is a direct bond, O or CR⁴R^sand A² is (Ce-C|₂)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹ ; m is 1 ; E is Ο; X² is NH; X³ is CH2; R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C6-Ci2)aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (Ce-C|2)aryL

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is CH2; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-C|o)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Ce-CnJaryl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C₂-C9)hctcroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is C1I2; R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Ce-Ci2)aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C₂-C9)hctcroaryl.

The présent invention further relates to the compound of Formula 1, wherein n is 1 ; 2 or 3;,t is 0, 1 or 2; y is 0 or 1 ; z is 0,1 or 2; X¹ is CR¹ ; m is 1 ; E is Ο; X² is NH; X³ is CH2; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cw)cycloalkyl ring or spiro (Cî-Cio)cycloaikoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)hetcroaryl; X^s is a direct bond, O or CR‘*R^sand A² is (C6-Ci₂)aryl.

The présent invention further relates to the compound of Formula I, wherein n is ; 2 or 3; t is 0,1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹ ; m is 1 ; E is Ο; X² îs NH; X³ is

CH₂; R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2Cojhcteroaryl; X⁵ is a direct bond, O or CR⁴R⁵and A² is (C6-Ci2)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is CH2; X³ is NH; R⁴ and R^s are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C6-Ci2)aryl; X³ is a direct bond, O or CR⁴R⁵and A² is (C6-Ci2)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; Eis Ο; X² is CH₂; X³ is NH; R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Ce-Ci2)aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (Ce-Cujaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is CH2; X³ is NH; R⁴ and R³ are taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cjo)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Ce-Cnjaryl; X³ is a direct bond, O or CR⁴R³and A² is (C2-C9)heteroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1 ; 2 or 3; t is 0,1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is Ο; X² is CH2; X³ is NH; R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Ce-Ci2)aryl; X⁵ is a direct bond, O or CR⁴R³ and A² is (C2-C<>)heteroaryÎ.

The présent invention further relates to the compound of Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is Ο; X² is CH2; X³ is NH; R⁴ and R³ are taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C?)hctcroaryl; X³ is a direct bond, O or CR⁴R³ and A² is (Ce-Ct2)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is CH2; X³ is NH; R⁴ and R³ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2Cp)heteroaryl; X³ is a direct bond, O or CR⁴R³ and A² is (Ce-C^aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is S; X² is NH; X³ is NH; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C6-C]2)aryl; X³ is a direct bond, O or CR⁴R⁵and A² is (C6-Ci2)aryl.

The présent invention further relates to the compound of Formula I, wherein n is l; 2 or 3; t is 0, l or 2; y is 0 or l; z is 0,1 or 2; X¹ is CR¹; m is 1; E is S; X² is NH; X³ is NH; R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C(5-C(2)aryl; X^s is a direct bond, O or CR⁴R⁵ and A² is (Cô-Cnjaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is S; X² isNH; X³ is NH; R⁴ and R^s arc taken together with the carbon to which they are attached to form a spiro (Cî-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R^fi is a hydrogen or methyl; A¹ is (Ce-Cnjaryl; X⁵ is a direct bond, O or CR⁴R⁵and A² is (C2-C9)hctcroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is S; X² is NH; X³ is NH; R⁴ and R^s arc each independently methyl; R⁶ is a hydrogen or methyl; A* is (Cû-C|2)aryl; X⁵ is a direct bond, O or CR⁴R⁵and A² is (C2-C9)heteroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X* is CR¹; m is 1 ; E is S; X² is NH; X³ is NH; R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (Cj-Cio)cycloalkyl ring or spiro (C3-Cio)cyclo alkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C<>)hcteroaryl; X⁵ is a direct bond, O or CR⁴R⁵and A² is (Cô-Cnjaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X* is CR¹; m is 1; E is S; X² is NH; X³ is NH; R⁴ and R^s arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2Cgjhcteroaryl; X⁵ is a direct bond, O or CR⁴R^sand A² is (C6-Ci2)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; mis 1 ; E is SO2; X² is NH; X³is NH; R⁴ and R^s are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cto)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C6-Ci2)aryl; X^s is a direct bond, O or CR⁴R⁵ and A² is (Cg-C^aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is SO2; X² is NH; X³is NH; R⁴ and R^s arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Ce-Ci2)aryl; X^s is a direct bond, O or CR⁴R⁵ and A² is (Ce-Cnjaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, I or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is SO2; X² is NH; X³is NH; R⁴ and R⁵ arc taken together with the carbon to which they arc attached to form a spiro (C3-C[o)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C6-C|2)aryl; X^s is a direct bond, O or CR⁴R^S and A² is (C2-C9)heteroaryl.

The présent invention further relates to the compound of Formula 1, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or I ; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is SO2; X² is NH; X³is NH; R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Ce-Cujaryl; X^s ts a direct bond, O or CR⁴R⁵ and A² is (C₂-C9)heteroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is SO2; X² is NH; X³is NH; R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-Cç))hcteroaryl; X^s is a direct bond, O or CR⁴R^S and A² is (Cû-Ci2)aryl.

The présent invention further relates to the compound of Formula 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is SO2; X² is NH; X³is NH; R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2C9)hcteroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (Ce-Ci₂)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y îs 0 or 1 ; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; R⁴ and R^s arc taken together with the carbon to which they are attached to form a spiro (C3Clo)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C6-Ci2)aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C6-C|₂)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Cfi-Ci2)aryl; X⁵ is a direct bond, O or CR⁴Rⁱ and A² is (C6-Ci2)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; R⁴ and R^s are taken together with the carbon to which they arc attached to form a spiro (C3Cjo)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Ce-Ci2)aryl; X⁵ is a direct bond, O or CR⁴R⁵and A² is (C2-C9)hcteroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C6-Ci2)aryl; X^s is a direct bond, O or CR⁴R⁵and A² is (C2-C9)hctcroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spire (C3Cio)cycloalkyl ring or spire (C3-C|o)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C<))hcteroaryl; X^s is a direct bond, O or CR⁴R⁵ and A² is (Cû-CnjaryL

The présent invention further relates to the compound of Formula 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C₂-C9)heteroaryl; X⁵ is a direct bond, O or CR⁴R⁵and A² is (Cs-Ci2)aryl.

The présent invention further relates to the compound of Formula 1, wherein n is

1; 2 or 3; t is 0,1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is CO-NH; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spire (C3-Cio)cycloalkyl ring or spire (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Ce-Ciîjaryl; X^s is a direct bond, O or CR⁴R⁵ and A² is (C6-Ci₂)aryl.

The présent invention further relates to the compound of Formula I, wherein n is ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is Ο; X² is NH; X³ is CO-NH; R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C6-Ci2)aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (Ce-Cnjaryl.

The présent invention further relates to the compound of Formula I, wherein n is

1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is Ο; X² is NH; X³ is

CO-NH; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spire (C3-Cio)cycloalkyl ring or spire (C3-Cio)cycloalkoxyring; R⁶ is a hydrogen or methyl; A¹ is (C6-Ci2)aryl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C2-C9)heteroaryl.

1; 2 or 3; t is 0,1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ îs CR¹; m is 1; Eis Ο; X² is NH; X³ is CO-NH; R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C6-Ci2)aryl; X^s is a direct bond, O or CR⁴R^S and A² is (C2-C9)heteroaryl.

The présent invention fiirther relates to the compound of Formula I, wherein n is

1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; EisΟ; X² is NH; X³ is

CO-NH; R⁴ and R³ arc taken together with the carbon to which they are attached to form a spire (C3-Cio)cycloalkyl ring or spire (C3-Cio)cycloalkoxy ring; R⁶ is a hydiogen or methyl; A¹ is (C2-C<>)hcteroaryl; X⁵ is a direct bond, O or CR⁴R⁵and A² is (C6-Ci₂)aryl.

The présent invention further relates to the compound of Formula l, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² isNH; X³ is CO-NH; R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2Cp)heteroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (Ce-C^aryl.

The présent invention further relates to the compound of Formula 1, wherein n is 1; 2or3;tis0, 1 or2;yis0or l;zis 0, 1 or2;X^l is CR¹; mis 1; p is l;EisO; X²is O; X³ is NH; R¹ is H; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (Cî-Cjojcycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C6-Ci2)aryl; X^s is a direct bond, O or CR⁴R^sand A² is (C2Cçijheterocycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ isCR^mis l;pis 1; Eis Ο; X² is O; X³ is NH; R¹ is H; R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ ïs (Cô-Ci2)aryl; X^s is a direct bond, O or CR⁴R⁵ and A² is (C₂-C9)heterocycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹ ; m is 1 ; p is 1 ; E is Ο; X² is O; X³ is NH; R¹ is H; R⁴ and R^s arc taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-Cp)hcterocycloalkyl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C₆-C₁₂)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; p is 1; E is Ο; X² is O; X³ is Nil; R¹ is II; R⁴ and R^s arc each independently methyl; R⁶ is a hydrogen or methyl; A* is (C2-Cç))heterocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (Câ-Ci₂)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2or 3; t is 0,1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ isCR¹;m is 1; E isΟ; X² isNH; X³ is NH; R⁴ and R⁵ arc taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Cô-Ci2)aryl; X⁵ is a direct bond, O or CR⁴ R⁵ and A² is (C2Cp)hetero cyclo alkyl.

The présent invention further relates to the compound of Formula 1, wherein n is ; 2 or 3; t is0,1 or 2; y is 0or 1 ; z is 0, 1 or 2; X¹ is CR¹; mis 1 ; Eis Ο; X² is NH;X³ is

NH; R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C6-Ci2)aryl; X^s is a direct bond, O or CR⁴R^S and A² is (C₂-C9)hcterocycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, I or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is NH; R⁴ and R⁵ arc taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (Cj-Ciojcycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heterocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (CeC12)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or2;yis0or 1; zisO, 1 or2;X‘ is CR¹; mis 1; EisO;X²isNH; X³ is NH; R⁴ and R^s arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2Cojhctcrocycloalkyl; X^s is a direct bond, O or CR⁴R⁵and A² is (C6-Ci2)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² isNH; X³ is CH2; R⁴ and R^s are taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (Ca-Cnflcycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Ce-Cujaryl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C2Cg)hcterocycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is I; 2or 3; t is 0, 1 or 2; y is 0 or 1; zis 0, 1 or 2; X¹ is CR¹; mis I; Eis Ο; X² isNH; X³ is CH2; R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C6-C|2)aryi; X^s is a direct bond, O or CR⁴R^sand A² is (C₂-Cs)heterocycloalkyl,

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X* is CR¹; m is 1; E is Ο; X² is NH; X³ is CH2; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)hetcrocycloalkyl; X⁵ is a direct bond, O or CR⁴R^S and A² is (CeCi₂)aryl.

1; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is Ο; X² is NH; X³ is

CH₂; R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2C9)heterocycloalkyl; X^s is a direct bond, O or CR⁴R^sand A² is (Ce-Cj2)aryL

1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is CH₂; X³ is

NH; R⁴ and R⁵ arc taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Cs-Cujaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2Cg)hctcrocycloalkyl.

The présent invention further relates to the compound of Formula 1, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, I or 2; X¹ is CR¹ ; m is 1 ; E is Ο; X² is CH2; X³ is NH; R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Cô-Ci2)aryl; X^s is a direct bond, O or CR⁴R^S and A² is (C2-C<))heterocycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X* is CR¹ ; m is 1 ; E is Ο; X² is CH2; X³ is NH; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cjo)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heterocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (CgCnjaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is CH2; X³ is NH; R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2Cr))heterocycloalkyl; X^s is a direct bond, O or CR⁴R⁵ and A² is (Ce-Ciîjaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2or3;tis0, 1 or 2; y is 0 or 1; z is 0, 1 or2;X^] is CR¹; m is 1; E is S; X² is NH; X³ is NH; R⁴ and R^s arc taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Ce-Cijjaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2C9)heterocycloalkyl.

The présent invention further relates to the compound of Formula 1, wherein n is 1; 2 or 3; t îs 0, 1 or 2; y is 0 or 1; z is 0,1 or 2; X¹ is CR¹; m is 1; E is S; X²is NH; X³ is NH; R⁴ and R^s arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Cc-Ci2)aryl; X⁵ îs a direct bond, O or CR⁴R^S and A² is (Cî-Cpjhetcrocycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is S; X² is NH; X³ is N H; R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Cî-Cyjhetcrocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (CôCi2)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m îs 1; E is S; X² is NH; X³ is NH; R⁴ and R^s arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2Cÿjhcterocycloalkyl; X^s is a direct bond, O or CR⁴R⁵and A² is (Cfi-Ci2)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0,1 or 2; y is 0 or 1; z is 0, l or 2; X¹ is CR¹; m is 1; E is SO2; X² is NH; X³is NH; R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C6-Ci2)aryl; X⁵ is a direct bond, O or CR⁴R⁵and A² is (C₂Cyjhctcrocycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is SO2; X² is NH; X³is NH; R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C6-Ci2)aryl; X^s is a direct bond, O or CR⁴R^S and A² is (C2-C9)hetcrocycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z îs 0,1 or 2; X¹ is CR¹; m is 1; E is SO2; X² is NH; X³is NH; R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C'3~Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heterocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (CeCi2)aryl.

The présent invention further relates to the compound of Formula 1, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X* is CR¹; m is 1 ; E is SO2; X² is NH; X³is NH; R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2Cpjheterocycloalkyl; X⁵ is a direct bond, O or CR⁴R^sand A² is (Ce-Ci2)aryl.

1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; R⁴ and

R^s are taken together with the carbon to which they are attached to form a spiro (C3C'io)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C6-Ci2)aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2-C9)hcterocycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; R⁴ and

R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C6-C]2)aryl; X^s is a direct bond, O or CR⁴R^S and A² is (C2-Cg)heterocycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3Cio)cycloalkyl ring or spiro (C3-Cjo)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heterocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C6-Cj2)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X* is N; m is 0; E is Ο; X³ is NH; R⁴ and R⁵ are each independently methyl; R^c is a hydrogen or methyl; A¹ is (C2Ci>)heterocycloalkyl; X^s is a direct bond, O or CR⁴R^S and A² is (Cû-Ci2)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is CO-NH; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Cû-Ci2)aryl; X⁵ is a direct bond, O or CR⁴R^sand A² is (C₂C<))hcterocycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is Oor 1; zis 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² isNH; X³ is CO-NH; R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C6-Ci₂)aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2-C<>)heterocycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is CO-NH; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-Cg)heterocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C^Ci2)aryl.

1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0,1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is

CO-NH; R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C₂Cç>)heterocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵and A² is (C6-Ci2)aryl.

1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; p is 1; E is Ο; X² is O;

X³ is NH; R¹ is H; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (Cî-Cio)cycloalky[ ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A* is (C2-C<>)heteroaryl; X⁵ is a direct bond, O or CR⁴R^Î and A² is (C₂-Ci>)hcterocycloalkyl.

The présent invention further relates to the compound of Formula l, wherein n is l; 2 or 3; t is 0, l or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; p is 1; E is Ο; X² is O; X³ is NH; R¹ is H; R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)hctcroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C₂C9)hetcrocyc loa Iky l.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2or3;tis0, 1 or2;yis0or 1; zisO, 1 or2;X' ÎsCR’;mis 1; p is 1; E is Ο; X² is O; X³ is NH; R¹ is H; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)hetcrocycloalkyi; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C₂-C9)heteroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y isOor l;zis0, 1 or 2; X¹ is CR¹; mis l;pis 1; Eis O;X²isO; X³ is NH; R¹ is H; R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heterocycloalkyl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C₂C9)hetcroaryl.

The présent invention further relates to the compound of Formula 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is NH; R⁴ and R^s are taken together with the carbon to which they are attached to form a spiro (C3-C[o)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)hctcroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2C9)heterocycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y îs 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is NH; R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2C9)hctcroaryl; X^s is a direct bond, O or CR⁴R^S and A² is (C₂-C9)heterocycloalkyl.

1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X* is CR¹; m is l; E is Ο; X² is NH; X³ is

NH; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heterocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2Cojheteroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is NH; R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A^! is (C2Cpjheterocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (Cî-C^heteroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0,1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is CH2; R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)hctcroaryl; X⁵ is a direct bond, O or CR⁴R⁵and A² is (C2Cpjhetcrocycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; Eis Ο; X² is NH; X³ is CII2; R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2C9)hcteroaryl; X^s is a direct bond, O or CR⁴ R⁵ and A² is (C2-C9)heterocycloalkyl.

The présent invention further relates to the compound of Formula 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0or 1; z is 0, 1 or 2; X¹ is CR¹; mis 1; Eis Ο; X² isNH;X³ is CH 2; R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)hctcrocycloalkyl; X^s is a direct bond, O or CR⁴R⁵ and A² is (C2C9)heteroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z îs 0, 1 or 2; X¹ is CR¹; m is 1 ; E is Ο; X² is NH; X³ is CH2; R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2C9)heterocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵and A² is (C2-Ci>)heteroaryL

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, I or 2; X¹ is CR¹; m is 1; E is Ο; X² is CH2; X³ is NH; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heteroaryl; X⁵ is a direct bond, O or CR⁴R⁵and A² is (C2C9)heterocycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is l; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is CH2; X³ is

NH; R⁴ and R⁵ arc cach independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2C^heteroaryl; X⁵ is a direct bond, O or CR⁴R^sand A² is (C2-Ci>)heterocycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is CH2; X³ is 5 NH; R⁴ and R^s are taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-Cg)hctcrocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2CiOheteroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 10 1; 2 or 3; t isO, 1 or 2; y isOor 1; z is 0, 1 or 2; X¹ isCR^l;mis l;EisO;X² is CH2; X³ is

NH; R⁴ and R^s arc cach independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2Cç>)heterocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (Ca-Cgjhetcroaryl.

The présent invention further relates to the compound of Formula I, wherein n is ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹ ; m is 1 ; E is S; X² is NH; X³ is

NH; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)hetcroaryl; X⁵ is a direct bond, O or CR⁴R^sand A² is (C2C9)heterocycloalky 1.

The présent invention further relates to the compound of Formula I, wherein n is 20 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is S; X² is NH; X³ is

NH; R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2C9)hctcroaryl; X⁵ is a direct bond, O or CR⁴R⁵and A² is (C2-C9)hetcrocycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 25 I;2or3;tis0, I or 2; y isOor l;zis0, 1 or2;X* isCR^mis 1; E is S; X² is NH; X³ is NH; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Cz-Cgjhetcrocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2Cgjheteroaryl.

1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, I or 2; X¹ is CR¹; m is 1; E is S; X² is NH; X³ is NH; R⁴ and R⁵ are cach independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2Cg)heterocycloalkyl; X^s is a direct bond, O or CR⁴R⁵and A² is (C2-C9)hetcroaryl,

The présent invention further relates to the compound of Formula I, wherein n is l; 2 or 3; t is 0, l or 2; y is 0 or l; z is 0, I or 2; X¹ is CR¹; m is 1; E is SO2; X² is NH; X³is NH; R⁴ and R⁵ are taken together with the carbon to which they arc attached to form a spiro (Cj-CioJcycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-Cp)hctcroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2Grihctcrocycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is SO₂; X² is NH; X³is NH; R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2Cpjheteroaryl; X⁵ is a direct bond, O or CR⁴R³ and A² is (C2-C<))heterocycloalkyl.

The présent invention further relates to the compound of Formula 1, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹ ; m is 1 ; E is SO2; X² is NH; X³is NH; R⁴ and R³ are taken together with the carbon to which they are attached to form a spiro (C3-Cto)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A* is (C2-C9)heterocycloalkyl; X³ is a direct bond, O or CR⁴R^S and A² is (C2Cgjhetcroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is SO2; X² isNH; X³is NH; R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2C<>)hctcrocycloalkyl; X³ is a direct bond, O or CR⁴R³and A² is (C2-C9)hctcroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or I ; z is 0,1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heteroaryl; X³ is a direct bond, O or CR⁴R⁵and A² is (C2-C9)heterocycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t îs 0, 1 or 2; y is 0 or 1; z is 0, I or 2; X¹ is N; m is 0; E is Ο; X³ is NH; R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Ci-Cçjhetcroaryl; X⁵ is a direct bond, O or CR⁴R³ and A² is (C2-C9)hetcrocycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (C3Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)hetcrocycloalkyl; X³ is a direct bond, O or CR⁴R³ and A² is (Cz-Cçjhcteroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; R⁴ and R^s arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2Cojhctcrocycloalkyl; X^s is a direct bond, O or CR⁴R^S and A² is (Cî-Cçjhctcroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; Eis Ο; X² is NH; X³ is CO-NH; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (Ca-Ciojcycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-Ct>)hetcroaryl; X^s is a direct bond, O or CR⁴R⁵and A² is (C2Cç>)he tero cycloa I kyl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is CO-NH; R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2Ct))hcteroaryl; X^s is a direct bond, O or CR⁴R^sand A² is (C2-Cg)heterocycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is I; E is Ο; X² is NH;X³ is CO-NH; R⁴ and R^s arc taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-C]o)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-Cp)hetcrocycloalkyl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C2Cylhctcroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is0,1 or 2; y is 0or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; Eis Ο; X² is NH;X³ is CO-NH; R⁴ and R^s are each independently methyl; R^e is a hydrogen or methyl; A* is (C₂Cç>)heterocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵and A² is (C2-C9)heteroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0,1 or 2; X¹ is CR¹; m is 1; p is 1; E is Ο; X² is O; X³ is NH; R¹ is H; R⁴ and R^s are taken together with the carbon to which they are attached to form a spiro (C₃-Cio)cycloalkyl ring or spiro (C3-Cjo)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heteroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2-C9)heteroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; p is 1; E is Ο; X² is O; X³ is NH; R¹ is H; R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A* is (C2-C9)hctcroaryl; X^s is a direct bond, O or CR⁴R^S and A² is (C2-C9)heteroaryl.

The présent invention further relates to the compound of Formula l, wherein n is l; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is NH; R⁴ and R⁵ arc taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-Cg)hcteroaryl; X⁵ is a direct bond, O or CR⁴R^sand A² is (C₂Cç>)hctcroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0,1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is Ο; X² is NH; X³ is NH; R⁴ and R⁵ are each independently methyl; R⁶ îs a hydrogen or methyl; A¹ is (C₂C<))hetcroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2-C<))hetcroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is Ο; X² îs NH; X³ is CH2; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heteroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C₂Cÿjheteroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, I or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is CH2; R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2Cgjhctcroaryl; X^s is a direct bond, O or CR⁴R⁵ and A² is (C2-C9)hctcroaryL

The présent invention further relates to the compound of Formula 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0,1 or 2; X¹ is CR¹; m îs 1; E is Ο; X² is CH2; X³ is NH; R⁴ and R^s are taken together with the carbon to which they are attached to form a spiro (C3-Cto)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Ca-Cgjheteroaryl; X^s is a direct bond, O or CR⁴R⁵ and A² is (C2C9)heteroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is Ο; X² is CH2; X³ is NH; R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2Cpjhcteroaryl; X⁵ is a direct bond, O or CR⁴R^îand A² is (C2-C9)heteroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is S; X² is NH; X³ is NH; R⁴ and R^s arc taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heteroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C₂C<>)heteroaryl.

The présent invention further relates to the compound of Formula 1, wherein n îs 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is S; X² is NH; X³ is NH; R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2Cp)heteroaryl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C2-C<))hctcroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, i or 2; X¹ is CR¹; m is 1; E is SO2; X² is NH; X³is NH; R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (CvCiojcycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-Cp)heteroaryl; X^s is a direct bond, O or CR⁴R^S and A² is (C₂Cÿ)heteroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is SO2; X² is NH; X³îs NH; R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2Cp)heteroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2-Ci>)heteroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1 ; 2 or 3; t is 0, I or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; R⁴ and R⁵ arc taken together with the carbon to which they arc attached to form a spiro (C3Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-Cg)heteroaryl; X^s is a direct bond, O or CR⁴R^Î and A² is (C2-C9)heteroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ isN; m is 0; E is Ο; X³ is NH; R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-Cç))hcteroaryl; X^s is a direct bond, O or CR⁴R^S and A² is (C2-C<>)hcteroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is CO-NH; R⁴ and R⁵ are taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (CrCpjhcteroaryl; X^s is a direct bond, O or CR⁴R^S and A² is (C₂Cp)heteroaryl.

The présent invention further relates to the compound of Formula 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is Ο; X² is NH; X³ is

CO-NH; R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A* is (C₂Co)heteroaryl; X⁵ is a direct bond, O or CR⁴R⁵and A² is (C2-Cç>)heteroaryl.

The présent invention further relates to the compound of Formula I, wherein n is l; 2 or 3; t is 0, l or 2; y is 0 or l; z is 0, 1 or 2; X¹ is CR¹; m is 1; p is 1; E is Ο; X² is O; X³ is NH; R¹ is H; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-C]o)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C6-Ci2)aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C3Cio)cycloalkyl.

The présent invention further relates to the compound of Formula 1, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; p is 1 ; E is Ο; X² is O; X³ is NH; R¹ is H; R⁴ and R^J are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Cû-C]2)aryl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C3-Cio)cycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; p is 1; E is Ο; X² is O; X³ is NH; R¹ is H; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-C|o)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C3-Cjo)cycloalkyl; X^s is a direct bond, O or CR⁴R⁵and A² is (C6-Ci₂)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0,1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; p is 1; E is Ο; X² is O; X³ is NH; R¹ is H; R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C3-Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵and A² is (Cs-Cujaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or2;yis0or l;zis0, 1 or 2; X¹ isCR‘;mis l;Eis Ο; X² is NH; X³ is NH; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Cfi-Ci₂)aryl; X⁵ is a direct bond, O or CR⁴R⁵and A² is (C3-Cio)cycloalkyl.

The présent invention further relates to the compound of Formula 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0,1 or 2; X¹ is CR¹; m is 1; E is Ο; X² isNH; X³ is NH; R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Cô-Ci2)aryl; X^s is a direct bond, O or CR⁴R⁵ and A² is (C3-Cio)cycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is Ο; X² is NH; X³ is

NH; R⁴ and R^s are taken together with the carbon to which they arc attached to form a spiro (Cî-Cio)cycloaLkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A^l is (C3-Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C6-Ct₂)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0,1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is NH; R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C3Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (Ce-Cnjaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is CH₂; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycioalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C6-Cj2)aryl; X^s is a direct bond, O or CR⁴R⁵ and A² is (C3-Cio)cycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0,1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ îs CR¹; m is 1; Eis Ο; X² isNH; X³ is CH2; R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A* is (Cô-Ci2)aryl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C3-Cio)cycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is CH2; R⁴ and R⁵ arc taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C3-C|o)cycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C6-Ci₂)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, I or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is CH2; R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A* is (C3Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (Cô-Ci2)aryl.

The présent invention further relates to the compound of Formula 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0,1 or 2; X¹ is CR’;m is 1; E is Ο; X² is CH2; X³ is NH; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Cô-Ci2)aryl; X^s is a direct bond, O or CR⁴R^S and A² is (C3-Cio)cycloalkyl.

NH; R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C6-Ci2)aryl; X⁵ is a direct bond, O or CR⁴R^sand A² is (C3-Cio)cycloalkyl.

The présent invention further relates to the compound of Formula 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is CH2; X³ is NH; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (Cî-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C3-Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C6-Ci2)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X* is CR¹; m is 1; E is Ο; X² is CH2; X³ is NH; R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C3Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C6-Cj2)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is S; X² is NH; X³ is NH; R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (C3-C]o)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R^e is a hydrogen or methyl; A¹ is (Ce-C|₂)aryl; X⁵ is a direct bond, O or CR⁴R^sand A² is (C3-Cio)cycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0,1 or 2; y is0or 1; zis0,1 or 2; X¹ is CR¹; mis 1; E is S; X² isNH; X³ is NH; R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C6-Ci₂)aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C3-Cio)cycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; zis 0, 1 or 2; X¹ is CR¹; m is 1; E Îs S; X²is NH; X³ is NH; R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C3-Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵and A² is (C6-Ci₂)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is S; X² is NH; X³ is NH; R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C3Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R^sand A² is (C6-Ci₂)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0,1 or 2; y is 0 or 1; z is 0,1 or 2; X¹ is CR¹; m is 1; E is SO2; X² is NH; X³is NH; R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (C3-C|o)cycloalkyl ring or spiro (C3-Cjo)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C6-C|2)aryl; X^s is a direct bond, O or CR⁴R^sand A² is (C3-Cio)cycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0,1 or 2; y is Oor 1; zis 0, 1 or 2; X¹ is CR¹; mis 1; Eis SÛ2;X² isNH;X³is NH; R⁴ and R⁵ arc each independently methyi; R⁶ is a hydrogen or methyi; A¹ is (Cû-Ci2)aryl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C3-Cio)cycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0or 1; zis 0, 1 or 2; X¹ is CR¹; m is 1; Eis SO2; X² isΝΗ; X³is NH; R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro «h-Ciojcycloaikoxy ring; R⁶ is a hydrogen or methyi; A¹ is (C3-Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (Cs-C^aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is SO2; X² is NH; X³is NH; R⁴ and R⁵ are each independently methyi; R⁶ is a hydrogen or methyi; A¹ is (C3Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵and A² is (C6-Ci2)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; R⁴ and R^s are taken together with the carbon to which they arc attached to form a spiro (C3Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyi; A¹ is (Câ-Ci2)aryl; X⁵ is a direct bond, O or CR⁴R⁵and A² is (C3-Cio)cycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0,1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; R⁴ and R⁵ arc each independently methyi; R⁶ is a hydrogen or methyi; A¹ is (C6-Ci2)aryl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C3-Cio)cycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1 ; 2 or 3; t is 0,1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; R⁴ and R^s are taken together with the carbon to which they arc attached to form a spiro (C3Cio)cycloalkyl ring or spiro (C₃-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyi; A¹ is (C3-Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵and A² is (C6-C)2)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0,1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; R⁴ and R⁵ are each independently methyi; R⁶ is a hydrogen or methyi; A¹ is (C3-Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C6-Ci2)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; Eis Ο; X² isNH; X³ is

CO-NH; R⁴ and R^s are taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R^fi is a hydrogen or methyl; A¹ is (Cs-Ci2)aryl; X^s is a direct bond, O or CR⁴R^sand A² is (C3-C]o)cycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is Ο; X² is NH; X³ is CO-NH; R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Cû-Cnjaryl; X⁵ is a direct bond, O or CR⁴R⁵and A² is (C3-Cio)cycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is CO-NH; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C3-Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C6-Cj2)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is Ο; X² is NH; X³ is CO-NH; R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C3Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C6-Ci2)aryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is l; p is 1; E is Ο; X² is O; X³ is NH; R¹ is H; R⁴ and R³ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C<;)hctcroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C3-Cio)cycloalkyl.

The présent invention further relates to the compound of Formula 1, wherein n is 1; 2or3;tisO, 1 or2;yis0or l;zis 0,1 or 2; X¹ isCR^!;mis 1; pis 1; Eis O;X² isO; X³ is NH; R¹ is H; R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-Cg)heteroaryl; X⁵ is a direct bond, O or CR⁴R⁵and A² is (C3-C]o)cycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1 ; 2 or 3; t is 0,1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; p is 1 ; E is Ο; X² is O; X³ is NH; R¹ is H; R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (C3-Cjo)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C3-Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R^sand A² is (C2-C<>)heteroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; p is I; E is Ο; X² is O;

X³ is NH; R* is H; R⁴ and R^s arc cach independentiy methyl; R⁶ is a hydrogen or methyl; A¹ is (C3-Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C2-C9)heteroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is Ο; X² is NH; X³ is NH; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C₂-C9)hetcroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C3Cio)cycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹ ; m is 1 ; E is Ο; X² is NH; X³ is NH; R⁴ and R⁵ are cach independentiy methyl; R⁶ is a hydrogen or methyl; A¹ is (C2C9)hctcroaryl; X⁵ is a direct bond, O or CR⁴R^sand A² is (CrCI(;)cycloiilkyL

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is NH; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cjo)cycloalkyl ring or spiro (C3-Cjo)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C3-Cio)cycloalkyl; X^s is a direct bond, O or CR⁴R^S and A² is (C₂C9)hetcroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0,1 or 2; y is 0 or 1; z is 0,1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is NH; R⁴ and R^s arc each independentiy methyl; R⁶ is a hydrogen or methyl; A¹ is (C3Cio)cycloalkyl; X^s is a direct bond, O or CR⁴R^sand A² is (C2-C9)hcteroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0,1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is CH2; R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-C|o)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)hetcroaryl; X^s is a direct bond, O or CR⁴R⁵ and A² is (C3Cio)cycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0,1 or 2; X¹ is CR¹; m is 1 ; E is Ο; X² is NH; X³ is

CH₂; R⁴ and R⁵ are each independentiy methyl; R⁶ is a hydrogen or methyl; A¹ is (C₂Cgjhcteroaryl; X⁵ is a direct bond, O or CR‘‘R⁵ and A² is (C3-Cio)cycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X* is CR¹; m is 1; E is Ο; X² is NH; X³ is CH2; R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C3-Cio)cycloalkyl; X³ is a direct bond, O or CR⁴R⁵ and A² is (C2Cç>)heteroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is CH2; R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A* is (C3Cio)cycloalkyl; X³ is a direct bond, O or CR⁴R^sand A² is (C2-Ci))hetcroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is CH₂; X³ is NH; R⁴ and R³ arc taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycioalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-Cg)hctcroaryl; X³ is a direct bond, O or CR⁴R⁵and A² is (C3C|o)cycloalkyl.

The présent invention further relates to the compound of Formula 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is CH2; X³ is NH; R⁴ and R³ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C₂Cgjhctcroaryl; X³ is a direct bond, O or CR⁴R³and A² is (C3-Cio)cycloalkyl,

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0,1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is CH2; X³ is NH; R⁴ and R³ arc taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C3-Cio)cycloalkyl; X³ is a direct bond, O or CR⁴R³ and A² is (C2C^heteroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is Ο; X² is CH2; X³ is NH; R⁴ and R³ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C3Cio)cycloalkyl; X³ is a direct bond, O or CR⁴R³ and A² is (C2-C9)hetcroaryl.

I;2or3;tis0,1 or2;yis0or l;zis 0, 1 or2;X* is CR¹; mis 1; Eis S;X² isNH; X³ is

N H; R⁴ and R³ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3~Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C₂-C9)hetcroaryl; X⁵ is a direct bond, O or CR⁴R^sand A² is (CjCio)cycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹ ; m is 1 ; E is S; X² is NI-I; X³ is NH; R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C₂Cçjhetcroaryl; X^s is a direct bond, O or CR⁴R^sand A² is (C3-Cio)cycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0,1 or 2; X¹ is CR¹; m îs 1; E is S; X² is NH; X³ is NH; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C3-C|o)cycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C₂Cg)hcteroaryl,

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0,1 or 2; y is 0 or 1 ; z is 0,1 or 2; X¹ is CR¹; m is 1; E is S; X² is NH; X³ is NH; R⁴ and R⁵ are cach independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C3Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C₂-Cp)hetcroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2or3;tis0, 1 or 2; y is 0 or l;zis0, 1 or 2; X¹ is CR¹; mis 1 ; E is SO2; X² is NH; X³is NH; R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Ci₀)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C₂-Ci))hetcroaryl; X^s is a direct bond, O or CR⁴R^S and A² is (C3Cio)cycioalkyl.

The présent invention further relates to the compound of Formula 1, wherein n is 1; 2 or 3; t is 0, I or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is SO2; X² is NH; X³is NH; R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2Cp)heteroaryl; X^s is a direct bond, O or CR⁴R⁵ and A² is (C3-Cio)cycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is SO2; X² is NH; X³is NH; R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C3-Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C2Cgjheteroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t îsO, i or 2; y is 0 or 1; zisO, 1 or 2; X¹ is CR¹; m is 1; E is SO₂; X² is NI-I; X³ is NH; R⁴ and R⁵ arc cach independently methyl; R⁶ is a hydrogen or methyl; A* is (C3Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C2-C9)hcteroaryl.

The présent invention further relates to the compound of Formula I, wherein n is l; 2 or 3; t is 0, l or 2; y is 0 or l; z is 0, l or 2; X¹ is N; m is 0; E is Ο; X³ is NH; R⁴ and R^s arc taken together with the carbon to which they are attached to form a spiro (C3Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)hetcroaryl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C3-Cio)cycloalkyl,

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heteroaryl; X^s is a direct bond, O or CR⁴R^S and A² is (C3-Cio)cycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (C3Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C3-Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵and A² is (C2-C9)heteroaryl.

The présent invention further relates to the compound of Formula I, wherein n is I; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ isNH; R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C3-Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵and A² is (C2-Cg)hctcroaryl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0or I; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² isNH; X³ is CO-N H; R⁴ and R^S arc taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heteroaryl; X^s is a direct bond, O or CR⁴R^sand A² is (C3Cio)cycloalkyl.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is CO-NH; R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2C9)heteroaryl; X^s is a direct bond, O or CR⁴R^sand A² is (C3-C|o)cycloalkyl.

1; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is

CO-NH; R⁴ and R^s arc taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycioalkoxy ring; R⁶ is a hydrogen or methyl; A* is (C3-Cio)cycloalkyl; X^s is a direct bond, O or CR⁴R^sand A² is (C₂Cgjheteroaryl.

The présent invention further relates to the compound of Formula 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is Nil; X³ is CO-NH; R⁴ and R^s arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C3Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C₂-C<))hcteroaryl.

The présent invention further relates to the compound of Formula I, wherein A¹ is (C3-Cio)cycloalkyl.

Λ

The présent invention further relates to the compound of Formula 1, wherein A is (C₃-C1 o)cyc I oa lky L

The présent invention further relates to the compound of Formula I, or a pharmaceutically acceptable sait or prodrug thereof, selected from the group consisting of:

l-azabicyclo[2.2.2]oct-3-yl [2-(2,4'-difluorobiphenyl-4-yl)propan-2-yl]carbamate; l-azabicyclo[2.2.2]oct-3-yl {2-[4-fl,3-benzothiazol-6-yl)phenyl]propan-2-yl}carbamate; l-azabicyclo[3.2.2]non-4-yl {l-[5-(4-fluorophenyl)pyridin-2-yl]cyclopropyl}carbamatc;

l-azabicyclo[2.2.2]oct-3-yl {l-[3-(4-fluorophcnoxy)phcnyl]cyclopropyl} carbamate;

-azabicyclo[2.2.2]oct-3-yl {1 -[4-( 1,3-benzothiazol-5-yl)phcnyl]cyclopropyl}carbamate;

-azabicyclo[2.2.2]oct-3-yl [ 1 -(4'-fluoro-3^,-mcthoxybiphenyl-4yl)cyclopropyl]carbamatc; l-azabicyclo[2.2.2]oct-3-yl [3-(4'-fluorobiphcnyl-4-yl)oxctan-3-yl]carbamatc;

l-azabicyclo[2.2.2]oct-3-yl (l-[6-(4-fluorophcnoxy)pyridin-2-yl]cyclopropyl) carbamate; l-azabicyclo[2.2.2]oct-3-yl [3-(4'-fluorobiphcnyl-4-yl)pentan-3-yl]carbamatc;

l-azabicyclo[2.2.2]oct-3-yl {2-[2-(4-fluorophcnyl)-2H-indazol-6-yl]propan-2 yl} carbamate;

l-azabicyclo[2.2.2]oct-3-yl {2-[2-(IH-pyrrol-l-yl)pyridin-4-yl]propan-2-yl}carbamate; l-(3-cthyl-l-azabicycio[2.2.2]oct-3-yl)-3-[l-(4’-fluorobiphenyl-4-yl)cyclopropyl]urea;

N-(l-azabicyclo[2.2.2]oct-3-yl)-N'-[l-(4'-fluorobiphcnyl-4yl)cyclopropyl]cthanediamide; l-azabicyclo[2.2.2]oct-3-yl (l-{4[(4,4difluorocyclohcxyl)oxy]phcnyl}cyclopropyl) carbamate;

-(4-methyl-1 -azabicyclo[3.2.2]non-4-yl)-3-[ 1 -(5-phenylpyridin-2-yl)cyclopropyl]urea;

l-[l-(4'-fluorobiphcnyI-4-yl)cyclopropyl]-l-mcthyl-3-(3-methyl-l-azabicyclo[2.2.2]oct3-yl)urca;

l-[ 1 -(4^,-fluorobiphcnyl-4-yl)cyclopropyI]-l-mcthyl-3-(3-methyl-1 -azabicyclo[2.2.2]oct3-yl)urea;

1- {2-[4'-(2-mcthoxycthoxy)biphcnyl-4-yl]propan-2-yl}-3-(3-mcthyl-lazabicyclo[2.2.2]oct-3-yl)urea;

2- (l-azabicyclo[3.2.2]non-4-yl)-N-[l-(5-phcnylpyridin-2-yl)cyclopropyl]acctamidc;

3- (4'-fluorobiphenyl-4-yl)-3-mcthyl-N-(4-methyl-l-azabicyclo[3.2.2]non-4yl)butanamide;

N-[2-(biphcnyl-4-yl)propan-2-yl]-N'-(3-methyl-l-azabicyclo[2.2.2]oct-3-yl)sulfuric diamide;

N-[2-(4'-fluorobÎphcnyl-4-yl)propan-2-yl]-N'-(3-methyl-l-azabicyclo[2.2.2]oct-3yl)sulfuric diamide;

l-(3-butyl-l-azabicyclo[2.2.2]oct-3-yl)-3-{2-[l-(4-fluorophenyl)-lH-pyrazol-4yl]propan-2-yl}urea;

l-azabicyclo[2.2.2]oct-3-yl [4-(4-fluorophcnyl)-2-mcthylbut-3-yn-2-yl]carbamatc; l-(3-butyl-l-azabicyclo[2.2.2]oct-3-yl)-3-[4-(4-fluorophenyl)-2-methylbut-3-yn-2yljurea;

N-[l-(4'-fluorobiphenyl-4-yl)cyclopropyl]-l,4-diazabicyclo[3.2.2]nonane-4-carboxamide; l-(2-(4'-fluoro-[l,r-biphcnyl]-4-yl)propan-2-yl)-3-(3-mcthyl-l-azabicyclo[3.2.2]nonan3-yl)urca;

l-(2-(4'-fluoro-[l,r-biphenyl]-4-yl)propan-2-yl)-3-(4-methyl-l-azabicyclo[4.2.2]dccan-4yl)urca;

l-(2-(4'-fluoro-[l,l'-biphcnyl]-4-yl)propan-2-yl)-3-(3-mcthyl-l-azabicycio[4.2.2]dccan-3yl)urca; and

-(2-(4 ’-fluoro-[ 1,1 ’-biphcnyl]-4-yl)propan-2-yl)-3-(5-mcthyl-l -azabicyclo[4.2.2]decan-5yl)urea.

The présent invention further relates to a pharmaceutical composition for treating a disease or disorder mediated by glucosylccramidc synthase (GCS) or a disease or disorder in which GCS is implicatcd in a subject in need of such treatment comprising administering to the subject an effective amount of the compound of Formula I.

The présent invention further relates to a method for treating a disease or disorder mediated by glucosylceramidc synthase (GCS) or a disease or disorder in which GCS is implicatcd in a subject in need of such treatment comprising administering to the subject an effective amount of the compound of Formula I.

The présent invention further relates to a method for treating a discase or disorder such as cancer.

The présent invention further relates to a method for treating a disease or disorder such as a mctabolic disorder.

The présent invention further relates to a method for treating a disease or disorder such as a neuropathie disease.

The présent invention further relates to a method wherein the neuropathie disease is Alzheimcr’s disease.

The présent invention further relates to a method wherein the neuropathie disease is Parkinson’s disease.

The présent invention further relates to a method for treating a disease or disorder such as a cystic disease. The cystic diseases include, but are not limited to rénal cystic diseases such as: acquircd rénal cystic disease (ARCD), dialysis-associatcd cystic disease, autosomal dominant polycystic kidney disease (ADPKD), autosomal récessive polycystic kidney disease (ARPKD), congénital multicystic kidney (CMK), multi cystic dysplastic kidney, end-stage rénal disease (ESRD), medullary sponge kidney (MSK), ncphronophthisis-mcdullary cystic kidney disease complex (NMCD), nephronophthisisurcmic medullary cystic disease complex, juvénile nephronophthisis, medullary cystic disease, rénal cell carcinoma (RCC), tuberous sclcrosis (TS), von Hippel-Lindau syndrome (VHLS).

The présent invention further relates to methods for treating, amcliorating or preventing cystic diseases.

The présent invention further relates to the method for inducing dccreascd glucosylceramide synthase catalytic activity in a cell, in vitro, comprising contacting the cell with an effect amount of the compound of Formula l.

The présent invention further relates to the compound of Formula I ((5)Quinuclidin-3-yl (2-(4'-(2-methoxyethoxy)-[l,r-biphenyl]-4-yl)propan-2-yl)carbamatc), represented by the following structural formula,

or a pharmaceutically acceptable sait or prodrug thereof.

The présent invention further relates to the compound of Formula I (4-Fluoro-l(5-fluoro-4-(4-((2-methoxyethoxy)methyl)phcnyl)pyrimidin-2-yl)-N-(4-mcthyl-lazabicyclo[3.2.2]nonan-4-yl)piperidine-4-carboxamidc), represented by the following structural formula,

or a pharmaceutically acceptable sait or prodrug thereof.

The présent invention further relates to the compound of Formula 1, (4-Fluoro-l(4-(4-((2-mcthoxyethoxy)methyl)phcnyl)pyrimidin-2-yl)-N-(3-methylquinuclidin-3yl)pipcridine-4-carboxamidc) represented by the following structural formula,

The présent invention further relates to the compound of Formula I, (4-Fluoro-l(4-(4-((2-mc thoxycthoxy)mcthyl)pheny 1) pyri m i din-2-yl)-N-(4-methy 1-1 azabicyclo[3.2.2]nonan-4-yl)piperidine-4-carboxamidc) represented by the following structural formula,

The présent invention further relates to the compound of Formula I, (4-Fluoro-l(4-(4-(mcthoxymcthyI)phcnyl)pyrimidin-2-yi)-N-(3-mcthylquinuclidin-3-yl)pipcridinc-4carboxamidc) represented by the following structural formula,

The présent invention further relates to the compound of Formula I, (4-Fluoro-l(4-(4-(mcthoxymcthyl)phcnyl)pyrimidin-2-yl)'N-(4-mcthyl-l-azabicyclo[3.2.2]nonan-4yl)pipcridinc-4-carboxamidc) represented by the following structural formula,

The présent invention further relates to the compound of Formula I, (4-Fluoro-l(4-(4-(2-methoxycthoxy)phcnyl)pyrimidin-2-yl)-N-(3-methylquinuclidin-3-yl)piperidinc15 4-carboxamide) represented by the following structural formula,

The présent invention further relates to the compound of Formula I, (4-Fluoro-l(4-(4-(2-methoxyethoxy)phcnyl)pyrimidin-2-yl)-N-(4-mcthyl-l-azabicyclo[3.2.2]nonan5 4-yl)piperidine-4-carboxamidc) represented by the following structural formula,

The présent invention further relates to the compound of Formula 1, (4-Fluoro-l10 (4-(4-(2-fluoroethoxy)phcnyl)pyrimidin-2-yl)-N-(quinuclidin-3-yl)piperidine-4carboxamidc) represented by the following structural formula,

The présent invention further relates to the compound of Formula I, (4-Fluoro-l(4-(4-(2-fluorocthoxy)phcnyl)pyrimidin-2-yl)-N-(4-mcthyl-l-azabicyclo[3.2.2]nonan-4yl)pipcridinc-4-carboxamidc) represented by the following structural formula,

The présent invention further relates to a method of treating a subject diagnosed as having a lysosomal storage disease, the method including administering to the subject an effective amount of the compound of formula I, and in certain embodiments the compound is represented by following structural formula,

or a pharmaceutically acceptable sait or prodrug thereof.

In certain embodiments of the invention, the lysosomal storage disease results from a defect in the glycosphingolipid pathway.

In certain embodiments of the invention, the lysosomal storage disease is Gaucher, Fabry, GMi-gangliosidosis, Gm2 Activator deficiency, Tay-Sachs or Sandhoff.

The présent invention further relates to a method of treating a subject diagnosed as having a lysosomal storage disease, the method including administering to the subject an effective amount of the compound of formula I and administering to the subject a therapeutically effective amount of a lysosomal enzyme.

In certain embodiments of the invention, the lysosomal enzyme is glucocerebrosidasc, alpha-galactosidase A, Hexosaminidase A, Hexosaminidase B or Gm i -ganglioside-p-ga lactosidasc.

In certain embodiments of the invention, the subjcct has clevated levels of a lysosomal substrate prior to treatment and once undergoing treatment the subject has lower combined amounts of the lysosomal substrate in the urine and plasma than a subjcct treated with either the lysosomal enzyme or compound alonc.

In certain embodiments of the invention, the substrate is globotriaosylceramide or lyso-globotriaosylceramide, and combinations thereof.

The présent invention further relates to a method of reducing glucosylceramidc synthase (GCS) activity in a subject diagnosed as having a lysosomal storage disease, including administering to the patient an effective amount of the compound of formula I, either alonc or as a combination therapy with an enzyme replacement therapy.

The présent invention further relates to a method of reducing accumulation of a GCS-derivcd material in a subjcct diagnosed as having a lysosomal storage disease, including administering to the patient an effective amount of the compound of formula 1, either alone or as a combination therapy with an enzyme replacement therapy.

This invention provides a method of combination therapy for treatment of a subjcct diagnosed as having a lysosomal storage disease comprising alternating between administration of an enzyme replacement therapy and a small molécule therapy.

This invention provides a method of combination therapy for treatment of a subject diagnosed as having a lysosomal storage disease comprising simultaneously administering an enzyme replacement therapy and a small molécule therapy.

The présent invention further relates to a method of treating a subject diagnosed as having a cystic disease, the method including administering to the subjcct an effective amount of the compound of Formula I, and in certain embodiments the compound is represented by following structural formula,

In certain embodiments of the invention, the cystic discases is acquired rénal cystic discase (AR.CD), diaiysis-associated cystic disease, autosomal dominant polycystic kidncy disease (ADPKD), autosomal récessive polycystic kidney disease (ARPK.D), congénital multicystic kidncy (CMK), multi cystic dysplastic kidney, end-stage rénal disease (ESRD), medullary sponge kidney (MSK), nephronophthisis-mcdullary cystic kidney disease complex (NMCD), nephronophthisis-uremic medullary cystic discase complex, juvénile nephronophthisis, medullary cystic disease, rénal cell carcinoma (RCC), tuberous sclerosis (TS), von Hippel-Lindau syndrome (VHLS).

The présent invention further relates to the compound of Formula I, wherein X³is a direct bond.

The présent invention further relates to the compound of Formula I, wherein X⁴is a direct bond.

₄ i

The présent invention further relates to the compound of Formula 1, wherein X and X⁴ are each independently a direct bond.

The présent invention further relates to the compound of Formula I, wherein m is 1 ; E is Ο; X² is O and X³ is direct bond.

The présent invention further relates to the compound of Formula I, wherein m is 1; E is Ο; X² is NH and X³ is direct bond.

The présent invention further relates to the compound of Formula 1, wherein m is 1 ; E is Ο; X² is CH₂ and X³ is direct bond.

The présent invention further relates to the compound of Formula I, wherein m is 1 ; E is S; X² is NH and X³ is direct bond.

The présent invention further relates to the compound of Formula I, wherein m is 0; E is Ο; X¹ is NH and X³ is direct bond.

The présent invention further relates to the compound of Formula I, wherein m is 1; p is 0; X² is NH-SO2 and X³ is direct bond.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is O and X³is direct bond,

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0,1 or 2; y is 0 or 1; z is 0,1 or 2; X¹ is CR¹; m is 1; E is Ο; X² isNH and X³ is direct bond.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; mis 1; E isΟ; X² is CH2 and X³ is direct bond.

The présent invention further relates to the compound of Formula 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or I; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is S; X² is NH and X³is direct bond,

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 0; E is Ο; X¹ is NH and X³ is direct bond.

The présent invention further relates to the compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; p is 0; X² is NH-SO₂and X³ is direct bond.

The présent invention further relates to the compound of Formula I, wherein X⁵ is a direct bond, O, S, SO₂, CR⁴R^S; (Ci-Cû)alkyl, (Ci-Ce)alkyloxy, (Ci-Cfi)alkenyl or (C|Cfi)alkenyloxy.

The présent invention further relates to the compound of Formula I, wherein X⁵ is -O- (CrC6)alkyl, - R⁷-(C3-Cio)cycloalkyl, (C₃-Cio)cycloaLkyl - R⁷-,- R⁷- (C6-C12)aryl, (C6Ci2)aryl - R⁷-, - R⁷- (Cî-C^heteroaryl, (C2-C<))heteroaryl- R⁷-, - R⁷- (C2Cç))heterocycioalkyl, and (C2-C9)hctcrocycloalkyl - R⁷-, wherein R⁷ is a direct bond, O, S, SO2, CR⁴R⁵; (Ci-C₆)alkyl, (C_rC₆)alkyloxy, -O- (Ci-C₆)alkyl, (Ci-C₆)alkenyl or (CjCe)alkenyloxy.

The présent invention further relates to the compound of Formula 1, wherein A is H, (C3-Cio)cycloalkyl, (C6-Ci₂)aryl, (C₂-C9)heteroaryl, (C₂-C9)hcterocycloalkyl or benzo(C₂-C9)hetcrocycloalkyl optionally substituted with one or more substituents seiected from the group consisting of halo, (CrCsjalkyl optionally substituted by one to three halo; (CrCcjalkylenyl, amino, (C]-Cc) alkylamino, (Cj-Cejdialkylamino, (Ci-Cf,)alkoxy, O(C₃Cfi cycloalkyl), (Cî-Cô) cycloalkoxy, nitro, CN, OH, (Ci-Cs)alkyloxy optionally substituted by onc to three halo; (C₃-Ce) cycloalkyl, (Ci-Ce) alkoxycarbonyl, (Cj-Ce) alkylcarbonyl or (Ci-Cô) haloalkyl.

The présent invention further relates to the compound of Formula I, wherein A is (C3-Cio)cycloalkyl, (Ce-Ci₂)aryl, (C₂-C9)hctcroaryl, (C₂-C9)hetcrocycloalkyl or bcnzo(C₂Cÿjheterocycloalkyl substituted with onc or more substituents seiected from the group consisting of (C₂-C9)hctcrocycloalkyl, R R N-CO- wherein R and R are each independently seiected from the group consisting of hydrogen and (Ci-Ce)alkyl or R⁸ and R⁹ can be taken together with the nitrogen to which they are attached to form a (C₂Cpjheterocycloalkyi or (C₂-C9)hctcrocycloalkyl group optionally substituted by onc to three halo groups, (Ci-Cejalkylsulfonyl optionally substituted by one or two groups selected from (C]-C6)alkoxy and (C3-Cio)cycloalkyl;

(Cj-Cejalkyl substituted by one to four substituents selected from the group consisting of hydroxy, cyano, (Ci-Cô)alkoxy, (Ci-CgJalkoxyfCi-CeJalkoxy, (C₂Cçjheterocycloalkyl, (C₂-C9)heteroaryl optionally substituted by (Ci-Cc)alkoxy; or (C3Cio)cycloalkoxy optionally substituted by (Ci-Ce)alkoxy;

or (Ci-C(i)alkyloxy substituted by one to four substituents selected from the group consisting of hydroxy, cyano, (Ci-Ce)alkoxy, (C|-C6)alkoxy(Ci-C6)alkoxy, (C₂C9)hcterocycloalkyl, (C2-Cg)hetcroaryi optionally substituted by (CrCô)alkoxy; or (C3Cio)cycloalkoxy optionally substituted by (C|-Cc>)alkoxy;

The présent invention further relates to the compound of Formula I, wherein X³ is O, -NH, -CH2-, CO, - CH(Ci-C6) alkyl, SO2NH, -CO-NH- or-NR³; X⁴isCR⁴R^s, CH2 CR⁴R^sor CH2 -(Cj-Ce) alkyl-CR⁴R^J;and A² is (C3-Cio)cycloalkyl, (C6-Ci₂)aryl, (C₂Cpjhetcroaryl, (C₂-C9)hetcrocycloalkyl or bcnzo(C₂-C9)hetcrocycloalkyl substituted with one or more substituents selected from the group consisting of, (C₂-C9)hetcrocycloalkyl,

R⁸R⁹N-CO- wherein R⁸ and R⁹ are each independently selected from the group consisting of hydrogen and (Ci-Ce)alkyl or R and R can be taken together with the nitrogen to which they are attached to form a (C₂-Cg)heterocycloalkyl or (C₂Cgjheterocycloalkyl group optionally substituted by one to three halo groups, (C r Ce)alkylsulfonyl optionally substituted by onc or two groups selected from (Ci-Ce)alkoxy and (C3-Cio)cycloalkyl;

(Ci-Cô)alkyl substituted by one to four substituents selected from the group consisting of hydroxy, cyano, (Ci-Ce)alkoxy, (Cj-C6)alkoxy(Ci-C6)alkoxy, (C₂C9)hctcrocycloalkyl, (C₂-C9)hcteroaryl optionally substituted by (Ci-Ce)alkoxy; or (C3·· Cio)cycloalkoxy optionally substituted by (Cj-Ce)alkoxy;

or (Ci-Cejalkyloxy substituted by one to four substituents selected from the group consisting of hydroxy, cyano, (Ci-C₆)alkoxy, (C|-C₆)alkoxy(Ci-C6)alkoxy, (C₂Cgjheterocycloalkyl, (C₂-Cp)hetcroaryl optionally substituted by (Cj-Ceialkoxy; or (C3Cio)cycloalkoxy optionally substituted by (Ci-C6)alkoxy.

The présent invention further relates to the Compound of Formula l, wherein X³ is a direct bond.

The présent invention further relates to the Compound of Formula l, wherein X⁴is a direct bond.

The présent invention further relates to the Compound of Formula I, wherein X³and X⁴ are each independentiy a direct bond.

The présent invention further relates to the Compound of Formula 1, wherein m is 1; E is Ο; X² is O and X³ is direct bond.

The présent invention further relates to the Compound of Formula 1, wherein m is 1; E is Ο; X² is NH and X³ is direct bond.

The présent invention further relates to the Compound of Formula 1, wherein m is 1; E is Ο; X² is CH₂ and X³ is direct bond.

The présent invention further relates to the Compound of Formula 1, wherein m is 1; E is S; X² is NH and X³ is direct bond.

The présent invention further relates to the Compound of Formula I, wherein m is 1; p is 0; X² is NH-SO₂ and X³ is direct bond.

The présent invention further relates to the Compound of Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is O and X³is direct bond.

The présent invention further relates to the Compound of Formula I, wherein n is 1; 2 or 3; fis 0,1 or 2; y is 0 or 1; z is 0,1 or 2; X¹ is CR¹; mis 1; Eis Ο; X² is NH and X³ is direct bond.

The présent invention further relates to the Compound of Formula 1, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹ ; m is 1 ; E is Ο; X² is CH₂ and X³ is direct bond.

The présent invention further relates to the Compound of Formula 1, wherein n is 1; 2 or3;t is 0,1 or2; yisOor l;zis 0, 1 or2;X* isCR‘;mis 1; EisS; X² isNHandX³is direct bond.

The présent invention further relates to the Compound of Formula 1, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 0; E is Ο; X¹ is NH and X³ is direct bond.

The présent invention further relates to the Compound of Formula 1, wherein X^s is a direct bond, O, S, SO2, CR⁴R⁵; (Ci-Cûjalkyl, (Ci-Cejalkyloxy, (Ci-C6)alkenyl or (CiCs)alkenyloxy.

The présent invention further relates to the Compound of Formula I, wherein X⁵ is -O- (Ci-Ce)alkyl, - R⁷-(C3-Cio)cycloalkyl, (C3-Cio)cycioalkyl - R⁷-,- R⁷- (Ce-Ci2)aryl, (CûCi2)aryl - R⁷-, - R⁷- (C2-C9)hctcroaryl, (C2-C9)hcteroaryl- R⁷-, - R⁷- (C2Cpjhctcrocycloalkyl, and (C2-C9)hcterocycloalkyl - R -, wherein R is a direct bond, O, S, SO2, CR⁴R^S; (C!-C6)alkyl, (Ci-C₆)alkyloxy, -O- (Ci-C₆)alkyl, (Ci-C₆)aikenyl or (C,Ce)alkenyloxy.

The présent invention further relates to the Compound of Formula I, wherein A² is H, (C3-Cio)cycloalkyl, (Ce-C^Jaryl, (C2-C<))hctcroaryl, (C2-Cg)heterocycloalkyl or benzo(C2-Ci>)hetcrocycloalkyl optionally substituted with one or more substituents selected from the group consisting of halo, (C|-Cf,)alkyl optionally substituted by one to three halo; (Ci-C/alkylenyl, amino, (Ci-Cf,) alkylamîno, (Ci-Ce)dialkylamino, (Ci-Cf)alkoxy, O(C3Cf cycloalkyl), (C3-C6) cycloalkoxy, nitro, CN, OH, (Ci-Ce)alkyloxy optionally substituted by one to three halo; (C3-C6) cycloalkyl, (Ci-Cû) alkoxycarbonyl, (Ci-Ce) alkylcarbonyl or (Ci-Ce) haloalkyl.

The présent invention further relates to the Compound of Formula I, wherein A is (C3-Cio)cycloalkyl, (Ce-C^aryl, (C2-Cp)heteroaryl, (C2-C<))heterocycloalkyl or benzo(C2C^heterocycloalkyl wherein A is substituted with one or more substituents selected from the group consisting of (C2-C9)hetcrocycloalkyl, K^SR⁹N-CO- wherein R⁸ and R⁹ are each independently selected from the group consisting of hydrogen and (Ci-Cfi)alkyl or R⁸ and R⁹ can bc taken together with the nitrogen to which they are attached to form a (C2Cpjhetcrocycloalkyl or (C2-Cp)hctcrocycloalkyl group optionally substituted by onc to three halo groups, (Ci-Cejalkylsulfonyl optionally substituted by one or two groups selected from (Ci-Ce)alkoxy and (C3-Cio)cycloalkyl;

(Ci-Cô)alkyl substituted by onc to four substituents selected from the group consisting of hydroxy, cyano, (Ci-Ce)alkoxy, (Ci-C&)alkoxy(Ci-C6)alkoxy, (C2Ct))heterocycloalkyl, (C2-C9)hctcroaryl optionally substituted by (Ci-Ce)alkoxy; or (C3C10)cycloalkoxy optionally substituted by (Ci-Cû)alkoxy; and (Ci-Ce)alkyloxy substituted by one to four substituents selected from the group consisting of hydroxy, cyano, (Ci-Cs)alkoxy, (Ci-Cs)alkoxy(C|-C6)alkoxy, (C2Cpjhcterocycloalkyl, (Cî-Cgjhetcroaryl optionally substituted by (Ci-Ce)alkoxy; or (C3Cio)cycloalkoxy optionally substituted by (Ci-Côjalkoxy.

The présent invention further relates to the Compound of Formula I, wherein X³ is O, -NH, -CH2-, CO, - CH(Ci-C6) alkyl, SO2NH, -CO-NH- or-NR³; X⁴isCR⁴R⁵, CH2 CRR⁵or CH2 -(Ci-C6) alkyl-CR⁴R⁵;and A² is (C3-C_l0)cycloalkyl, (C₆-C_l2)aryl, (C₂Cgjhctcroaryl, (C₂-Cg)hctcrocycloalkyl or benzo(C₂-Co)hctcrocycloalkyl wherein A² is substituted with one or more substituents selected from the group consisting of, (C2Ci))hetcrocycloalkyl, R⁸R⁹N-CO- wherein R⁸ and R⁹ are each independently selected from the group consisting of hydrogen and (Ci-Cejalkyl or R⁸ and R⁹ can bc taken together with the nitrogen to which they are attached to form a (C2-Cp)hcterocycloalkyl or (C₂-Cg)heterocycloalkyl group optionally substituted by one to three halo groups, (CiCejalkylsulfonyl optionally substituted by one or two groups selected from (Ci-Cejalkoxy and (C3-Cjo)cycloalkyl;

(C]-C6)alkyl substituted by one to four substituents selected from the group consisting of hydroxy, cyano, (Ci-Ce)alkoxy, (C|-C6)alkoxy(Ci-C6)alkoxy, (C₂C9)hcterocycloalkyl, (C₂-C9)heteroaryl optionally substituted by (Ci-Cs)alkoxy; or (C3Cio)cycloalkoxy optionally substituted by (Ci-Cû)alkoxy;

or (Ci-Ce)alkyloxy substituted by one to four substituents selected from the group consisting of hydroxy, cyano, (Ci-C6)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkoxy, (C₂Cg)hcterocycloalkyl, (C₂-C9)hetcroaryl optionally substituted by (Ci-Cejaikoxy; or (C3Cio)cycloalkoxy optionally substituted by (Ci-C<,)alkoxy.

The présent invention further relates to the Compound of Formula I, wherein A* is phenyl.

The présent invention further relates to the Compound of Formula 1, wherein X⁵ is a direct bond.

The présent invention further relates to the Compound of Formula I, wherein A² is phenyl substituted by (Ci-Ce) alkoxy(Ci-Ce) alkoxy.

The présent invention further relates to the Compound of Formula I, wherein n is 1; t is 0; y is 1; z is 1; X¹ is CR¹; m is 1; p is 1; E is 0; X² is Ο; X³ is NH; R¹ is H; X⁴ is CR⁴R⁵ wherein R4 and R5 are each independently methyl; R⁶ is a hydrogen; A¹ is phenyl; X³ is a direct bond, O or CR⁴R⁵ and A2 is phenyl substituted by (Ci-Ce) alkoxy(Ci-Cô) alkoxy.

The présent invention further relates to a compound of the formula

or a pharmaceutically acceptable sait or prodrug thereof.

The présent invention further relates to the Compound of Formula I, wherein A¹ is piperdinc optionally substituted by halo.

The présent invention further relates to the Compound of Formula 1, wherein X⁵ is pyrimidine optionally substituted by halo.

In the various combination thérapies of the invention, it will be understood that administering small molécule therapy may occur prior to, concurrently with, or after, administration of enzyme replacement therapy. Similarly, administering enzyme replacement therapy may occur prior to, concurrently with, or after, administration of small molécule therapy.

Définitions

As used herein, the term “pharmaceutically acceptable sait” means either a pharmaceutically acceptable acid addition sait or a pharmaceutically acceptable base addition sait of a currcntly disclosed compound that may be administered without any résultant substantial undesirable biologicai effect(s) or any résultant deleterious intcraction(s) with any other component of a pharmaceutical composition in which it may be contained.

As used herein, the term “prodrug” means a pharmacological derivative of a parent drug molécule that requircs biotransformation, either spontancous or enzymatic, within the organism to release the active drug. For example, prodrugs are variations or dérivatives of the compounds of Formula 1 that have groups cleavable under certain metabolic conditions, which when cleavcd, become the compounds of Formula I. Such prodrugs then are pharmaceutically active in vivo, when they undergo solvolysis under physiological conditions or undergo enzymatic dégradation. Prodrug compounds herein may be called single, double, triple, etc., dcpcnding on the number of biotransformation steps required to release the active drug within the organism, and the number of functionalitics présent in a prccursor-type form. Prodrug forms often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (See, Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elscvier, Amsterdam 1985 and Silverman,

The Organic Chemistry of Drug Design and Drug Action, pp. 352-401, Academie Press, San Diego, Calif., 1992). Prodrugs commonly known in the art include wcllknown acid dérivatives, such as, for example, esters prepared by reaction of the parent acids with a suitable alcohol, amides prepared by reaction ofthe parent acid compound with an amine, basic groups reacted to form an acylated base dérivative, etc. Of course, other prodrug dérivatives may be combined with other features disclosed herein to cnhance bioavailability. As such, thosc of skill in the art will apprcciate that certain of the presently disclosed compounds having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds having an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues which arc covalently joined through peptide bonds to free amino, hydroxy or carboxylic acid groups of the presently disclosed compounds. The amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbois and also include 4-hydroxyproline, hydroxylysine, demosine, isodcmosinc, 3mcthylhistidinc, norvalin, bcta-alaninc, gamma-aminobutyric acid, citrullinc homocystéine, homoscrine, omithine and méthionine sulfone. Prodrugs also include compounds having a carbonate, carbamate, amide or alkyl ester moiety covalently bondcd to any of the above substituents disclosed herein.

As used herein, the term “(Ci-Cû)alkyl” means a saturated linear or branched free radical consisting essentially of 1 to 6 carbon atoms and a corresponding number of hydrogen atoms. Exemplary (Ci-Ccjalkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc. Of course, other (Ci-Ce)alkyl groups will be readily apparent to those of skill in the art given the benefit of the présent disclosure.

As used herein, the term “(C3-Cio)cycloalkyl” means a nonaromatic saturated free radical forming at least one ring consisting essentially of 3 to 10 carbon atoms and a corresponding number of hydrogen atoms. As such, (C3-Cio)cycloalkyl groups can bc monocyclic or multicyciic. Individual rings of such multicyclic cycloalkyl groups can hâve different connectivities, e.g., fused, bridged, spiro, etc. in addition to covalent bond substitution. Exemplary (C3-Cio)cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbomanyl, bicyclo[3.2.l]octanyl, octahydro-pentalenyl, spiro[4.5]dccanyl, cyclopropyl substîtuted with cyclobutyl, cyclobutyl substîtuted with cyclopentyl, cyclohexyl substîtuted with cyclopropyl, etc. Of course, other (CjCio)cycloalkyl groups will be readily apparent to those of skill in the art given the benefit of the présent disclosure.

As used herein, the term “(Cî-C^hctcrocycloalkyl” means a nonaromatic free radical having 3 to 10 atoms (i.e., ring atoms) that form at least onc ring, wherein 2 to 9 of the ring atoms are carbon and the rcmaining ring atom(s) (i.e., hetero ring atom(s)) is selected from the group consisting of nitrogen, sulfur, and oxygen. As such, (C2Cpjhcterocycloalkyl groups can be monocyclic or multicyclic. Individual rings of such multicyclic heterocycloalkyl groups can hâve different connectivities, e.g., fuscd, bridged, spiro, etc. in addition to covalent bond substitution. Exemplary (C2-C9)hctcrocycloalkyl groups inciude pyrrolidinyl, tctrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, azetidinyl, oxiranyl, methylenedioxyl, chromenyl, barbituryl, îsoxazolidinyl, l,3-oxazolidin-3-yl, isothiazolidinyl, l,3-thiazolidin-3-yl, 1,2pyrazoIidin-2-yl, 1,3-pyrazolidin-l-yl, pipcridinyl, thiomorpholinyl, 1,2tctrahydrothiazin-2-yl, l,3-tctrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, l,2-tetrahydrodiazîn-2-yl, 1,3-tetrahydrodiazin-l-yl, tctrahydroazepinyl, piperazinyl, piperizin-2-onyl, piperizin-3-onyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyl, imidazolidinyl, 2-imidazolidinyl, 1,4-dioxanyl, 8-azabicyclo[3.2,l]octanyl, 3-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1 ]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5diazabicyclo[2.2.2]octanyl, octahydro-2H-pyrido[l,2-a]pyrazinyl, 3azabicyclo[4.1 .OJheptanyl, 3-azabicyclo[3.1,0]hexanyl

2-azaspiro[4.4]nonanyl, 7-oxa-l-aza-spiro[4.4]nonanyl, 7-azabicyclo[2.2.2]hcptanyl, octahydro-lH-indolyl, etc. In general, the (C2-C9)heterocycloalkyl group typically is attached to the main structure via a carbon atom or a nitrogen atom. Of course, other (C2Cç>)heterocycloalkyl groups will be readily apparent to those of skill in the art given the benefit of the présent disclosure.

As used herein, the term “(C2-C9)hcteroaryl” means an aromatic free radical having 5 to 10 atoms (i.e., ring atoms) that form at least one ring, wherein 2 to 9 of the ring atoms are carbon and the remaining ring atom(s) (i.e., hetero ring atom(s)) is selected from the group consisting of nitrogen, sulfur, and oxygen. As such, (C2-C9)heteroaryl groups can be monocyclic or multicyclic. Individual rings of such multicyclic heteroaryl groups can hâve different connectivities, e.g., fused, etc. in addition to covalent bond substitution. Exemplary (C2-C9) heteroaryl groups include furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadîazolyl, 1,2,3thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyi, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H-[l]pyrindinyl, benzo[b]thiophcnyl, 5,6,7,8-tctrahydro-quinolin-3-yl, bcnzoxazolyl, bcnzothiazolyl, bcnzisothiazolyl, bcnzisoxazolyl, bcnzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobcnzofuranyl, isoindolyl, indolyl, indolizinyl, îndazolyl, îsoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, qutnazolinyl and benzoxazinyl, etc. In general, the (C2-C9)heteroaryl group typically is attached to tire main structure via a carbon atom, however, those of skill in the art will rcalizc when certain other atoms, e.g., hetero ring atoms, can be attached to the main structure. Of course, other (C2-C9)hetcroaryl groups will be readily apparent to those of skill in the art given the benefit of the présent disclosure.

As used herein, the term “(C6-Cio)aryl” means phenyl or naphthyl.

As used herein, the term “halo” means fluorine, chlorinc, bromine, or iodine.

As used herein, the term “amino means a free radical having a nitrogen atom and 1 to 2 hydrogen atoms. As such, the term amino gcnerally refers to primary and secondary amines. In that regard, as used herein and in the appended claims, a tertiary amine is rcprcscntcd by the general formula RR’N-, wherein R and R’ arc carbon radicals that may or may not be identical. Nevcrtheless, the term “amino” gcnerally may be used herein to describe a primary, secondary, or tertiary amine, and those of skill in the art will readily be able to asccrtain the identification of which in view of the context in which this term is used in the présent disclosure.

As used herein, the term “combination therapy” means treating a patient with two or more therapeutic platforms (e.g., enzyme replacement therapy and small molécule therapy) in rotating, altemating and/or simultancous treatment schedules. Examples of treatment schedules may include, but arc not limited to: (1) enzyme replacement therapy, then small molécule therapy; (2) small molécule therapy, then enzyme replacement therapy; (3) enzyme replacement therapy concurrent with small molécule therapy, and (4) and any combination of the foregoing. Combination therapy may provide a temporal overlap of therapeutic platforms, as needed, depending on the clinical course of a given storage disease in a given subject.

As used herein, the term “enzyme replacement thcrapy”, or “ERT” means administering an exogenously-produced natural or recombinant enzyme to a patient who is in need thereof. In the case of a lysosomal storage disease, for exampie, the patient accumulâtes harmful levels of a substratc (i.c., material stored) in lysosomes duc to a dcficiency or dcfect in an enzyme rcsponsible for metabolizing the substrate, or due to a deficiency in an enzymatic activator rcquired for proper enzymatic fonction. Enzyme replacement therapy is provided to the patient to reducc the levels of (i.e., dcbulk) accumulatcd substrate in affected tissucs. Table 1 provides a list of lysosomal storage diseases and identifies the corresponding enzyme deficiency and accumulated substrate for each discase. Enzyme replacement thérapies for treating lysosomal storage discases arc known in the art. In accordance with a combination thcrapy of the invention, the lysosomal enzymes identified in Table 1 can be used for enzyme replacement thcrapy to reduce the levels of corresponding substrate in a patient diagnosed with the respective lysosomal storage disease.

As used herein, effective amount of an enzyme or small molécule, when delivered to a subject in a combination thcrapy of the invention, is an amount sufficicnt to improve the clinical course of a lysosomal storage disease, where clinical improvement is measured by any of the variety of defined parameters well known to the skilled artisan.

Abbreviations

ACN refers to acelonitrile.

DMF refers to N,N-dimethylformamide. DMSO refers to dimcthylsulfoxide. EtOAc refers to ethyl acetate.

EtOH refers to éthanol.

Hunig’s Base refers to diisopropylethyl amine (“DIPEA”).

MeOH refers to methanol.

NaOH refers to sodium hydroxide. THF refers to tetrahydroforan. TFA refers to trifluoroacetic acid.

Additional fcaturcs and advantages of compounds disclosed herein will be apparent from the following detailed description of certain embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure l présents the mctabolic pathway for the potential synthesis of Gb3 and Iyso-Gb3. 5 Documented synthctic pathways are shown with black arrows and undocumented (potential) pathways are shown with grey arrows.

Figure 2 présents the chemical structure of (S)-Quinuclidin-3-yl (2-(4'-(2mcthoxycthoxy)-[ l, l '-biphcnyl]-4-yl)propan-2-yl)carbamate.

Figure 3 présents the effectsofaGCS inhibitor, (S)-Quinuclidin-3-yl (2-(4-(2methoxycthoxy)-[l,l'-biphcny[]-4-yl)propan-2-yl)carbamate, in a mouse model of polycystic kidney disease, jck mice, at several dose levels.

DETAILED DESCRIPTION

Although spécifie embodiments of the présent disclosure will now be described with reference to the préparations and schemes, it should be understood that such embodiments are by way of example only and merely illustrative of but a small number of the many possible spécifie embodiments which can represent applications of the principles of the présent disclosure. Various changes and modifications will be obvious to those of skill in the art given the benefit of the présent disclosure and are deemed to be within the spirit and scope of the présent disclosure as further defined in the appended claims.

Unless defined otherwise, ail technical and scientific terms used herein hâve the same meaning as commonly understood by one having ordinary skill in the art to which this disclosure belongs. Although other compounds or methods can be used in practice or testing, certain preferred methods are now described in the context of the following préparations and schemes.

The présent invention refers to a compound represented by the following structura! formula,

or a pharmaceuticaily acceptable sait or prodrug thereof, wherein: nis 1,2 or 3;

m is 0 or 1 ;

p is 0 or 1 ;

t îs 0, l or 2;

y is l or 2; z is 0, l or 2; E is S, O, NH, NOH, NNO₂, NCN, NR, NOR or NSO₂R; X'is CR^l when m is l or N when m is 0;

X² is O, -NH, -CH₂-, SO₂, NH-SO₂;CH(Ci-C₆) alkyl or-NR² ;

X³ is a direct bond, O, -NH, -CH₂-, CO, - CH(Ci-Ce) alkyl, SO₂NH, -CO-NH- orNR³;

X⁵ is a direct bond, O, S, SO2, CR⁴R^S; (Ci-C6)alkyl, (Ci-Cejalkyloxy, -O- (CiCe)alkyl, (Ci-Cf,)alkcnyl, (Ci-Cû)alkcnyloxy, - R⁷-(C3-Cio)cycloalkyl, (C3-C|o)cycloalkyl R⁷-,- R⁷- (C6-Cl2)aryl, (C₆-C|₂)aryl - R⁷-, - R⁷- (C2-C<))hetcroaryl, (C2-C9)hetcroaryl- R⁷-, R⁷- (C2-C₉)hctcrocycloalkyl, and (C₂-C₉)heterocycloalkyl - R⁷-, wherein R⁷ is a direct bond, O, S, SO2, CR⁴R⁵; (Ci-Ce)alkyl, (Ci-C6)alkyloxy, -O- (Ci-Côjalkyl, (Ci-Cejalkenyl, (Ci-Cejalkcnyloxy ; and further wherein when X⁵ is defined as - R⁷-(C3-Cio)cycloalkyl, (C3Cio)cycloalkyl - R⁷-,- R⁷- (C6-C|2)aryl, (Ce-Ci2)aryl - R⁷-, - R⁷- (C2-C9)hctcroaryl, (C₂Cÿjhctcroaryl- R⁷-, - R⁷- (C2-Ci))hctcrocycloalkyl, and (C2-C9)heterocycloalkyl-R7-, wherein the (C3-Cio)cycloalkyl, (C6-C|2)aryl, (C2-C<))hcteroaryl, (C2-C9)heterocycloalkyl groups arc optionally substituted by one or more substituents selected from the group consisting of halo, (Ci-Cô)alkyl, (Ci-C6)alkylcnyl, amino, (Ci-Ce) alkylamino, (C|Cejdialkylamino, (Ci-C6)alkoxy, O(C3-Ce cycloalkyl), (Cj-Cf) cycloalkoxy, nitro, CN, OH, (Ci-Cfi)alkyloxy, (Cs-Ce) cycloalkyl, (Ci-Cf,) alkoxycarbonyl, (Ci-Cf) alkylcarbonyl, (CjCg) haloalkyl, (C2-C9)heterocycloalkyl, R⁸R⁹N-CO- wherein R⁸ and R⁹ arc each independently selected from the group consisting of hydrogen and (Ci-Cf)alkyl or R⁸ and R⁹ can be taken together with the nitrogen to which they arc attached to form a (C2C₉)hcterocycloalkyl or (C₂-C9)hetcrocycloalkyl group optionally substituted by one to three halo groups, (Ci-Cejalkylsulfonyï optionally substituted by one or two groups selected from (Ci-Ce)alkoxy and (C3-Cio)cycloalkyl;

(Ci-Cfi)alkyl substituted by onc to four substituents selected from the group consisting of halo, hydroxy, cyano, (Cj-Cô)alkoxy, (C]-C6)alkoxy(Ci-Cô)alkoxy, (C₂Cgjheterocycloalkyl, (C₂-C9)hctcroaryl optionally substituted by (Ci-C₆)alkoxy; or (C₃Cio)cycloalkoxy optionally substituted by (C]-Ce)alkoxy; and (Ci-Côjalkyloxy substituted by one to four substituents selected from the group consisting of halo, hydroxy, cyano, (Ci-Cf,)alkoxy, (Ci-C6)alkoxy(C]-C6)alkoxy, (C₂60

Cgjhctcrocycloalkyl, (C^-C^hcteraaryl optionally substituted by (Ci-Côjalkoxy; or (C3Cw)cycloalkoxy optionally substituted by (Ci-Ce)alkoxy;

R is (C(;-Ci2)aryl, (C2-Cg)hcteroaryl, (Ci-Cejalkyl, (C2-C9)heteroaryl(C]-Ce)alkyl; R¹ is H,CN, (Ci-Cûjalkylcarbonyl, or (Ci-Cc)alkyl;

R² and R³ arc each independently -H, (Ci-Ce)alkyl optionally substituted by onc or more substituents selected from the group consisting of halogen, (Ci-Cf,)alkyl, (Ce-Cujaryl, (C2-C9)heteroaryl, (Ci-C6)alkyl(C6-Ci2)aryl, halo(Cô-Ci2)aryl, and halo(C2-C9)heteroaryl, or optionally when X² is -NR² and X³ is -NR³, R² and R³ may bc taken together with the nitrogen atoms to which they arc attached form a non-aromatic heterocyclic ring optionally substituted by with one or more substituents selected from halogen, (Ci-Ce)alkyl, (CeCi2)aryl, (C2-C9)hctcroaryl, (Ci-C6)alkyl(C6-Cj2)aryl, halo(C6-C]2)aryl, and halo(C2C9)heteroaryl;

R⁴ and R⁵ are independently selected from H, (Ci-CVjalkyl, or taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring;

R⁶ is -H, halogen, -CN, (Ce-Cnjaryl, (C6-Ci2)aryloxy, (Ci-Csjalkyloxy; (Ci-Ce)alkyl optionally substituted by one to four halo or (Cj-Cf,)alkyl;

A¹ is (C2-Ce)alkynyl; (C3-Cio)cycloalkyl, (Ce-C^jaryl, (C2-C9)heteroaryl, (C2Cçlhctcrocycloalkyl or bcnzo(C2-C9)hctcrocycloalkyI optionally substituted with onc or more substituents selected from the group consisting of halo, (CrCe)alkyl optionally substituted by one to three halo; (Ci-Cfi)alkcnyl, amino, (Ci-Csjalkylamino, (CiCfijdialkylamino, (Ci-Ce)alkoxy, nitro, CN, -OH, (Ci-Ce)alkyloxy optionally substituted by one to three halo; (Ci-Cc,)alkoxycarbonyl, and (Cj-Ce) alkylcarbonyl;

A² is H, (C3-Cio)cycloalkyl, (Cc-Cniaryl, (C2-C9)hctcroaryl, (C2Cg)hcterocycloalkyl or benzo(C2-C9)hetcrocycloalkyl optionally substituted with one or more substituents selected from the group consisting of halo, (C[-Ce)alkyl optionally substituted by onc to three halo; (Ci-Cejalkylcnyl, amino, (Ci-Ce) atkylamino, (C 1Cejdialkylamino, (Ci-Ce)alkoxy, O(C3-Ce cycloalkyl), (C3-C6) cycloalkoxy, nitro, CN, OH, (Ci-Ceiaikyloxy optionally substituted by one to three halo; (C3-C6) cycloalkyl, (Ci-Ce) alkoxycarbonyl, (C1-C5) alkylcarbonyl, (Ci-Ce) haloalkyl, (C2-C9)heterocycloalkyl,

R⁸R⁹N-CO- wherein R⁸ and R⁹ are each independently selected from the group consisting of hydrogen and (Cj-Câ)alkyl or R⁸ and R⁹ can be taken together with the nitrogen to which they arc attached to form a (Ca-Cgjheterocycloalkyl or (C261

Cçjhcterocycloalkyl group optionally substituted by one to threc halo groups, (Cr Ce)alkylsulfonyl optionally substituted by one or two groups selected from (Ci-Cfi)alkoxy and (C3-Cio)cycloalkyl;

(Ci-Câ)alkyl substituted by one to four substituents selected from the group consisting ofhydroxy, cyano, (Ci-Cû)alkoxy, (Ci-C6)alkoxy(Ci-C<5)alkoxy, (C₂C<))heterocycloalkyl, (C₂-C9)hetcroaryl optionally substituted by (Ci-Cô)alkoxy; or (C3Cio)cycloalkoxy optionally substituted by (Ci-Cc)alkoxy;

or (Ci-Ce)alkyloxy substituted by one to four substituents selected from the group consisting ofhydroxy, cyano, (Ci-Côjalkoxy, (Ci-Cf,)alkoxy(Ci-C6)alkoxy, (C₂Cgjhetcrocycloalkyl, (C₂-Cp)heteroaryl optionally substituted by (C]-Ce)alkoxy; or (C3Cio)cycloalkoxy optionally substituted by (Ci-Ce)alkoxy;

with the proviso that the sum of n +1 + y + z is not greater than 6;

with the proviso that when p is 0; X² is NH-SO₂ and X³ is NH;

with the proviso that when n is 1 ; t is 0; y is 1 ; z is 1; X² is NH; E is Ο; X³ is NH; A is H and X is a direct bond; A is not unsubstituted phenyl, hatophenyl or isopropenyl phenyl;

with the proviso that when n is 1; t is 0; y is 1 ; z is 1 ; X² is O; E is Ο; X³ is NH; A¹is (C6-C|₂)aryl and X⁵ is a direct bond; A² is H and R⁴is H then R⁵ is not cyclohexyl;

with the proviso that when n is 1; t is 0; y is 1 ; z is 1 ; X² is NH; E is Ο; X³ is CH₂; R⁴ and R^s arc both hydrogen; A² is H and X^s is a direct bond; then A¹ is not unsubstituted phenyl; and with the proviso that when X³ is O, -NH, -CH2-, CO, - CH(Ci-Cô) alkyl, SO2NH, CO-NH- or -NR³;and X⁴ is CR⁴R⁵, CH2 CR⁴R⁵ or CH2 -(C]-C6) alkyl-CR⁴R⁵; then A²must bc (Cî-Ciojcycloalkyl, (C(-,-Ci2)aryl, (C₂-C9)heteroaryl, (C₂-C9)heterocycloalkyl or benzo(C₂-C9)heterocycloaIkyl substituted with onc or more substituents selected from the group consisting of, (C₂-C9)heterocycloalkyl, R⁸R⁹N-CO- wherein R⁸ and R⁹ are each independently selected from the group consisting of hydrogen and (Ci-Ce)alkyl or R⁸ and R⁹ can bc taken together with the nitrogen to which they are attached to form a (C₂C9)hetcrocycloalkyl or (C₂-C9)hetcrocycloalkyl group optionally substituted by one to three halo groups, (Cj-C^jalkylsulfonyl optionally substituted by one or two groups selected from (Ci-Ce)alkoxy and (C3-Cio)cycloalkyl;

(C]-Cô)alkyl substituted by onc to four substituents selected from the group consisting ofhydroxy, cyano, (Ci-C6)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkoxy, (C₂62

Cyjhctcrocycloalkyl, (C₂-C9)hctcroaryl option^ally substituted by (Ci-Ce)alkoxy; or (C3Cio)cycloalkoxy optionally substituted by (Ci-Ce)alkoxy;

or (Ci-Cs)alkyloxy substituted by one to four substituents selected from the group consisting of hydroxy, cyano, (Ci-Cû)alkoxy, (C|-C6)alkoxy(Cj-C6)alkoxy, (C₂C9)hctcrocycloalkyl, (C₂-C9)hctcroaryl optionally substituted by (Ct-Cô)alkoxy; or (C3Cio)cycloalkoxy optionally substituted by (Ci-Cô)alkoxy.

The présent invention further relates to a compound according to Formula I, wherein n is 1 ; t is I ; y is I and z is 1.

The présent invention further relates to a compound according to Formula 1, wherein n is 2; t is 0; y is 1 and z is 1.

The présent invention further relates to a compound according to Formula I, wherein n is 2; t is 1; y is 1 and z is 1.

The présent invention further relates to a compound according to Formula I, wherein n is 3; t is 0; y is 1 and z is 1.

The présent invention further relates to a compound according to Formula 1, wherein n is 1 ; t is 2; y is 1 and z is 1.

The présent invention further relates to a compound according to Formula I, wherein n is 1 ; t is 0; y is 1 and z is 0.

The présent invention further relates to a compound according to Formula I, wherein n is 1; t is I; y is 1 and z is 0.

The présent invention further relates to a compound according to Formula I, wherein n is 2; t is 0; y is 1 and z is 0.

The présent invention further relates to a compound according to Formula I, wherein n is 2; t is I; y is 1 and z is 0.

The présent invention further relates to a compound according to Formula I, wherein n is 3; t is 0; y is 1 and z is 0.

The présent invention further relates to a compound according to Formula I, wherein n is 1 ; t is 2; y is 1 and z is 0.

The présent invention further relates to a compound according to Formula I, wherein n is 1 ; t is I ; y is 2 and z is 0.

The présent invention further relates to a compound according to Formula I, wherein n is 2; t is 0; y is 2 and z is 0.

The présent invention further relates to a compound according to Formula I, wherein m is 0 and X¹ is N.

The présent invention further relates to a compound according to Formula I, wherein m is l ; E is Ο; X² is NH and X³ is NH.

The présent invention further relates to a compound according to Formula I, wherein m is l ; E is Ο; X² is CH2 and X³ is NH.

The présent invention further relates to a compound according to Formula I, wherein m is 1; E is Ο; X² is NH and X³ is CH2.

The présent invention further relates to a compound according to Formula I, wherein m is 1; E is S; X² is NH and X³ is NH.

The présent invention further relates to a compound according to Formula 1, wherein m is 0; E is Ο; X¹ is NH and X³ is NH.

The présent invention further relates to a compound according to Formula I, wherein m is 1; E is Ο; X² is NH and X³ is CO-NH.

The présent invention further relates to a compound according to Formula I, wherein m is I; p is 0; X² is NH-SO2 and X³ is NH.

The présent invention further relates to a compound according to Formula I, wherein R⁴ and R⁵ arc each (Ci-Ce)alkyl or taken together with the carbon to which they are attached to form a spiro (C3-Cio)cyclo- alkyl ring or a spiro (C3-C10)cycloalkoxy ring.

The présent invention further relates to a compound according to Formula I, wherein R⁴ and R⁵ are each (Ci-Cjalkyl or taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cyclo- alkyl ring or a spiro (C₃-Cio)cycloalkoxy ring, and further wherein X⁴ is CR⁴R^S wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring.

The présent invention further relates to a compound according to Formula I, wherein R⁴ and R⁵ are each (Ci-Cejalkyl or taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cyclo- alkyl ring or a spiro (C3-Cio)cycloalkoxy ring, and further wherein X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C₃-Cio)cycloalkyl ring, and further wherein X⁴ is CR⁴R^S wherein R⁴ and R^s are taken together with the carbon to which they are attached to form a spiro cyclopropyl ring.

The présent invention further relates to a compound according to Formula I, wherein R⁴ and R^s arc each (Ci-C jalkyl or taken together with the carbon to which they are attached to form a spiro (C3-Cio)cyclo- alkyl ring or a spiro (C3-Cio)cycloalkoxy ring, and further wherein X⁴ is CR⁴R^S wherein R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkoxy ring.

The présent invention further relates to a compound according to Formula I, wherein Al is (Cî-Cgjhetcroaryl.

The présent invention further relates to a compound according to Formula I, wherein A¹ is (C2-Co)heteroaryl, and further wherein A¹ îs thiophenc, thiazole, isothiazole, furanc, oxazole, isoxazoie, pyrrole, imidazole, pyrazole, triazole, pyridine, pymiridine, pyridazine, indole, benzotiazole, benzoisoxazolc, benzopyrazole, bcnzoimidazole, benzofuran, bcnzooxazolc or benzoisoxazolc.

The présent invention further relates to a compound according to Formula 1, wherein A¹ is (C2-C9)hetcrocycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein A¹ is (C2-C9)heterocycloalkyl, and further wherein A¹ is pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tctrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, azctidinyl, oxiranyl, methylcncdioxyl, chromenyl, barbituryl, isoxazolîdinyl, 1,3oxazolidin-3-yl, isothiazolidinyl, l,3-thiazolidin-3-yl, l,2-pyrazolidin-2-yl, 1,3pyrazolidin-l-yl, piperidinyl, thiomorpholînyl, 1,2-tetrahydrothiazîn-2-yl, 1,3tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, l,2-tetrahydrodiazîn-2-yl, 1,3-tetrahydrodiazin-l-yl, tctrahydroazepinyl, piperazinyl, piperizin-2-onyl, pipcrizin-3onyl, chromanyl, 2-pyrrolinyl, 3-pynrolinyl, imidazolidinyl, 2-imidazolidinyl, 1,4dioxanyl, 8-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 3,8diazabicyclo[3.2.1 ]octanyl, 2,5-diazabicyclo[2.2.1 Jhcptanyl, 2,5diazabicyclo[2.2.2]octanyl, octahydro-2H-pyrido[l ,2-a]pyrazinyl, 3azabicyclo[4.1.0]hcptanyl, 3-azabicyclo[3.1.0]hexanyl 2-azaspiro[4.4]nonanyl, 7-oxa-laza-spiro[4.4]nonanyl, 7-azabicyclo[2.2.2]heptanyl, octahydro-lH-indolyl, 2,6diazaspiro[3.3]hcptane, 2-azaspiro[3.3]hcptanc, 2,7-diazaspiro[4.4]nonane, azepanc, 1,4diazcpanc, 3,6-diazabicyclo[3.1.1]hcptane, 2-azabicyclo[2.2.1]heptane, 7azabicyclo[2.2.2]octane, 3-azabicyclo[3.1.1]heptane or 6-azabicyclo[3.1.1]heptane.

The présent invention further relates to a compound according to Formula I, wherein A¹ is benzo(C2-C9)heterocycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein A¹ is bcnzo(C₂-C9)hetcrocycloalkyl, and further wherein A¹ is 2,3dihydrobenzo[b][l,4] dioxine or 2,2-difluorobenzo[d][l,3]dioxole.

The présent invention further relates to a compound according to Formula I, X⁵ is a direct bond.

The présent invention further relates to a compound according to Formula I, wherein X⁵ is a CR⁴R⁵.

The présent invention further relates to a compound according to Formula I, wherein X⁵ is CR⁴R^S wherein R⁴ and R^s arc each methyl,

The présent invention further relates to a compound according to Formula I, wherein X^s is CR’R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring.

The présent invention further relates to a compound according to Formula I, wherein X^s is CR⁴R^S wherein R⁴ and R⁵ are taken together with the carbon to which they arc attached to form a spiro (Cs-Ciojcycloalkyl ring, wherein X⁵ is CR⁴R⁵ wherein R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro cyclopropyl ring.

The présent invention further relates to a compound according to Formula I, wherein X⁵ is a CR⁴R^S, wherein R⁴ and R⁵ are taken together with the carbon to which they arc attached to form a spiro (C3-Cjo)cycloalkoxy ring.

The présent invention further relates to a compound according to Formula l, H wherein A is (Ce-C 1₂)ary l.

The présent invention further relates to a compound according to Formula I, wherein A² is (C₂-Cg)heteroaryl.

The présent invention fiirthcr relates to a compound according to Formula I, wherein A² is (C₂-C9)hcteroaryl, further wherein A² is pyridine.

The présent invention further relates to a compound according to Formula I, wherein A² is (C₂-C9)heterocycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein A² is (C2-C9)hctcrocycloalkyl, further wherein A² is (C2-C9)hetcrocycloalkyl further wherein A² is pyrrolidinyl, tctrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, azetidinyl, oxiranyl, methylencdioxyl, chromenyl, barbituryl, isoxazolidinyl, l,3-oxazolidin-3-yl, isothiazolidinyl, l,3-thiazolidin-3-yl, 1,2pyrazolidin-2-yl, 1,3-pyrazolidin-l-yl, piperidinyl, thiomorpholinyl, 1,2tctrahydrothiazin-2-yl, l,3-tctrahydrothiazin-3-yl, tctrahydrothiadiazinyl,morpholinyl, l,2-tctrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-l-yl, tctrahydroazcpinyl, piperazinyl, pipcrizin-2-onyl, piperizin-3-onyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyl, imidazolidinyl, 2-imidazolidinyl, 1,4-dioxanyl, 8-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1 ]octanyl, 2,5-diazabicyclo[2.2.1 ]hcptanyl, 2,566 diazabicyclo[2.2.2]octanyl, octahydro-2H-pyrido[ l ,2-a]pyrazinyl, 3azabicyclo[4.l.0]hcptanyl, 3-azabicyclo[3.l.0]hcxanyl 2-azaspiro[4.4]nonanyl, 7-oxa-laza-spiro[4.4]nonanyl, 7-azabicyclo[2.2.2]heptanyl or octahydro-1 H-indolyl.

The présent invention further relates to a compound according to Formula l, wherein A² is benzofCî-CgJhctcrocycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein A² is benzo(C2-C9)hetcrocycloalkyl further wherein A² is 2,3dihydrobenzo[b][l ,4] dioxine or 2,2-difluorobcnzo[d][ l ,3]dioxole.

The présent invention further relates to a compound according to Formula I, where R* is hydrogen or methyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, l or 2; X¹ is CR¹; m is 1; p is 1; E is Ο; X² is Ο; X3 is NH; R¹ is H; X⁴ is CR⁴R^S wherein R⁴ and R⁵ are taken together with the carbon to which they arc attached to form a spiro (Cî-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Ce Cj2)aryl; X^s is a direct bond, O or CR⁴R^S and A² is (C₆-C_l2)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; p is 1; E is Ο; X² is Ο; X³ is NH; R¹ is H; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Ce Ci2)aryl; X^s is a direct bond, O or CR⁴R^Sand A² is (Ce-Ci2)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; p is 1; E is Ο; X² is Ο; X3 is NH; R¹ is H; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cto)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Ce Cujaryi; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (Cz-Cgjhctcroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; p is I; E is Ο; X² is Ο; X³ is NH; R¹ is H; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are cach independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Ce Cnjaryl; X^s is a direct bond, O or CR⁴R⁵and A² is (C2-C9)heteroaryl.

The présent invention further relates to a compound according to Formula 1, wherein n is 1; 2 or 3; t is 0,1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; p is 1; E is

Ο; X² is Ο; X³ is ΝΗ; R¹ is H; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Cî-Cgjheteroaryl; X^s is a direct bond, O or CR⁴R^S and A² is (Ce-Ci2)aryl.

The présent invention further relates to a compound according to Formula 1, wherein n is 1; 2 or 3; t is 0,1 or 2; y is 0 or 1; z is 0,1 or 2; X¹ is CR¹; m is 1; p is 1; E is Ο; X² is Ο; X³ isNH; R¹ is H; X⁴ is CR⁴R⁵ wherein R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-C<;)hcteroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C6-C|₂)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is NH; X⁴ is CR⁴R^S wherein R⁴ and R^s are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Ce Ci2)aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C₆-C₁₂)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Ce Ci2)aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (CfC12)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0,1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is NH; X⁴ is CR⁴R^S wherein R⁴ and R^s are taken together with the carbon to which they are attached to form a spiro (C3-Cjo)cycloalkyl ring or spiro (C3Ciojcycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C6.Ci2)aryl; X^s is a direct bond, O or CR⁴R⁵ and A² is (C2-C<>)heteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2or3; tisO, 1 or2;yis0or l;zis0, 1 or2;X^] isCR^mis 1; E is O;X²is NH; X³ is NH; X⁴ is CR⁴R^S wherein R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Cs.C]2)aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2Cpjhcteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0,1 or 2; y is 0 or 1; z is 0, 1 or 2; XI is CR¹; m is 1; E is Ο; X² is NH; X³ is NH; X⁴ is CR⁴R^S wherein R⁴ and R⁵ are taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cto)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Cî-C^hcteroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C6-Ci2)aryl.

The présent invention further relates to a compound according to Formula 1, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X^! is CR¹ ; m is 1 ; E is Ο; X²is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R^s arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-Cg)hctcroaryl; X^s is a direct bond, O or CR⁴R⁵ and A² is (C₆-C_l2)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1 ; 2 or 3; t is 0, I or 2; y is 0 or 1 ; z is 0,1 or 2; X^! is CR¹; m is 1 ; E is Ο; X²is NH; X³ is CH2; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Ce Ci2)aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C6-Ci₂)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1 ; 2 or 3; t is 0,1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is Ο; X²is NH; X³ is CH2; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C6_Ci2)aryl; X^s is a direct bond, O or CR⁴R^S and A² is (CûCi2)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; l is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CRI; m is 1; E is Ο; X²is NH; X³ is CH2; X⁴is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C6.C|₂)aryl; X⁵ is a direct bond,

O or CR⁴R⁵ and A² is (C2-C9)hcteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, I or 2; y is 0 or 1; z is 0,1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is CH2; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Ce.Cj2)aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C230 C9)heteroaryl,

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X is CR ; m is 1; E is Ο; X is NH; X³ is CH2; X⁴ is CR⁴R^S wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C369

Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)hcteroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (Ce-Ci2)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is CH2; X⁴ is CR⁴R⁵ wherein R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heteroaryl; X^s is a direct bond, O or CR⁴R^Î and A² is (C6-C|₂)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is CH²; X³ is NH; X⁴ is CR⁴R^S wherein R⁴ and R⁵ are taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (CsCio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A* is (Ce Cn)aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C₆-C|₂)aryl.

The présent invention further relates to a compound according to Formula 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is CH²; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R^s arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Ce-C|2)aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (CeCi2)aryl,

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is CH²; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Ce Ci2)aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2-C9)heteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; zis 0, 1 or 2; X¹ is CR¹; m is 1; E is O;X²is CH²; X³ is NH; X⁴ is CR⁴R^S wherein R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Ce Ci2)aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2C9)hcteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is ^]; E is Ο; X²is CH²; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C370

Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)hetcroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C6-Ci2)aryl.

The présent invention fiirther relates to a compound according to Formula I, wherein n is 1 ; 2 or3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CRI; m is 1; E is Ο; X²îs CH²; X³ is NH; X⁴ is CR⁴R^S wherein R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)hcteroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C6-Ci2)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, I or 2; X* is CR¹; m is 1; E is S; X²is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Cô.Ci2)aryl; X⁵ is a direct bond, O or CR⁴R^s and A² is (C6-Ci₂)aryl.

The présent invention fiirther relates to a compound according to Formula ], wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is S; X²is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Cô Ci2)aryl; X⁵ is a direct bond, O or CR⁴R^S and A² is (CeC[2)aryl.

The présent invention fiirther relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0,1 or 2; X¹ is CR¹; m is 1; E is S; X²is NH; X³ is NH; X⁴ is CR⁴R^S wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cto)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C(j.Ci2)aryi; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C₂-C9)heteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n îs 1; 2 or 3; t is 0, l or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; mis 1; E is S; X²is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Ce-C|2)aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² îs (C2Cgjheteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1 ; 2 or 3; t is 0,1 or 2; y is 0 or 1 ; z is 0, l or 2; X¹ is CR¹; m is 1 ; E is S; X²is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C377

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0,1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is S; X²is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)hctcroaryl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C₆-Ci₂)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is SO2; X² is NH; X³ is NH; X⁴ is CR⁴R^S wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (Cj-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C6.Ci2)aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C₆-C₁₂)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is SO2; X² is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C6.Ci2)aryl; X^s is a direct bond, O or CR⁴R⁵ and A² is (CeCi2)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is SO2; X² is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Cé-C^aryl; X^s is a direct bond, O or CR⁴R⁵ and A² is (C2-C9)heteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is SO2; X² is NH; X³ is NH; X⁴ is CR⁴R^S wherein R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C6-C12)aryl; X^s is a direct bond, O or CR⁴R⁵ and A² is (C₂C9)heteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is SO₂; X² is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R^s arc taken together with the carbon to which they arc attached to form a spiro (C3-C|o)cycloalkyl ring or spiro (C372

Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-Cg)heteroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C6-Ci2)aryl.

The présent invention further relates to a compound according to Formula 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is SO2; X² îs NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R^s arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-C<))hetcroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C₆-C₁₂)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1 ; 2 or 3; t is 0,1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cto)cycioalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C6 Ci2)aryl; X^s is a direct bond, O or CR⁴R^S and A² is (CeCi2)aryl.

The présent invention further relates to a compound according to Formula 1, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R^s arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Cfi.Cj2)aryl; X^s is a direct bond, O or CR⁴R⁵ and A² is (Ce-Cnjaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1 ; 2 or 3; t is 0,1 or 2; y is 0 or 1 ; z îs 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; X⁴ is CR⁴R^s wherein R⁴ and R⁵ arc taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Cô Ci₂)aryl; X^s is a direct bond, O or CR⁴R^S and A² is (C2Cgjheteroaryl,

The présent invention further relates to a compound according to Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Ce Ci2)aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2-Ct))heteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; X⁴ is CR⁴R^S wherein R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2~C9)hcteroaryI; X^s is a direct bond, O or CR⁴R^S and A² is (C₆-Ci2)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is I; 2 or 3; t is 0, l or 2; y is 0 or l; z is 0, l or 2; X¹ is N; m is 0; E is Ο; X³ is NH; X⁴ is CR⁴R^s wherein R⁴ and R^s are each independentiy methyl; R⁶ is a hydrogen or methyl; A¹ is (Cî-C^heteroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (Cc-Ci₂)aryl.

The présent invention further relates to a compound according to Formula 1, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹ ; m is 1 ; E is Ο; X²is NH; X³ is CO-NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C&.C|₂)aryl; X^s is a direct bond, O or CR⁴R^s and A² is (Ce-Cnjaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is CO-NH; X⁴ is CR⁴R^s wherein R⁴ and R^s are each independentiy methyl; R⁶is a hydrogen or methyl; A¹ is (C6-Ci2)aryl; X^s is a direct bond, O or CR⁴R^S and A² is (C'eCi2)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is CO-NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Ce Ci2)aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2-C<>)hetcroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is Ο; X²is NH; X³ îs CO-NH; X⁴ is CR⁴R^S wherein R⁴ and R^s are cach independentiy methyl; R⁶is a hydrogen or methyl; A¹ is (C6-Ci2)aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2Cp)heteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is CO-NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (C3-C|o)cycloalkyl ring or spiro (C3C]o)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heteroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C6-CJ2)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0,1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is CO-NH; X⁴ is CR⁴R⁵ wherein R⁴ and R^s arc each independently methyl; R⁶is a hydrogen or methyl; A¹ is (C2-C9)hetcroaryl; X^s is a direct bond, O or CR⁴R⁵ and A²is (C₆-Ci2)aryl.

The présent invention further relates to a compound according to Formula 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; p is 1; E is Ο; X² is Ο; X³ is NH; R¹ is H; X⁴ is CR⁴R⁵ wherein R⁴ and R^s are taken together with the carbon to which they arc attached to form a spiro (C3-Cjo)cycloalkyl ring or spiro (C3C|o)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Ce Ci2)aryl; X^s is a direct bond, O or CR⁴R^S and A² is (C2-Cs>)hctcrocycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; p is 1; E is Ο; X² is Ο; X³ is NH; R¹ is H; X⁴ is CR⁴R³ wherein R⁴ and R³ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Ce Ci2)aryl; X³ is a direct bond, O or CR⁴R³and A² is (C2-C9)heterocycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, I or 2; y is 0 or 1; z is 0, I or 2; X¹ is CR¹; m is 1; p is 1; E is Ο; X² is Ο; X³ is NH; R¹ is H; X⁴ is CR⁴R³ wherein R⁴ and R^s are taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (^-Cjheterocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (Ce-Cnjaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; p is 1; E is Ο; X² îs Ο; X³ is NH; R¹ is H; X⁴ is CR⁴R^S wherein R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is ^-Cjhetcrocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C6-Ci2)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E îs Ο; X²is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R^s are taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C6.Ci2)aryl; X³ is a direct bond, O or CR⁴R^S and A² is ^-Cjhctcrocycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C6.C|2)aryl; X⁵ is a direct bond, O or CR⁴R³ and A² is (C2Cg)heterocycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is NH; X⁴ is CR⁴R^S wherein R⁴ and R? are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heterocycloalkyl; X^s is a direct bond, O or CR⁴R⁵ and A² is (Cô-C|2)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is NH; X⁴ îs CR⁴R³ wherein R⁴ and R³ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-Cg)hcterocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (Cô-Ci2)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is CH²; X⁴ is CR⁴R³ wherein R⁴ and R³ are taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Cû Ci2)aryl; X³ is a direct bond, O or CR⁴R³ and A² is (C2-C9)heterocycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is CH²; X⁴ is CR⁴R³ wherein R⁴ and R³ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C6-C|2)aryl; X³ is a direct bond, O or CR⁴R³ and A² is (C2Cçjhcterocycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is CH²; X⁴ is CR⁴R³ wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Ci0)cycloalkyi ring or spiro (C3Cjo)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-Cg)heterocycloalkyl; X³ is a direct bond, O or CR⁴R³ and A² is (C<5-Ci₂)aryL

The présent invention further relates to a compound according to Formula I, wherein n is I; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² îs NH; X³ is CH²; X⁴ is CR⁴R³ wherein R⁴ and R³ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Cj-Cçjheterocycloalkyl; X^s is a direct bond, O or CR⁴R^S and A² is (Ce-Ci2)aryl.

The présent invention further relates to a compound according to Formula 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, I or 2; X¹ is CR¹; m is 1; E is Ο; X²is CH²; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R^s are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Ce-Cnjaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2-C9)hcterocycloalkyl.

The présent invention further relates to a compound according to Formula 1, wherein n is 1; 2 or 3; t is 0,1 or 2; y is 0 or 1; z is 0,1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is CH²; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Cô-Cujaryl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C2Cpjheterocycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is Ο; X²is CH²; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ arc taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3C|o)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)hctcrocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C6-Ci2)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is I; 2 or 3; t is 0,1 or 2; y is 0 or 1; z is 0,1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is CH²; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heterocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C₆-Ci2)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1 ; 2 or 3; t is 0, I or 2; y is 0 or 1 ; z is 0, 1 or 2; X is CR ; m is 1 ; E is S; X is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C6-Ci2)aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2-C9)hcterocycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is I ; E is S; X²is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Ce-Cujaryl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C₂Ci>)heterocycloalkyL

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is S; X²is NH; X³ is NH; X⁴ is CR⁴R^S wherein R⁴ and R⁵ arc taken together with the carbon to which they arc attached to form a spiro (Cî-Ciojcycloalkyl ring or spiro (C₃Cjo)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C^z-C9)hetcrocycloalkyl; X^J is a direct bond, O or CR⁴R⁵ and A² is (Cô-Ci2)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0,1 or 2; X¹ is CR¹; m is 1; E is S; X²is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)hetcrocycloalkyl; X⁵ is a direct bond, O or CR⁴R^S and A² is (Ce-Ci2)aryL

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is SO2; X² is NH; X³ is NH; X⁴ is CR⁴R^S wherein R⁴ and R^s are taken together with the carbon to which they arc attached to form a spiro (C3-C10) cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Ce Ci2)aryl; X⁵ is a direct bond, O or CR⁴R^î and A² is (C2-C9)heterocyclo alkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is SO₂; X² is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Cô.Ci2)aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2C9)heterocycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0,1 or 2; X¹ is CR¹; m is 1; E is SO₂; X² is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)hetcrocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C6-Ci2)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or l; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is SO2; X² is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-Ct))hctcrocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (Ce-Ci2)aryL

The présent invention further relates to a compound according to Formula 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or I ; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C6-Ci2)aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2C9)heterocycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0,1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; X⁴ is CR⁴R^s wherein R⁴ and R^s arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Ce Cnjaryl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C2Cg)heterocycloalkyL

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R^s are taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-C[o)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-Ci>)licterocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C6-Ci2)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Cî-Cgjheterocycloalkyl; X^s is a direct bond, O or CR⁴R⁵ and A² is (CeCi₂)aryl.

The présent invention further relates to a compound according to Formula ï, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is CO-NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Ce C^jaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2-C9)hetcrocycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is CO-NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Ce Ci2)aryl; X^s is a direct bond, O or CR⁴R⁵ and A² is (C2Cç>)heterocycloalky 1.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²5 is NH; X³ is CO-NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (Cj-Cio)cycloaikyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heterocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (Ce-C|2)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X* is CR¹; m is 1; E is Ο; X²is NH; X³ is CO-NH; X⁴ is CR⁴R⁵ wherein R⁴ and R^s arc each independently methyl; R⁶is a hydrogen or methyl; A¹ is (C2-C9)hctcrocycloalkyl; X⁵ is a direct bond, O or CR⁴R^Sand A² is (C6-C|2)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; p is 1; E is Ο; X² is Ο; X³ is NH; R¹ is H; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ arc taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R^û is a hydrogen or methyl; A¹ is (C2-C9)heteroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2-C9)heterocycloalkyl.

The présent invention further relates to a compound according to Formula I, whereinnis 1; 2 or 3; t isO, I or 2; y is 0 or l;z is 0, 1 or 2; X¹ is CR¹; mis 1; pis 1; Eis Ο; X² is Ο; X³ is NH; R¹ is H; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-Cç)heteroaryl; X^s is a direct bond, O or CR⁴R^s and A² is (C2-C9)hctcrocycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or l;z is 0, 1 or 2; X¹ isCR';mis 1; p is 1; E is Ο; X² is Ο; X³ is NH; R¹ is H; X⁴ is CR⁴R^S wherein R⁴ and R^s are taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R^û is a hydrogen or methyl; A¹ is (C₂-C9)heterocycloalkyl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C₂-C9)hcteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2or 3; t is 0, 1 or 2; y isO or 1; z isO, 1 or 2; X¹ is CR¹; mis 1; p is 1; E is

Ο; X² is Ο; X³ is NH; R¹ is H; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Cî-Cçjhctcrocycloalkyl; X^s is a direct bond, O or CR⁴R³ and A² is (C₂-C9)heteroaryl.

The présent invention further relates to a compound according to Formula 1, wherein n is 1 ; 2 or 3; t is 0,1 or 2; y is 0 or 1 ; z is 0,1 or 2; X¹ is CR¹; m is 1 ; E is Ο; X²is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R^s arc taken together with the carbon to which they are attached to form a spiro (Ca-Ciojcycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)hcteroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2-C9)heterocycloalkyl.

The présent invention further relates to a compound according to Formula 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or I; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is NH; X⁴ is CR⁴R^S wherein R⁴ and R⁵ are each independently methyl; R^û is a hydrogen or methyl; A¹ is (C2-Cÿ)hcteroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C₂-C9)heterocycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is Ο; X²îs NH; X³ îs NH; X⁴ is CR⁴R^S wherein R⁴ and R⁵ arc taken together wîth the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C₂-C9)heterocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2-C9) heteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R^s are each independently methyl; R⁶ îs a hydrogen or methyl; A¹ is (C2-C9)heterocycloalkyl; X³ is a direct bond, O or CR⁴R³ and A² is (C2-C9)hcteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is CH²; X⁴ is CR⁴R⁵ wherein R⁴ and R^s are taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heteroaryl; X³ is a direct bond, O or CR⁴R⁵ and A² is (C2-C9)heterocycloalkyl.

The présent invention further relates to a compound according to Formula 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X is CR ; m is 1; E is Ο; X is NH; X³ is CH²; X⁴ is CR⁴R³ wherein R⁴ and R³ are each independently methyl; R⁶ is a hydrogen or methyl; A* is (C₂-C9)hctcroaryl; X^s is a direct bond, O or CR⁴R^S and A² is (C2-C9)hetcrocycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is l ; 2 or 3; t is 0, l or 2; y is 0 or l ; z is 0, l or 2; X* is CR¹ ; m is 1 ; E is Ο; X²5 is N H; X³ is CH²; X⁴ is CR⁴R^S wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)hcterocycloalkyl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C₂-C9)hetcroaryl.

The présent invention further relates to a compound according to Formula 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or I; z is 0, 1 or 2; X* is CR¹; m is ’; E is Ο; X²is NH; X³ is CH²; X⁴ is CR⁴R⁵ wherein R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heterocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2-C9) heteroaryl

The présent invention further relates to a compound according to Formula 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is CH²; X³ is NH; X⁴ is CR⁴R^S wherein R⁴ and R^s are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heteroaryl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C2-C9)hetcrocycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X* is CR¹; m is 1; E is Ο; X²is CH²; X³ is NH; X⁴ is CR⁴R³ wherein R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C₂-C9)hctcroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2-C9)hctcrocycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is CH²; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ arc taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Cî-Cgjhcterocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (Cî-Cgjhctcroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or2; y is Oor 1; z is 0, 1 or 2; X* isCR¹; m is 1; E is Ο; X² is CH²; X³ is NH; X⁴ is CR⁴R^S wherein R⁴ and R^s arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-Cy)hetcrocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C₂-C9)heteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is S; X²is NH; X³ is NH; X⁴ is CR⁴R^S wherein R⁴ and R^s are taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)hcteroaryl; X⁵ is a direct bond, O or CR⁴R^Î and A² is (C2-C9)heterocycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is S; X²is NH; X³ is NH; X⁴ is CR⁴R^S wherein R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)hetcroaryl; X^s is a direct bond, O or CR⁴R^S and A² is (C2-C9)heterocycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹ ; m is 1 ; E is S; X²is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heterocycloalkyl; X^s is a direct bond, O or CR⁴R⁵ and A² is (C2-C9)heteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0,1 or 2; y is 0 or 1; z is 0,1 or 2;X’ is CR¹; m is 1; E is S; X²is NH; X³ is NH; X⁴ is CR⁴R^S wherein R⁴ and R^s are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cjo)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heterocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2-C9)hcteroaryl.

The présent invention further relates to a compound according to Formula 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0,1 or 2; X¹ is CR¹; m is 1; E is S; X²is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)hetcrocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2-Ci>)heteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is SO₂; X² is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C383

Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C₂-C9)hctcroaryl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C2-C9)heterocycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; yis 0 or 1; zis 0, 1 or 2; X¹ is CR¹; m is 1; E is SO₂;

X² is NH; X³ is NH; X⁴ is CR⁴R^S wherein R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heteroaryl; X^s is a direct bond, O or CR⁴R^S and A² is (C2-C9)hetcrocycloalkyl.

The présent invention further relates to a compound according to Formula 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is SO₂;

X² is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (CrCgjhcterocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C₂-C9)heteroaryl.

The présent invention further relates to a compound according to Formula 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0,1 or 2; X¹ is CR¹; m is 1; E is SO2; X² is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heterocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C₂-C9)heteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X is N; m is 0; E is Ο; X is NH; X⁴ is CR⁴R^S wherein R⁴ and R^s are taken together with the carbon to which they arc attached to form a spiro (C3-C|o)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heteroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2-C9)hetcrocycloalkyl.

The présent invention further relates to a compound according to Formula 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)hcteroaryl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C2C9)hcterocycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1 ; 2 or 3; t is 0,1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is

NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A* is (C₂-C9)hetcrocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and

Λ

A is (C2-C9)heteroaryl.

The présent invention fiirther relates to a compound according to Formula I, wherein nis I;2or3;tis0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ isN;m is 0; Eis Ο; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heterocycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2Cgjhetcroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, l or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is CO-NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)hetcroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2-C9)heterocycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is Ο; X²is NH; X³ is CO-NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are each independently methyl; R⁶is a hydrogen or methyl; A¹ is (C2-C9)hetcroaryl; X⁵ is a direct bond, O or CR⁴R^S and A²is (C₂-C9)heterocycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is CO-NH; X⁴ is CR⁴R^S wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3C]o)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heterocycloalkyl; X^s îs a direct bond, O or CR⁴R⁵ and A² is (C2-C9)hcteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is CO-NH; X⁴ is CR⁴R^S wherein R⁴ and R^s are each independently methyl; R⁶is a hydrogen or methyl; A¹ is (C2-C9)hctcrocycloalkyl; X⁵ is a direct bond, O or CR⁴R^S «J and A is (C2-C9)heteroaryl.

The présent invention further relates to a compound according to Formula 1, wherein n is 1 ; 2 or 3; t îs 0,1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; p is 1 ; E is Ο; X² is Ο; X³ is NH; R¹ is H; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C385

Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-Co)heteroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C₂-C9)hetcroaryl.

The présent invention further relates to a compound according to Formula i, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; p is 1; E is Ο; X² is Ο; X³ is NH; R¹ is H; X⁴ is CR⁴R^S wherein R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heteroaryl; X⁵ is a direct bond, O or CR⁴ R⁵ and A² is (Cî-Cyjhetcroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3~Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ îs (C₂-C9)heteroaryl; X^s is a direct bond, O or CR⁴R^S and A² is (C2-C9)heteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z îs 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C₂-C9)heteroaryl; X^s is a direct bond, O or CR⁴R^S and A² is (C2-C9)heteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X* is CR¹; m is 1; E is Ο; X²îs NH; X³ îs CH₂; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C?Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)hcteroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2-C9)hctcroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is CH2; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heteroaryl; X^s is a direct bond, O or CR⁴R⁵ and A² is (Cî-Cpjhetcroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0,1 or 2; X¹ is CR¹; m is 1 ; E is Ο; X²is CH2; X³ îs NH; X⁴ is CR⁴R⁵ wherein R⁴ and R^s are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C386

Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A* is (C2-Cç>)hctcroaryl; X⁵ is a direct bond, O or CR⁴R³ and A² is (C2-Cg)heteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is l; 2 or 3; t is 0, l or 2; y is 0 or l; z is 0, l or 2; X¹ is CR¹; m is 1; E is Ο; X²is CH2; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-Cg)hcteroaryl; X³ is a direct bond, O or CR⁴R⁵ and A² is (C2-Ci))hcteroaryL

The présent invention further relates to a compound according to Formula I, wherein n is I; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is S; X²is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R^s arc taken together with the carbon to which they are attached to form a spiro (C3-C|o)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-Cg)hcteroaryl; X³ is a direct bond, O or CR⁴R⁵ and A² is (C₂-C9)hetcroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is S; X²is NH; X³ is NH; X⁴ is CR⁴R³ wherein R⁴ and R³ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-Cg)heteroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2-C<))hcteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X* is CR¹; m is 1; E is SO2; X² is NH; X³ is NH; X⁴ is CR⁴R³ wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (Ca-Ciojcycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-Cg)heteroaryl; X³ is a direct bond, O or CR⁴R³ and A² is (C₂-Cg)heteroaryl.

The présent invention further relates to a compound according to Formula 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is SO2; X² is NH; X³ is NH; X⁴ is CR⁴R³ wherein R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-Cg)hetcroaryl; X^s is a direct bond, O or CR⁴R³ and A² is (C2“Cg)heteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is

NH; X⁴ is CR⁴R³ wherein R⁴ and R³ are taken together with the carbon to which they are attached to form a spiro (C3-Cjo)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-Cg)hetcroaryl; X^s is a direct bond, O or CR⁴R⁵ and A² is (C₂-C9)heteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ arc cach independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heteroaryl; X³ is a direct bond, O or CR⁴R⁵ and A² is (C2Cg)hcteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0,1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E îs Ο; X²is NH; X³ is CO-NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ arc taken together with the carbon to which they arc attached to form a spiro (C3-Cto)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)heteroaryl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C2-C9)heteroaryl.

The présent invention further relates to a compound according to Formula 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0,1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is CO-NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are each independently methyl; R⁶is a hydrogen or methyl; A¹ is (C2-C9)hetcroaryl; X³ is a direct bond, O or CR⁴R⁵ and A²is (C2-C9)heteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; p is 1 ; E is Ο; X² is Ο; X³ is NH; R¹ is H; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cjo)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Ce C_i2)aryl; X³ is a direct bond, O or CR⁴ R³ and A² is (C3-Cio)cycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, l or 2; X¹ is CR¹; m is 1; p is 1; E is Ο; X² is O; X³ is NH; R¹ is H; X⁴ is CR⁴R³ wherein R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C₆ Ci₂)aryl; X³ is a direct bond, O or CR⁴R⁵ and A² is (C3Cio)cycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; p is 1; E is

Ο; X² is Ο; X³ is NH; R¹ is H; X⁴ is CR⁴R³ wherein R⁴ and R³ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C317263

Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C3-Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C6-Ci₂)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X* is CR¹; m is 1; p is 1; E is Ο; X² is Ο; X³ is NH; R¹ is H; X⁴ is CR⁴R⁵ wherein R⁴ and R^s are each independentiy methyl; R⁶ is a hydrogen or methyl; A¹ is (C3-Cio)cycloalkyi; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C₆-C₁₂)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R^s are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloaikyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Ce Ci₂)aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C3-Cio)cycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein nis 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or2;X* is CR¹; mis 1; E is Ο; X²is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ arc cach independentiy methyl; R^fi is a hydrogen or methyl; A¹ is (Ce Ci₂)aryl; X³ is a direct bond, O or CR⁴R^S and A² is (C3Cio)cycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; tis 0, 1 or 2; yîs 0 or l;z is 0, 1 or2;X* is CR¹; m is 1; E is Ο; X²is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R³ arc taken together with the carbon to which they are attached to form a spiro (C3-Cjo)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Cî-Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C6-Cj₂)aryl.

The présent invention further relates to a compound according to Formula I, wherein nis 1; 2 or 3; t is 0, 1 or2;yis0or l;zis0, I or2;X‘ isCR¹; mis I; E is Ο; X²is NH; X³ is NH; X⁴ is CR⁴R^S wherein R⁴ and R³ are each independentiy methyl; R⁶ is a hydrogen or methyl; A¹ is (C3-Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C₆-C₁₂)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is I; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is I; E is Ο; X² is NH; X³ is CH₂; X⁴ is CR.⁴R^S wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloatkyl ring or spiro (Ca89

C|o)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A* is (Ce Ci2>aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C3-Cio)cycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is CH2; X⁴ is CR⁴R⁵ wherein R⁴ and R^s arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Ce Cnjaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C3Cio)cycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is Ο; X²is NH; X³ is CH2; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C3-Cjo)cycloalkyl; X^s is a direct bond, O or CR⁴R⁵ and A² is (Ce-C^jaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y îs 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is CH2; X⁴ is CR⁴R^S wherein R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A* is (C3-Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (Cc-Ci2)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is CH2; X³ is NH; X⁴ is CR⁴R^S wherein R⁴ and R^s are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3C|o)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ îs (Cc-Ci2)aryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C3-C10)cycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or I; z is 0, 1 or 2; X* is CR¹; m is 1; E is Ο; X²is CH2; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R^s are each independently methyl; R^â is a hydrogen or methyl; A¹ is (Cô-Cj2)aryl; X⁵ îs a direct bond, O or CR⁴R⁵ and A² is (C3Cio)cycloatkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is CH2; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C390

Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyi; A¹ is (C3-Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (Ce-Cnjaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is CH2; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R^s arc cach independently methyi; R⁶ is a hydrogen or methyi; A¹ is (C3-Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C₆-Ci2)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is S; X²is NH; X³ is NH; X⁴ is CR⁴R^S wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyi; A¹ is (Ce-Cnjaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C3-Cio)cycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is S; X²is NH; X³ Îs NH; X⁴ is CR⁴R^S wherein R⁴ and R^s are each independently methyi; R⁶ is a hydrogen or methyi; A¹ is (Ce-Cnjaryl; X^s is a direct bond, O or CR⁴R⁵ and A² is (C3Cio)cycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0,1 or 2; X¹ is CR¹; m is 1; E is S; X²is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyi; A¹ is (C3-Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C₆-Ci2)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is S; X²is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R^s are cach independently methyi; R⁶ is a hydrogen or methyi; A¹ is (C3-Ci0)cycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C6-C₁₂)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, I or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is SO2;

X² is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C317263

Cio)cyc!oalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Cc-Cujaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (Cj-Cio)cycloalkyl.

The présent invention further relates to a compound according to Formula 1, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹ ; m is 1 ; E is SO2; X² is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Cs-Ci2)aryl; X^s is a direct bond, O or CR⁴R⁵ and A² is (C3Cjo)cycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is SO2; X² is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (Cj-CnOcycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C3-Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C6-Ci2)aryl.

The présent invention further relates to a compound according to Formula 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is SO2; X² is NH; X³ is NH; X⁴ is CR⁴R^S wherein R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C3-Cio)cycloalkyl; X^s is a direct bond, O or CR⁴R⁵ and A² is (C₆-Cj₂)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (C3-C|o)cycloalkyl ring or spiro (C3-Cio)cycioalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Cc-Cnjaryl; X⁵ is a direct bond, O or CR.⁴R^S and A² is (C3Cio)cycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (Ce-Ciîjaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C3-Cio)cycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0,1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-C]o)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C3-Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C₆-Ci2)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is l; 2 or 3; t is 0, l or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C3-Cio)cycloalkyl; X^s is a direct bond, O or CR⁴R⁵ and A² is (C₆-C|2)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is CO-NH; X⁴ is CR⁴R^S wherein R⁴ and R^s arc taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Ce Ci2)aryl; X⁵ is a direct bond, O or CR⁴R^S and A² is (Cj-Cjoïcycloalkyi.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is CO-NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ arc each independently methyl; R⁶is a hydrogen or methyl; A¹ is (Ce Ci2)aryl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C3Cjo)cycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is Ο; X²is NH; X³ is CO-NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C3-Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C6-Ci2)aryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is CO-NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are each independently methyl; R⁶is a hydrogen or methyl; A* is (C3-Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R^S and A²is (Ce-Cnjaryl.

The présent invention further relates to a compound according to Formula 1, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0,1 or 2; X* is CR¹; m is 1 ; p is 1 ; E is Ο; X² is Ο; X³ is NH; R* is H; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C₂-Cy)heteroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C3-Cio)cycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X* is CR¹; m is 1; p is 1 ; E is

Ο; X² is Ο; X³ is ΝΗ; R? is H; X⁴ is CR⁴R⁵ wherein R⁴ and R³ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-Cç)heteroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (Cj-CioJcycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1 ; 2 or 3; t is 0,1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹ ; m is 1 ; p is 1 ; E is Ο; X² is Ο; X³ is NH; R¹ is H; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ arc taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycioalkyl ring or spiro (C3Cl0)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A* is (C3-Cio)cycloalkyl; X^s is a direct bond, O or CR⁴R⁵ and A² is (C2-C9)heteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; p is 1; E is Ο; X² is Ο; X³ is NH; R¹ is H; X⁴ is CR⁴R^S wherein R⁴ and R⁵ arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C3-C|o)cycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C₂-C9)heteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0,1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is NH; X⁴ is CR⁴ R³ wherein R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C₂-C9)heteroaryl; X³ is a direct bond, O or CR⁴R⁵ and A² is (C3-Cio)cycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is NH; X⁴ is CR⁴R³ wherein R⁴ and R⁵ are each independently methyl; R^û is a hydrogen or methyl; A¹ is (C₂-C9)heteroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C3-Cio)cycioalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ arc taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C₃Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C3-Cio)cycloalkyl; X³ is a direct bond, O or CR⁴R³ and A² is (C2-C9) heteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is NH; X⁴ is CR⁴R³ wherein R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A* is (C₃-Ci₀)cycloalkyl; X^s is a direct bond, O or CR⁴R⁵ and A² is (C₂-Cg)heteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is l ; 2 or 3; t is 0, l or 2; y is 0 or l ; z is 0, l or 2; X¹ is CR¹; m is 1 ; E is Ο; X²is NH; X³ is CH2; X⁴ is CR⁴R^S wherein R⁴ and R^s are taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalliyl ring or spiro (C₃Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-Cg)hcteroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C3-C|o)cycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2or 3; t is 0, 1 or 2; y is 0 or 1; z is 0,1 or 2;X‘ is CR¹; mis 1; E is Ο; X²is NH; X³ is CH2; X⁴ îs CR⁴R^S wherein R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)hetcroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C₃-Cio)cycloalkyl.

The présent invention further relates to a compound according to Formula 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is Ο; X²is NH; X³ is CH2; X⁴ is CR⁴R^S wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C₃Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C3-Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C2-Ci))hetcroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0,1 or 2; y is 0 or 1; z is 0,1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is CH2; X⁴ is CR⁴R⁵ wherein R⁴ and R^s are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C₃-Cio)cycloalkyl; X^s is a direct bond, O or CR⁴R⁵ and A² is (C2-C<))heteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or2;X^[ isCR^mis l;EisO;X²is CH2; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they arc attached to form a spiro (C3-C|o)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-Cç>)hetcroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C₃-Cio)cycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0,1 or 2; X* is CR¹; m is 1; E is Ο; X² is CH₂; X³ is NH; X⁴ is CR⁴R^S wherein R⁴ and R⁵ are each independently methyl; R⁶ îs a hydrogen or methyl; A¹ is (C2-C9)hctcroaryl; X^s is a direct bond, O or CR⁴R⁵ and A² is (C3-Cio)cycloalkyl,

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X^[ is CR¹; m is 1; E is Ο; X²5 is CH2; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R^s are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3C to)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C3-Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C2-C9) heteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is CH2; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are cach independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C3-Cio)cycloalkyl; X^s is a direct bond, O or CR⁴R^S and A² is (C2-C9)heteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0,1 or 2; y is 0 or 1; z is 0, I or 2; X¹ is CR¹; m is 1; E is S; X²is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3C io)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (Co-Cçijhctcroaryl; X^s is a direct bond, O or CR⁴R⁵ and A² is (C3-C₁o)cycloalkyl.

The présent invention further relates to a compound according to Formula 1, wherein n is 1; 2 or 3; t is 0,1 or 2; y is 0 or 1; z is 0, 1 or 2; X is CR ; m is 1; E is S; X is NH; X³ is NH; X⁴ is CR⁴R^S wherein R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)hetcroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C3-Cio)cycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0,1 or 2; X¹ is CR¹; m is 1; E is S; X²is NH; X³ is NH; X⁴ is CR⁴R^Î wherein R⁴ and R⁵ are taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C3-Cio)cycloalkyl; X⁵ is a direct 30 bond, O or CR⁴R^S and A² is (C2-Cg)hetcroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1 ; 2 or 3; t is 0,1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is I ; E is S; X² is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C₃-Cto)cycloalkyl; X^s is a direct bond, O or CR⁴R^S and A² is (C2-C9)hetcroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0,1 or 2; X¹ is CR¹; m is 1; E is SO2; X² is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R^û is a hydrogen or methyl; A¹ is (C₂-C9)heteroaryl; X^s is a direct bond, O or CR⁴R⁵ and A² is (C3-Cio)cycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is SO2; X² is NH; X³ is NH; X⁴ is CR⁴R^S wherein R⁴ and R^s arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)hetcroaryl; X^s is a direct bond, O or CR⁴R⁵ and A² is (C3-C]o)cycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is SO2; X² is NH; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R^s are taken together with the carbon to which they are attached to form a spiro (C₃-Cio)cycloalkyl ring or spiro (C₃Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C3-Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C2-C9)hetcroaryl.

The présent invention further relates to a compound according to Formula 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is SO2; X² is NH; X³ is NH; X⁴ is CR⁴R^S wherein R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C3-C|o)cycloalkyl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C2-C9)heteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; X⁴ is CR⁴R^S wherein R⁴ and R^s are taken together with the carbon to which they are attached to form a spiro (Cj-C[o)cycloalkyl ring or spiro (C3-Cjo)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C2-C9)hctcroaryl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C₃-Cio)cycloalkyl.

NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C2-C<»)hctcroaryl; X⁵ is a direct bond, O or CR⁴R^S and A² is (CjCio)cycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is N; m is 0; E is Ο; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they are attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3-Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C3-Ci0)cycloalkyl; X^s is a direct bond, O or CR⁴R⁵ and A² is (C2-C9)heteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, I or 2; y is 0 or 1 ; z is 0, I or 2; X* is N; m is 0; E is Ο; X³ is NH; X⁴ is CR⁴R⁵ wherein R⁴ and R^s arc each independently methyl; R⁶ is a hydrogen or methyl; A¹ is (C3-Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C₂Cgjheteroaryl.

The présent invention further relates to a compound according to Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is Ο; X²is NH; X³ is CO-NH; X⁴ is CR⁴R⁵ wherein R⁴ and R⁵ are taken together with the carbon to which they arc attached to form a spiro (C3-C10)cycloalkyl ring or spiro (C3Cio)cycioalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C₂-C9)hctcroaryl; X⁵ is a direct bond, O or CR⁴R^S and A² is (C3-C|o)cycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH; X³ is CO-NH; X⁴ is CR⁴R^S wherein R⁴ and R⁵ are each independently methyl; R⁶is a hydrogen or methyl; A¹ is (Cî-Cçjhctcroaryl; X^s is a direct bond, O or CR⁴R⁵ and A²is (C3-C]o)cycloalkyl.

The présent invention further relates to a compound according to Formula 1, wherein n is 1 ; 2 or 3; t is 0, i or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is Ο; X²is NH; X³ is CO-NH; X⁴ is CR⁴R^S wherein R⁴ and R⁵ are taken together with the carbon to which they arc attached to form a spiro (C3-Cio)cycloalkyl ring or spiro (C3Cio)cycloalkoxy ring; R⁶ is a hydrogen or methyl; A¹ is (C3-Cio)cycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A² is (C2-C9)heteroaryl.

The présent invention further relates to an A compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is NH; X³ is CO-NH; X⁴ is CR⁴R⁵ wherein R⁴ and R^s are each independently methyl; R^û is a hydrogen or methyl; A¹ is (Cj-Ciojcycloalkyl; X⁵ is a direct bond, O or CR⁴R⁵ and A²is (C2-C9)heteroaryl.

The présent invention further relates to a compound according to Formula I, wherein A¹ is (Cî-Cio)cycloalkyl.

The présent invention further relates to a compound according to Formula I, wherein A² is (C3-Cio)cycloalkyl.

The présent invention further relates to a compound according to Formula I, or a pharmaceutically acceptable sait or prodrug thereof, selected from the group consisting of:

l-azabicyclo[2.2.2]oct-3-yl [2-(2,4’-difluorobiphcnyl-4-yl)propan-2-yl]carbamatc; l-azabicyclo[2.2.2]oct-3-yl (2-(4-(l,3-benzothiazol-6-yl)phenyl]propan-2-yl}carbamatc; l-azabicyclo[3.2.2]non-4-yl {1 -[5-(4-fluorophenyl)pyridin-2-yl]cyclopropyl}carbamatc;

l-azabicyclo[2.2.2]oct-3-yl (l-[3-(4-fluorophcnoxy)phenyl]cyclopropyl)carbamate; l-azabicyclo[2.2.2]oct-3-yl (l-[4-(l,3-benzothiazol-5-yl)phenyl]cyclopropyl)carbamate;

I-azabicyclo[2.2.2]oct-3-yl [ 1 -(4'-fluoro-3'-mcthoxybiphenyl-4yl)cyclopropyl]carbamate; l-azabicyclo[2.2.2]oct-3-yl [3-(4'-fluorobiphenyl-4-yl)oxetan-3-yl]carbamatc;

l-azabicyclo[2.2.2]oct-3-yl (l-[6-(4-fluorophcnoxy)pyridin-2-yl]cyclopropyl}carbamate; l-azabicyclo[2.2,2]oct-3-yl (3-(4^,-fluorobiphenyl-4-yl)pcntan-3-yl]carbamate;

l-azabicyclo[2.2.2]oct-3-yl {2-[2-(4-fluorophenyl)-2H-indazol-6-yl]propan-2 yl}carbamatc;

l-azabicyclo[2.2.2]oct-3-yl (2-[2-(lH-pyrrol-l-yl)pyridin-4-yl]propan-2-yl}carbamate;

-(3-ethyl-l -azabicyclo[2.2.2]oct-3-yl)-3-[ 1 -(4'-fluorobiphenyl-4-yl)cyclopropyl]urea; N-(l-azabicyclo[2.2.2]oct-3-yl)-N^,-[l-(4'-fluorobiphcnyl-4yl)cyclopropyl]ethanediamidc;

-azabicyc lo[2.2.2]oct-3-yl(l-{4 [(4,4di fluorocyclohexyl )oxy ] phenyl} cyclopropyl) carbamatc;

-(4-methyl-1 -azabicyclo[3.2.2]non-4-yl)-3-[ 1 -(5-phcnylpyridin-2-yl)cyclopropyl]urea;

-[ 1 -( 4 fl uorobipheny 1-4-y 1 )cyclopropyl ] -1 -methy 1-3 -(3-methy 1-1 -azabicyclo[2.2.2 ] oct3-yl)urea;

1- [l-(4'-fluorobîphenyl-4-yl)cyclopropyl]-l-mcthyl-3-(3-methyl-l-azabicyclo[2.2.2]oct3-yl)urea;

- (2-[4'-(2-mcthoxyethoxy)biphenyl-4-yl]propan-2-yl} -3-(3-methyl-1 azabicyclo[2.2.2]oct-3-yl)urca;

2- (l-azabicyclo[3.2.2]non-4-yl)-N-[l-(5-phenylpyridin-2-yl)cyclopropyl]acetamide;

3-(4'-fluorobiphenyl-4-yl)-3-mcthyl-N-(4-mcthyl-l-azabicyclo[3.2.2]non-4yl)butanamide;

N-[2-(4^,-fluorobiphenyl-4-yl)piOpan-2-yl]-N'-(3-methyl-l-azabicyclo[2.2.2]oct-3yl)sulfuric diamide;

l-(3-butyl-l-azabicyclo[2.2.2]oct-3-yl)-3-{2-[l-(4-fluorophcnyl)-lH-pyrazol-4yl]propan-2-yl)urca;

l-azabicyclo[2.2.2]oct-3-yl [4-(4-fluorophenyl)-2-methylbut-3-yn-2-yl]carbamatc; l-(3-butyl-l-azabicyclo[2.2.2]oct-3-yl)-3-[4-(4-fluorophcnyl)-2-mcthylbut-3-yn-2yljurea;

N-[l-(4'-fluorobiphcnyl-4-yl)cyclopropyl]-l,4-diazabicyclo[3.2.2]nonanc-4-carboxamidc; l-(2-(4'-fluoro-[l,r-biphenyl]-4-yl)propan-2-yl)-3-(3-mcthyl-l-azabicyclo[3.2.2]nonan-

3-yl)urea;

l-(2-(4'-fluoro-[l,r-biphenyl]-4-yl)propan-2-yl)-3-(4-methyl-l-azabicyclo[4.2.2]decan-4yl)urea;

l - (2-(4’-fl uoro-[ 1,1 '-b ipheny 1 ] -4-y l)propan-2-y 1)-3-(3 -methyl-1 -azabicyclo [4.2.2] decan-3 yl)urea; and l-(2-(4^,-fIuoro-[l,r-biphcnyl]-4-yl)propan-2-yl)-3-(5-methyl-l-azabicyclo[4.2.2]dccan-5yl)urea.

The présent invention further relates to a pharmaceutical composition for treating a disease or disorder mediated by glucosylceramide synthase (GCS) or a disease or disorder in which GCS is implicatcd in a subject in need of such treatment comprising administering to the subject an effective amount of a compound according to Formula I.

The présent invention further relates to a method for treating a disease or disorder mediated by glucosylceramide synthase (GCS) or a disease or disorder in which GCS is implicated in a subject in need of such treatment comprising administering to the subject an effective amount of a compound according to Formula 1.

The présent invention further relates to a method for treating a disease or disorder mediated by glucosylceramide synthase (GCS) or a discase or disorder in which GCS is implicated in a subject in need of such treatment comprising administering to the subject an effective amount of a compound according to Formula Iwherein the disease or disorder is cancer.

ΊΟΟ

The présent invention further relates to a method for treating a disease or disorder mediated by glucosylceramidc synthase (GCS) or a disease or disorder in which GCS is implicated in a subject in need of such treatment comprising administering to the subject an effective amount of a compound according to Formula 1, wherein the disease or disorder is a metabolic disorder.

The présent invention further relates to a method for treating a disease or disorder mediated by glucosylceramidc synthase (GCS) or a disease or disorder in which GCS is implicated in a subject in need of such treatment comprising administering to the subject an effective amount of a compound according to Formula I, wherein the disease or disorder is a neuropathie disease.

The présent invention further relates to a method for treating a disease or disorder mediated by glucosylceramidc synthase (GCS) or a discase or disorder in which GCS is implicated in a subject in need of such treatment comprising administering to the subject an effective amount of a compound according to Formula I, wherein the disease or disorder is a neuropathie disease, wherein the neuropathie discase is Alzhcimers disease.

The présent invention further relates to a method for treating a disease or disorder mediated by glucosylceramidc synthase (GCS) or a discase or disorder in which GCS is implicated in a subject in need of such treatment comprising administering to the subject an effective amount of a compound according to Formula I, wherein the disease or disorder is a neuropathie disease, wherein the neuropathie disease is Parkinsons disease.

The présent invention further relates to a method for inducing decreascd glucosylceramidc synthase catalytic activity in a cell, in vitro, comprising contacting the cell with an effect amount of a compound according to Formula I.

The présent invention further relates to a method of treating a subject diagnoscd as having a lysosomal storage discase, comprising administering to the subject an effective amount of the compound according to Formula I.

The présent invention further relates to a method of treating a subject diagnosed as having a lysosomal storage discase, comprising administering to the subject an effective amount of the compound according to Formula I, wherein the lysosomal storage disease résulte from a dcfcct in the glycosphingolipîd pathway.

The présent invention further relates to a method of treating a subject diagnosed as having a lysosomal storage disease, comprising administering to the subject an effective amount of the compound according to Formula I, wherein the lysosomal storage disease rcsults from a defect in the glycosphingolipîd pathway, wherein the lysosomal storage

ΙΟΊ discase is selected from the group consisting of Gaucher, Fabry, GMl-gangliosidosis, GM2 Activator deficiency, Tay-Sachs and SandhofT,

The présent invention further relates to a method of treating a subject diagnosed as having a lysosomal storage disease, comprising administering to the subject an effective amount of the compound according to Formula I, wherein the lysosomal storage disease results from a defect in the glycosphingolipid pathway, wherein the lysosomal storage disease is selected from the group consisting of Gaucher, Fabry, GMl-gangliosidosis, GM2 Activator deficiency, Tay-Sachs and Sandhoff, wherein the lysosomal storage disease is Fabry.

The présent invention fiirther relates to a method of treating a subject diagnosed as having a lysosomal storage disease, comprising administering to the subject an effective amount of the compound according to Formula I, further comprising the step of administering to the subject a thcrapcutically effective amount of a lysosomal enzyme.

The présent invention further relates to a method of treating a subject diagnosed as having a lysosomal storage discase, comprising administering to the subject an effective amount of the compound according to Formula 1, further comprising the step of administering to the subject a therapeutically effective amount of a lysosomal enzyme, wherein the lysosomal enzyme is selected from the group consisting of glucocerebrosidasc, alpha-galactosidase A, Hcxosaminidase A, Hexosaminidase B and GM 1 -ganglioside-p-galactosidasc.

The présent invention further relates to a method of treating a subject diagnosed as having a lysosomal storage disease, comprising administering to the subject an effective amount of the compound according to Formula I, further comprising the step of administering to the subject a therapeutically effective amount of a lysosomal enzyme, wherein the lysosomal enzyme is alpha-galactosidase A.

The présent invention further relates to a method of treating a subject diagnosed as having a lysosomal storage disease, comprising administering to the subject an effective amount of the compound according to Formula 1, further comprising the step of administering to the subject a therapeutically effective amount of a lysosomal enzyme, wherein prior to treatment the subject has elevated levels of a lysosomal substrate.

The présent invention further relates to a method of treating a subject diagnosed as having a lysosomal storage disease, comprising administering to the subject an effective amount of the compound according to Formula I, further comprising the step of administering to the subject a therapeutically effective amount of a lysosomal enzyme,

102 wherein prior to treatment the subject has elevated levels of a lysosomal substratc, wherein the subject undergoing treatment has lower combined amounts of the lysosomal substrate in the urine and plasma than a subject treated with either the lysosomal enzyme or compound alonc.

The présent invention further relates to a method of treating a subject diagnoscd as having a lysosomal storage disease, comprising administering to the subject an effective amount of the compound according to Formula I, further comprising the step of administering to the subject a thcrapcutically effective amount of a lysosomal enzyme, wherein prior to treatment the subject has elevated levels of a lysosomal substrate, wherein the subject undergoing treatment has lower combined amounts of the lysosomal substrate in the urine and plasma than a subject treated with either the lysosomal enzyme or compound alone, wherein the substratc is selected from the group consisting of globotriaosylccramide and lyso-globotriaosylceramide, and combinations thereof.

The présent invention further relates to a method of treating a subject diagnosed as having a lysosomal storage disease, comprising administering to the subject an effective amount of the compound according to Formula I, wherein the compound is represented

or a pharmaceutically acceptable sait or prodrug thereof.

The présent invention further relates to a method of reducing glucosylceramidc synthase (GCS) activity in a subject diagnoscd as having a lysosomal storage disease, comprising administering to the patient an effective amount of the compound according to Formula I, either alone or as a combination therapy with an enzyme replacement therapy.

103

The présent invention further relates to a method of reducing accumulation of a GCS-derived material in a subject diagnosed as having a lysosomal storage disease, comprising administering to the patient an effective amount of the compound according to Formula I, either alone or as a combination therapy with an enzyme replacement therapy.

The présent invention further relates to a compound according to Formula I, wherein X³ is a direct bond.

The présent invention further relates to a compound according to Formula I, wherein X⁴ is a direct bond.

The présent invention further relates to a compound according to Formula 1, wherein X³ and X⁴ are each independently a direct bond.

The présent invention further relates to a compound according to Formula I, wherein m is 1; E is Ο; X² is O and X³ is direct bond.

The présent invention further relates to a compound according to Formula I, wherein m is 1 ; E is Ο; X² is NH and X³ is direct bond.

The présent invention further relates to a compound according to Formula I, wherein m is 1; E is Ο; X² is CH₂ and X³ is direct bond.

The présent invention further relates to a compound according to Formula I, wherein m is 1; E is S; X² is NH and X³ is direct bond.

The présent invention further relates to a compound according to Formula I, wherein m is 0; E is Ο; X¹ is NFI and X³ is direct bond.

The présent invention further relates to a compound according to Formula I, wherein m is 1; p is 0; X² is NH-SO₂ and X³ is direct bond.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0,1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is O and X³ is direct bond.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is NH and X³ is direct bond.

The présent invention further relates to a compound according to Formula I, wherein n is 1 ; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X²is CH₂ and X³ is direct bond.

Ί04

The présent invention further relates to a compound according to Formula l, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X is CR ; m is 1; E is S; X is N H and X³ is direct bond.

The présent invention further relates to a compound according to Formula l, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 0; E is Ο; X¹is NH and X³ is direct bond.

The présent invention further relates to a compound according to Formula I, wherein n is 1; 2 or 3; t is 0,1 or 2; y is 0 or 1; z is 0, 1 or 2; X¹ is CR¹; m is 1; p is 0; X²is NH-SO2 and X³ is direct bond.

The présent invention further relates to a compound according to Formula I, wherein X^s is a direct bond, O, S, SO2, CR⁴R⁵; (Ci-Cû)alkyl, (Ci-Cejalkyloxy, (CjC6)alkenyl or (Ci-Cfi)alkenyloxy.

The présent invention further relates to a compound according to Formula I, wherein A² is H, (C₃-Cio)cycloalkyl, (Ce-Cnjaryl, (C₂-C9)heteroaryl, (C₂Cç)heterocycloalkyl or bcnzo(C₂-Ct))hetcrocycloalkyl optionally substituted with one or more substituents selected from the group consisting of halo, (Ci-C6)alkyl optionally substituted by one to three halo; (Ci-Cejalkylenyl, amino, (Ci-Ce) alkylamino, (CiCejdialkylamino, (Ci-Cô)alkoxy, O(C₃-C6 cycloalkyl), (C3-Cû) cycloalkoxy, nitro, CN, OH, (Ci-C(>)alkyloxy optionally substituted by one to three halo; (C3-C6) cycloalkyl, (CjCe) alkoxycarbonyl, (Ci-Ce) alkylcarbonyl or (Ci-Ce) haloalkyl.

The présent invention further relates to a compound according to Formula I, wherein X³ is O, -NH, -CH2-, CO, - CH(Ci-Cfi) alkyl, SO2NH, -CO-NH- or-NR³; X⁴ is CR⁴R⁵, CI-I2 CR⁴R⁵ or CH2 -<Ci-C6) alkyl-CR⁴R⁵;and A² is (C3-Ci₀)cycloalkyl, (C₆Ci2)aryl, (C2-C<))hetcroaryl, (C₂-Cg)heterocycloalkyl or benzo(C2-Cg)heterocycloalkyl wherein A is substituted with one or more substituents selected from the group consisting of, (C₂-C<>)hcterocycloalkyl, R⁸R⁹N-CO- wherein R⁸ and R⁹ are each independently selected from the group consisting of hydrogen and (Ci-Cc)alkyl or R⁸ and R⁹ can bc taken together with the nitrogen to which they arc attached to form a (C₂C<))hetcrocycloalkyl or (C2-C9)hetcrocyclo alkyl group optionally substituted by one to three halo groups, (Ci-Ce)alkylsulfonyl optionally substituted by onc or two groups selected from (Ci-Cejalkoxy and (C3-Cio)cycloalkyl;

(Ci-Ce)alkyl substituted by one to four substituents selected from the group consisting ofhydroxy, cyano, (Ci-Ce)alkoxy, (Ci-Cr,)alkoxy(Ci-C6)alkoxy, (C₂17263

105

Cjhctcrocycloalkyl, (Cj-Cjhctcroaryl optionally substituted by (Ci-Cô)alkoxy; or (C3Cio)cycloalkoxy optionally substituted by (Ci-Cô)alkoxy;

or (Ci-Cejalkyloxy substituted by one to four substituents selected from tlie group consisting of hydroxy, cyano, (Ci-Ce)alkoxy, (C[-C6)alkoxy(Ci-C6)alkoxy, (C25 Cjhcterocycloalkyl, (C2-C<>)heteroaryl optionally substituted by (Cj-Ccjalkoxy; or (C3Cio)cycloaikoxy optionally substituted by (Ci-Ce)alkoxy.

The présent invention further relates to a compound according to Formula I, wherein A¹ is phenyl.

The présent invention further relates to a compound according to Formula I, wherein X is a direct bond.

The présent invention further relates to a compound according to Formula I, «J wherein A is phenyl substituted by (Cj-Cô) alkoxy(Ci-Ce) alkoxy.

The présent invention further relates to a compound according to Formula I, wherein A¹ is piperdine optionally substituted by halo.

The présent invention further relates to a compound according to Formula I, wherein X⁵ is pyrimidinc optionally substituted by halo.

106

PREPARATION A

107

PREPARATION B

PREPARATION C

NC----A₁---X

C-4

108

PREPARATION D

109

PREPARATION E

D-2

110

PREPARATION F

EtO₂CX₃X4A₁---X5---A₂ t

HO2CX3X4A1—x₅—a₂

F-1

111

PREPARATION G

XjXiA;----X₅---X

>5---^A2

112

SCHEME l

A-1 or A-2

'4

113

SCHEME 2

A-1 or A-2 or B-1

or

114

SCHEME 3

115

SCHEME 4

A-1 or

H

A-2

X3X4A1

Xs a₂

XI

116 ln réaction l of Préparation A, the compound of formula A-7 is converted to the corresponding compound of formula A-l, wherein X is OH, by rcducing A-7 with a rcducing agent, preferably lithium aluminum hydride in aprotic solvent such tetrahydrofuran. The reaction is stirred at a température between 0°C and room température for a time period between about 15 minutes to about 2 hours, preferably about 30 minutes. Altcmatively, the compound of formula A-7 is converted to the corresponding compound of formula A-l, wherein X is OH, by rcducing A-7 under approximately 1 atmosphère of hydrogen in presence of a catalyst, preferably platinum oxide, and a polar solvent such methanol or éthanol for a period of 2 hours to 6 hours, preferably 4 hours. Altcmatively, the compound of formula A-7 is converted to the corresponding compound of formula A-l, wherein X is NH, by rcacting A-7 with hydroxylamine hydrochloridc and sodium acetate in a polar solvent such éthanol, methanol, isopropanol, preferably isopropanol. The reaction mixture is stirred at a température between 50-80°C for a period of 2 hours to 7 hours, preferably 3 hours. Subsequently, the compound so formed above îs converted to compound of formula A-l with a rcducing agent, preferably sodium mctallic in a polar protic solvent such éthanol, methanol, propanol, preferably «-propanol. The réaction is stirred ovemight at 50-80°C, preferably solvent reflux température.

In reaction 2 of Préparation A, the compound of formula A-7 is converted to the corresponding compound of formula A-5, wherein RI, n and z arc as defîned above, by adding a solution of RI-magnésium bromide in ether to a solution of A-7 in a aprotic solvent, such as ether, at a température between about -60° C to about -90° C, preferably about -78° C for a time period between about 1 hour to about 4 hours, preferably about 2 hours. Altcmatively, the compound of formula A-7 can be reacted with Rl-lithium to afford the compound of formula A-5.

In reaction 3 of Préparation A, the compound of formula A-5 is converted to the corresponding compound of formula A-4, wherein RI, n and z are as defîned above, by treating A-5 with a strong acid, preferably sulfuric acid, in the presence of acetonitrile. The reaction is stirred ovemight at room température.

In reaction 4 of Préparation A, the compound of formula A-4 is converted to the corresponding compound of formula A-3, wherein RI, n and z arc as defîned above, by treating A-4 with an acid, preferably hydrochloric acid. The réaction is stirred at reflux for a period of 18 hours to 72 hours, preferably 24 hours and basified to pH=8 by treatment with an inorganic base in aqueous solution, such as sodium hydroxide.

117

In réaction 5 of Préparation A, the compound of formula A-7 is converted to the corresponding compound of formula A-6, wherein RI, n and z are as defined above, by rcacting A-7 with a triphenyl phosphonium ylidc to give the corresponding alkene compound of formula A-6. The reaction is stirred at room température for ovemight.

In réaction 6 of Préparation A, the compound of formula A-6 is converted to the corresponding compound of formula A-3, wherein RI, n and z are as defined above, by rcducing A-6 under approximately 1 atmosphère of hydrogen in the presence of a catalyst, preferably palladium on carbon, and a polar solvent, such as methanol, éthanol or ethyl acétate. The réaction is stirred at room température for a time period between about 2 hours to about 24 hour, preferably about 18 hours. Subsequcntly, the compound so formed is treated with a base, preferably lithium hydroxide, in a mixture of solvent such tetrahydrofuran, methanol and water to afford the compound of A-3. The reaction is stirred ovemight at room température.

In reaction 1 of Préparation B, the compound of formula B-2 is converted to the corresponding compound of formula B-l, by reducing B-2 with a rcducing agent, preferably lithium aluminum hydride in aprotic solvent such tetrahydrofuran. The reaction is stirred at a température between 0°C and room température for a time period between about 15 minutes to about 2 hours, preferably about 30 minutes.

In réaction 1 of Préparation C, the compound of C-4 is converted to the corresponding compound of formula C-3, wherein X is bromine or chloride, by rcacting C-4 with boronic acid in the présence of a catalyst, preferably 1,1'bis(diphenylphosphino)ferroccnc-palladium(ll)-dichloridc, and potassium carbonate. The réaction is microwaved in a mixture of dimcthoxyethanc and water at a température between about 130° C to about 170° C, preferably about 150° C, for a time period between about 15 min to about 1 hour, preferably about 30 min. Altematively, the reaction can be performed using solvent such dioxane and stirred ovemight at 100° C under conventional heating.

In réaction 2 of Préparation C, the compound of C-3 is converted to the corresponding compound of formula C-1, wherein f is 1 to 8 and Al, X5 and A2 are as defined above, by adding ethyl magnésium bromide dropwîse to a mixture of C-3 and titanium isopropoxide in ether. The reaction is stirred at a température between about 50° C to about -90° C, preferably about -70° C. The resulting reaction mixture is allowed to warm to about 20° C to about 30° C, preferably about 25° C, and allowed to stir for an

118 additional time period between about 30 minutes to about 2 hours, preferably about l hour. Boron trifluoride dicthyl etherate is then added to the mixture dropwise at a température between about 20° C to about 30° C, preferably about 25° C.

In reaction 3 of Préparation C, the compound of C-3 is converted to the corresponding compound of formula C-2, wherein Al, X5 and A2 are as defined above, by first stirring a suspension of cérium (III) chloride in an aprotic solvent, such as tetrahyrofuran, at room température for time period between about 30 minutes to about 2 hours, preferably about l hour. The resulting suspension is cooled to a température between about -60° C to about -90° C, preferably about -78° C and an organolîthium agent is added, preferably methyi lithium in an ether solution. The resulting organocerium complex is allowed to form for a time period between about 30 minutes to about 2 hours, preferably about l hour, followed by the addition of C-3 in an aprotic solvent, such as tetrahydrofuran. The resulting reaction mixture is then warmed to room température and allowed to stir for time period between about 16 hours to about 20 hours, preferably about 18 hours.

In reaction 1 of Préparation D, the compound of D-5, wherein R is CO2Et or CN and X is bromine or chloride, is converted to the corresponding compound of formula D3, by reacting D-5 with an alkyl dihalidc such 1,2-dibromocthanc. Subscquently, the compound so formed is treated with an inorganic base such lithium hydroxide or potassium hydroxide, in a mixture of solvent such tetrahydrofuran, methanol, glycol and water to afford the compound of D-3, wherein f is 1 to 8. The réaction is stirred ovemight at a température between 25°C and 130°C. Altematively, to form the corresponding compound of formula D-3, wherein X is X5-A2, D-5 must first bc reacted according to the procedure discussed above ΐη réaction 1 of Préparation C.

In reaction 2 of Préparation D, the compound of D-3 is converted to the corresponding compound of formula D-l by reacting D-3 with a base such triethylamine and diphenylphosphoryl azide in aprotic solvent such toluene. The reaction was heated to a température range between 80°C-l 10°C, preferably at 110°C for 15 min to 1 hour, preferably 30 minutes. The so formed intermediate is then treated with ieri-butyl alcohol for ovemight period at 60-110 °C, preferably 90 °C. Subsequently, the so formed carbamatc is converted to the corresponding compound of formula D-l, wherein fis 1 to 8, by a treatment under acidic media using preferably trifluoroacetic acid in dichloromethane at room température for a period of 30 min to 5 hours, preferably 2 hours.

119

In reaction 3 of Préparation D, the compound of D-5, wherein R is CO2Et or CN and X is bromine or chloride, is converted to the corresponding compound of formula D4, by reacting D-5 with an alkyl halidc such Met Subsequently, the compound so formed 5 is treated with an inorganic base such lithium hydroxide or potassium hydroxide, in a mixture of solvent such tetrahydrofuran, methanol, glycol and water to afford the compound of D-4. The réaction is stirred ovemight at a température between 25°C and 130°C. Altemativeiy, to form the corresponding compound of formula D-4, wherein X is X5-A2, D-5 must first be reacted according to the procedure discusscd above in reaction 10 1 of Préparation Ç.

In reaction 4 of Préparation D, the compound of D-4 is converted to the corresponding compound of formula D-2, by reacting D-4 with a base such triethylamine and diphenylphosphoryl azidc in aprotic solvent such toluene. The réaction was heated to a température range between 80°C-l 10°C, preferably at 110°C for 15 min to 1 hour, preferably 30 minutes. The so formed intermediate is then treated with tert-butyl alcohol for ovemight period at 60-110 °C, preferably 90 °C. Subsequently, the so formed carbamate is converted to the corresponding compound of formula D-l by a treatment under acidic media using preferably trifluoroacetic acid in dichloromethane at room température for a period of 30 min to 5 hours, preferably 2 hours.

In réaction 1 of Préparation E, the compound of formula E-2, wherein X is bromide or chloride, is converted to the corresponding compound of formula E-l, by reacting E-2 with methyl magnésium bromide in ether, at a température between about 60° C to about -90° C, preferably about -78° C for a time period between about 30min to about 3 hours, preferably about 2 hours. Altemativeiy, to form the corresponding compound of formula E-l, wherein X is X5-A2, E-2 must first be reacted according to the procedure discussed above in reaction 1 of Préparation Ç.

In reaction 2 of Préparation E, the compound of formula E-l is converted to the corresponding compound of D-2 by treating E-l with a strong acid, preferably sulfuric acid, in the presence of chloroacetonitrile. The reaction is stirred ovemight at room 30 température. Subsequently, the so formed compound is treated with thiourea in a polar protic solvent such éthanol for an ovemight period at 80°C to form the corresponding compound of formula D-2. Altemativeiy, E-l is treated with sodium azide and trifluoroacctic acid in an aprotic solvent such dichloromethane at a température range of 10°C to room température, preferably 0°C. The so formed compound is reduced in

120 présence of triphcnylphosphinc in a solution of tetrahydrofuran and water to form corresponding compound of formula D-2. The reaction is stirred at a température range 25-80°C, preferably at room température for a period of 2 hours to 24 hours, preferably 18 hours.

In Réaction 1 of Préparation F, by adding an arylboronate or arylboronic acid component, sodium carbonate and a catalyst, such as [1,1'bis(diphenylphosphino)fcrroccnc]dichloropalladium(II), to a solution of the aryl halidc component in 5:1 (v/v) dioxanc/watcr (-0.15 M) or 5:1 (v/v) N,N-dimcthylformamidc. The mixture so formed is heated to a température between about 80°C to about 100°C, preferably to about 90°C, for a time period between 8 hours to about 16 hours, preferably about 14 hours.

In Réaction 2 of Préparation F, the compound of formula X-X5-A2 so formed is converted to the corresponding compound of formula EtO2CX3X3X4Al-X5-A2 by a (1) transition métal catalyzed coupling or (2) nucloeophilic aromatic substitution réaction between the aryl halidc and amine.

In Réaction 3 of Préparation F, the compound of formula X-X5-A2 so formed is converted to the corresponding compound of formula EtO2CX3X3X4Al-X5-X’ by a (1) transition métal catalyzed coupling or (2) nucloeophilic aromatic substitution reaction between the aryl halide and amine.

In reaction 4 of Préparation F, by adding an arylboronate or arylboronic acid component, sodium carbonate and a catalyst, such as [1,1 bis(diphenylphosphino)ferrocene]dichloropalladium(II), to a solution of the aryl halide component in 5:1 (v/v) dioxanc/water (-0.15 M) or 5:1 (v/v) N,N-dimcthylformamidc. The mixture so formed is heated to a température between about 80°C to about 100°C, preferably to about 90°C, for a time period between 8 hours to about 16 hours, preferably about 14 hours.

In réaction 5 of Préparation F, the compound of formula EtO2CX3X3X4Al-X5A2 so formed is converted to the corresponding compound of formula F-l by an ester hydrolysis réaction.

In reaction 1 of Préparation G, the compound of formula X3X4A1-X5-X is converted to the corresponding compound of formula G-3 by adding an arylboronate or arylboronic acid component, sodium carbonate and a catalyst, such as [ 1, Γbis(diphenylphosphino)fcrroccne]dichloropalladium(II), to a solution of the aryl halide

121 component in 5:l (v/v) dioxanc/watcr (-0.15 M)or5:l (v/v) M/V-dimethylformamidc. The mixture so formed is heated to a température between about 80°C to about 100°C, preferably to about 90°C, for a time period between 8 hours to about 16 hours, preferably about 14 hours.

In reaction 2 of Préparation G, the compound of Formula G-3 is converted to the corresponding compound of G-l by cooling (0 °C) a solution of the secondary amine component and triethylamine in methylenc chloride and adding methyl chloroformate. The réaction is then allowed to warm to room température and stirred for time period between about 4 hours to about 8 hours, preferably about 6 hours. The réaction solution is then washed with aqueous sodium bicarbonate solution and brine, dried (NaîSO^) and concentrated. The crude methyl carbamate is used, without purification, in the next step. To a solution of this intermediate in toluène is added, in order, activated 4Â molecular sieves, the alcohol component and sodium hydride. The reaction is heated at reflux overnight, filtered and concentrated.

In réaction 3 of Préparation G, the compound of Formula G-3 is converted to the corresponding compound of G-2 by adding triphosgene in toluène to a solution of the amine component in chloroform. The réaction is stirred for a time period between about l hour to about 4 hours, preferably 2 hours, and then concentrated. The residue is taken up in chloroform and cooied (0 °C). With stirring, the second amine component and triethylamine (2 équivalents) arc added, in order. The réaction is stirred overnight at room température and then concentrated.

In reaction l of Scheme 1, the compounds of formula A-l or A-2 are converted to the corresponding compounds of Formula II, wherein f is 1 to 8, or III, respectively, by adding triphosgene to a suspension of C-l or C-2 and triethylamine in a aprotic solvent, such as tetrahydrofuran. The réaction is stirred at room température for a time period between about 5 minutes to about 20 minutes, preferably about 15 minutes, and a small amount of ether was added. The triethylammonium sait generated is filtered off. Separatcly, sodium hydride is added to a suspension of A-l or A-2, wherein X is OH or NH, in an aprotic solvent, such as tetrahydrofuran, at 0°C or room température. The reaction is stirred at room température for a time period between about 5 minutes to about 20 minutes, preferably about 15 minutes, and the isocyanate tetrahydrofuran/ether solution so formed above is added dropwise. Altematively, the compounds of Formula II and III may be formed by reacting the compounds of D3 or D4 with A-l and A-2 in

122 presence of a base such triethylamine and diphenylphosphoryl azidc in aprotic solvent such tolucne as described in procedure discusscd above in reaction 4 of Préparation D.

In réaction l of Scheme 2, the compounds of formula A-l, A-2 or B-l are convcrted to the corresponding compounds of Formula IV, V, VI and VII, wherein f is l to 8, respectivcly, by adding triphosgene to a suspension of C-l, C-2, D-l or D-2 and triethylamine in a aprotic solvent, such as tetrahydrofuran or toluène. The reaction is stirred at room température for a time period between about 5 minutes to about 20 minutes, preferably about 15 minutes, and a small amount of ether was added. Subsequently, A-l or A-2, wherein X is NH, is added to the isocyanate solution so formed above and the reaction is stirred at a température range of 25-l00°C, preferably at room température for a period of about 2 hours to 24 hours, preferably 18 hours.

In reaction 1 of Scheme 3, the compound of formula A-3 is convertcd to the corresponding compounds of Formula VIII, wherein f is 1 to 8, and IX, respectively by reacting A3 with Cl, C-2, D-l or D-2 via peptidic coupling using carbodiimide coupling agent such l-ethyl-3-(3-dimethylaminopropyl) carbodiimide and 1-hydroxy-benzotriazole or 2-(lH-7-Azabcnzotriazol-l-yl)-l,l,3,3-tctramcthyl uronium hexafluorophosphate in solvent such tetrahydrofuran or dimethylformamide. The reaction is stirred at room température for overnight.

In réaction I of Scheme 4, the compound of formula A-2 is converted to the corresponding compound of formula XI by reacting, via amidc coupling, the compound of formula A-2 and the compound of formula F-l. Specifically, to a solution of the primary amine component in chloroform was added 4-dimethylaminopyridine (0.1 équivalent) and di-Zeri-butyl dtcarbonatc. The mixture was stirred for 1 hour before adding the secondary amine component and heating to reflux overnight.

In réaction 1 of Scheme 4, the tert-butoxy carbonyl protected compound of formula A-2 is convcrted to the corresponding compound of formula XI by a reacting, via condensation reaction, the compound of formula A-2 and the compound of formula G-3. Specifically, to a solution of the primary amine component in chloroform (concentration -0.1 M) was added 4-dimcthylaminopyridinc and di-Zeri-butyl dicarbonate. The mixture was stirred for 1 hour before adding the secondary amine component and heating to reflux overnight.

In réaction 1 of Scheme 4, the compound of formula A-l is converted to the corresponding compound of formula XI by a reacting, via acylation réaction, the compound of formula A-l and the compound of formula G-l by cooling (0 °C) a solution

123 of the secondary amine component and triethylamine in methylene chloride and adding methyl chloroformate. The reaction is then allowed to warm to room température and stirred for time period between about 4 hours to about 8 hours, preferably about 6 hours, The réaction solution is then washed with aqueous sodium bicarbonate solution and brine, dried (NaîSCTi) and concentrated. The crude methyl carbamate is used, without purification, in the next step. To a solution of this intermediate in toluene is added, in order, activated 4Â molecular sieves, the alcohol component and sodium hydride. The réaction is heated at reflux ovemight, filtered and concentrated.

In réaction 1 of Scheme 4, the compound of formula A-2 is convcrted to the corresponding compound of formula XI by a reacting, via acylation reaction, the compound of formula A-2 and the compound of formula G-2 by adding triphosgene in toluene to a solution of the amine component in chloroform. The réaction is stirred for a time period between about 1 hour to about 4 hours, preferably 2 hours, and then concentrated. The residue is taken up in chloroform and cooled (0 °C). With stirring, the second amine component and triethylamine (2 équivalents) are added, in order. The réaction is stirred ovemight at room température and then concentrated.

Aithough spécifie embodiments of the présent disclosure will now be described with référence to the préparations and schemes, it should be understood that such embodiments are by way of exampie only and merely illustrative of but a small number of the many possible spécifie embodiments which can represent applications of the principlcs of the présent disclosure. Various changes and modifications will be obvious to those of skill in the art given the benefit of the présent disclosure and are deemed to be within the spirit and scopc of the présent disclosure as further defined in the appended claims.

Unless defined otherwise, ail tcchnical and scientific terms used herein hâve the same meaning as commonly understood by one having ordinary skill in the art to which this disclosure belongs. Aithough other compounds or methods can be used in practice or testing, certain preferred methods are now described in the context of the following préparations and schemes.

Ali pharmaceutically acceptable salts, prodrugs, tautomers, hydrates and solvatés of the compounds presently disclosed are also within the scope of the présent disclosure.

Prcsently disclosed compounds that are basic in nature are generally capable of forming a wide variety of different salts with various inorganic and/or organic acids.

Aithough such salts arc gcnerally pharmaceutically acceptable for administration to

124 animais and humans, it is often désirable in practice to initially isolate a compound from the réaction mixture as a pharmaceutically unacceptable sait and then simply convert the latter back to the free base compound by treatment with an alkaline reagent, and subsequently convert the free base to a pharmaceutically acceptable acid addition sait. The acid addition salts of the base compounds can be readily prepared using conventional techniques, e.g., by treating the base compound with a substantially équivalent amount of the chosen minerai or organic acid in an aqueous solvent medium or in a suitable organic solvent such as, for exampie, methanol or éthanol. Upon careful évaporation of the solvent, the desired solid sait is obtained.

Acids which can be used to prépare the pharmaceutically acceptable acid addition salts of the base compounds are those which can form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartratc or bitartratc, succinate, malcate, fumarate, gluconate, saccharate, benzoatc, methanesulfonate andpamoatc [i.e., l,r-mcthylcne-bis-(2-hydroxy-3-naphthoate)] salts.

Prescntly disclosed compounds that are acidic in nature, e.g., contain a COOH or tetrazole moiety, are generally capable of forming a wide variety of different salts with various inorganic and/or organic bases. Although such salts are generally pharmaceutically acceptable for administration to animais and humans, it is often désirable in practice to initially isolate a compound from the réaction mixture as a pharmaceutically unacceptable sait and then simply convert the latter back to the free acid compound by treatment with an acidic reagent, and subsequently convert the free acid to a pharmaceutically acceptable base addition sait. These base addition salts can be readily prepared using conventional techniques, e.g., by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resultîng solution to dryness, preferably under reduced pressure. Altematively, they also can be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali métal alkoxidc together, and then evaporating the resultîng solution to dryness in the same manner as before. In either case, stoichiometric quantities of rcagents are preferably employed in order to ensure completeness of reaction and maximum product yields of the desired solid sait.

Bases which can be used to préparé the pharmaceutically acceptable base addition salts of the base compounds are those which can form non-toxic base addition salts, i.e., salts containing pharmacologically acceptable cations, such as, alkali métal cations (e.g.,

125 potassium and sodium), alkaline earth mctal cations (e.g., calcium and magnésium), ammonium or other water-soluble amine addition salts such as N-mcthylglucamine(mcglumine), lower alkanolammonium and other such bases of organic amines.

Isotopically-labelcd compounds arc also within the scope of the présent disclosure. As used herein, an “isotopically-labelcd compound” refers to a presently disclosed compound including pharmaceutical salts and prodrugs thereof, each as described herein, in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporatcd into compounds presently disclosed include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ²H, ³H, ^l3C, ^l4C, ^lsN, ^l8O, ^l70,³¹ P, ³²P, ³⁵S, ¹⁸F, and ³⁶C1, respectively.

By isotopically-labcling the presently disclosed compounds, the compounds may be useful in drug and/or substrate tissue distribution assays. Tritiated (³H) and carbon-14 15 (¹⁴C) labeled compounds are particulariy preferred for their easc of préparation and detectability. Further, substitution with heavier isotopes such as deuterium (²H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds presently disclosed, 20 including pharmaceutical salts and prodrugs thereof, can bc prepared by any means known in the art.

Stereoisomers (e.g., cis and trans isomers) and ail optical isomers of a presently disclosed compound (e.g., R and S enantiomers), as well as racemic, diastereomeric and other mixtures of such isomers arc within the scope of the présent disclosure.

The compounds, salts, prodrugs, hydrates, and solvatés presently disclosed can exist in several tautomeric forms, including the enol and imine form, and the keto and enamine form and géométrie isomers and mixtures thereof. Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer prédominâtes. Even though one tautomer may be described, ail tautomers are within the scope of the présent 30 disclosure.

Atropisomcrs are also within the scope of the présent disclosure. Atropisomers refer to compounds that can be separated into rotationally restricted isomers.

The présent disclosure also provides pharmaceutical compositions comprising at least one presently disclosed compound and at least one pharmaceutically acceptable

126 carrier. The pharmaceuticaily acceptable carrier can bc any such carrier known in the art including those described in, for example, Remington's Pharmaceutical Sciences, Mack Publishing Co., (A. R. Gennaro cdît. 1985). Pharmaceutical compositions of the compounds prcsently disclosed may be prepared by conventîonal means known in the art including, for example, mixing at least one prescntly disclosed compound with a pharmaceuticaily acceptable carrier.

Presently disclosed pharmaceutical compositions can bc used in an animal or human. Thus, a presently disclosed compound can be formulated as a pharmaceutical composition for oral, buccal, parentéral (e.g., intravenous, intramuscular or subeutaneous), topical, rectal or intranasal administration or in a form suîtable for administration by inhalation or insufflation.

The compounds presently disclosed may also bc formulated for sustaîned delivery according to methods well known to those of ordinary skill in the art. Examples of such formulations can be found in United States Patents 3,119,742, 3,492,397, 3,538,214, 4,060,598, and 4,173,626.

For oral administration, the pharmaceutical composition may take the form of, for example, a tablct or capsule prepared by conventîonal means with a pharmaceuticaily acceptable excipient(s) such as a binding agent (e.g., prcgelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); filler (e.g., lactose, microcrystallinc cellulose or calcium phosphate); lubricant (e.g., magnésium stéarate, talc or silica); disintegrant (e.g., potato starch or sodium starch glycolatc); and/or wetting agent (e.g., sodium lauryl sulphatc). The tablcts may be coated by methods well known in the art. Liquid préparations for oral administration may take the form of a, for example, solution, syrup or suspension, or they may be presented as a dry product for constitution with water or other suîtable vehicle before use. Such liquid préparations may be prepared by conventîonal means with a pharmaceuticaily acceptable additive(s) such as a suspending agent (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqucous vehicle (e.g., almond oil, oily esters or ethyl alcohol); and/or preservative (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).

For buccal administration, the composition may take the form of tablets or lozenges formulated in a conventîonal manner.

Presently disclosed compounds may bc formulated for parentéral administration by injection, including using conventîonal cathctcrization techniques or infusion.

127

Formulations for injection may be presented in unit dosage form, e.g., in amputes or in multi-dose containers, with an added preservative. The compositions may takc such forms as suspensions, solutions or émulsions in oily or aqueous vehicles, and may contain a formulating agent such as a suspending, stabilizing and/or dispersing agent recognized by those of skill in the art. Altematively, the active ingrédient may be in powder form for reconstitution with a suitable vehicle, e.g., stérile pyrogen-free water, before use.

For topical administration, a prcsently disclosed compound may bc formulated as an ointment or cream.

Presently disclosed compounds may also bc formulated in rectal compositions such as suppositories or rétention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, presently disclosed compounds may be convenicntly delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aérosol spray 15 présentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethanc, trichlorofluoromethane, dichlorotetrafluorocthane, carbon dioxide or other suitable gas. In the case of a pressurized aérosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the presently disclosed compound. Capsules and cartridgcs (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a presently disclosed compound and a suitable powder base such as lactose or starch.

A proposed dose of a prcsently disclosed compound for oral, parentéral or buccal 25 administration to the average adult human for the treatment or prévention of a TPOrelated disease state is about 0.1 mg to about 2000 mg. In certain embodiments, the proposed dose is from about 0.1 mg to about 200 mg of the active ingrédient per unit dose. Irrespective of the amount of the proposed dose, administration of the compound can occur, for example, 1 to 4 times per day.

Aérosol formulations for the treatment or prévention of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or “pufï” of aérosol contains about 20mg to about 10,000mg, preferably, about 20mg to about lOOOmg of a prcsently disclosed compound. The overall daily dose with an aérosol will be within the range from about 10Omg to about 100 mg. In certain embodiments, the

128 overall daily dose with an aérosol gencrally will be within the range from about lOOmg to about 10 mg. Administration may be several times daily, for example 2, 3,4 or 8 times, giving for example, 1, 2 or 3 doses each time.

Aérosol combination formulations for the treatment or prévention of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or “puff’ of aérosol contains from about 0.01 mg to about 1000 mg of a combination comprising a presently disclosed compound. In certain embodiments, each metered dose or “puff’ of aérosol contains about 0.01 mg to about 100 mg of a combination comprising a presently disclosed compound. In certain embodiments, each metered dose or “puff’ of aérosol contains about 1 mg to about 10 mg ofa combination comprising a presently disclosed compound. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each time.

Pharmaceutical compositions and methods of treatment or prévention comprising administering prodrugs of at least one presently disclosed compound arc also within the scopc of the présent disclosure.

Glucosylceramide Synthase Assays

Inhibition of glucosylceramide synthase activity can be measured with one or more assays. A first assay is a microsomal assay that directly mcasures the conversion of ccramidc to glucosylceramide by HPLC. Microsomes arc a source of glucosylceramide synthase activity in the microsomal assay. A second assay is a cell based, phcnotypic assay that monitors cell surface expression of the downstream lipid GM3 by antibody mediated immunofluorescence. Spécifie protocols are provided below.

Glucosylceramide synthase activity microsomal assay: An enzyme assay using microsomes as a source of glucosylccramidc.synthase activity. Fluorescent ccramide substratc is delivered to membrane-bound enzyme as a complex with albumin. After reaction, ceramidc and glucosylceramide are separated and quantitated by reverse-phase HPLC with fluorescence détection. Enzymatic activity was assessed using a fluorescent labeled substratc and microsomes as a source of glucosylceramide synthase. Cg NBDCeramidc was complexed with albumin for dclivcry to microsomes that were isolated according to the procedure described below. The final concentration of Cg NBDCeramide in the stock was 0.5 mM; the final concentration of BSA was 0.5 mM.

129

Séparation and quantitation of substrate and product (glucosyiceramidc) were achieved by reverse-phase HPLC with fluorescence détection.

Procedure

Préparation of Microsomes from A375 human melanoma cells;

Microsomes were isolated from A375 human melanoma cells. Eight to tcn million cells were harvcsted by trypsinization and washed with ice cold PBS. Cells were resuspended in the ice cold lysis buffer, containing protease inhibitors. Cell lysatc was sonicatcd on ice using a probe sonicator. After sonication the cell lysatc was separated from débris by centrifugation at 10,000g for 10 minutes at 4°C. The supematant was removed and clearcd by additional centrifugation at 100,000g for 1 hour at 4°C. The pellet was then resuspended in the lysis buffer, aliquoted and stored at -80°C prior to use.

Glucosylceramide Synthase Assay

To déterminé glucosylceramide synthase inhibition, substrates at 2x of their Km (fluorescent ceramide and UDP- glucose, 3 μΜ and 4 μΜ respectively) and microsomes (1:50 dilution) were combined 1:1 and incubated at room température for 1 hour in the dark on a plate shaker. The réaction was stopped by the addition of 150 μΐ of 100 μΜ Cg ceramide in 50% aq. isopropanol; 10 μΐ ofthe final mix was analyzed on HPLC (with fluorescence detector). The mobile phase was performed in 1% formic acid in 81% methanol, 19% water with flow rate 0.5 mL/min. Fluorescence was detected with λ_θχ= 470 nm and λ_βΓη= 530 nm. Under these conditions, NBD Ce GluCcr had a rétention time of about 1.7 min and NBD Ce Cer elutes from the column after about 2.1 min. Both peaks were separated from each other and the baseline and were integrated automatically by the HPLC software. The percent conversion of substrate to product was used as the readout for inhibitor testing.

GM3 Fluorcscent-Linkcd Immunosorbent Assay (FLISA): This is phcnotypic assay that mcasures both GM3 expression in conjunction with the viability of Bl 6 or C32 cells following treatment with compounds. Cell surface GM3 expression was determined by antibody mediated fluorescence and cell viability was assessed in each well.

130

Procedure

Compounds were diluted in media and platcd in 384 well plates in DMSO. Bl6 and C32 cells were assayed at dcnsities of 20,000 cells/ml and 62,500 cells/ml respectively per well. Each titration curvc containcd 10 points that were assayed in duplicatc on each test run. The plates were incubated for 48 hours at 37 °C, 5% CO2 and were then washed once with TBS. Anti GM3 antibody was added to each well and the plates were then incubated for an additional one hour at room température. Plates were subsequently washed twice and incubated for an additional hour with the labeled secondary antibody. Following the final incubation, the plates were washed twice and the fluorescence at λθ_χ=D640/20 nm and λθτη =657 nm detected on fluorescent reader. After GM3 fluorescence had been determined, cell viability was assessed using the ATPlitc assay (Pcrkin Elmer) according to the manufacturer^ instructions.

Assay results:

Individual assay results of certain exemplified compounds in these assays are presented in Table l. The results of the microsomal assay are expressed as “GCS IC50”, which represents the concentration of the compound causing 50% inhibition of glucosylccramidc synthasc activity. The results of the cell based assays (performed in two different cell Systems, i.e. BI6 mouse mclanoma or C32 human melanoma cells) are expressed as “GM3 Bl6 IC50” or “GM3 C32 IC50” for the B16 assay and the C32 assay, respectively. These values represent the concentration of the compound causing 50% inhibition of GM3 expression on the cell surface.

Glucosylceramide synthasc inhibition in a model of poiycvstic kidnev disease.

Mice homozygous for the Nck8jck mutation develop polycystic kidney disease (“jck mice”. Histology reveals that the kidneys of some 3 day old pups from heterozygous parents had small isolated cysts lined by cuboidal epithélial cells, and 15 day old pups had cysts lined by flattencd epithelia. Disease is progressive but not évident by kidney palpation until at least 4 to 5 weeks of âge. Homozygotes generally romain active until shortly before death and usually die between 20 and 25 weeks of âge. Homozygous females arc fertile but do not consistently carc for their litters; homozygous males are fertile but dccrcascd fertility is reported after 15 weeks of âge. No histologie abnormalitics are found in the liver, spleen, or pancréas. (Atala et al., 1993).

131

To evaluate the effects of a GCS inhibitor on polycystic kidney disease, a compound of interest can be administered in the feed of jck mice at one or more dose levels. Administration of the compound can be started at anytimc after birth, e.g. starting administration between 3 and 4 weeks of âge, and can continue for as long as desired. The effect of the compound on the disease phenotype can be evaluated by measurement of body weight, blood urea nitrogen (“BUN”), and sérum GLl during the in-life phase. Additional effects on kidney/body weight (K/BW), cyst volume, BUN, kidney GLl, and sérum GLl can be measured at the end of life time point of the study.

Glucosylceramide synthase inhibition in a Fabry mouse model.

A study can be designcd to evaluate whether substrate inhibition (i.e. substrate réduction therapy or “SRT”) using a compounds of the invention types could reduce the accumulation of the storage material globotriaosylceramidc (Gb3) and lysoglobotriaosylceramide (Iyso-Gb3). A Fabry mouse model can be used to evaluate substrate réduction therapy (SRT) with the GCS inhibitor compounds in reducing the levels of both Gb3 and Iyso-Gb3 in the plasma, kidney and urine of Fabry mice. Reccntly it has been proposed that urinary Iyso-Gb3 may represent a reliable biomarker of clinical relevance for Fabry disease (Aerts et al., PNAS USA 105:2812-2817 (2008); and AurayBlais et al., Clin Chîm Acta 411:1906-1914 (2010)). The mctabolic origin of the Iyso-Gb3 is not known and can conccivably be derived through either déacylation of Gb3 or through anabolic synthesis from glucosylsphingosinc.

In Figure 1, black arrows indicate demonstrated pathways, gray arrows are undocumented pathways. Enzyme replacement therapy using α-galactosidasc is known to dégrade both Gb3 and Iyso-Gb3. Accordingly, SRT using a GCS inhibitor would bc most effective at limiting Iyso-Gb3 accumulation if the Iyso-Gb3 is generated primarily through déacylation of Gb3, a GCS dépendent pathway. These experiements can be used to demonstrate that SRT using GCS inhibitors in a mouse model of Fabry disease reduces both Gb3 and Iyso-Gb3, thus supporting the use of compounds of the invention as viable therapeutic options for Fabry patients.

EXPERIMENTAL

132

Scvcral approachcs are being used or pursucd for the treatment of LSDs, most of which focus on enzyme replacement therapy for use alone in disease management. Numerous approved enzyme replacement thérapies are commercially available for treating LSDs (e.g., Myozyme® for Pompe disease, Aldurazyme® for Mucopolysaccharidosis 1, Cerezyme® for Gaucher disease and Fabrazyme® for Fabry disease). Addïtionally, the inventors have identified a number of small molécules for use alonc in the management of LSDs. The thcrapcutic methods of the invention described herein providc treatment options for the practitioner faced with management of various lysosomal storage diseases, as described in detail below.

In certain aspects of the invention, the compounds of the présent invention may be used to treat a mctabolic discase, such as a lysosomal storage disease (LSD), either alonc or as a combination therapy with an enzyme replacement therapy. In other aspects of the invention, the compounds of the présent invention may bc used to inhibit or reducc GCS activity in a subject diagnoscd with a mctabolic disease, such as an LSD, either alone or as a combination therapy with an enzyme replacement therapy. In other aspects of the invention, the compounds of the présent invention may be used to rcduce and/or inhibit the accumulation of a stored material (e.g., lysosomal substrate) in a subject diagnoscd with a mctabolic disease, such as an LSD. In certain embodiments of the foregoing aspects, the LSD is Gaucher (type 1, type 2 or type 3), Fabry, G_M]-gangliosidosis or Gm2gangliosidoscs (e.g., GM2 Activator Dcficicncy, Tay-Sachs and Sandhoff). Table 1 lists numerous LSDs and identifies the corresponding déficient enzyme that may be used as an ERT in the foregoing aspects of the invention.

In other scénarios it may bc necessary to providc SMT to a patient whose condition requircs the réduction of substrates in the brain and thus is not treatable by systemic administration of ERT. While direct intracerebroventricular or intrathecal

133 administration can rcducc substrate levels in the brain, systcmic administration of ERT is not amcnable for LSD’s with Central Ncrvous System (CNS) involvement due to its incapacity to cross the Blood Brain Barrier (BBB) and SMT may prove bénéficiai in patients having residual enzymatic activities in the CNS.

In accordance with the présent invention, SMT is provided to a patient to treat a cancer and/or metabolic disease, such as, a lysosomal storage discase. The SMT may include one or more small molécules. The SMT includes admmistering to the patient compounds of the présent invention. In particular embodiments, the compound is (S)Quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate or Quinuciidin-3-yl (2-(4'-fiuoro-[l,r-biphenyl]-3-yl)propan-2-yl)carbamate, or combinations thereof.

In certain embodiments, compounds of the invention, such as, for example, (S)Quinuclidin-3-yl (2-(2-(4-fluorophcnyl)thiazol-4-yl)propan-2-yl)carbamate and Quinuclidin-3-yl (Z-^'-fluoro-UJ'-biphenylj-B-ylJpropan^-yljcarbamatc may be used for treatment of virtually any storage disease resulting from a defect in the glycosphingolipid pathway (e.g. Gaucher (i.e., type 1, type 2 type 3), Fabry, Gmigangliosidosis, GM2-gangliosidoscs (e.g., GM2 Activator Deficicncy, Tay-Sachs and Sandhofï)). In a particularly preferred embodiment, (S)-Quinuclidin-3-yl (2-(2-(4fluorophcnyl)thiazol-4-yl)propan-2-yl)carbamatc or a pharmaceutically acceptable sait or prodrug thereof is used to inhibit and/or rcducc the accumulation of Gb3 and/or Iyso-Gb3 in a patient with Fabry discase, either alone or as a combination therapy with enzyme replacement therapy (see Examples). In a preferred embodiment, the enzyme replacement therapy includes administering alpha-galactosidase A to the Fabry patient. Indeed, the Exampies below demonstrate that a GCS inhibitor of the invention effcctively reduccs Gb3 and Iyso-Gb3 storage in a mouse model of Fabry disease, thus supporting its use as a

134 viable approach for the treatment of Fabry disease. Furthermore, in vivo combination therapy data provided in the Examples strongly suggcst that a combined therapeutic approach could be both additive and complemcntary.

In certain embodiments, compounds of the invention, such as, for example, (S)Quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate and Quinuclidin-3-yl (2-(4'-fluoro-[l,r-biphcnyl]-3-yl)propan-2-yl)carbamate may bc used for rcducing the level of GluCcr and GluSph in the brain of a subject diagnoscd with neuropathie Gaucher disease, either alone or in combination with ERT (e.g., glucocerebrosidase administration).

Dosage regimens for a small molécule therapy component of a combination therapy of the invention are generally determined by the skilled clinician and are cxpected to vary signifïcantiy depending on the particular storage disease being treated and the clinical status of the particular affected individual. The general principles for determining a dosage regimen for a given SMT of the invention for the treatment of any storage disease are well known to the skilled artisan. Guidance for dosage regimens can be obtained from any of the many well known référencés in the art on this topic. Further guidance is available, inter alia, from a review of the spécifie référencés cited herein. In certain embodiments, such dosages may range from about 0.5 mg/kg to about 300 mg/kg, preferably from about 5 mg/kg to about 60 mg/kg (e.g., 5 mg/kg, 10 mg/kg, 15, mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg and 60 mg/kg) by intraperitoneal, oral or équivalent administration from onc to five times daily. Such dosages may range from about 5 mg/kg to about 5 g/kg, preferably from about 10 mg/kg to about 1 g/kg by oral, intraperitoneal or équivalent administration from one to five times daily. In onc embodiment, doses range from about about 10 mg/day to about 500 mg/day (e.g., 10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day,

135 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, I20 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/day, 190 mg/day, 200 mg/day, 210 mg/day, 220 mg/day, 230 mg/day, 240 mg/day, 250 mg/day, 260 mg/day, 270 mg/day, 280 mg/day, 290 mg/day, 300 mg/day). A particularly preferred oral dose range is from about 50 mg to about 100 mg, wherein the dose is administered twice daily. A particular oral dose range for a compound ofthe présent invention is from about 5 mg/kg/day to about 600 mg/kg/day. In a particular oral dose range for a compound of the présent invention is from about 1 mg/kg/day to about 120 mg/kg/day, e.g., 1 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 15 mg/kg/day, 20 mg/kg/day, 25 mg/kg/day, 30 mg/kg/day, 35 mg/kg/day, 40 mg/kg/day , 45 mg/kg/day , 50 mg/kg/day , 55 mg/kg/day or 60 mg/kg/day, 65 mg/kg/day, 70 mg/kg/day, 75 mg/kg/day, 80 mg/kg/day, 85 mg/kg/day, 90 mg/kg/day, 95 mg/kg/day, 100 mg/kg/day, 105 mg/kg/day, 110 mg/kg/day ,115 mg/kg/day or 120 mg/kg/day.

In certain embodiments, the invention relates to combination thérapies of SMT using compounds of the invention and ERT therapy for the treatment of lysosomal storage discases. A partial list of known lysosomal storage discascs that can be treated in accordance with the invention is set forth in Table 1, including common disease name, material stored, and corresponding enzyme deficiency (adapted from Table 38-4 of Kolodny et al., 1998, Id.).

TABLE 1

Lysosomal Storage Discascs

Disease Material Stored Enzyme Deficiency

Sphingolipidoses

136

Gaucher	G lucocerebros i de, glucosylsphingosine	Glucocerebrosidasc
Niemann-Pick	Sphingomyelin	Sphingomyclinase
Niemann-Pick B	Sphingomyelin	Sphingomyelinase
Farber	Ccramide	Ceramidasc
GMi-gangliosidosis	GMi-ganglioside, glycoprotein	GMi-gangliosidc-βgalactosidasc
GM2-gangliosidosis (Sandhoff)	G_M2-ganglioside, globosidc	Hexosaminidase A and B
Tay-Sachs	GM2-ganglioside	Hexosaminidase A
Krabbe	Galactosylceramîde	β-Galactocerebrosidase
Mucopolvsaccharidoses
Hurlcr-Schcie (MPS I)	Dcrmatan sulfate, heparin Sulfate	a-L-iduronidase
Huntcr (MPS II)	Dcrmatan sulfate, heparin sulfate	Iduronate sulfatase
Sanfilinno (MPS III)
Type A	Heparan sulfate	Hep aran-N-sulfatase
Type B	Heparan sulfate	N-acetyl-a-glucosaminidase
Type C	Heparan sulfate	Acetyl CoA:a-glucosaminide acctyl-transferase
Type D	Heparan sulfate	N-acetyl-a-glucosamine-6sulfatase
Marauio (MPS IV)
Type A	Kcratan sulfate	Galactosamine-6-sulfatase
Type B	Kcratan sulfate	β-galactosidase
Maroteaux-Lamy (MPS VI)	Dcrmatan sulfate	Galactosamine-4-sul fatase

(arylsulfatase B)

Sly (MPS VII)

Dcrmatan sulfate, heparan β-glucuronidasc

137

Sulfate

5	Mucosulfatidosis	Sulfatidcs, mucopolysaccharides	Arylsulfatase A, B and C, other sulfatases
	Mucolipidoses
10	Sialidoses	Sialylo l igosaccharides, glycoprotcins	a-neuraminidase
15	Mucolipidosis II	Sialyloligosaccharides, glycoprotcins, glycolipids	High sérum, low fîbroblast enzymes; N-acetylglucosamine-1 -phosphate transferase
	Mucolipidosis ΙΠ	Glycoprotcins, glycolipids	Same as above
	Mucolipidosis IV	Glycolipids, glycoproteins	Mcolnl transm protein

Other Dîseases of Complcx Carbohydrate Metabolism

25	Fabry	Globotriaosylceramide(Gb3), α-galactosidase A Iyso-Gb3
	Schindlcr	Ο-Iinked glycopcptides	a-N-acctylgalactosaminidase
30	Pompe	Glycogcn	a-glucosidase
	Sialic acîd storage disease	Free sialic acid	Unknown
35	Fucosidosis	Fucoglycolipids, fucosyloligosaccharides	a-fucosidase
	Mannosidosis	Mannosyloligosaccharides	a-mannosidasc
	Aspartylglucosaminuria	Aspartylglucosamine	Aspartylglucosamine amidase
	Wolman	Cholcsteryl esters,	Acid lipasc

Triglycérides

Neuronal Ceroid Lipofuscinoses (NCLsl*

Infantile NCL	Granular osmophilic deposits,	Palmitoyl-protein
45	Saposins A and D thioesterase	thioesterase (PPTl)
Late Infantile	Curvilinear profiles,	Tripeptidyl protease l
	ATP synthasc subunit c	(TPPl)
50 Finnish variant	Fingerprint/Rectilinear profiles, CLN5

138

Variant

Juvénile

Adult

Northcm Epilepsy

ATP synthase subunit c

Fingerprint/Rectilincar profiles, CLN6 ATP synthase subunit c

Fingcrprint profile, ATP synthase subunit c

Variable

Rectilïnear profile, ATP synthase subunit c

CLN3

Unknown

CLN8

Turkish variant

Fingcrprint/Rectilinear profiles - constituents unknown

Unknown

Lysosomal discases of cholestérol transport and metabolism

Nicmann-Pick type C

Unesterificd cholestérol NPC l or NPC2 * Davidson et al., The Neuronal Ceroid Lipofuscinosis, Clinical Features and Molecular Basis of Disease. In Barrangcr JA and Cabrcra-Salazar MA (Eds) Lysosomal Storage Disorders. 2007. pp. 371-388. Springer, New York, U.S.A.

Any method known to the skillcd artisan may bc used to monitor disease status and the effectiveness of a combination therapy of the invention. Clinical monitors of discase status may include but are not limited to organ volume (e.g. liver, spleen), hemoglobin, érythrocyte count, hematocrit, thrombocytopenia, cachexia (wasting), and plasma chitinasc levels (e.g. chitotriosidasc). Chitotriosidasc, an enzyme of the chitinasc family, is known to bc produced by macrophages in high levels in subjects with lysosomal storage diseases (see Guo et al., 1995, J. Inhcrit. Metab. Dis. 18, 717-722; den Tandt et al., 1996, J. Inhcrit. Metab. Dis. 19, 344-350; Dodclson de Kremcr et al., 1997, Mcdicina (Buenos Aires) 57, 677-684; Czartoryska et al., 2000, Clin. Biochem. 33,147149; Czartoryska et al., 1998, Clin. Biochcm. 31, 417-420; Mistry et al., 1997, Bailliercs Clin. Haematol. 10, 817-838; Young et al., 1997, J. Inherit. Metab. Dis. 20, 595-602;

139

Hollak et al., 1994, J. Clin. Invest. 93, 1288-1292). Chîtotriosidase is preferably measured in conjunction with angiotensin converting enzyme and non tartrate résistant acid phosphatase to monitor response to treatment of Gaucher patients.

Methods and formulations for administering the combination thérapies of the invention include ail methods and formulations well known in the art (see, e.g., Remington's Pharmaceutical Sciences, 1980 and subséquent years, 16th ed. and subséquent éditions, A. Oslo editor, Easton Pa.; Controlled Drug Delivery, 1987, 2nd rev., Joseph R. Robinson & Vincent II. L. Lee, eds., Marcel Dekker, ISBN: 0824775880; Encyclopedia of Controlled Drug Delivery, 1999, Edith Mathiowitz, John Wiley & Sons, ISBN: 0471148288; U.S. Pat. No. 6,066,626 and référencés cited therein; see also, référencés cited in sections below).

According to the invention, the following general approaches are provided for combination therapy in the treatment of lysosomal storage diseases. Each general approach involves combining enzyme replacement therapy with small molécule therapy in a manner consistent with optimizing clinical benefit while minimizing disadvantages associated with using each therapy alone.

In one embodiment of the invention, enzyme replacement therapy (alone or in combination with small molécule therapy) is administered to initiale treatment (i.e,, to debulkthe subject), and small molécule therapy is administered after the de-bulking phase to achieve and maintain a stable, long-tcrm therapeutic effect without the need for frequent intravenous ERT injections. For example, enzyme replacement therapy may be administered intravenously (e.g. over a one to two hour period) once, on a weekly basis, once every two weeks, or once every two months, for several weeks or months, or longer (e.g., untii an involved indicator organ such as spleen or liver shows a decreasc in size). Moreover, the ERT phase of initiai de-bulking treatment can be performed alone or in

140 combination with a small molécule therapy. A small molécule therapeutic component is particularly preferred where the small molécule is compatible with oral administration, thus providing further relief from frequent intravenous intervention.

Altemating among ERT and S MT, or supplementing SMT with ERT as needed, provides a strategy for simultaneously taking advantage of the strengths and addressing the wcaknesses associated with each therapy when used alone. An advantage of ERT, whether used for dc-bulking and/or for more long-tcrm carc, is the much broader clinical expérience available to inform the practitioncr's decisions. Moreover, a subject can be effectively titrated with ERT during the de-bulking phase by, for example, monitoring biochemical métabolites in urine or other body samples, or by measuring affected organ volume. A disadvantage of ERT, however, is the frequency of the administration rcquired, typically involving intravenous injection on a wcekly or bi-weckly basis due to the constant rc-accumulation of the substratc. The use of small molécule therapy to rcduce the amount of or inhibit substrate accumulation in a patient can in tum rcduce the administration frequency of ERT. For example, a bi-weckly enzyme replacement therapy dosing regimen can bc offered an ERT holiday (e.g., using a SMT) so that frequent enzyme injections arc not required therapy. Furthermore, treating a lysosomat storage disease with combination therapy can provide complementary therapeutic approachcs. Indeed, as demonstrated in the Examples below, a combination therapy of SMT and ERT can providc significant improvements over either therapeutic platform alone. These data suggest that combination therapy using SMT and ERT can be both additive and complementary. In one embodiment, ERT may be used as a de-bulking strategy (i.e., to initiate treatment), followed by or simultaneously supplemented with SMT using a compound of the présent invention. In another embodiment, a patient is first treated with SMT using a compound of the présent invention, followed by or simultaneously

141 supplcmcntcd with ERT. In other embodiments, a SMT is used to inhibit or rcducc further accumulation of substrate (or rc-accumulât ion of substrate if used after debulking with ERT) in a patient with a lysosomal storage disease, and optionally provided ERT as needed to reduce any further substrate accumulation. In one embodiment, this invention provides a method of combination therapy for treatment of a subject diagnosed as having a lysosomal storage disease comprising altemating between administration of an enzyme replacement therapy and a small molécule therapy. In another embodiment, this invention provides a method of combination therapy for treatment of a subject diagnosed as having a lysosomal storage discase comprising simultaneously administering an enzyme replacement therapy and a small molécule therapy. In the various combination thérapies of the invention, it will be understood that administering small molccule therapy may occur prior to, concurrently with, or after, administration of enzyme replacement therapy. Similarly, administering enzyme replacement therapy may occur prior to, concurrently with, or after, administration of small molccule therapy.

In any of the embodiments of the invention, the lysosomal storage discase is selected from the group consisting of Gaucher (types l, 2 and 3), Niemann-Pick, Farber, GMi-gangliosidosis, G_M2-gangliosidoscs (e.g., GM2 Activator Deficiency, Tay-Sachs and Sandhoff), Krabbe, Hurler-Scheie (MPS I), Hunter (MPS II), Sanfilippo (MPS III) Type A, Sanfilippo (MPS III) Type B, Sanfilippo (MPS III) Type C, Sanfilippo (MPS III) Type D, Marquio (MPS IV) Type A, Marquio (MPS IV) Type B, Marotcaux-Lamy (MPS VI), Sly (MPS Vil), mucosulfatidosis, sialidoses, mucolipidosis II, mucolipidosis III, mucolipidosis IV, Fabry, Schindler, Pompe, sialic acid storage disease, fucosidosis, mannosidosis, aspartylglucosaminuria, Wolman, and neuronal ceroîd lipofucsinoses.

Further, the ERT provides an effective amount of at least one of the following enzymes; glucocerebrosidase, sphingomyclinase, ceramidase, GMi-ganglioside-beta17263

142 galactosidasc, hcxosaminida.se A, hexosaminidasc B, beta-galactoccrcbrosidase, alpha-Liduronidase, iduronate sulfatase, heparan-N-sulfatase, N-acetyl-alpha-glucosaminidase, acctyl CoA:alpha-glucosaminide acetyl-transfcrase, N-acctyl-alpha-glucosamine-6sulfatasc, galactosamine-6-su)fatasc, beta-galactosidasc, galactosamine-4-sulfatase (arylsulfatase B), bcta-glucuronidase, arylsulfatase A, arylsulfatase C, alphaneuraminidase, N-acetyl-glucosamine-l -phosphate transferase, alpha-galactosidase A, aipha-N-acetylgalactosaminidasc, alpha-glucosidasc, alpha-fucosidasc, alphamannosidase, aspartylglucosamine amidasc, acid lipase, palmitoyl-protein thioesterase (CLN-1), PPT1, TPP1, CLN3, CLN5, CLN6, CLN8, NPC1 or NPC2.

In accordance with the invention, the SMT and/or ERT produce a diminution in at least one of the following stored materials; glucoccrebroside, sphingomyelin, ceramide, GMi-ganglioside, GM2-ganglioside, globoside, galactosylccramide, dermatan sulfate, hcparan sulfate, keratan sulfate, sulfatides, mucopolysaccharides, sialyloligosaccharides, glycoproteîns, sialyloligosaccharides, glycolipids, globotriaosylceramidc, O-linked glycopeptides, glycogen, free sialic acid, fucoglycolipids, fiicosyloligosaccharides, mannosyloligosaccharidcs, aspartylglucosamine, cholesteryl esters, triglycérides, granular osmophilic deposits — Saposins A and D, ATP synthase subunit c, NPC1 or NPC2.

In certain embodiments of the invention, the small molécule therapy comprises administering to the subject an effective amount of (S)-Quinuclidin-3-yl (2-(2-(4fluorophcnyl)thiazol-4-yl)propan-2-yl)carbamatc (see Fig. 2A). In other embodiments, the small molécule therapy comprises administering to the subject an effective amount of Quinuclidin-3-yl (2-(4^,-fluoro-[l,r-biphcnyl]-3-yl)propan-2-yl)carbamatc (see Fig. 2B). The small molécule therapy may include admininstering to a subject one or more compounds. In certain embodiments, at least one of the compounds is a compound of the présent invention, such as those shown in Figs. 2A and/or 2B.

143

Enzyme replacement thcrapy can provokc unwantcd immune responses. Accordingly, immunosuppressant agents may bc used together with an enzyme replacement thcrapy component of a combination lherapy of the invention. Such agents may also be used with a small molécule therapy component, but the need for intervention here is generally less likely. Any immunosuppressant agent known to the skilled artisan may be employcd together with a combination therapy of the invention. Such immunosuppressant agents include but arc not limited to cyclosporine, FK.506, rapamycin, CTLA4-lg, and anti-TNF agents such as ctancrcept (see e.g. Moder, 2000, Ann. Allcrgy Asthma Immunol. 84, 280-284; Nevins, 2000, Curr. Opin. Pcdiatr. 12, 146150; Kurlberg et al., 2000, Scand. J. Immunol. 51,224-230; Ideguchi et al., 2000, Neuroscience 95,217-226; Potteret al., 1999, Ann. N.Y. Acad. Sci. 875, 159-174; Slavik et al., 1999, Immunol. Rcs. 19, 1-24; Gaziev et al., 1999, Bone Marrow Transplant. 25, 689-696; Henry, 1999, Clin. Transplant. 13, 209-220; Gummcrt et al., 1999, J. Am. Soc. Nephrol. 10,1366-1380; Qi et al, 2000, Transplantation 69, 1275-1283). The anti-IL2 receptor (.alpha.-subunit) antibody daclizumab (e.g. Zenapax.TM.), which has been demonstrated effective in transplant patients, can also bc used as an immunosuppressant agent (see e.g. Wiseman et al., 1999, Drugs 58, 1029-1042; Beniaminovitz et al., 2000, N. Engl J. Med. 342, 613-619; Ponticclli et al., 1999, Drugs R. D. 1, 55-60; Berard et al., 1999, Pharmacotherapy 19, 1127-1137; Eckhoff et al., 2000, Transplantation 69,18671872; Ekbcrg et al., 2000, Transpi. Int. 13, 151-159). Additional immunosuppressant agents include but are not limited to anti-CD2 (Branco et al., 1999, Transplantation 68, 1588-1596; Przcpiorka et al., 1998, Blood 92, 4066-4071), anti-CD4 (MarinovaMutafchieva et al., 2000, Arthritis Rhcum. 43, 638-644; Fishwild et al., 1999, Clin. Immunol. 92, 138-152), and anti-CD40 ligand (Hong et al., 2000, Scmin. Nephrol. 20,

744

108-125; Chirmulc et al., 2000, J. Virol. 74, 3345-3352; Ito et al., 2000, J. Immunol. 164, 1230-1235).

Any combination of immunosuppressant agents known to the skilled artisan can bc used together with a combination therapy of the invention. One immunosuppressant agent combination of particular utïlîty is tacrolimus (FK506) plus sirolimus (rapamycin) plus daclizumab (anti-IL2 receptor .alpha.-subunit antibody). This combination is proven effective as an alternative to steroids and cyclosporine, and when specifically targeting the liver. Moreovcr, this combination has recently been shown to permit successful pancreatic islet cell transplants. See Denise Grady, The New York Times, Saturday, May 27, 2000, pages Al and Ail. See also A. M. Shapiro et al., Jul. 27, 2000, Islet Transplantation In Sevcn Patients With Type 1 Diabètes Mellitus Using A Glucocorticoid-Frec Immunosuppressive Rcgimen, N. Engl. J. Med. 343, 230-238; Ryan et al., 2001, Diabètes 50, 710-719. Plasmaphoresis by any method known in the art may also be used to remove or dcplete antibodies that may develop against various components of a combination therapy.

Immune status indicators of use with the invention inciude but are not limited to antibodies and any of the cytokines known to the skilled artisan, e.g., the interleukins, CSFs and interférons (sec generally, Leonard et al., 2000, J. Allcrgy Clin. Immunol. 105, 877-888; Obcrholzcr et al., 2000, Crit. Care Med. 28 (4 Suppl.), N3-N12; Rubinstein et al., 1998, Cytokine Growth Factor Rev. 9, 175-181). For exampie, antibodies specifically immunoreactive with the replacement enzyme can be monitored to détermine immune status of the subject. Among the two dozen or so interleukins known, particularly preferred immune status indicators arc IL-1 .alpha., IL-2, IL-4, IL-8 and IL-10. Among the colony stimulating factors (CSFs), particularly preferred immune status indicators are G745

CSF, GM-CSF and M-CSF. Among the interferons, onc or more alpha, beta or gamma interferons are preferred as immune status îndicators.

In the sections which follow, various components that may bc used for eight spécifie lysosomal storage diseases are provided (i.e,, Gaucher (including types 1, 2 and 3), Fabry, Nicmann-Pick B, Hunter, Morquio, Maroteaux-Lamy, Pompe, and HurlerScheie). In subséquent sections, further enabling disclosure for enzyme replacement thcrapy and small molécule thcrapy components of a combination thcrapy of the invention are provided.

Gaucher

As noted above, Gaucher's disease is caused by the deficiency of the enzyme glucocerebrosidase (beta-D-glucosyl-N-acylsphingosine glucohydrolase, EC 3.2.1.45) and accumulation of glucocerebroside (glucosylceramidc). For an enzyme replacement therapy component of a combination thcrapy of the invention for the treatment of Gaucher's disease, a number of refcrences are available which set forth satisfactory dosage regîmens and other useful information relating to treatment (see Morales, 1996, Gaucher's Disease: A Review, The Annals of Pharmacothcrapy 30, 381-388; Rosenthal et al., 1995, Enzyme Replacement Thcrapy for Gaucher Discase: Skclctal Responses to Macrophagc-targetcd Glucocerebrosidase, Pediatrics 96, 629-637; Barton et aL, 1991, Replacement Thcrapy for Inherited Enzyme Deficiency—Macrophage-targeted Glucocerebrosidase for Gaucher’s Disease, New England Journal of Mcdicine 324,14641470; Grabowski et al., 1995, Enzyme Therapy in Type 1 Gaucher Disease: Comparative Efficacy of Mannose-terminated Glucocerebrosidase from Naturel and Recombinant Sources, Annals of Internai Medicine 122, 33-39; Pastores et al., 1993, Enzyme Thcrapy in Gaucher Disease Type 1: Dosage Efficacy and Adverse Effects in 33 Patients treated

146 for 6 to 24 Months, Blood 82,408-416); and Weinreb et al., Am. J. Med.;l 13(2):112-9 (2002).

In one embodiment, an ERT dosage rcgimcn of from 2.5 units per kilogram (U/kg) three times a week to 60 U/kg once every two weeks is provided, where the enzyme is administered by intravenous infusion over 1-2 hours. A unit of glucoccrcbrosidasc is defined as the amount of enzyme that catalyzes the hydrolysis of one micromolc of the synthetic substratc para-nitrophcnyl-p-D-glucopyranosidc per minute at 37 °C. In another embodiment, a dosage regimen of from 1 U/kg three times a week to 120 U/kg once every two weeks is provided. In yct another embodiment, a dosage regimen of from 0.25 U/kg daily or three times a week to 600 U/kg once every two to six weeks is provided.

Sincc 1991, alglucerase (Ccrcdase®) has been available from Genzyme Corporation. Alglucerase is a placcntally-dcrived modified form of glucocerebrosidasc. In 1994, imiglucerasc (Cerezyme®) also bccame available from Genzyme Corporation. Imiglucerase is a modified form of glucocerebrosidasc derived from expression of recombinant DNA in a mammalian cell culture System (Chinese hamster ovary cells). Imiglucerase is a monomcric glycoprotein of 497 amino acids containing four N-linkcd glycosylation sites. Imiglucerase has the advantages of a thcorctically unlîmited supply and a reduced chance of biological contaminants relative to placcntally-derived agluccrasc. Thèse enzymes arc modified at their glycosylation sites to expose mannose residucs, a mancuver which improves lysosomal targeting via the mannosc-6-phosphatc receptor. Imiglucerase differs from placcntal glucocerebrosidasc by one amino acid at position 495 where histidine is substituted for arginine. Several dosage regimens of these products are known to bc effective (sec Morales, 1996, Id.; Rosenthal et al., 1995, Id.; Barton et al., 1991, Id.; Grabowski et al., 1995, Id.; Pastores et al., 1993, Id.). For

147 example, a dosage regimen of 60 U/kg once every two weeks is of clinlcal benefit in subjects with moderatc to severe disease. The références citcd above and the package inscris for these products should be consulted by the skilled practitioner for additional dosage regimen and administration information. Sec also U.S. Pat. Nos. 5,236,838 and

5,549,892 assigned to Genzyme Corporation.

As noted above, Gaucher Disease results from a dcficiency of the lysosomal enzyme glucoccrcbrosidasc (GC). In the most common phenotype of Gaucher disease (type l), pathology is limited to the réticuloendothélial and skeletal Systems and there are no neuropathie symptoms. See Barranger, Glucosylceramide lipidosis: Gaucher disease. In: Scriver CR BA, Sly WS, Valle D, editor. The Metabolic Basis of Inhcrited Disease. New York: McGraw-Hill. pp. 3635-3668 (2001). In neuropathie Gaucher disease (nGD), subdivided into type 2 and type 3 Gaucher discase, the dcficiency of glucocercbrosidase (GC) causes glucosylceramide (GluCer; GL-1) and glucosylsphingosine (GluSph) to accumulate in the brain, leading to neurologie impairment. Type 2 Gaucher discase is characterized by early onset, rapid progression, extensive pathology in the viscera and central nervous system, and death usually by 2 years of âge. Type 3 Gaucher disease, also known as subacutc nGD, is an intermediate phenotype with varying âge of onset and different degrees of severity and rates of progression. Goker-Alpan et al., The Journal of Pediatrics 143: 273-276 (2003). A récent development has produced the K14 Inl/Lnl mouse model of type 2 Gaucher disease (hereinafter, the “K 14 mouse”); this mouse model closely récapitulâtes the human disease showing ataxia, seizures, spasticity and a reduced médian lifespan of only 14 days. Enquist et al., PNAS 104: 17483-17488 (2007).

As in patients with nGD, sevcral mouse models of the disease hâve increased

Ievels of GluCer and GluSph in the brain due to the defîciency in GC activity. Liu et al.,

PNAS 95: 2503-2508 (1998) and Nilsson, J. Neurochcm 39: 709-718 (1982). The “K14”

148 mice display a neuropathie phenotype that shares many pathologie features with type 2 Gaucher disease, such as neurodegeneration, astrogliosis, microglial prolifération, and incrcascd levels of GluCcr and GluSph in spécifie brain régions. Enquist et al. (2007).

Clinical management of patients affectcd by nGD poses a challenge for treating physicians both because of the severity of type 2 disease and the inability of the current thérapies to cross the blood brain barrier (BBB). Current treatment of non-nGD relies on the intravenous delivery of recombinant human glucoccrcbrosidasc (Imigluccrasc; Cerezyme™) to replace the missing enzyme or the administration of glucosylccramide synthase inhibitors to attenuate substrate (GL-l ) production. Howevcr, these drugs do not cross the blood brain barrier, and thus are not cxpected to provide therapeutic benefît for nGD patients. Current small molécule glucosylccramide synthase inhibitors in the clinic are not likely to address the neuropathie phenotypes of nGD. An évaluation of a compound of the présent invention, Quinuclidin-3-yl (2-(4'-fluoro-[l,r-biphcnyl]-3yl)propan-2-yl)carbamate (hereinafter, “Gzl6l”), in the K.14 mouse model of type 2 Gaucher disease demonstrated that it could indeed reduce brain GluCer and GluSph (see Examplcs 122-125). It also reduced brain neuropathology and extended the lifespan of this model. Morcover, a combined approach using both enzyme replacement and small molécule substrate réduction may represent a superior therapy for type 2 Gaucher disease. Fabrv

As noted prcviously, Fabry's disease is causcd by the dcficicncy of the lysosomal enzyme alpha-galactosidase A. The enzymatic defect leads to systemic déposition of glycosphingolipids having terminal alpha-galactosyl moieties, predominantly globotriaosylceramide (GL3 or Gb3) and, to a lesser extent, galabiosylceramide and blood group B glycosphingolipids.

149

Several assays are available to monitor disease progression and to détermine when to switch from onc treatment modality to another. In one embodiment, an assay to déterminé the spécifie activity of alpha-galactosidasc A in a tissue sample may be used. In another embodiment, an assay to déterminé the accumulation of Gb3 may be used. In another embodiment, the practitioner may assay for déposition of glycosphingolipid substrates in body fluids and in lysosomes of vascular endothélial, périthélia] and smooth muscle cells of blood vessels. Other clinical manifestations which may be useful indicators of discase management include proteinuria, or other signs of rénal impairment such as red cells or lipid globules in the urine, and elevated érythrocyte sédimentation rate. Onc can also monitor anémia, dccreased sérum iron concentration, high concentration of beta-thromboglobulin, and elevated réticulocyte counts or platclct aggregation. Indccd, any approach for monitoring discase progression which is known to the skilled artisanmay beused (Secgenerally DesnickRJ ct al., 1995, .alphaGalactosidase A Deficiency: Fabry Disease, In: The Metabolic and Molecular Bases of Inhcritcd Disease, Scriver ct al., eds., McGraw-Hill, N.Y., 7.sup.th ed., pages 2741-2784). A preferred surrogatc marker is pain for monitoring Fabry disease management. Other preferred methods include the measurement of total clearance of the enzyme and/or substrate from a bodily fluid or biopsy specimen. A preferred dosage regimen for enzyme replacement therapy in Fabry disease is 1-10 mg/kg i.v. every other day. A dosage regimen from 0.1 to 100 mg/kg i.v. at a ffcqucncy of from every other day to once weekly or every two weeks can be used.

Niemann-Pick B

As previously noted, Niemann-Pick B disease is caused by reduced activity of the lysosomal enzyme acid sphingomyclinasc and accumulation of membrane lipid, primarily sphingomyelin. An effective dosage of replacement acid sphingomyelinase to be

150 delivered may range from about 0.01 mg/kg to about 10 mg/kg body weight at a frcquency of from every other day to weekly, once every two weeks, or once every two months. In other embodiments an effective dosage may range from about 0.03 mg/kg to about 1 mg/kg; from about 0.03 mg/kg to about 0.1 mg/kg; and/or from about 0.3 mg/kg to about 0.6 mg/kg. In a particular embodiment, a patient is administering acid sphingomyclinasc in an escalating dose regimen at the following sequential doses: 0.1 mg/kg; 0.3 mg/kg; 0.6 mg/kg; and 1.0 mg/kg, wherein each dose of acid sphingomyelinase is administered at least twicc, and each dose is administered at two week intervals, and wherein the patient is monitored for toxic side effects before elevating the dose to the next level (See U.S. Patent Application Publication No. 2011/0052559,

Hurler-Schcîe (MPS I)

Hurler, Schcie, and Hurler-Schcîe disease, also known as MPS I, arc causcd by inactivation of alpha-iduronidasc and accumulation of dermatan sulfate and heparan sulfate. Several assays are available to monitor MPS I disease progression. For example, alpha-iduronidase enzyme activity can bc monitored in tissue bîopsy specimens or cultured cells obtained from pcripheral blood. In addition, a convenient measure of disease progression in MPS I and other mucopolysaccharidoses is the urinary excrétion of the glycosaminoglycans dermatan sulfate and heparan sulfate (see Neufeld et al., 1995, Id.). In a particular embodiment, alpha-iduronidase enzyme is administered once weekly as an intravenous infusion at a dosage of 0.58 mg/kg of body weight.

Hunter (MPS II)

Hunter's discase (a.k.a. MPS II) is caused by inactivation of iduronate sulfatase and accumulation of dermatan sulfate and heparan sulfate. Hunter's disease présents clinically in severe and mild forms. A dosage regimen of therapeutic enzyme from 1.5

151 mg/kg evcry two wccks to 50 mg/kg every wcck is preferred.

Morquio (MPS IV)

Morquio's syndrome (a.k.a. MPS IV) results from accumulation of keratan sulfate due to inactivation of either of two enzymes. In MPS IVA the inactivatcd enzyme is galactosamine-6-sulfatase and in MPS 1VB the inactivatcd enzyme is beta-galactosidase. A dosage regimen of therapeutic enzyme from 1.5 mg/kg every two weeks to 50 mg/kg every week is preferred.

Maroteaux-Lamy (MPS VI)

Maroteaux-Lamy syndrome (a.k.a. MPS VI) is caused by inactivation of alactosamine-4-sulfatase (arylsulfatase B) and accumulation of dermatan sulfate. A dosage regimen of from 1.5 mg/kg every two weeks to 50 mg/kg every week is a preferred range of effective therapeutic enzyme provided by ERT. Optimally, the dosage employed is less than or cqual to 10 mg/kg per week. A preferred surrogate marker for MPS VI disease progression is proteoglycan levels.

Pompe

Pompe's disease is caused by inactivation of the acid alpha-glucosidase enzyme and accumulation of glycogen. The acid alpha-glucosidase gene résides on human chromosome 17 and is designated GAA. H. G. Hers first proposed the concept of inbom lysosomal disease based on his studios of this disease, which he referred to as type II glycogen storage disease (GSD II) and which is now also termed acid maltasc dcficicncy (AMD) (see Hers, 1965, Gastroenterology 48,625). In a particuiar embodiment, GAA is administered every 2 wccks as an intravenous infusion at a dosage of 20 mg/kg body weight.

Sevcral assays arc available to monitor Pompe disease progression. Any assay known to the skilled artisan may be used. For example, one can assay for intra-lysosomal

152 accumulation of glycogen granules, particularly in myocardium, liver and skeletal muscle fibers obtained from biopsy. Alpha-glucosidase enzyme activity can also be monitored in biopsy specimens or eultured cells obtained from periphcral biood. Sérum élévation of crcatine kinase (CK) can be monitored as an indication of disease progression. Sérum CK can bc elevated up to ten-fold in infantile-onsct patients and is usually elevated to a lesscr degree in adult-onset patients. See Hirschhom R, 1995, Glycogen Storage Disease Type II: Acid alpha-Glucosidasc (Acid Maltasc) Dcficicncy, In: The Metabolic and Molecular Bases of Inhcritcd Disease, Scriver et al., eds., McGraw-Hill, N.Y., 7.sup.th ed., pages 2443-2464.

Enzyme Replacement Therapy

The following sections set forth spécifie disclosure and alternative embodiments available for the enzyme replacement therapy component of a combination therapy of the invention. Generally, dosage regimens for an enzyme replacement therapy component of a combination therapy of the invention are generally determined by the skilled clinician. Several examples of dosage regimens for the treatment of Gauchcr's disease with glucocerebrosidasc are provided above. The general principles for determîning a dosage regimen for any given ERT component of a combination therapy of the invention for the treatment of any LSD will be apparent to the skilled artisan from publically available information, such as, for example, a review of the spécifie références cited in the sections for cach spécifie LSD. An ERT may bc adminîstered to a patient by intravenous infusion. Intraccrebroventricular and/or întrathecal infusion may be used (e.g., in addition to intravenous infusion) to administer ERT to a patient diagnosed with a lysosomal storage disease having CNS manifestations.

Any method known in the art may bc used for the manufacture of the enzymes to be used in an enzyme replacement therapy component of a combination therapy of the

153 invention. Many such methods arc known and include but are not limited to the Gene Activation technology devcloped by Shire pic (see U.S. Pat. Nos. 5,968,502 and 5,272,071).

Rénal cysts occur in one third of pcople older than 50 years. While most arc simple cysts, rénal cystîc disease has multiple étiologies. Broad categories of the cystic disease include the following:

Congénital - Congénital cystic dysplasia;

Genetic - Autosomal récessive polycystic kidney disease (ARPKD), autosomal dominant polycystic kidney disease (ADPKD), nephronophthisis-medullary cystic kidney disease complex (NMCD);

Acquired - Simple cysts, acquired cystic disease;

Cysts associated with systemie discase - Von Hippel-Lindau syndrome (VHLS), tuberous sclerosis (TS) and

Malignancy - Rénal cell carcinoma (RCC).

The most common larger cysts arc acquired cysts, simple cysts, and cysts with ADPKD. Smaller cysts are associated with ARPKD, NMCD, and medullary sponge kidney (MSK). In adults, rénal angiomyolipomas and RCC also may demonstrate cystic Lésions.

Polycystic Kidney Disease (PKD)

Polycystic kidney disease (PKD) dcscribcs scveral conditions in which fluid-fîlled cysts form in the kidneys. Cysts generally develop in weak segments of the tubulcs that carry urine from the glomcruli. The cyst's growth displaces healthy kidney tissue. The

154 kidncys cxpand to accommodatc the cyst, which can wcigh as much as 20 pounds. There arc many forms of PKD, both inherited forms and noninherited.

Autosomal dominant PKD (ADPKD) is the most common, inherited form. Symptoms of ADPKD usually develop between the âges of 30 and 40, but they can begin earlier, even in childhood. About 90 percent of ail PKD cases arc autosomal dominant PKD. ADPKD rcsults from mutation in the PKDl gcnc that encodes polycystin-l (85% of the cases) or PKD2 gene that cncodcs polycystin-l (15% of the cases).

Autosomal récessive PKD (ARPKD) is a rare, inherited form. Symptoms of autosomal récessive PKD begin in the earlicst months of life, even in the womb.

Acquired cystic kidney disease (ACKD) dcvelops in association with long-term kidney problems, especially in patients who hâve kidney failure and who have been on dialysis for a long time. Therefore it tends to occur in later ycars of life. It is not an inherited form of PKD.

The rénal cystic discascs include, but are not limited to rénal cyctic diseascs such as: acquired rénal cystic discase (ARCD), dialysis-associated cystic disease, autosomal dominant polycystic kidney disease (ADPKD), autosomal récessive polycystic kidney discase (ARPKD), congénital multicystic kidney (CMK), multicystic dysplastic kidney, end-stage rénal disease (ESRD), mcdullary sponge kidney, MSK, nephronophthisismcdullary cystic kidney disease complex (NMCD), nephronophthisisuremie medullary cystic disease complex, juvénile nephronophthisis, medullary cystic disease, rénal cell carcinoma (RCC), tuberous sclcrosis (TS), von Hippel-Lindau syndrome (VHLS).

755

When PKD causes kidneys to fail, which usually happcns after many years, the patient rcquires dialysis or kidney transplantation. About onc-half of pcople with the major type of PKD progress to kidney failure. PKD can cause cysts in the liver and problems in other organs, such as the heart and biood vessels in the brain. These complications distinguish PKD from the usually harmless simple cysts that often form în the kidneys in later years of life.

In the United States, about 600,000 pcople, and worldwide about 12.5 million people hâve PKD, and it is a lcading cause of kidney failure. Three factors détermine cyst classification: its cause (acquired, inherited), its features (complicated, simple, multiple, single), and its location (outer (cortical) or inner (medullary) kidney tissue).

At this time, PKD has no cure. The treatments for PKD include mcdicine and surgery to reducc pain, antibiotics to résolve infections, dialysis to replace functions of failcd kidneys and kidney transplantation. Therefore, there is a need for developing more efficient treatments of PKD.

SUMMARY

In onc embodiment, provided herein are methods for treating, ameliorating or preventing multiple cystic discases. The cystic discases include, but are not limited to rénal cyctic diseases such as: acquired rénal cystic disease (ARCD), dialysis-associated cystic disease, autosomal dominant polycystic kidney disease (ADPKD), autosomal récessive polycystic kidney disease (ARPKD), congénital multicystîc kidney (CMK),

156 multi cystic dysplastîc kidncy, cnd-stage rénal disease (ESRD), medullary sponge kidney (MSK), nephronophthisis-medullary cystic kidncy disease complex (NMCD), ncphronophthisis-uremic medullary cystic discase complex, juvénile nephronophthisis, medullary cystic disease, rénal cell carcinoma (RCC), tuberous sclcrosis (TS), von Hippel-Lindau syndrome (VHLS). In one embodiment, provided herein are methods for treatment, amelioration or prévention of polycystic kidney disease.

Small Molécule Therapy

The following section also sets forth spécifie disclosurcs and alternative embodiments available for the small molécule therapy component of a combination therapy of the invention. Dosage regimens for a small molécule therapy component of a combination thcrapy of the invention are generally determined by the skilled clinician and arc expected to vary significantly depending on the particular storage disease being treated and the clinical status of the particular affected individual. The general principles for determining a dosage regimen for a given SMT component of any combination thcrapy of the invention for the treatment of any storage disease are well known to the skilled artisan. Guidance for dosage regimens can be obtained from any of the many wellknown references in the art on this topic. Further guidance is available, inter alia, from a review of the spécifie références cited herein.

Generally, compounds of the présent invention, such as, for example, (S)Quinuclidin-3-yl (2-(2-(4-fluorophcnyl)thiazol-4-yl)propan-2-yl)carbamate and Quinuclidin-3-yl (2-(4'-fluoro-[l,l'-biphenyl]-3-yl)propan-2-yl)carbamate may be used in the combination thérapies of the invention for treatment of virtually any storage disease resulting from a lésion in the glycosphingolipid pathway (e.g. Gaucher, Fabry, G_Migangliosidosis and GM2-gangliosidoses (e.g., GM2 Activator Deficiency, Tay-Sachs and Sandhofï)). Likcwise, aminoglycosides (e.g. gentamicin, G418) maybe used in the

157 combination thérapies of the invention for any storage disease individual having a prématuré stop-codon mutation (i.e., nonsense mutation). Such mutations arc particularly prévalent in Hurler syndrome. A small molécule thcrapy component of a combination thcrapy of the invention is particularly preferred where there is a central nervous system manifestation to the storage disease being treated (e.g., Sandhoff, Tay-Sachs, NiemannPick Type A, and Gaucher types 2 and 3), since small molécules can generally cross the blood-brain barricr with case when comparcd to other thérapies.

Preferred dosages of substrate inhibitors used in a combination thcrapy of the invention arc easily determined by the skillcd artisan. In certain embodiments, such dosages may range from about 0.5 mg/kg to about 300 mg/kg, preferably from about 5 mg/kg to about 60 mg/kg (e.g., 5 mg/kg, 10 mg/kg, 15, mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg and 60 mg/kg) by intraperitoneal, oral or équivalent administration from onc to five times daily. Such dosages may range from about 5 mg/kg to about 5 g/kg, preferably from about 10 mg/kg to about 1 g/kg by oral, intraperitoneal or équivalent administration from onc to five times daily. In onc embodiment, doses range from about 10 mg/day to about 500 mg/day (e.g., 10 mg/day, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/day, 190 mg/day, 200 mg/day, 210 mg/day, 220 mg/day, 230 mg/day, 240 mg/day, 250 mg/day, 260 mg/day, 270 mg/day, 280 mg/day, 290 mg/day, 300 mg/day). A particularly preferred oral dose range is from about 50 mg to about 100 mg, wherein the dose is administered twice daily. A particular oral dose range for a compound of the présent invention is from about 5 mg/kg/day to about 600 mg/kg/day. In a particular oral dose range for a compound of the présent invention is from about 1 mg/kg/day to about 100 mg/kg/day, e.g., 1 mg/kg/day, 5 mg/kg/day, 10

158 mg/kg/day, 15 mg/kg/day, 20 mg/kg/day, 25 mg/kg/day, 30 mg/kg/day, 35 mg/kg/day, 40 mg/kg/day , 45 mg/kg/day, 50 mg/kg/day, 55 mg/kg/day or 60 mg/kg/day, 65 mg/kg/day, 70 mg/kg/day, 75 mg/kg/day, 80 mg/kg/day, 85 mg/kg/day, 90 mg/kg/day, 95 mg/kg/day or 100 mg/kg/day.

A rotating combination of therapeutic platforms (i.e., enzyme replacement and small molécule therapy) is preferred. Howcvcr, subjccts may also be treated by ovcrlapptng both approachcs as needed, as determined by the skilled clinician. Examples of treatment schedules may inciude but are not limited to: (1) SMT followed by ERT; (2) ERT followed by SMT; and (3) ERT and SMT provided at about the same time. As noted previously, temporal overlap of therapeutic platforms may also be performed, as needed, depending on the clinical course of a given storage disease in a given subject.

Treatment intcrvals for various combination thérapies can vary widely and may generally be different among different storage diseases and different individuals depending on how aggrcssivcly storage products arc accumulated. For exampie, Fabry storage product accumulation may bc slow compared to rapid storage product accumulation in Pompe. Titration of a particular storage disease in a particular individual is carried out by the skilled artisan by monitoring the clinical signs of disease progression and treatment success.

The various macromolecules that accumulatc in lysosomal storage diseases are not uniformly distributed, but instead arc deposited in certain preferred anatomie sites for each disease. However, an exogenously supplicd enzyme is generally taken up by cells of the réticuloendothélial system and sorted to the lysosomal compartmcnt where it acts to hydrolyze the accumulated substrate. Moreover, cellular uptake of therapeutic enzyme can bc augmented by certain mancuvcrs to increase lysosomal targeting (see e.g. U.S. Pat. No. 5,549,892 by Friedman et al., assigned to Genzyme Corporation, which describes

759 recombinant glucocerebrosîdasc having improved pharmacokinetics by virtue of rcmodeled oligosaccharide side chains recognized by cell surface mannose receptors which arc endocytoscd and transported to lysosomes).

Some treatment modalities target some aflfccted organs better than others. In Fabry, for example, if ERT does not reach the kidney well cnough for a satisfactory clinical outcomc, SMT can be used to rcduce the substrate levels in the kidney. As demonstrated in Example 112 and Fig. 6B, SMT effectively reduced Gb3 levels (i.e., the substratc accumulatcd in Fabry patients) in the urine of a Fabry mouse model to a greater extent than ERT. The kidneys arc believed to bc the major source of urine Gb3. In contrast, Fig. 6B shows ERT effectively reduced the Gb3 levels in the plasma to a greater extent than SMT. These results demonstrate that a combination therapy of ERT and SMT provides a complemcntary therapeutic strategy that takes advantage of the strengths and addresses the weaknesses associated with each therapy employed alone. SMT is able to cross the BBB, providing a powerful approach, when combined with ERT, for treating LSDs having CNS manifestations, such as Nicmann Pick Type A and Neuropathie Gaucher disease (nGD). Moreover, substrate réduction by SMT combined with enzyme replacement address the storage problem at separate and distinct intervention points which may enhance clinical outcomc.

It will be understood that reference to simultaneous or concurrent administration of two or more thérapies does not require that they bc administered at the same time, just that they be acting in the subject at the same time.

General Procedure A: Trisubstituted urca formation via TV-t-butoxycarbonyl functionalized primary amine component

To a stirred solution of the primary amine component (1 équivalent) in chloroform (concentration ~0.1 M) was added 4-dimethylaminopyridine (0.1 équivalent) and di-teributyl dicarbonatc (1 équivalent). The mixture was stirred for 1 hour before adding the

160 sccondary amine component (l équivalent) and heating to reflux ovemight. The réaction was then concentrated and the residue purified by préparative HPLC.

General Procedure B: Tetrasubstitutcd urea formation with trinhosgene

To a stirred solution of triphosgene (0.7 équivalent) in toluene (~0.7 M) was added a solution of the first amine component (1 équivalent) in chloroform (-0.5 M). The reaction was stirred for 2 hours and then concentrated. The residue was taken up in chloroform (-0.3 M) and cooled (0 °C). With stirring, the second amine component (1.1 équivalent) and tricthylaminc (2 équivalents) were added, in order. The réaction was stirred ovemight at room température and then concentrated. The residue taken up in aqueous sodium carbonate solution and extracted with chloroform. The combined extracts were dried (Na₂SÛ4) and concentrated. The crude material was purified by préparative HPLC or flash chromatography over Cis-rcvcrscd phase silica.

General Procedure C: Trisubstituted carbamate formation via W-methoxycarbonyl fiinctionalized amine component

To a stirred and cooled (0 °C) solution of the secondary amine component (1 équivalent) and tricthylaminc (4 équivalents) in methylene chloride (-0.2 M) was added methyl chloroformatc (3 équivalents). The reaction was allowed to warm to room température and stirred for 6 hours. The réaction solution was then washed with aqueous sodium bicarbonate solution and brine, dried (Na₂SO4) and concentrated. The crude methyl carbamate was used, without purification, in the next step. To a solution of this intermediate (1 équivalent) in toluene (-0.2 M) was added, in order, activated 4Â molecular sieves, the alcohol component (1.4 équivalents) and sodium hydride (60% dispersion in minerai oil; 0.25 équivalent). The reaction was heated at reflux ovemight, filtered and concentrated. The residue was purified by flash chromatography over Cigreversed phase silica.

General Procedure D: Amide formation using jV-G-dirricthvIarriinopronvl)-?¹/'ethylcarbodiimide hydrochloride

To a stirred solution of the carboxylic acid component (1 équivalent) in NJMdimethylformamide (-0.1 M) was added the amine component (1.1 équivalent), N,Ndiisopropylethylaminc (2.2 équivalents), /V-(3-dimethylaminopropyl)-Mcthylcarbodiimidc hydrochloride (1.1 équivalents) and 1-hydroxybenzotriazole hydrate

161 (l.l équivalents). Stirring was continucd ovemight and then the reaction solution was diluted with water and extracted with chloroform. The combined cxtracts were washed brine, dried (NaîSC^) and concentrated. The residue was purified by préparative HPLC.

General Procedure E: Amide formation usina 0-f7-azabenzotriazol-l-yl)-N,N,N'.N tetramethyluronium hcxafluoronliosnhatc

To a stirred solution of the carboxylic acid component (l.l équivalents) in N,Ndimethylformamide (—0.25 M) was added the amine component (l équivalent) and O-(7azabenzotriazol-l-yl)-jV,7V,?/',/V'-tetramethyluronium hexafluorophosphatc (l.l équivalents). The mixture was cooled (0 ^QC) and treated, dropwise, with tricthyiaminc (2.2 équivalents). The réaction was allowed to warm to room température, stirred ovemight and then concentrated. The residue was taken up in aqueous sodium carbonate and extracted with ethyl acetate. The combined organic layers were dried (NaîSO^ and concentrated and the crude material was purified by flash chromatography over silica using a chloroform/mcthanol/ammonia cluant.

General Procedure F: Biarvl coupling using Suzuki conditions

To a stirred solution of the aryl halidc component (l équivalent) in 5:l (v/v) dioxane/water (~0,15 M) or 5:l (v/v) N,N-dimcthylformamide (~0.l5 M), was added the arylboronate or arylboronic acid component (1-1.5 équivalents), sodium carbonate (2-3 équivalents) and [l,r-bis(diphenylphosphino)fcrrocene]dichloropalladium(ll) (0.05 équivalents). The mixture was heated (90 °C) ovemight and then filtered through a plug of Celite. The Celite was rinscd with ethyl acetate and the combined filtrate was washed with brine, dried (NaîSO-i) and concentrated. The residue was purified by flash chromatography over silica.

General Procedure G: Dcprotcction of f-butoxycarbonylamino group with trifluoroacetic acid

To stirred solution of the i-butoxycarbonylamino protectcd starting material in dichloromethane (~0.15 M), was added trifluoroacetic acid (20-50 équivalents). The réaction was stirred at room température until TLC monitoring indicated the reaction was complète (generally 30-120 minutes). The réaction was concentrated and the residue taken up in aqueous sodium hydroxide and extracted with ethyl acetate. The combined

162 cxtracts were washed with brine, dried (Na₂SO4) and concentrated to afford the product, which could be used without purification or, optionally, subjected to flash chromatography over silica.

General Procedure H: Urea/carbamate formation using an isocyanate generated via a mixed anhydridc/Curtius Rcarrangcmcnt route

To a stirred solution of the carboxylic acid component (1 équivalent) in tetrahydrofuran (—0.1 M) was added triethylamine (2 équivalents). The reaction was cooled (0 °C) and treated with isobutyl chloroformate (1.5 équivalents). After 1 hour at 0 °C, a solution of sodium azidc (2 équivalents) in water (~1 M) was added and the réaction was allowed to warm to room température. After ovemight stirring, the réaction was diluted with water and extracted with ethyl acetate. The combined extracts were washed with aqueous sodium bicarbonate solution and brine, dried (Na2SO4) and concentrated. The crude acyl azidc was further dried via cocvaporation with toluene and then taken up in toluene (~0.1 M). The stirred solution was refluxed for 2-2.5 hours, cooled and treated with either an amine component (1-1.5 équivalents) or alcohol component (1.25-2 équivalents). The reaction was heated at reflux ovemight and then concentrated. The residue was taken up in either ethyl acetate or chloroform and washed with aqueous sodium carbonate, (Na2SO4) and concentrated. The crude product was purified by flash chromatography over silica using chloroform/methanol (less polar carbamatcs) or chloroform/methanol/ammonia (more polar carbamatcs and ureas) solvent gradients.

General Procedure 1: Urea/carbamate formation using an isocyanate generated via a diphenylphosphoryi azide/Curtius Rearrangement route

To a stirred solution of the carboxylic acid component (1 équivalent) in toluene (-0.25 M) was added triethylamine (2.5 équivalents) and diphenyl phosphoryl azidc (1.25 équivalents), The mixture was heated at reflux for 30 minutes and then cooled to room température. The amine or alcohol component (1.2-1.5 équivalents) was added and the réaction was heated at reflux for another 3-18 hours (less time for ureas, more time for carbamatcs). After this time, the réaction was concentrated and the residue partitioned between ethyl acetate and aqueous sodium carbonate solution. The organic layer was

163 dried (Na2SO4) and concentrated and the resulting crude product was purified by flash chromatography over reversed phase silica using a water/acetonitrilc gradient.

General Procedure J: Urca/carbamatc formation using an isocyanate generated with phosgene

To a stirred solution of the benzylamine component (1 équivalent) in toluene (-0.2 M) was added a 1.9 M solution of phosgene in toluene (4 équivalents). The réaction was heated at reflux for 4 hours and then concentrated. In the case of urea targets, the crude isocyanate was taken up in chloroform (~0.2 M), treated with the second amine component and stirred ovemight at room température. In the case of the carbamate targets, the crude isocyanate was dissolved in toluene (-0.2 M), treated with the alcohol component and heated at reflux ovemight. The urea or carbamate reaction solution was then concentrated, partitioncd between aqueous sodium carbonate solution and chloroform. The organic solution was dried (Na2SO4) and concentrated. Crude product was purified by flash chromatography over silica using chloroform/mcthanol (less polar carbamates) or chloroform/mcthanol/ammonia (more polar carbamates and ureas) solvent gradients.

Préparation A

Intermediate 1

3-MethylquinucIidin-3-amine

A well-stirred 3.0 M solution of mcthyllithium in diethyl ether (67.0 mL, 201 mmol) was diluted with additional diethyl ether (150 mL), cooled to -78 °C and treated, dropwîse, with a solution of quinuclidin-3-one (12.5 g, 100 mmol) in diethyl ether (100 mL). The resulting solution was maintained at -78 °C for 1 hour and then allowed to warm to room température. After ovemight stirring, the reaction was recooled (0 °C) and treated, dropwîse, with water (60 mL). The mixture was concentrated and the resulting residue was purified by flash chromatography over ncutral aluminum oxide using a chioroform/methanol gradient (0-20% methanol) to give 3-methylquinuclidin-3-ol (10.0 g, 71%) as a light yellow solid. To stirred acetonitrile (250 mL) at 0 °C, was slowly added concentrated sulfiiric acid (100 mL). The resulting solution was added dropwîse to a

164 mixture of 3-mcthylquinuclidin-3-ol (9.10 g, 64.5 mmol) in acetonitrile (250 mL) at 0 °C. The réaction mixture was stirred at room température for 60 hours, cooled to (0 °C) and then basified (pH ~l0) with aqueous sodium hydroxide solution. The mixture was extracted with 5:l (v/v) chloroform/isopropanol. The combined organic layers were concentrated and the residue was diluted with 2N hydrochloric acid. After washing with 5:l (v/v) chloroform/isopropanol, the aqueous layer was basified with 2N aqueous sodium hydroxide and extracted with 5:1 (v/v) chloroform/isopropanol. The combined organic layers were washed with water, dried (NaîSC).») and concentrated to afford 7V-(3methylquinuclidin-3-yl)acetamide as a light yellow oil (9.50 g, 82%). A solution of the above acetamide intermediate (9.50 g, 52.0 mmol) in concentrated hydrochloric acid (100 mL) was refluxed for 3 days. After cooling in an icc bath, the reaction was treated with cnough aqueous sodium hydroxide solution to achieve pH -1. The mixture was washed with 5:1 (v/v) chloroform/isopropanol. The aqueous layer was then basified with 2N aqueous sodium hydroxide solution and extracted with 5:1 (v/v) chloroform/isopropanol. The combined extracts were washed with water, dried (NaîSOj and concentrated to afford the title compound as a light yellow semi-solid (5.00 g, 69%). ^]H NMR (500 MHz, DMSO-i/j d 2.72-2.39 (m, 6H), 2.01-1.96 (m, IH), 1.67-1.61 (m, IH), 1.43-1.36 (m, 2H), 1.23-1.17 (m, IH), 1.09 (s, 3H) ppm. ^I3C NMR (125 MHz, DMSO-i/j d 65.3, 48.3, 46.6,46.4, 34.2, 30.0,24.8, 22.8 ppm.

Préparation B

Intermediate 2

3-Ethylquinuclidin-3-amine

A cooled (0 °C) and wcll-stirred 0.5 M solution of ethyllithium in benzenc/cyclohexanc (100 mL, 50 mmol) was diluted with tetrahydrofuran (50 mL) and treated, dropwise over ~5 minutes, with a solution of quinuclidin-3-one (3.13 g, 25.0 mmol) in tetrahydrofuran (20 mL). After 2 hours, the cooling bath was removed and the réaction was stirred ovemight. The reaction was quenched by the slow addition of water (10 mL). The resulting mixture was concentrated onto silica and purified by flash chromatography over silica using a chloroform/methanol/ammonia eluant to afford 3ethylquinuclidin-3-ol as a waxy, amber solid (2.43 g, 63%). To a stirred and cooled (0 °C) solution of this product (2.31 g, 14.9 mmol) in acetonitrile (20 mL) was added, dropwise over ~20 minutes, concentrated sulfuric acid (40 mL). The mixture was stirred ovemight

165 and allowed to slowly warm to room température. The reaction was then poured over crushed îce. While stirring, concentrated ammonium hydroxide (~l 10 mL) was slowly added (final pH ~l0). The solution was extracted with 4:l (v/v) chloroform/isopropanol and the combined cxtracts were dried (Na₂SO4) and concentrated onto silica. The crude product was purified by flash chromatography using a chloroform/mcthanol/ammonia gradient to afford A/-(3-cthylquinuclidin-3-yl)acctamide as a waxy, amber solid (2.16 g, 74%). A solution of this product (5.48 g, 28.0 mmol) in a mixture of water (60 mL) and concentrated hydrochloric acid (60 mL) was heated at reflux for 3 days. After this time, the solution was concentrated to providc the dihydrochloride of title compound, which was used without purification, as a light brown solid (4.75 g, 75%). *H NMR (400 MHz, CD₃OD) δ 3.65-3.55 (m, 2H), 3.52-3.27 (m, 4H), 2.51-2.45 (m, IH), 2.27-2.00 (m, 6H), 1.06 (t, J = 7.5 Hz, 3H) ppm. In réactions which rcquirc libération of the free base, an cquimolar quantity of triethylamine was added with the dihydrochloride sait. Altematively, the product could be isolated as a free base by dissolving the dihydrochloride sait in aqueous sodium hydroxide solution and extracting with 4:l (v/v) chloroform/isopropanol. After drying (Na₂SO4), the combined extracts were concentrated to afford the product as a pale amber oil. ^fH NMR (400 MHz, CD3OD) δ 2.94-2.84 (m, IH), 2.83-2.55 (m, 5H), 2.05-1.94 (m, IH), 1.83-1.73 (m, IH), 1.73-1.60 (m, 2H), 0.91 (t, J= 7.4 Hz, 3H) ppm.

Préparation C

Intermediate 3 l-Azabicyc!o[3.2.2|nonan-4-ol

A stirred and cooled (0 °C) 2.0 M solution of trimethylsilyldiazomethane in hexanes (43.9 mL, 87.9 mmol) was treated, dropwise, with a solution of 3-quinuclidinonc (10.0 g, 79.9 mmol) in THF (80 mL). Methanol (44 mL) was added and the reaction was stirred ovemight and allowed to warm to room température. The reaction was then treated with acetic acid (1.0 mL). After a fcw minutes, a saturated solution of aqueous sodium carbonate (40 mL) was added and the layers were separated. The organic layer was combined with additional ethyl acctatc cxtracts, dried (Na₂SO<0 and concentrated. The resulting yellow oil was purified by flash chromatography over neutral alumina using a methylene chloride/mcthanol cluant to afford l-azabicyclo[3.2.2]nonan-4-one as a white solid (6.80 g, 61%). To a stirred and cooled (0 °C) solution of this product (6.80 g, 48.8

166 mmol) in tctrahydrofuran (100 mL) was added, portion wise, lithium aluminum hydride (1.85 g, 48.8 mmol). After vigorous hydrogen gas évolution ceased, the reaction was allowcd to warm to room température and then heated at reflux for l hour. The solution was then cooled (0 °C) and quenchcd by the successive, dropwise, addition of water (l .8 mL), 10% sodium hydroxide solution (1.8 mL), and water again (5.5 mL). The colorless precipitate was removed by filtration through Celite, which was then washed with tetrahydrofuran. The combined filtrate was dried (NajSO-i) and concentrated to afford the title compound as a white solid (5.60 g, 81%). ’H NMR (400 MHz, CDCI3) I I B.90-3.86 (m, IH), 3.09-3.03 (m, IH), 2.96-2.91 (dd, J = 9.2, 6.8 Hz, IH), 2.86-2.75 (m, 3H), 2.712.64 (m, IH), 2.34-2.27 (br s, IH), 1.98-1.86 (m, 3H), 1.71-1.59 (m, 3H), 1.51-135 (m, IH) ppm.

Préparation D

Intermediate 4 l-Azabicyclo[3.2.2|nonan-4-amme

To a stirred solution of l-azabicyclo[3.2.2]nonan-4-one (Préparation C) (10.0 g, 71.8 mmol) in isopropanol (50 mL) was added sodium acetate ( 11.80 g, 143.7 mmol) and hydroxylamine hydrochloride (5.50 g, 79.1 mmol). The mixture was heated at reflux for 3 hours and then cooled to room température. The réaction was filtered and concentrated to afford the oxime intermediate, which was used in the next step without purification, as a white solid (11.00 g, 99%). A stirred solution of this product (11.0 g, 71.3 mmol) in npropanol (120 mL) was heated to reflux température. Sodium métal (16.5 g, 718 mmol) was added, portion wise, over 30 minutes. Reflux was continucd ovemight and then the reaction was then cooled to room température and treated with brine (20 mL). The mixture was extracted with n-propanol (2 x 50 mL) and the combined organic layers were concentrated. The residue was diluted with chloroform and the remaining solids were filtered off. The filtrate was dried (Na2SO^) and concentrated to afford the title compound as a light yellow semi-solid (6.70 g, 74%). *H NMR (500 MHz, CDCI3) d 3.17-3.13 (m, IH), 3.10-3.07 (m, IH), 3.05-3.01 (m, IH), 2.91-2.88 (m, 3H), 2.77-2.70 (m, IH), 1.921.87 (m, IH), 1.83-1.80 (m, IH), 1.71-1.68 (m, 3H), 1.59-1.48 (m, 2H), 133 (br s, 2H) ppm.

Préparation E

167

Intermediate 5

4-Methyl-l-azabicyclo[3.2.2|nonan-4-amine

The title compound was prepared from l-azabicyclo[3.2.2]nonan-4-onc (Préparation C) by the same procedure used to convert quinuclidin-3-one to 3mcthylquinuclidin-3-aminc in Préparation A. *H NMR (500 MHz, DMSO-oy δ 2.84-2.65 (m, 6H), 2.01-1.97 (m, IH), 1.69-1.24 (m, 8H), 1.09 (s, 3H) ppm.

Préparation F

Intermediate 6

1,4-Diazabicyclo[3.2.2]nonane

To a stirred solution of l,4-diazabicyclo[3.2.2]nonan-3-one (1.00 g, 7.13 mmol) in

1,4-dioxanc (7.2 mL) at room température was added lithium aluminum hydridc [2.0M/THF] (4.1 mL, 8.2 mmol). The reaction mixture was then heated at reflux for 6 hours. After cooling to room température, the réaction was quenched by the sequcntial addition of water (200 QL), 15% a

The mixture was filtered through Celite which was subsequently washed with ethyl acetate. The combined filtrate was concentrated to afford the title compound as a light brown solid (0.82 g, 90%) which was used without purification. *H NMR (400 MHz, CDClj) □ 3.28-3.25 (m, IH), 2.99-2.95 (m, 8H), 1.86-1.80 (m, 3H), 1.69-1.64 (m, 2H) ppm.

Préparation G

Intermediate 7

1-Azabicyclo [3.2.2] no nan-3-ol

To a stirred and cooled (0 °C) solution of ethyl 2-hydroxyacetate (20.0 g, 19.0 mmol) in tetrahydrofuran (250 mL) was added tetrabutylammonium iodîdc (7.01 g, 19.0 mmol) and sodium hydridc (60% in minerai oil, 7.60 g, 19.0 mmol). The mixture was stirred at 0 °C for 30 minutes before adding benzyl bromide (32.3 g, 19.0 mmol). The reaction was stirred ovemight and allowed to warm to room température. The mixture was then cooled (0 °C), quenched with aqueous ammonium chloride (100 mL) and

168 extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (Na2SÛ4) and concentrated. The residue was purified by flash chromatography over silica using a hexanc/cthyl acetate eluant to afford ethyl 2(benzyloxy)acetate as a yellow oil (14.7 g, 57%). To a stirred and cooled (0 °C) solution of this product (13.6 g, 70.0 mmol) in tetrahydrofuran (150 mL) was added dimethyl methylphosphonate (11.3 g, 91.1 mmol) followed by a 2.0 M solution of lithium diisopropylamide in tetrahydrofuran/heptanc/cthylbenzene (74.0 mL, 148 mmol). The reaction was stirred at 0 °C for 3 hours beforc quenching with cnough 5.0 M aqueous hydrochloric acid to bring the pH to -4. The resulting mixture was then extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO<i) and concentrated. The residue was purified by flash chromatography over silica using a hexane/cthyl acetate eluant to afford dimethyl (3-(benzyloxy)-2-oxopropyl)phosphonate as a light yellow oil (10.1 g, 54%). To a stirred and cooled (0 °C) solution of this intermediate (9.89 g, 36.4 mmol) in tetrahydrofuran (100 mL) was added sodium hydride (60% in minerai oil; 1.60 g, 40.0 mmol). The mixture was stirred at 0 °C for 30 minutes before adding, dropwise, a solution of tert-butyl 4-oxo-piperidine-l-carboxylate (5.79 g, 29.1 mmol) in tetrahydrofuran (50 mL). The resulting mixture was stirred at 0 °C for 2 hours, then quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na₂SC>4), and concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford tert-butyl 4-(3-(benzyloxy)-2oxopropylidene)piperidine-l-carboxylate as a light yellow oil (6.50 g, 52%). This material (6.50 g, 18.8 mmol), 10% Pd/C (1.00 g) and ethyl acetate (50 mL) were placed in a Parr bottle and hydrogenated for 5 hours at room température. The mixture was filtered through Celite and concentrated to afford tert-butyl 4-(3-hydroxy-2oxopropyl)piperidine-l-carboxylate as a yellow oil (4.80 g, 99%). To a stirred solution of this product (4.80 g, 18.7 mmol) in methylene chloride (8 mL) was added carbon tetrabromide (12.4 g, 37.4 mmol) and triphcnylphosphinc (9.80 g, 37.4 mmol). After 3 hours, the reaction was concentrated and the residue purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford tert-butyl 4-(3-bromo-2oxopropyl)pipcridinc-l-carboxylate as a white solid (3.30 g, 56%). To a stirred and cooled (0 °C) solution of this product (3.30 g, 10.3 mmol) in methylene chloride (50 mL) was added trifluoroacelic acid (12.0 mL, 145 mmol). The mixture was stimed at 0 °C for 30 min before concentrating to afford crude l-bromo-3-(pipcridin-4-yl)acetone

169 trifluoroacetate, which was used without purification in the next step. To a stirred solution of diisopropylethylaminc (20 mL) in acetonitrile (800 mL) at reflux was added a solution of the crude intermediate in acetonitrile (150 mL), dropwise over 4 hours (syringe pump). Reflux was continued ovemight and then the mixture was concentrated. The resulting residue was partitioned between aqueous potassium carbonate solution and 9:l (v/v) chloroform/methanol. The organic layer was combined with a second extract using the same solvent mixture, dried (Na₂SÛ4) and concentrated. The crude material was purified flash chromatography over silica using a 95/4.5/0.5 (v/v) chloroform/methanol/ammonium hydroxide eluant to afford l-azabicyclo[3.2.2]nonan-3onc as a brown solid (770 mg, 54%). To a stirred and cooled (0 °C) solution of this intermediate (770 mg, 5.54 mmol) in tetrahydrofuran (10 mL), was added lithium alumïnum hydridc (211 mg, 5.54 mmol), portion wise. After vigorous hydrogen gas évolution ceased, the reaction mixture was allowed to warm to room température and then heated at reflux for 1 hour. The solution was cooled to 0 °C and qucnched by the successive dropwise addition of water (0.2 mL), 10% aqueous sodium hydroxide solution (0.2 mL) and water again (0.6 mL). The colorless precipitate was removed by filtration through Celite, which was subsequently washed with tetrahydrofuran. The combined filtrate was dried (Na₂SO4) and concentrated to afford the title compound as yellow solid (770 mg, 99%).

Préparation H

Intermediate 8 l-AzabicycIo[3.2.2|nonan-3-amine

The title compound was prepared from l-azabicyclo[3.2.2]nonan-3-one (Préparation G) by the same procedure used to couvert l-azabicyclo[3.2.2]nonan-4-one to l-azabîcycIo[3.2.2]nonan-4-amine in Préparation D.

Préparation I

Intermediates 9,10

Enantiomers of 4-Methvl-1-azabicycIo[3.2.2jnonan-4-ainine

170

Racemic 7V-(4-methyl-i-azabicyclo[3.2.2]nonan-4-yl)acetamidc (Préparation E) was resolvcd into its component enantiomers using a Thar SFC Prep 80 instrument and the following séparation conditions: CHIRALCEL OZ-H column (30 x 250 mm, 5 mm particle size) with a carbon dîoxide/acctonitrile/isopropanol/dicthylaminc (55/30/15/0.2) mobile phase and a flow rate of 60 g/mîn. The enantiomers eluted at 6.34 and 9.55 minutes. Using the acetamide hydrolysis conditions described in Préparation A, the early eluting isomer was dcacctylated to generate Intermediate 9 and the later eluting isomer was dcacctylated to generate Intermediate 10. The absolute stereochcmistry of the enantiomers was not determined.

Préparation J

Intermediates 11,12

Enantiomers of 3-Methylquinuclidin-3-amine

Racemic N-(3-mcthylquinuclidin-3-yl)acctamidc (Préparation A) was resolved into its component enantiomers using a Thar SFC Prep 80 instrument and the following séparation conditions: CHIRALCEL IC-H column (30 x 250 mm, 5 Dm particle si:

with a carbon dioxide/isopropanol/dicthylamine (50/50/0.1) mobile phase and a flow rate of 60 ghnin. The enantiomers eluted at 3.12 and 8.17 minutes. Using the acetamide hydrolysis conditions described in Préparation A, the carly eluting isomer was dcacctylated to générale Intermediate 11 and the later eluting isomer was dcacetylatcd to generate Intermediate 10. Intermediate 12 was then amide coupled (General Procedure D) to (S)-(+)-2-phcnylpropionic acid to generate a single enantiomer of (2S)-N-(3mcthylquinuclidin-3-yI)-2-phenylpropanamidc. A crystal of this compound was produced and subjccted to X-ray crystal lography, revealing the amide to be in the (2’R,3S)configuration. Thus, it was determined that Intermediate 11 is (S)-3-methylquinuclidin-3aminc and Intermediate 12 is (R)-3-methylquinuclidin-3-amine.

Préparation K

Intermediates 13,14

Enantiomers of 3-Ethylquinuclidin-3-amine

171

Racemic N-(3-cthylquinuclÎdin-3“yl)acetamide (Préparation B) was rcsolvcd into its component enantiomers using a Thar SFC Prep 80 instrument and the following séparation conditions: CHIRALCEL IC-H column (30 x 250 mm, 5 dm partide si:

with a carbon dioxide/ethanol/diethylamine (60/40/0.2) mobile phase and a flow rate of g/min. The enantiomers eluted at 3.31 and 4.70 minutes. Using the acetamide hydrolysis conditions described in Préparation A, the early eluting isomer was dcacetylatcd to generate Intermediate 13 and the later eluting isomer was deacctylated to generate Intermediate 14. The absolute stereochemistry ofthe enantiomers was not determined.

Préparation L

Intermediates 15,16

Enantiomers of l-Azabicyclo[3.2.2]nonan-4-ol

A stirred solution of racemic l-azabicyclo[3.2.2]nonan-4-ol (Préparation C; 23.0 g, 16.3 mmol) in acetic anhydride (100 mL) was heated at reflux for 1 hour. The mixture was concentrated and the residue was taken up in aqueous sodium bicarbonate solution and extracted with 5:1 (v/v) chloroform/isopropanol. The combined extracts were washed with brine, dried (Na2SO4) and concentrated to afford l-azabicyclo[3.2.2]nonan-4-yl acetate. This material was rcsolved into its component enantiomers using a Thar SFC

Prep 80 instrument and the following séparation conditions: CHIRALCEL OZ-H column (30 x 250 mm, 5 Dm partide size) diethylamîne (55/30/15/0.2) mobile phase and a flow rate of 60 g/min. The enantiomers eluted at 3.39 minutes (10.5 g collected) and 6.54 minutes (11.3 g collected), The later eluting acetate enantiomer (11.0 g, 60.0 mmol) was taken up in 2N aqueous sodium hydroxide solution. The stirred mixture was heated at 50 °C for 1 hour before cooling and extracting with 5:1 (v/v) chloroform/isopropanol. The combined cxtracts were dried (Na2SO4) and concentrated to afford Intermediate 16 as light yellow solid (8.00 g, 94%).

The early eluting acetate isomer was deprotected in the same manner to afford

Intermediate 15. The absolute stereochemistry of the enantiomers was not determined.

Préparation M

172

Intermediate I7

3-Propylquinuclidin-3-aminc dihydrochloridc

A stirred and cooled (-78 °C) 2.0 M solution of propylmagnesium chloride in diethyl ether (100 mL, 200 mmol) was diluted with tetra hydrofuran (150 mL) and treated, dropwise over ~20 minutes, with a solution of quinuclidin-3-onc (13.45 g, 107.5 mmol) in tetrahydrofuran (90 mL). The cooling bath was allowed to slowly warm to room température and the mixture was stirred ovemight. The réaction was then heated at reflux for 30 minutes, cooled (0 °C) and qucnched by the slow addition of water (60 mL). The mixture was concentrated to remove organic solvent, diluted with aqueous ammonium chloride solution (250 mL) and extracted with 4:1 (v/v) chloroform/isopropanol. The combined extracts wcrc dried (Na2SO4) and concentrated onto silica. Flash chromatography over silica using a chloroform/mclhanol/ammonia gradient provided 3propylquinuclidin-3-ol as a white solid (5.57 g, 31%). To a stirred and cooled (0 °C) solution of this product (5.55 g, 32.8 mmol) in acctonitrile (30 mL) was added, dropwise over 15 minutes, concentrated sulfuric acid (40 mL). The cooling bath was allowed to slowly warm to room température and the mixture was stirred ovemight. The reaction was then poured over crushed ice. The resultîng icc slurry was stirred and slowly treated with concentrated ammonium hydroxidc solution (100 mL). After the ice fully melted, the mixture was extracted with 4:1 (v/v) chloroform/isopropanol. The combined extracts were dried (Na2SO4) and concentrated onto silica. Flash chromatography over silica using a chloroform/mcthanol/ammonia gradient provided N-(3-propylquinuclidin-3yi)acetamide as a faint amber gum (6.94 g, 100%). A solution of this product (6.94 g,

32.8 mmol) in a mixture of water (90 mL) and concentrated hydrochloric acid (90 mL) was heated at reflux for 4 days. After this time, the solution was concentrated to provide the title compound as a white solid (6.44 g, 81%) which was used without purification. In réactions which requirc libération of the free base, an equimolar quantity of triethylamine was added with the dihydrochloride sait. IH NMR (400 MHz, DMSO-d6) □ 11.27 (br

IH), 8.91 (brs, 3H), 3.52-3.30 (m, 2H), 3.28-3.06 (m, 4H), 2.35-2.24 (m, IH), 2.24-2.08 (m, IH), 1.97-1.71 (m, 5H), 1.48-1.21 (m, 2H), 0.89 (t, J = 7.1 Hz, 3H)ppm.

173

Example l

4-([l,l^,-BiphenyI]-4-yl)-jV-(3-methylquinucljdm-3-yl)piperazÎne-l-carboxamÎde

Using General Procedure A and the reaction inputs l -([1, l'-biphcnyl]-4yl)piperazine and Intermediate 1, the title compound was prepared. NMR (500 MHz, DMSO-r/s) 5 7.56 (d, J = 7.5 Hz, 2H), 7.54 (d, J= 8.0 Hz, 2H), 7.41 (t, J= 7.5 Hz, 2H),

7.27 (t, 7.5 Hz, IH), 7.05 (d, J= 8.5 Hz, 2H), 5.99 (s, IH), 3.44 (t, J= 5.0 Hz, 4H),

3.15 (t, 5.0 Hz, 4H), 2.96-2.93 (m, IH), 2.67-2.57 (m, 5H), 2.12-2.11 (m, IH), 1.751.64 (m, 2H), 1.41- 1.23 (m, 5H) ppm. ^I3C NMR (125 MHz, CDC1₃) Ô 157.0, 150.2,

140.7, 132.9, 128.7, 127.9, 126.6, 126.6, 116.4, 63.5, 52.7, 50.8, 48.9, 46.6, 43.9, 31.3,

25.3, 23.3, 22.6 ppm. Purity; >99% (214 & 254 nm) LCMS; rétention time: 1.99 min; (M+H⁴) 405.3.

Example 2 4-([l,r-Biphenyl]-4-yl)-7V-(quinuclidin-3-yl)piperazine-l-carboxamide

Using General Procedure A and the reaction inputs 1 -([1,1 '-biphenylJ-4yl)piperazine and qui nue lidin-3-amine, the title compound was prepared. ’H NMR (500 MHz, CDCI3) δ 7.57-7.52 (m, 4H), 7.41 (t, J= 8.0 Hz, 2H), 7.29 (t, J= 7.5 Hz, IH), 7.00 (d, J= 8.5 Hz, 2H), 4.61 (s, IH), 3.88 (m, IH), 3.57 (t, J= 5.0 Hz, 4H), 3.41-3.36 (m, IH), 3.26 (t, J = 5.0 Hz, 4H), 2.90-2.80 (m, 4H), 2.53-2.50 (m, IH), 1.95-1.94 (m, IH), 1.74-1.66 (m, 3H), 1.49 (m, IH) ppm. ¹³C NMR (125 MHz, CDCI3) δ 157.4, 150.2,

140.7, 133.0, 128.7, 127.9, 126.6, 126.5, 116.5, 56.6, 48.9, 47.9, 47.4, 46.7, 43.7, 26.1,

25.9, 20.2 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.44 min; (M+H⁴) 391.2.

Example 3 4-([l,l^,-Biphenyll-4-yl)-A^r-(l-azabicyclo[3.2.2]nonan-4-yl)piperazine-l-carboxamide Using General Procedure A and the reaction inputs 1-([1,1 -biphenyl]-4yl)piperazine and Intermediate 4, the title compound was prepared. ^!H NMR (500 MHz, CDCI3) δ 7.56-7.52 (m, 4H), 7.41 (t, J= 8.0 Hz, 2H), 7.29 (t, J= 8.0 Hz, IH), 7.00-6.98 (d, J= 9.0 Hz, 2H), 4.50 (d, J= 7.0 Hz, IH), 4.01-3.96 (m, IH), 3.55 (t, J= 5.0 Hz, 4H),

3.25 (t, ./= 5.0 Hz, 4H), 3.19-2.76 (m, 6H), 2.05-1.57 (m, 7H) ppm. ^I3C NMR (125 MHz, CDCI3) δ 156.8, 150.2, 140.7, 133.0, 128.7, 128.7, 127.9, 126.6, 116.5, 56.1, 53.0, 49.0,

48.9, 44.3, 43.7, 34.8, 32.0, 26.6, 22.4 ppm. Purity: >98% (214 & 254 nm) LCMS; rétention time: 1.45 min; (M+H⁴} 405.2.

774

Exampie 4

4-(|l,r-Biphenyl|-4-yl)-A^r-(4-methyl-l-azabicyclo[3.2.2|i)onan-4-yl)piperazine-lcarboxamide

Using General Procedure A and the reaction inputs l -([ I, l'-biphenyl]-4yl)piperazinc and Intermediate 5, the title compound was prepared. *H NMR (500 MHz, CDCls) δ 7.56-7.52 (m, 4H), 7.41 (t, J= 7.5 Hz, 2H), 7.29 (t, J = 7.5 Hz, IH), 7.00-6.98 (d, ./=8,5 Hz, 2H), 4.40 (s, IH), 3.54-3.26 (m, 4H), 3.25-3.02 (m, 4H), 3.00-2.81 (m, 6H), 2.39-2.37 (m, IH), 2.17 (m, IH), 1.96-1.51 (m, 8H) ppm. ^l3C NMR (125 MHz, CDC1₃) δ 157.0, 150.2, 140.7, 132.9, 128.7, 127.9, 126.6, 126.6, 116.4, 59.1, 53.2,48.9,

47.6, 46.4, 43.9, 39.8, 36.5, 25.8, 24.5, 24.2 ppm. Purity: >98% (214 & 254 nm) LCMS; rétention time: 1.29 min; (M+H) 419.2.

Example 5 (4-([l,l'-Biphenyl]-4-yl)piperazin-l-yl)(l,4-diazabicyclo|3.2.2]nonan-4-yl)methanone Using General Procedure B and the reaction inputs l-([l,l'-biphenyl]-4yl)pipcrazine and Intermediate 6, the title compound was prepared. ^JH NMR (400 MHz, CDCI3) δ 7.57-7.52 (m, 4 H), 7.40 (t, J= 8.0 Hz, 2H), 7.28 (t, J= 7.2 Hz, IH), 7.01-6.98 (d, J= 8.8 Hz, 2H), 4.12-4.11 (m, IH), 3.52 (t, J = 6.0 Hz, 2H), 3.38-3.36 (m, 4H), 3.253.23 (m, 4H), 3.07-2.96 (m, 6H), 2.07-2.00 (m, 2H), 1.80-1.72 (m, 2H) ppm. ¹³C NMR (100 MHz, CDCI3) Ô 163.7, 150.5, 140.8, 132.8, 128.7, 127.8, 126.5, 116.4, 56.5, 49.2, 49.0, 47.2, 46.4, 45.7, 27.2 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time:

1.26 min; (M+H⁴) 391.2.

Example 6

Quinuclidin-3-yl 4-([l,r-biphenyl]-4-yl)piperazine-l-carboxyIate

Using General Procedure C and the reaction inputs 1 -([1,1 ’-biphenyl]-4yl)pipcrazine and quinuclidin-3-ol, the title compound was prepared. *H NMR (500 MHz, CDCI3) δ 7.58-7.54 (m, 4 H), 7.43 (t, J= 7.5 Hz, 2H), 7.31 (t, J= 7.5 Hz, IH), 7.02 (d, J = 8.0 Hz, 2H), 4.81 (m, IH), 3.68 (t, J= 4.5 Hz, 4H), 3.31-3.24 (m, 5 H), 2.95-2.78 (m, 5H), 2.11-2.10 (m, IH), 1.87-1.46 (m, 4H)ppm. ¹³CNMR(125 MHz, CDCI3) δ 155.0,

150.4, 140.7, 133.1, 128.7, 127.8, 126.6,126.5, 116.7, 72.1,55.7,49.2,47.4, 46.4, 43.6, 25.5,24.5,19.7 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.32 min; (M+H⁴) 392.2.

175

Exampie 7 4-Phenyl-JV-(quinuclÎdin-3-yl)pipcrazmc-l-carboxamidc

Using General Procedure A and the reaction inputs l -phcnylpiperazine and quinuclidin-3-amine, the title compound was prepared. ’H NMR (500 MHz, CDCI3) δ 7.31-7.28 (m, 2H), 6.95-6.89 (m, 3H), 4.74-4.72 (m, IH), 3.91-3.89 (m, IH), 3.56 (t,./ = 5.0 Hz, 4H), 3.38-3.37 (m, IH), 3.21 (t, J= 5.0 Hz, 4H), 2.87-2.82 (m, 4H), 2.60-2.59 (m, IH), 1.97-1.96(m, IH), 1.72-1.25 (m, 4H) ppm. ^,3CNMR(125 MHz, CDCI₃)Ô

157.4, 151.0,129.2, 120.3, 116.5, 56.4, 49.1,47.8,47.4, 46.6, 43.8, 26.1,25.7, 20.1 ppm. Purity: >98% (214 & 254 nm) LCMS; rétention time: 1.04 min; (M+H*) 315.1.

Example 8 /V-(l-Azabicyclo[3.2.2]nonan-4-yl)-4-phenylpiperazine-l-carboxamide

Using General Procedure A and the reaction inputs 1 -phenylpiperazine and Intermediate 4, the title compound was prepared. *H NMR (500 MHz, CDCI3) δ 7.31-

7.28 (m, 2H), 6.95-6.90 (m, 3H), 4.58 (d, J = 7.0 Hz, IH), 4.04-3.99 (m, 1 H), 3.55-3.53 (m, 4H), 3.28-3.19 (m, 5H), 3.11-3.05 (m, IH), 2.99-2.96(m, 3H), 2.87-2.81 (m, IH), 2.09-1.59 (m, 7H) ppm. ¹³CNMR(125 MHz, CDCI3) δ 156.8, 151.0, 129., 120.3, 116.4, 56.0, 53.0, 49.1,49.0, 44.4, 43.7, 34.8, 31.9, 26.5, 22.2 ppm. Purity: >96% (214 & 254 nm) LCMS; rétention time: 1.60 min; (M+H*) 329.3.

Example 9 7V-(3-Metliylquinuclidin-3-yl)-4-phenylpiperazine-l-carboxamide

Using General Procedure A and the reaction inputs 1-phcnylpiperazine and Intermediate 1, the title compound was prepared. *H NMR (500 MHz, CDCI3) δ 7.30-

7.27 (m,2H), 6.94-6.88 (m,3H),4.41 (s, 1H),3.51 (t,J = 5.0 Hz, 4H), 3.19 (t,J= 5.0 Hz, 4H), 3.01-2.92 (m, 2H), 2.84-2.79 (m, 4H), 2.07-2.06 (m, IH), 1.86-1.78 (m, 2H), 1.561.44 (m,5H) ppm. ^l3CNMR(100 MHz, CDCI3) δ 157.1, 151.0, 129.2, 120.3, 116,4,

63.5,52.6,49.1,46.5,46.4,43.9, 31.3,25.3,23.3,22.6 ppm. Purity: >98% (214 & 254 nm) LCMS; rétention time 1.63 min; (M+H⁴) 329.3.

Example 10 /V-(4-Mcthyl-l-azabicyclo[3.2.2|nonari-4-yl)-4-phcnylpipcrazinc-l-carboxamide

176

Using General Procedure A and the réaction inputs 1-phenylpiperazine and Intermediate 5, the title compound was prepared. ’H NMR (500 MHz, CDCI3) δ 7.317.26 (m, 2H), 6.95-6.89 (m, 3H), 4.42 (s, IH), 3.54-3.51 (m, 4H), 3.22-3.20 (m, 4 H), 3.07-2.96 (m, 4H), 2.90-2.84 (m, 2H), 2.42-2.40 (m, IH), 1.97-1.92 (m, IH), 1.88-1.82 (m, 2H), 1.73-1.50 (m, 6H) ppm. ^I3C NMR (125 MHz, CDCI3) δ 157.0, 151.0, 129.2,

120.3, 116.4, 59.0, 53.1, 49.1, 47.6, 46.3, 44.0, 39.5, 36.5, 25.7, 24.2, 24.0 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.63 min; (M+H⁴} 343.3.

Example 11 l,4-Diazabicyclo[3.2.2]nonan-4~yl(4-phenylpiperazin-l-yl)methanoi!e

Using General Procedure B and the reaction inputs 1 -phenylpiperazine and Intermediate 6, the title compound was prepared. ^lH NMR (500 MHz, CDCI3) δ 7.25 (t, .7 = 8.0 Hz, 2H), 6.92 (d, J= 8.0 Hz, 2H), 6.86 (t, J= 7.5 Hz, IH), 4.09 (m, IH), 3.48 (t, J=

5.5 Hz, 2H), 3.30-3.32 (m, 4H), 3.18-3.17 (m, 4H), 3.03-2.96 (m, 6H), 2.01 (m, 2H), 1.75-1.71 (m, 2H)ppm. ^l3CNMR(100 MHz, CDCI3) δ 163.7, 151.2, 129.1,120.1,116.3,

56.4, 49.1,47.2,46.3, 45.6, 27.2 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.70 min; (M+H⁺) 315.3.

Example 12

Quinuclidin-3-yl 4-phenylpiperazine-I-carboxylate

Using General Procedure C and the reaction inputs 1-phenylpiperazine and quinuclidin-3-ol, the title compound was prepared. *H NMR (500 MHz, CDCla) δ 7.31-

7,28 (m, 2H), 6.96-6.90 (m, 3H), 4.79-4.78 (m, IH), 3.66 (t, J= 5.0 Hz, 4H), 3.28-3.25 (m, IH), 3.17 (m, 4H), 2.93-2.74 (m, 5H), 2.08-2.07 (m, IH), 1.85-1.44 (m, 4H) ppm. ¹³C NMR (125 MHz, CDCh) δ 155.0,151.2, 129.2, 120.5,116.7, 72.1, 55.8, 49.4,47.4, 46.5,

43.7, 25.5, 24.5, 19.7 ppm. Purity; >99% (214 & 254 nm) LCMS; rétention time: 1,11 min; (M+H⁴} 316.1.

Example 13 4-(ll,r-Biphenyl]-3-yI)-A^f-(quinudidin-3-yl)piperazine-l-carboxamide

Using General Procedure A and the reaction inputs l-([l,l'-biphcnyl]-3yl)piperazine and quinuclidin-3-amine, the title compound was prepared. *H NMR (500 MHz, CDCI3) δ 7.59 (d, J= 7.5 Hz, 2H), 7.45 (t, J= 7.5 Hz, 2H), 7.37 (dd, J= 8.5, 1.0 Hz, 2H), 7.14-7.13 (m, 2H), 6.95-6.93 (m, IH), 4.62 (d, J = 6.0 Hz, IH), 3.89-3.88 (m,

777 l H), 3.58 (m, J = 5.5 Hz, 4H), 3.42-3.38 (m, l H), 3.28 (t,./ = 5.5 Hz, 4H), 2.89-2.81 (m, 4H), 2.53-2.50 (m, IH), 1.96-1.94 (m, IH) 1.70-1.48 (m, 4H) ppm. ^I3C NMR (125 MHz, CDClj) Ô 157.4, 151.4, 142.5, 141.6, 129,6, 128.7, 127.3, 127.2, 119.4, 115.5, 115.4,

56.8, 49.2, 47.9, 47.5, 46.7, 43.8, 26.1, 26.0, 20.3 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.27 min; (M+H*) 391.3.

Example 14

4-((1,l-Biphenyl]-3-yl)-/V-(l-azabicyclo[3.2.2]nonan-4-yl)piperazine-l-carboxamide

Using General Procedure A and the réaction inputs 1-((1 ,l'-biphenyl]-3yl)piperazine and Intermediate 4, the title compound was prepared. *H NMR (500 MHz, CDC1₃) Ô 7.59-7.57 (d, J= 8.5 Hz, 2H), 7.45 (t, 7.5 Hz, 2H), 7.36 (t, J= 8.0 Hz, 2H),

7.14-7.13 (m, 2H), 6.94-6.92 (m, IH), 4.57-4.55 (d,./= 7.0 Hz, IH), 4.01-3.98 (m, IH), 3.56 (t, 7= 5.0 Hz, 4H), 3.27 (t, J= 5.0 Hz, 4H), 3.20-3.17 (m, IH), 3.07-3.04 (m, IH), 2.97-2.78 (m, 4H), 2.11-1.58 (m, 7H)ppm. ^I3C NMR (125 MHz, CDC1₃)Ô 156.8, 151.4,

142.5,141.6,129.6, 128.7,127.3, 127.2, 119.4,115.5, 115.4, 56.,53.0,49.2,49.0,44.4, 43.7,34.7, 31.9,26.4,22.2 ppm. Purity: >98% (214 & 254 nm) LCMS; rétention time

1.27 min; (M+H⁺) 405.2.

Example 15

4-((1, l^,-BiplienyI]-3~yl)-A^r-(3-methyIquinuclidin-3-yl)piperazine-l-carboxamide

Using General Procedure A and the reaction inputs l-([l,r-biphenyl]-3yl)piperazine and Intermediate 1, the title compound was prepared. *H NMR (500 MHz, CDCI3) δ 7.59-7.58 (dd, 7= 7.5, 1.5 Hz, 2H), 7.44 (t, 7 = 7.5 Hz, 2H), 7.36 (t,7=7.5 Hz, 2H), 7.14-7.12 (m, 2H), 6.94 (m, IH), 4.44 (s, IH), 3.55 (t, J= 5.0 Hz, 4H), 3.27 (t, J = 5.0 Hz, 4H), 3.00-2.83 (m, 6H), 2.08 (m, IH), 1.85-1.83 (m, 2H), 1.57-1.45 (m, 5H) ppm. ¹³CNMR(125 MHz, CDCl₃)ô 157.0, 151.4, 142.5, 141.6, 129.6,128.7, 127.3, 127.3,

119.4, 115.4,115.3, 63.5, 52.6,49.2, 46.5,46.5, 43.9, 31.3, 25.3, 23.3, 22.6 ppm. Purity: >96% (214 & 254 nm) LCMS; rétention time: 1.97 min; (M+H⁺) 405.3.

Example 16

4-((1,1 ’-Biplienyl]-3-yl)-/V-(4-metliyl-l-azabicycIo|3.2.2| nonan-4-yl)piperazine-lcarboxamide

178

Using General Procedure A and the reaction inputs l-([l,l'-biphenyl]-3yl)piperazine and Intermediate 5, the title compound was prepared. ^lH NMR (500 MHz, CDCl₃) δ 7.60-7.35 (m, 6H), 7.14-7.13 (m, 2H), 6.94-6.93 (m, IH), 4.41 (s, IH), 3.563.54 (m, 4H), 3.29-3.27 (m, 4H), 3.02-2.85 (m, 6H), 2.42-2.40 (m, 111), 1.98-1.53 (m, 9H) ppm. ^I3C NMR (125 MHz, CDCI3) δ 157.0, 151.4, 142.4, 141.6,129.6, 128.7, 127.3,

127.2, 119.3, 115.4, 115.3, 55.0, 53.2, 49.2, 47.5, 46.3, 44.0, 39.7, 36.5, 25.7, 24.4, 24.2 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time 1.29 min; (M+H¹) 419.2.

Example 17 (4-([l,r-Biplienyl]-3-y))piperazin-l-yl)(l,4-diazabicyclo[3.2.2]nonan-4-yl)metIianone Using General Procedure B and the reaction inputs 1-((1, l'-biphenyl]-3yl)pipcrazine and Intermediate 6, the title compound was prepared. *H NMR (500 MHz, CDCI3) δ 7.60-7.58 (m, 2H), 7.46-7.43 (m, 2H), 7.36 (t, J= 8.0 Hz, 2H), 7.15-7.12 (m, 2H), 6.95-6.93 (m, IH), 4.14-4.13 (m, IH), 3.54-3.52 (m, 2H), 3.53 (t, J = 5.0 Hz, 4H),

3.27 (t, J= 5.0 Hz, 4H), 3.09-3.01 (m, 6H), 2.06-2.04 (m, 2H), 1.80-1.76 (m, 2H) ppm. ^I3C NMR (125 MHz, CDC1₃) δ 163.7, 155.5, 151.6, 142.4, 141.6, 129.5, 128.7, 128.5,

127.3, 119.3, 115.4, 56.4, 50.8,49.3,49.1,47.3,46.4,45.6, 27.1 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 2.01 min; (M+H*) 391.3.

Example 18

Quinucli(Iin-3-yl 4-((1,r-biphenyl]-3-yl)piperazine-l-carboxylate

Using General Procedure C and the reaction inputs l-([l,r-biphenyl]-3yl)piperazîne and quinuclidin-3-ol, the title compound was prepared. *H NMR (500 MHz, CDCl₃) δ 7.59 (d, J= 7.0 Hz, 2H), 7.45 (t, J= 7.5 Hz, 2H), 7.38-7.35 (m, 2H), 7.15-7.14 (m, 2H), 6.95-6.93 (m, IH), 4.80-4.78 (m, IH), 3.68 (t, J= 5.5 Hz, 4H), 3.28-3.24 (m, 5H), 2.92-2.75 (m, 5H), 2.08-2.08 (m, IH), 1.85-1.44 (m, 4H) ppm. ^l3C NMR (125 MHz, CDC1₃)Ô 155.0, 151.6,142.4, 141.5, 129.6, 128.7,127.3, 127.2, 119.6,115.8, 115.7,

72.1, 55.8,49.5, 47.4,46.4, 43.8, 43.6, 25.5, 24.5,19.7 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.33 min; (M+H⁴) 392.2.

Example 19 l-Azabicyclo(3.2.2]nonan-4-yl 4-((1,r-biphenyl]-3-yl)piperazine-l-carboxylate

Using General Procedure C and the réaction inputs 1-([1,1 '-biphenyl]-3yl)pipcrazinc and Intermediate 3, the title compound was prepared. *H NMR (500 MHz,

179

CDCI₃) δ 7.59-7.58 (d, ./ = 7.5 Hz, 2II), 7.45 (t,./ = 7.5 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.15-7.13 (m, 2H), 6.95-6.93 (m, IH), 4.96 (m, IH), 3.68-3.66 (m, 4H), 3.23-2.86 (m, 1 OH), 2.17-1.55 (m, 7H) ppm. ¹³CNMR(100 MHz, CDC1₃)Ô 154.8, 151.6, 142.4, 141.5,

129.6, 128.7, 127.3,127.2, 119.5, 115.7,115.6, 79.0,51.6,49.5, 47.8,45.2, 43.7, 33.4,

30.4, 24.5, 22.0 ppm. Purity; >99% (214 & 254 nm) LCMS; rétention time 1.16 min; (M+H⁺) 406.2.

Example 20

1-Azabicyclo[3.2.2(nonan-3-yl 4-((1,1'-biphenyl]-3-yl)piperazine-l-carboxylate

Using General Procedure C and the réaction inputs l-([l,l'-biphenyl]-3yl)pipcrazine and Intermediate 7, the title compound was prepared. ^lH NMR (500 MHz, CDCI3) δ 7.60 (d, ./ = 8.0 Hz, 2H), 7.46 (t,./= 7.5 Hz, 2H), 7.37 (t, J = 8.0 Hz, 2H), 7.15 (m, 2H), 6.95 (dd,./=9.0 Hz, 1.5 Hz, IH), 5.15 (m, IH), 3.67 (m, 4H), 3.50 (m, IH), 3.24-2.83 (m, 9H), 2.35 (m, IH), 2.13 (m, IH), 1.80-1.72 (m, 5H) ppm. ^I3C NMR (125 MHz, CDC13) δ 154.9, 151.6, 142.4, 141.6, 129.6, 128.7, 127.3, 127.2, 119.5, 115.8,

115.6, 72.1, 61.2, 49.5,48.5,45.4, 43.7, 39.1, 28.9, 26.9, 24.2 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time 1.40 min; (M+H*) 406.2.

Example 21

4-((1,1’-lïiphenyl]-3-yl)-7V-(3-ethylqiiinuclidm-3-yl)piperazine-I-carboxaniide

Using General Procedure A and the reaction inputs l-([l,l'-biphenyl]-3yl)pipcrazine and Intermediate 2, the title compound was prepared. *H NMR (500 MHz, CDC1₃) Ô 7.59-7.58 (d,./= 7.5 Hz, 2H), 7.45 (d, J= 7.5 Hz, 2H), 7.37-7.35 (m, 2H), 7.147.12 (m, 2H), 6.94-6.92 (m, 1 H), 4.43 (s, IH), 3.56-3.56 (m, 4H), 3.29-3.27 (m, 4H), 3.06-2.79 (m, 6H), 2.19-2.10 (m, 2H), 1.92-1.74 (m, 3H), 1.55-1.46 (m, 2H), 0.82 (t, J=

7.5 Hz, 3H) ppm. ^I3C NMR (125 MHz, CDC1₃) δ 156.8,151.4, 142.4,141.6, 129.6,

128.7, 127.3,127.2, 119.4, 115.4, 115.3, 63.2, 55.1, 50.5,49.3,46.9,46.7,44.0, 28.4,

28.1, 22.9, 22.5, 8.2 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time 1.51 min; (M+H⁺) 419.3.

Example 22

4-(4^,-Fluoro-[l,r-biphenyI]-3-yl)-jV-(4-inethyl-l-azabicyclo[3.2.2]nonan-4yl)piperazine-l-carboxainide

180

Using General Procedure F and the reaction inputs l -(3-bromophenyl)piperazine and 4-fluorophenylboronic acid, l-(4'-fluoro-[l,r-biphenyl]-3-yl)piperazine was prepared. This compound was reacted with Intermediate 5 using General Procedure A to generate the title compound. *H NMR (500 MHz, CDCI3) δ 9.22 (s, IH), 8.94 (s, 2H), 7.44 (t, J= 7.5 Hz, IH), 7.10-7.02 (m, 3H), 4.43 (s, IH), 3.58-3.56 (m, 4H), 3.31-3.29 (m, 4H), 3.06-2.85 (m, 6H), 2.42 (m, IH), 1.95-1.57 (m, 9H) ppm. ^I3CNMR(1OO MHz, CDC1₃)ô 157.5, 156.9, 154.9, 151.7, 135.4, 134.7, 130.3, 118.7, 116.6, 114.6, 59.1,53.2, 48.8,47.5, 46.3,43.9, 39.7, 36.5,25.7, 24.4, 24.2 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.01 min; (M+H⁺) 421.3.

Example 23 7V-(3-Ethylquinuclidin-3-yl)-4-(4'-nuoro-[l,l'-biphenyl|-3-yl)piperazme-lcarboxamide

Using General Procedure A and the réaction inputs l-(4'-fluoro-[l,r-biphenyl]-3yljpiperazinc (prepared as described in Example 22) and Intermediate 2, the title compound was prepared. ^lH NMR (500 MHz, CDCI3) Ô 7.54-7.52 (m, 2H), 7.35-7.33 (m, IH), 7.14-7.06 (m, 4H), 6.93-6.91 (d, J= 8.0 Hz, 1H),4.39 (s, IH), 3.55 (m,4H), 3.283.26 (m, 4H), 2.99-2.83 (m, 6H), 2.18-2.08 (m, 2H), 1.89-1.73 (m, 3H), 1.52-1.46 (m, 2H), 0.81 (t, J= 7.5 Hz, 3H) ppm. ^,3C NMR (125 MHz, CDCI3) ô 163.5, 161.4, 156.9,

151.4, 141.4, 137.1, 129.6, 128.8,128.7, 119.1, 115.7, 115.6, 115.4, 115.4, 63.2, 55.2,

49.2,46.9,46.7, 44,0, 28.4, 23.1,23.0, 22.6, 8.2 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.54 min; (M+H⁺) 437.3.

Example 24 l-AzabicycIo[3.2.2]nonan-4-yl 4-(4'-fluoro-[l,r-biphenyl]-3-yl)piperazine-Icarboxylate

Using General Procedure C and the reaction inputs l-(4'-fluotO-[l,r-biphenyl]-3yl)piperazine (prepared as described in Example 22) and Intermediate 3, the title compound was prepared. 'H NMR (500 MHz, CDCI3) δ 7.55-7.52 (m, 2H), 7.35 (t, J=

8.5 Hz, IH), 7.14-7.07 (m, 4H), 6.94-6.92 (m, IH), 4.96 (m, IH), 3.67 (t, J= 5.0 Hz, 4H), 3.23-2.80 (m, 10H), 2.16-1.53 (m, 7H) ppm. ¹³CNMR(125 MHz, CDC1₃)ô 162.5 (d,./ = 245.0 Hz), 154.8, 151.6, 141.4, 137.6 (d, J= 2.5 Hz), 129.6, 128.7 (d,J= 8.4 Hz), 119.3,

115.5 (d, J= 21.9 Hz), 79.1, 51.8, 49.5, 47.9, 45.3, 43.7, 33.5, 30.6, 24.7, 22.2 ppm. Purity: >95% (214 & 254 nm) LCMS; rétention time: 1.27 min; (M+l-I¹) 424.2.

181

Example 25

1-Azabicyclo[3.2.2] nonan-3-yI 4-(4'-fluoro-[l,r-biphcnyl]-3-yl)piperazine-lcarboxylate

Using General Procedure C and the reaction inputs l-(4'-fluoro-[l,r-biphenyl]-3yl)pipcrazine (prepared as described in Example 22) and Intermediate 7, the title compound was prepared. *H NMR (500 MHz, CDCI3) δ 7.57-7.47 (m, 6H), 7.13 (t, J =

8.5 Hz, 2H), 5.H (brs, IH), 5.00 (m, IH), 3.43-2.75 (m, 6H), 2.35-2.05 (m, 2H), 1.711.56 (m, 11H) ppm. ^I3C NMR (100 MHz, CDCI3) δ 163.4, 161.4, 138.5, 136.9, 128.6,

128.5, 127.0,125.3, 115.6, 115.5, 70.5,61.0, 55.0, 48.9,44.9,38.9, 29.5, 29.2,26.4, 23.9 ppm. Purity: >93% (214 & 254 nm) LCMS; rétention time: 1.42 min; (M+H¹) 397.2.

Example 26 7V-(4-Methyl-l-azabicyclo[3.2.2]nonan-4-yl)-4-(3-(pyrimidin-2-yl)phenyI)piperazine1-carboxamidc

Using General Procedure F and the reaction inputs 2-chloropyrimidine and i-butyl 4 -(3-(4,4,5,5 -tetramethy 1 -1,3,2-dîoxaborolan-2-yl )phenyl)piperazine-1 - carboxylate, tbutyl 4-(3-(pyrimidin-2-yl)phenyl)piperazinc-l-carboxylate was prepared. The N-tbutoxycarbonyl protecting group was removed from this compound using General Procedure G to afford 2-(3-(pipcrazin- l-yl)phcnyl)pyrimidinc. This product was, in turn, was reacted with Intermediate 5 using General Procedure A to generate the title compound. *H NMR (500 MHz, CDCI3) δ 8.82-8.81 (d, J= 4.5 Hz, 2H), 8.07-8.06 (d, J = 2.0 Hz, IH), 8.00-7.98 (d, J =7.5 Hz, IH), 7.42 (t, ./=7.5 Hz, IH), 7.20 (t, J = 4.5 Hz, IH), 7.08-7.06 (m, IH), 4.40 (s, IH), 3.56-3.54 (m, 4H), 3.33-3.31 (m, 4H), 3.00-2.86 (m, 6H), 2.39 (m, IH), 1.97-1.54 (m, 9H) ppm. ¹³C NMR (125 MHz, CDCI3) δ 164.8, 157.2, 156.9, 151.3, 138.5,129.5,120.1, 119.1, 118.8, 115.8, 59.0, 53.3,49.1,47.6,46.4, 44.0, 39.8,36.5,25.7,24.5,24.3 ppm. Purity; >99% (214 & 254 nm) LCMS; rétention time: 1.30 min; (M+H⁺) 421.3.

Example 27 /V-(4-Methyl~l-azabicyclo|3.2.2]nonan-4-yl)-4-(3-(pyriinidin-5-yl)phenyl)piperazme1-carboxamide

Using General Procedure F and the reaction inputs 5-bromopyrimidine and r-butyl

4-(3-(4,4,5,5-tctramethyl-l,3,2-dioxaborolan-2-yl)phenyl)piperazine-l-carboxylatc, t182 butyl 4-(3-(pyrimidin-5-yl)phenyl)piperazinc-l-carboxyîate was prepared. The tbutoxycarbonyl protecting group was removed from this compound using General Procedure G to afford 5-(3-(piperazin-l-yl)phcnyl)pyrimidine. This product was, in tum, was reacted with Intermediate 5 using General Procedure A to gcncratc the title compound. 'H NMR (500 MHz, CDCl₃) δ 9.20 (s, IH), 8.93 (s, 2H), 7.39 (t, J = 8.0 Hz, IH), 7.07-7.02 (m, 3H), 5.41 (s, IH), 3.83-3.81 (m, 2H), 3.01-2.81 (m, 8H), 2.39-2.24 (m, 2H), 1.96-1.51 (m, 13H) ppm. ^l3CNMR(125 MHz, CDCI3) δ 174.0, 157.4, 154.9, 152.1,

135.2, 134.9, 130.2, 118.0, 116.9, 114.8, 59.5, 53.1, 49.1, 49.1, 47.6, 46.1, 43.8, 39.2,

36.1, 28.9, 28.6, 25.1, 24.2, 24.1 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 0.90 min; (M+H⁴) 420.2.

Example 28 4-(3-IsopropyIphenyl)-7V-(4-methyl-l-azabicyclo[3.2.2|nonan-4-yl)piperazine-lcarboxamide

Using General Procedure F and the réaction inputs l-(3-bromophenyl)piperazine and 4,4,5,5-tetramcthyl-2-(prop- l-en-2-yl)-l ,3,2-dioxaborolane, 1 -(3-(prop-l -cn-2yl)phcnyl)pipcrazinc was prepared. A stirred suspension of this compound (0.500 g, 2.50 mmol) and 10% palladium on carbon (0.100 g) in cthylacetate (50 mL) was cyclcd between vacuum and a nitrogen purge sevcral times. After the last évacuation, the réaction was rcfillcd with hydrogen gas. The mixture was stirred ovemight and then filtered through Celite. The filtrate was combined with ethyl acetate rinsings of the Celite and concentrated to afford l-(3-isopropylphenyl)piperazine as a yellow oil (0.360 g, 72%). This compound was reacted with Intermediate 5 using General Procedure A to générale the title compound. 'H NMR (500 MHz, CDCI3) δ 7.13 (t, J = 8.0 Hz, IH), 6.736.66 (m, 3H), 4.36 (s, IH), 3.46-3.42 (m, 4H), 3.41-3.10 (m, 4H), 2.97-2.75 (m, 7H), 2.31-2.30 (m, IH), 1.87-1.72 (m, 3H), 1.63-1.42 (m, 6H), 1.18-1.16 (d, ./=7,0 Hz, 6H) ppm. ¹³C NMR (125 MHz, CDCI3) Ô 157.0, 151.1, 150.1, 129.1, 118.6, 115.0, 113.8, 59.0, 53.3, 49.4, 47.6, 46.3, 44.1, 39.8, 36.5, 34.5, 25.8, 24.5, 24.2, 24.1 ppm. Purity: 100% (214 & 254 nm) LCMS; rétention time: 1.88 min; (M+H⁴) 385.4.

Example 29

4-(3-Cyclohexylphenyl)-7V-(4-mcthyl-l-azabicyclo[3.2.2|nonan-4-yl)piperazine-lcarboxainidc

183

Exchanging 4,4,5,5-tetramcthyl-2-(prop-l-cn-2-yI)-l,3,2-dioxaborolane for 2(cyclohex-l-en-l-yI)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane, thesame réaction sequence outlincd in Example 28 was used to generate the title compound. ^lH NMR. (500 MHz, CDClj) Ô 7.20 (t, J = 8.0 Hz, IH), 6.79-6.73 (m, 3H), 4.40 (s, IH), 3.53-3.47 (m, 4H),

3.19- 3.18 (m, 4H), 3.06-2.83 (m, 6H), 2.48-2.39 (m, 2H), 1.95-1.23 (m, 19H) ppm. ¹³C NMR (125 MHz, CDClj) ô 157.0, 151.0, 149.3, 129.1, 119.0, 115.4, 113.9, 59.0, 53.3, 49.4, 47.6, 46.3, 45.0, 44.1, 39.7, 36.5, 34.5, 26.9, 26.2, 25.8, 24.4, 24.2 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.57 min; (M+H⁺) 425.4.

Example 30 4-([l,l^,-Biphenyl]-3-yI)-2-methyl-7V-(4-methyl-l-azabicyclo[3.2.2]nonan-4yl)pipcrazine-1 -carboxamide

To a stirred solution of 3-bromobiphcnyl (0.70 g, 3.00 mmol) in toluène (10 mL) was added Z-butyl 2-methylpipcrazine-l-carboxylate (0.720 g, 3.60 mmol), potassium tbutoxîdc (0.504 g, 4.50 mmol), tris(dibenzylidcneacetone)dipalladium(0) (0.090 g, 98.3 mmol) and tri-Z-butylphosphine (0.018 g, 89.0 mmol). The mixture was heated at 90 °C for 5 hours. At this time the reaction was cooled, diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na₂SO4) and concentrated. The residue was purified by flash chromatography over silica using a hcxanc/cthyl acctatc cluant to afford r-butyl 4-([l ,r-biphenyl]-3-y/)-2-methyIpipcrazine1-carboxylate (0.750 g, 71%) as a brown oil. The t-butoxycarbonyl protecting group was removed from this compound using General Procedure G to afford 1 -([1,1 '-biphenyl]-3yl)-3-mcthylpiperazinc. This intermediate was, in tum, was reacted with Intermediate 5 using General Procedure A to generate the title compound. *H NMR (500 MHz, CDCI3) Ô 7.60-7.34 (m, 6H), 7.12-7.11 (m, 2H), 6.92-6.90 (m, IH), 4.40-4.39 (d, J =6.5 Hz, IH),

4.19- 4.14 (m, IH), 3.87-3.33 (m, 4H), 3.09-2.88 (m, 8H), 2.46-2.43 (m, IH), 1.99-1.55 (m, 9H), 1.38 (t, J= 7.0 Hz, 3H) ppm. ^I3C NMR (125 MHz, CDClj) δ 156.7, 156.7, 151.9, 142.5, 141.6, 129.5, 128.7, 127.3,127.2, 119.1, 115.4,115.4, 115.3, 115.3,59.0,

54.3, 54.3, 53.2, 53.3,49.1,49.1, 47.9,47.8, 47.7,47.7,46.1,46.0, 39.8, 39.5, 39.1, 39.0,

36.7, 36.4, 25.9, 25.8, 25.4, 24.3, 24.3, 24.1, 24.0, 15.8,15.7 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.29 min; (M+H¹) 433.3,

184

Exampie 31

4-([l,r-Biphenyl|-3-yl)-3-methyl-jV-(4-methyl-l-azabicycIo[3.2.2|nonan-4yl)piperazine-l-carboxamide

Exchanging f-butyl 2-mcthylpipcrazme-l-carboxylate for f-butyl 3methylpipcrazine-1-carboxylate, the same reaction sequence outlined in Example 30 was used to generate the title compound. ^lH NMR (500 MHz, CDCh) δ 7.60-7.58 (d, J= 7.5 Hz, 2H), 7.45 (t, J= 7.5 Hz, 2H), 7.37-7.34 (m, 2H), 7.12-7.11 (m, 2H), 6.91-6.90 (m, IH), 4.39-4.37 (d, J= 9.0 Hz, IH), 3.93-2.85 (m, 13H), 2.41 (m, IH), 1.98-1.55 (m, 9H), 1.12-1.11 (m, 3H) ppm. ^t3CNMR(100 MHz,CDC1₃)Ô 156.8, 150.2,142.4, 141.6,129.6,

128.7,127.3, 127.3, 119.0,119.0,116.0, 116.0, 115.9,115.8,59.0,59.0,53.3, 53.2,51.9,

51.8, 49.1, 49.0, 47.7, 47.7, 46.2, 44.1,44.1,44.0, 43.8, 39.8, 39.6, 36,6, 36.5, 25.9, 25.8, 24.4, 24.3, 24.1, 24.1,13.7, 13.6 ppm. Purity: >98% (214 & 254 nm) LCMS; rétention time: 1.47 min; (M+H⁺) 433.4.

Exampie 32 4-([l,r-Biphenyl|-3-yl)-3-methyl-7V-(4-methyl-l-azabicyclo[3.2.2]nonan-4yl)piperazine-l-carboxamide

Exchanging f-butyl 2-mcthylpiperazine-l-carboxylate for r-butyl 3,3dimcthylpiperazinc-1 -carboxylate, the same réaction sequence outlined in Example 30 was used to generate the title compound. ^lH NMR (500 MHz, CDCI3) δ 7.59-7.57 (d,./ =

7.5 Hz, 2H), 7.45 (t, 7.5 Hz, 2H), 7.37-7.33 (m, 4H), 7.11-7.09 (m, IH), 4.54 (s, IH),

3.59-2.97 (m, 12H), 2.58 (m, IH), 2.01-1.55 (m, 9H), 1.12 (s, 6H)ppm. ^I3CNMR(125 MHz, CDCI3) δ 156.8, 149.1, 141.3,141.1, 128.7,128.5, 127.3, 127.1, 126.3, 126.1,

123.5, 58.8, 56.5, 55.1, 53.0, 48.0, 46.9,45.7,44.9, 38.2, 36.1, 26.0, 23.2, 22.8, 22.1, 22.0 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.00 min; (M+H⁺) 447.3.

Example 33 l-(4'-Fluoro-[l,l^,-biphenyl]-3-yl)-7V-(3-methylquinuclidin-3-yl)piperidine-4carboxamide

To a stirred solution of ethyl piperidme-4-carboxylate (1.60 g, 10.0 mmol) in methylene chloride (50 mL) was added 3-bromophenylborontc acid (4.10 g, 20.4 mmol), triethylamine (5.00 g, 49.4 mmol), coppcr(II) acetate (2.70 g, 1.49 mmol) and 4Â molecular sieves (2.00 g). The mixture, which was left open to the air, was stirred at room température for 24 hours. The reaction was then diluted with methylene chloride and

185 filtered through a plug of Celite. The filtrate was concentrated and the residue purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford ethyl l -(3bromophenyl)pipcridine-4-carboxylate as a yellow oil (0.930 g, 30%). Using General Procedure F and the boronic acid component, 4-fluorophcnylboronic acid (0.420 g, 3.00 mmol), this intermediate (0.642 g, 2.00 mmol) was subjected to Suzuki coupling to give ethyl l-(4^,-fluoro-[l,r-biphenyl]-3-yl)pipcridine-4-carboxylate as a black oil (0.589 g, 90%). A stirred solution of this compound (0.589 g, 1.80 mmol) in 1:1 (v/v) methanol/water was treated with solid sodium hydroxide (0,360 g, 9.00 mmol). After ovemight stirring, the reaction was concentrated. The residue was dissolved in water, made acidic (pH ~6) with the addition of IN hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to afford l-(4'-fluoro-[l,r-biphenyl]-3-yl)piperidine-4-carboxylic acid as a white solid (0.520 g, 96%). Using General Procedure D and Intermediate 1, this carboxylic acid was subjected to amidc coupling to generate the title compound as a white solid (0.033 g, 24%). 'H NMR (500 MHz, CDC13) δ 7.54-7.52 (m, 2 H), 7.32 (t, J= 8.0 Hz, IH), 7.13-6.92 (m, 5H), 5.55 (s, IH), 3.81-3.79 (m, 2H), 3.01-2.78 (m, 8H), 2.25-2.20 (m, 2H), 1.97-1.77 (m, 6H), 1.59-1.51 (m, 5H) ppm. ^I3CNMR(125 MHz,CDC13)S

174.3, 163.4, 161.4,151.9, 141.3, 137.9, 137.9, 129.5,128.8, 128.7, 118.6, 115.5, 115.4,

115.4, 63.3, 52.9, 49.5,46.6, 46.4, 43.7, 30.2, 29.0, 28.8, 24.4, 22.9, 22.4 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time 1.10 min; (M+H⁺) 422.2.

Exampie 34 l-(4^,-Fluoro-[l,l’-biphenyl|-3-yl)-/V-(4-methyH-azabicyclo[3.2.2]nonan-4yl)piperidine-4-carboxamide

Using General Procedure A and the reaction inputs, l-(4'-fluoro-[l,r-biphenyl]-3yl)piperidine-4-carboxylic acid (prepared as described in Example 33) and Intermediate 5, the title compound was prepared. ’H NMR (500 MHz, CDCI3) ô 7.53-7.51 (m, 2H), 7.31 (t,J=8.0 Hz, IH), 7.12-7.02(m,3H), 7.02-7.00 (d, J=7.5 Hz, IH), 6.93-6.91 (m, IH), 5.48 (s, IH), 3.80-3.78 (m, 2H), 3.05-2.76 (m, 8H), 2.40 (m, IH), 2.24-2.20 (m, IH),

1.95-1.50(m, 13H)ppm. ^t3CNMR(125 MHz, CDCI3) Ô 174.2, 163.4,161.4, 151.9,

141.3, 137.9, 137.9, 129.5, 128.8, 128.7, 118.6, 115.6, 115.5, 115.5, 115.4, 59.4, 531,

49.5, 49.5, 47.7,46.0, 44.0, 39.0, 36.0, 29.1, 28.9, 25.2, 24.1, 24.0 ppm. Purity; >99% (214 & 254 nm) LCMS; rétention time: 1.97 min; (ΜΉ-Γ) 436.4.

Ί86

Example 35 l-(fl,l'-Biphenyl]-3-yl)-/V-(3-methyIquinucIidin-3-yl)piperidine-4-carboxamide

Exchanging 4-fluorophenylboronic acid for phcnylboronic acid, tlie same reaction sequence outlined in Example 33 was used to gencratc the title compound. *H NMR (500 MHz, CDCl₃) δ 7.59-7.58 (d, J = 7.0 Hz, 2H), 7.44 (t, J = 7.0 Hz, 2H), 7.36-7.31 (m, 2H), 7.l4(s, IH), 7.09-7.07 (d, J= 7.5 Hz, IH), 6.95-6.93 (m, IH), 5.85 (brs, IH), 3.82-3.79 (m, 2H), 3.21-3.18 (m, IH), 3.03-2.79 (m, 7H), 2.34-2.29 (m, 2H), 1.96-1.82 (m, 6H), 1.65-1.47 (m, 5H) ppm. ^,3CNMR(125 MHz, CDCI3) δ 174.4, 151.9, 142,3, 141.8, 129.4,

128.6, 127.2,127.2, 118.7, 115.6, 115.6, 63.2, 52.9, 49.5, 46.6, 46.5, 43.7, 30.2, 29.0,

24.4, 22.9,22.4 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.08 min; (M+H¹) 404.2.

Example 36 l-([l,r-BiplienylJ-3-yi)-jV-(4-methyl-l-azabicyclo[3.2.2]nonan-4-yl)piperidine-4carboxamide

Exchanging 4-fluorophenylboronic acid for phenylboronic acid and Intermediate 1 for Intermediate 5, the same reaction sequence outlined in Example 33 was used to generate the title compound. 'H NMR (400 MHz, CDCI3) δ 7.60-7.58 (d, J= 8.0 Hz, 2H), 7.44 (t, J= 7.6 Hz, 2H), 7.37-7.32 (m, 2H), 7.15 (s, IH), 7.10-7.08 (d, J= 7.2 Hz, IH),

6.96-6.94 (d, J= 8.0 Hz, IH), 5.46 (s, IH), 3.83-3.80 (m, 2H), 3.08-2.78 (m, 8H), 2.41 (m, IH), 2.24-2.21 (m, IH), 2.01-1.52 (m, 13H) ppm. ^l3C NMR (100 MHz, CDCh) δ

174.2, 151.9, 142.3, 141.8, 129.4,128.6, 127.2, 127.2, 118.8,115.7, 115.6, 59.4, 53.1,

49.6, 49.5, 47.7,46.1,44.0, 39.1, 36.1, 29.1,289,25.1,24.2, 24.1 ppm. Purity: >95% (214 & 254 nm) LCMS; rétention time: 1.38 min; (M+H⁺) 418.3.

Example 37 l-(|l,r-Biphenyl|-4-yl)-/V-(3-metliylquinuclidin-3-yl)piperidine-4-carboxainide

Exchanging 4-fluorophenylboronic acid for phenylboronic acid and 3bromophenylboronic acid for 4-bromophcnylboronic acid, the same reaction sequence outlined in Example 33 was used to generate the title compound. 'H NMR (500 MHz, CDCh) δ 7.57-7.51 (m, 4H), 7.41 (t, J = 7.5 Hz, 2H), 7.29 (t, J =7.5 Hz, IH), 7.02-7.00 (d, J = 8.5 Hz, 2H), 5.75 (br s, IH), 3.81-3.79 (m, 2H), 3.14-2.78 (m, 8H), 2.29-2.25 (m, 2H), 1.99-1.80 (m, 6H), 1.63-1.50 (m, 5H) ppm. ^I3C NMR (125 MHz, CDCI3) δ 174.5,

150.7, 140.9, 132.1, 128.7, 127.7, 126.5, 126.4, 116.6, 62.7, 52.8, 49.2, 46.6, 46.3, 43.6,

187

29.9, 28.9, 28.8, 24.3, 22.6, 22.2 ppm. Purity: >98% (214 & 254 nm) LCMS; rétention time 1.97 min; (M+H ) 404.4.

Exampie 38 l-ifM’-BiphenylH-yD-jV-^-meihyl-l-azabicyclop.Z.ZInonan^-yBpiperidine-^· carboxamide

Exchanging 4-fluorophcnylboronic acid for phenylboronic acid, 3bromophenylboronic acid for 4-bromophenylboronic acid and Intermediate 1 for Intermediate 5, the same réaction sequence outlined in Example 33 was used to generate 10 the title compound. ^lH NMR (500 MHz, CDCI3) δ 7.60-7.56 (m, 4H), 7.45 (t, J= 7.5 Hz, 2H), 7.35 (t, J= 7.5 Hz, IH), 7.30-7.29 (d, J= 8.0 Hz, 2H), 4.43 (s, IH), 4.10-4.05 (m, 2H), 3.08-2.85 (m, 8H), 2.76-2.71 (m, IH), 2.44-2.42 (m, IH), 1.97-1.53 (m, 13H) ppm. ¹³CNMR(125 MHz, CDCI3) δ 157.0, 144.6, 140.9, 139.4, 128.7, 127.3, 127.1, 127.0,

58.9, 53.2, 47.7, 46.2, 45.0, 44.9,42.3, 39.7, 36.5, 33.1, 33.1, 25.9, 24.4, 24.1 ppm.

Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.99 min; (M+H*) 418.4.

Example 39 A^r-(4-Methyl-l-azabicyclo[3.2.2|nonan-4»yl)-l-(3-(pyrimidin-2-yl)phenyI)piperidine4-carboxainide

To a stincd solution of ethyl l-(3-bromophcnyl)pipcridinc-4-carboxylatc (prepared as described in Example 33; 0.800 g, 2.68 mmol) in dioxane (10 mL) was added bis(pinacolato)diboron (0.817 g, 3.22 mmol), potassium acetate (0.790 g, 8.04 mmol) and [l,l'-bis(diphcnylphosphino)fcnOcene]dichloropalladium(Il) (0.060 g, 73.5 mmol). The mixture was heated at 90 °C ovemight. After cooling, the reaction was filtered through Celite and concentrated. The residue was purified by flash chromatography over silica using a hexanc/cthyl acetate eluant to afford ethyl l-(3(4,4,5,5-tctramethyl-l,3,2-dioxaborolan-2-yl)phenyl)piperidine-4-carboxylate as a yellow solid (0.84 g, 91%). Using General Procedure F and the aryl halide component, 2chloropyrimidine (0.137 g, 1.20 mmol), this intermediate (0.430 g, 1.20 mmol) was subjectcd to Suzuki coupling to give ethyl l-(3-(pyrimidin-2-yl)phenyl)piperidine-4carboxylate as a colorless oil (0.200 g, 54%). To a stirred solution of this product (0.200 g, 0.642 mmol) in 1:1 methanol/watcr (4 mL) was added solid sodium hydroxide (0.128 g, 3.20 mmol). After ovemight stirring, the reaction was concentrated. The residue was dissolved in water, made acidic (pH ~6) with the addition of IN hydrochloric acid and

188 extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na₂SÜ4) and concentrated to afford l-(3-(pyrimidin-2-yl)phenyl)piperidinc-4-carboxylic acid as a white solid (0.150 g, 82%). Using General Procedure D and Intermediate 5, this carboxylic acid was subjccted to amide coupling to generate the title compound as a white solid (0.060 g, 27%). 'H NMR (500 MHz, CDC1₃) Ô 8.80-8.79 (d, J = 4.5 Hz, 2H), 8.06 (s, IH), 7.94-7.92 (d, J =8.0 Hz, IH), 7.38 (t, J= 8.0 Hz, IH), 7.18 (t,J= 5.0 Hz, IH), 7.09-7.07 (dd, J= 8.0 Hz & 2.0 Hz, IH), 5.49 (s, IH), 3.87-3.85 (m, 2H), 3.05-2.79 (m, 8H), 2.41-2.23 (m, 2H), 1.98-1.51 (m, 13H)ppm. ¹³CNMR(125 MHz, CDC1₃) δ 174.3,

164.9, 157.1, 151.8, 138.3, 129.3, 119.6, 119.2, 119.0, 116.0, 59.3, 53.0, 49.5,49.4,47.6, 46.0,44.0, 38.9, 36.0, 29.1, 28.9, 25.1,24.9,23.9 ppm. Purity: >96% (214 & 254 nm) LCMS; rétention time: 1.23 min; (M+H*) 420.3.

Exampie 40 7V-(4-Methyl-l-azabicycIo[3.2.2Inonan-4-yl)-l-(3-(pyrimidin-5-yl)phenyl)piperidine4-carboxamide

Exchanging 2-chloropyrimidine for 5-bromopyrimidine, the same reaction sequence outlincd in Example 39 was used to generate the title compound. ’H NMR (500 MHz, CDCI3) δ 9.20 (s, IH), 8.93 (s, 2H), 7.39 (t, J= 8.0 Hz, IH), 7.07-7.02 (m, 3H), 5.41 (s, IH), 3.83-3.81 (m, 2H), 3.01-2.81 (m, 8H), 2.39-2.24 (m, 2H), 1.96-1.51 (m, 13H) ppm. ^,3C NMR (125 MHz, CDCl₃)ô 174.0, 157.4, 154.9, 152.1,135.2, 134.9,

130.2, 118.0, 116.9,114.8, 59.5,53.1,49.1,49.1,47.6,46.1,43.8,39.2, 36.1, 28.9, 28.6, 25.1, 24.2, 24.1 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 0,90 min; (M+H*) 420.2.

Example 41 l-(4-(4-Fluorophenyl)pyrimidin-2-yl)-A'-(4-nietbyl-l-azabicycIo[3.2.2]nonan-4yl)piperidine-4-carboxamide

To a stirred solution of 2,4-dichloropyrimidine (3.00 g, 20.1 mmol) in toluene (25 mL) was added 4-fluorophenylboronic acid (2.82 g, 20.1 mmol), potassium carbonate (8.32 g, 60.3 mmol), tetrakis(triphenylphosphine)palladium(0) (0.630 g, 0.545 mmol) and 1:1 (v/v) cthanol/water (36 mL). The mixture was heated at 55 °C for 12 hours and then concentrated. The residue was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na₂SO4) and concentrated. The crude material was purified by flash chromatography over silica using a hexanc/cthyl acetate

189 cluant to afford 2-chIoro-4-(4-fluorophenyl)pyrimidine as a yellow solid (2.50 g, 6I %). To a stirred solution of this compound (1.27 g, 6.09 mmol) in Λζ/V-dimethylformarnidc (8 mL) was added ethyl piperidine-4-carboxylatc (0.959 g, 6.10 mmol) and césium carbonate (2.10 g, 6.44 mmol). The mixture was heated at 100 °C for 12 hours and then concentrated. The residue was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na₂SO<4) and concentrated. The crude material was purified by flash chromatography over silica using a hexanc/cthyl acetate eluantto afford ethyl l-(4’-fluoro-[l,r-biphenyl]-3-yl)piperidine-4-carboxylate as a yellow oil (1.60 g, 80%). To a stirred solution of this intermediate ( 1.60 g, 4.80 mmol) in

1:1 (v/v) methanol/water (20 mL) was added solid sodium hydroxide (0.968 g, 24.2 mmol). After 2 hours, the reaction was concentrated. The residue was dissolved in water, made acidic (pH -6) with the addition of IN hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na₂SC>4) and concentrated to afford l-(4^,-fluoro-[l,r-biphenyl]-3“yl)piperidine-4-carboxylic acid as a white solid (1.40 g, 97%). Using General Procedure D and Intermediate 5, this carboxylic acid was subjected to amide coupling to generate the title compound as a white solid (0.118 g, 27%). ‘H NMR (500 MHz, CDC1₃) δ 8.37 (d, J= 5.0 Hz, IH), 8.07-8.04 (m, 2H), 7.15 (t, J= 9.0 Hz, 2H), 6.89 (d, J= 10.0 Hz, IH), 5.38 (s, IH), 4.97-4.95 (m, 2H), 3.02-2.83 (m, 8H), 2.39-2.37 (m, 2H), 1.96-1.51 (m, 13H) ppm. ^l3CNMR(100 MHz,

CDC1₃)Ô 174.1, 165.3, 163.3, 163.2, 161,7, 158.4, 133.8, 129.0, 128.9, 115.7, 115.5,

105.2, 59.4, 53.1, 47.6, 46.1, 44.6,43.5, 39.3, 36,1,28.9, 28.7, 25.1, 24.3,24.2 ppm. Purity: >96% (214 & 254 nm) LCMS; rétention time: 1.44 min; (M+H⁺) 438.3.

Exampie 42 l-(4-(4-Fiuorophenyl)pyrimidin-2-yl)-/V-(4-methyl-l-azabicyclo[3.2.21nonan-4yl)piperidine-4-carboxamidc (single enantiomer A)

Using General Procedure D and the reaction inputs l-(4'-fluoro-[l,r-biphcnyl]-3yl)piperidine-4-carboxylic acid (prepared as described in Example 41) and Intermediate 9, the title compound was generated as single enantiomer of unknown absolute stercochcmistry. NMR data matchcd that of the Example 41 product. Purity: 96.9%, 97.2% (210 & 254 nm) UPLCMS; rétention time: 0.78 min; (M+H⁺) 438.3.

190

Example 43 l-(4-(4-Fluorophenyl)pyrimidin-2~yl)-7V-(4-methyl-l-azabicyclo[3.2.2]nonan-4yl)piperidine-4-carboxamidc (single enantiomer B)

Using General Procedure D and the réaction inputs l-(4'-fluoro-[l,l '-biphenyl]-3yl)piperidine-4-carboxylic acid (prepared as described in Example 41) and Intermediate 10, the title compound was generated as single enantiomer of unknown absolutc stcreochemistry. NMR data matchcd that of the Example 41 product. Purity: 100%, 99.4% (210 & 254 nm) UPLCMS; rétention time: 0.78 min; (M+H¹) 438.3.

Example 44 l-(4-(4-Fluorophenyl)pyrimidiii-2-yl)-7V-(3-methyIquinucIidin-3-yl)piperidine-4carboxamide

Using General Procedure D and the reaction inputs l-(4'-fluoro-[l,r-biphenyl]-3“ yl)piperidine-4-carboxylic acid (prepared as described in Example 41) and Intermediate 1, the title compound was prepared. ’H NMR (500 MHz, CDCI3) ô 8.30 (d, ./=4.5 Hz, IH), 8.07-8.04 (m, 2H), 7.16 (t, J= 8.5 Hz, 2H), 6.89 (d, J= 5.0 Hz, IH), 5.57 (s, IH),

4.97-4.94 (m, 2H), 3.04-2.84 (m, 8H), 2.40-2.21 (m, 2H), 1.97-1.51 (m, 1 IH) ppm. ¹³C NMR (125 MHz, CDC1₃)8 174.3, 165.3, 163.3, 163.2, 161.7,158.4, 133.8, 129.0, 128.9,

115.7, 115.5,105.2, 63.2, 52.9, 46.6,46.4, 44.3,43.5, 30.2, 28.8, 28.7, 24.3, 22.9, 22.4 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.27 min; (M+H¹) 424.2.

Example 45 l-(4-(4-Fluorophenyl)pyrimidin-2-yl)-7V-(qiiinuclidin-3-yl)piperidine-4-carboxamide

Using General Procedure E and the reaction inputs l-(4'-fluoro-[I,r-biphenyl]-3yl)piperidine-4-carboxylic acid (prepared as described in Example 41) and quinuclidin-3amine, the title compound was prepared as an off-white solid. *H NMR (400 MHz, DMSO-rfe) ô 8.43 (d, J= 5.0 Hz, IH), 8.26-8.13 (m, 2H), 7.86 (d, J= 7.1 Hz, 2H), 7.387.29 (m, 2H), 7.17 (d, J= 5.1 Hz, IH), 4.89-4.72 (m, 2H), 3.75-3.62 (m, IH), 3.09-2.87 (m, 3H), 2.85-2.72 (m, IH), 2.72-2.36 (m, 5H), 1.84-1.64 (m, 4H), 1.64-1.40 (m, 4H), 1.35-1.19 (m, lH)ppm. ^I3CNMR(100 MHz, DMSO-î/₆) 8 174.1,163.7 (d, J = 248.3 Hz), 162.1, 161.3, 158.9,133.4 (d, J =2.9 Hz), 129.1 (d,J= 8.7 Hz), 115.6 (d, .7 = 21.7 Hz), 105.0, 54.4,46.9, 46.3, 45.9, 43.1,43.1, 42.1, 28.4, 28.1, 25.6,25.6, 19.8 ppm. Purity: 95.2%, 99.6% (210 & 254 nm) UPLCMS; rétention time: 0.73 min; (M+H¹)

410.3.

191

Example 46

Ι-ίό-^-ΓΙιιοΓορΙιοηγΟργΓΛζίη-Ζ-γΟ-./ν-^-πιοίΙιγΙ-Ι-ΒζηίΜεγεΙοβ.Ζ.ΖΙηοηαη·^yl)piperidine-4-carboxamide

To a stirred solution of 2,6-dichloropyrazine (5.00 g, 33.6 mmol) in l,4-dioxane (l 50 mL) was added ethyl pipcridinc-4-carboxylate (5.54 g, 35.2 mmol) and triethylamine (5.2 mL, 37 mmol). The mixture heated at reflux ovemight and then concentrated. The residue was taken up in aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined extracts were dried (Na2SO₄) and concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford ethyl l-(6-chloropyrazin-2-yl)piperidinc-4carboxylatc as a yellowoil (8.50 g, 94%). To a stirred solution of this compound (l.OO g, 3.71 mmol) in 10:1 (v/v) 1,4-dioxanc/water (11 mL) was added 4-fluorophenylboronic acid (0.622 g, 4.44 mmol), sodium carbonate (0.785 g, 7.41 mmol) and [1,1bis(diphenylphosphino)ferrocene]dichloropalladium(Il) (0.136 g, 0.185 mmol). The mixture was heated at reflux ovemight. After coolîng, the réaction was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO₄) and concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford ethyl 1 -(6-(4-fluorophcnyl)pyrazin-2yl)pipcridine-4-carboxylatc as a yellow oil (1.20 g, 98%). To a stirred solution of this product in 1:1:1 (v/v/v) tetrahydrofuran/methanol/water was added solid sodium hydroxide (0.730 g, 18.3 mmol). After ovemight stirring, the reaction was concentrated. The residue was dissolved in water, made acidic (pH -6) with the addition of IN hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO₄) and concentrated to afford 1-(6-(4fluorophenyl)pyrazin-2-yl)piperidme-4-carboxylic acid as a yellow solid (0.600 g, 54%). Using General Procedure D and Intermediate 5, this carboxylic acid was subjectcd to amide coupling to generate the title compound as a white solid (0.100 g, 34%). ^lH NMR. (500 MHz, CDC1₃) δ 8.25 (s, IH), 8.07 (s, IH), 7.98-7.95 (m, 2H), 7.13 (t, J= 8.0 Hz, 2H), 5.54 (s, IH), 4.50-4.47 (m, 2H), 3.05-2.83 (m, 8H), 2.38-2.34 (m, 2H), 1.96-1.48 (m, 13H) ppm. ¹³C NMR (125 MHz, CDCI3) δ 173.9, 164.6,162.7,153.9, 148.3, 133.2, 129.0, 128.6,115.7, 115.6, 59.5, 53.1, 47.6,46.0, 44.2, 44.1,44.0, 39.0, 36.0, 28.5, 28.2, 25.1, 24.1,24.0 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.23 min; (M+H⁺) 438.0.

192

Example 47

1- (6-(4-Fluorophenyl)pyrazin-2-yl)-jV-(4-mcthyI-l-azabicyclo[3.2.2]nonan-4yl)pîperidine-4-carboxamide (single enantiomer A)

Using General Procedure D and the réaction inputs l-(6-(4-fluorophenyl)pyrazin-

2- yl)pipcridine-4-carboxylic acid (prepared as described in Example 46) and Intermediate

9, the title compound was generated as single enantiomer of unknown absolute stereochemistry. NMR data matched that of Example 46. Purity: 100%, 98.6% (214 & 254 nm) UPLCMS; rétention time: 0.79 min; (M+H⁴} 438.4,

Example 48

1- (6-(4-FIuorophenyl)pyrazin-2-yl)-A^r-(4-methyl-l-azabicyclo|3.2.2]nonan-4yl)piperidine-4-carboxamide (single enantiomer B)

Using General Procedure D and the reaction inputs l-(6-(4-fluorophcnyl)pyrazin-

10, the title compound was generated as single enantiomer of unknown absolute stereochemistry. NMR data matched that of Example 46. Purity: 100%, 100% (214 & 254 nm) UPLCMS; rétention time: 0.79 min; (M+H '} 438.4.

Example 49 î-(6-(4-Fluoroplienyl)pyrazin-2-yl)-A^r-(3-methylquinucl!din-3-yl)piperidine-4carboxamide

Using General Procedure E and the reaction inputs l-(6-(4-fluorophenyl)pyrazin2-yl)piperidine-4-carboxylic acid (prepared as described in Example 46) and Intermediate 1, the title compound was prepared as a light brown solid. *H NMR (400 MHz, DMSOd₆) Ô 8.41 (s, IH), 8.29 (m, IH), 8.16-8.08 (m, 2H), 7.47 (brs, IH), 7.36-7.28 (m, 2H), 4.54-4.41 (m, 2H), 3.02-2.85 (m, 3H), 2.73-2.41 (m, 6H), 2.16-2.08 (m, IH), 1.84-1.51 (m, 6H), 1.45-1.20 (m, 5H) ppm. ¹³C NMR (100 MHz, DMSO-î4) Ô 173.9, 162.9 (d, J= 246.8 Hz), 153.6, 146.9, 133.1 (d,J= 2.9 Hz), 129.8, 128.6 (d, J =8.7 Hz), 128.3, 115.6 (d, J= 21.6 Hz), 62.1, 51.8, 46.2,45.9,43.8,43.7, 42.1,29.1,27.9, 27.7, 24.2, 22.7,22.3 ppm. Purity: 100%, 97.7% (210 & 254 nm) UPLCMS; rétention time: 0.77 min; (M+H⁴}

424.2.

Example 50

193 l-(4-(4-Fluoroplienyl)-l^,5-triazin-2-yl)-7V-(4-methyl-l-azabicyclo|3.2.2|nonan-4yl)piperidine-4-carboxami(le

Exchanging 2,6-dichloropyrazine for 2,4-dichloro-l,3,5-triazinc, the same réaction sequence outlincd in Example 46 was used to generate the title compound. *H NMR (500 MHz, CDCl₃) δ 8.60 (s, IH), 8.43-8.40 (m, 2H), 7.12 (t, J = 8.5 Hz, 2H), 5.43 (s, IH), 5.02-4.88 (m, 2H), 3.04-2.82 (m, 8H), 2.40-2.36 (m, 2H), l.95-1,48 (m, 13H) ppm. ^I3CNMR (125 MHz, CDC1₃)Ô 173.6,169.6,166.4, 166.1, 164.4, 163.7, 132.5,

132.4, 130.8, 130.7, 115.5,115.3, 59.5, 53.0,47.5,46.1,44.0, 42.8,42.6, 39.1, 36.0, 28.8,

28.6, 25.0, 24.2, 24.1 ppm. Purity; >98% (214 & 254 nm) LCMS; rétention time: 1.20 min; (M+H ') 439.0.

Exampie 51

-(2-(4-Fluorophcnyl) pyrimid i ii-4-yl)-A-(4-inethyl-1 -azabicvclo 13.2.2 ] n onan-4yl)piperidine-4-carboxamide

To a stirred solution of 2,4-dichloropyrimidine (2.00 g, 13.4 mmol) in methanol (30 mL) was added ethyl pipcridine-4-carboxylate (1.73 g, 12.1 mmol) and triethylamine (1.49 g, 14.8 mmol). The mixture was heated at 65 °C ovemight. After cooling, the réaction was filtered free of solids and concentrated. The residue was purified by flash chromatography over silica using a hexanc/ethyl acetate cluant to afford ethyl l-(2chloropyrimidin-4-yl)pipcridinc-4-carboxylatc as a ycllow oil (2.50 g, 69%). To a stirred solution of this product in a mixture of jV,//-dimcthylformamidc (15 mL) and water (8 mL) was added 4-fluorophcnylboronic acid (0.780 g, 5.60 mmol), sodium carbonate (2.37 g, 22.4 mmol) and [l,r-bis(diphcnylphosphino)ferrocene]dichloropalladium(n) (0.204 g, 0.279 mmol). The mixture was heated at 90 °C for 6 hours and then concentrated. The residue was purified by flash chromatography over silica using a methylene chloride/mcthanol eluant to afford ethyl l-(2-(4-fluorophcnyl)pyrimidin-4-yl)pipcridine4-carboxylatc as a white solid (0.500 g, 27%). To a stirred solution of this intermediate in 1:1 (v/v) methanol/water (20 mL) was added solid sodium hydroxide (0.303 g, 7.58 mmol). After 3 hours, the reaction was concentrated. The residue was dissolved in water, made acidic (pH ~6) with the addition of IN hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na;SO^) and concentrated to afford l-(2-(4-fluorophenyl)pyrimidin-4-yl)piperidine-4-carboxylic acid as a white solid (0.430 g, 94%). Using General Procedure D and Intermediate 5, this carboxylic acid was subjccted to amide coupling to generate the title compound as a white

194 solid (0.096 g, 22%). 'H NMR (500 MHz, CDCI₃) ô 8.37 (d, J= 5.0 Hz, IH), 8.07-8.04 (m, 2H), 7.15 (t, J = 9.0 Hz, 2H), 6.89 (d, J = 10.0 Hz, IH), 5.38 (s, IH), 4.97-4.95 (m, 2H), 3.02-2.83 (m, 8H), 2.39-2.37 (m, 2H), 1.96-1.51 (m, 13H) ppm. ^l3C NMR (125 MHz, CDCI₃)Ô 174.1, 165.3,163.3,163.2, 161.7,158.4, 133.8, 129.0, 128.9,115.7,

115.5, 105.2, 59.4, 53.1,47.6,46.1,44.6,43.5, 39.3, 36.1, 28.9, 28.7, 25.1, 24.3, 24.2 ppm. Purity: >96% (214 & 254 nm) LCMS; rétention time: 1.44 min; (M+H⁺) 438.3.

Exampie 52

4-([l,l^,-Biphenyl]-3-yl)-A^r-(4-methyl-l-azabicyclo[3.2.2|nonan-4-yl)pîperidine-l10 carboxamide

To a stirred solution of terf-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)5,6-dihydropyridine-l(27/)-carboxylate (1.05 g, 3.40 mmol) in 5:1 (v/v) 1,4dioxane/water (30 mL) was added 3-bromobiphcnyl (0.660 g, 2.80 mmol), potassium carbonate (1.16 g, 8.39 mmol) and [1,115 bis(diphenylphosphino)fcrrocene]dichloropalladium(II) (0.102 g, 0.139 mmol). The mixture was heated at 80 °C overnight. After cooling, the reaction was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na₂SO4) and concentrated. The residue was purified by flash chromatography over neutral alumina using a hexane/ethyl acetate eluant to afford fert-butyl 4-([l,r-biphenyl]20 3-yl)-5,6-dihydropyridine-l(2/7)-carboxyiate as a light ycllow oil (0.900 g, 64%). A stirred suspension of this compound (0.900 g, 2.50 mmol) and 10% palladium on carbon (50% water; 0.180 g) in ethyl acetate (30 mL) was cyclcd between vacuum and a nitrogen several times. After the last évacuation, the reaction was refillcd with hydrogen gas. The mixture was stirred overnight and then filtered through Celite. The filtrate was combined with ethyl acetate rinsings of the Celite and concentrated to afford ZcrZ-butyl 4-([ 1, Γbiphenyl]-3-yl)piperidine-l-carboxylate as a yellow oil (0.898 g, 90%). To a stirred solution of this product (0.898 g, 2.66 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (2.5 mL). The mixture was stirred overnight and then concentrated. The residue was taken up in aqueous sodium carbonate solution and extracted with methylene chloride. The combined extracts were dried (Na₂SÜ4) and concentrated to afford 4-([l,r-biphenyI]-3-yl)pipcridinc as a light yellow oil (0.569 g, 90%). This compound was reacted with Intermediate 5 using General Procedure A to generate the title compound. *H NMR (500 MHz, CDC1₃) δ 7.60-7.58 (d, J= 7.5 Hz, 2H), 7.47-7.35 (m, 6H), 7.21-7.20 (d, J= 7.5 Hz, 1 H), 4.45 (s, 1 H), 4.11-4.05 (m, 2H), 3.06-2.98 (m,

195

4H), 2.94-2.88 (m, 4H), 2.76-1.75 (m, IH), 2.45 (m, IH), 1.96-1.87 (m, 5H), 1.78-1.55 (m, 8H) ppm. ^l3CNMR(125 MHz, CDC1₃) S 157.1, 146.0, 141.5, 141.2, 129.0, 128.7,

127.3, 127.2, 125.7, 125.7, 125.3, 58.8, 53.1, 47.7, 46.0,45.0, 45.0, 42.7, 39.0, 36.3, 33.2,

25.9, 23.9, 23.6 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.99 min; (M+H⁴) 418.4.

Example 53

4-([l,l'-Biplienyl|-4-yl)-A^,-(4-methyM-azabicyclo[3.2.2]nonan-4-yl)piperidme-lcarboxamide

Exchanging 4-bromobiphcnyl for 3-bromobiphcnyl, the same réaction sequence outlincd in Example 52 was used to generate the title compound. *H NMR (500 MHz, CDCI3) δ 7.60-7.56 (m, 4H), 7.45 (t, J= 7.5 Hz, 2H), 7.35 (t, 7.5 Hz, IH), 7.30-7.289 (d, J= 8.0 Hz, 2H), 4.43 (s, IH), 4.10-4.05 (m, 2H), 3.08-2.85 (m, 8H), 2.76-2.71 (m, IH), 2.44-2.42 (m, IH), 1.97-1.53 (m, 13H) ppm. ^I3CNMR (125 MHz, CDCI3) δ 157.0,

144.6, 140.9, 139.4, 128.7,127.3, 127.1, 127.0, 58.9, 53.2, 47.7, 46.2, 45.0,44.9, 42.3, 39.7, 36.5, 33.1, 33.1, 25.9, 24.4, 24.1 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.99 min; (M+H⁴) 418.4.

Example 54 l-(5-Fluoro-4-(4-fluorophcnyl)pyrimidin-2-yl)-/V-(3-metliyIquinucIidÎn-3yl)piperidine-4-carboxamide

Exchanging 2,4-dichloropyrimidinc for 2,4-dichloro-5-fluoropyrimidinc and Intermediate 5 for Intermediate 1, the same réaction sequence outlined in Example 41 was used to generate the title compound. 'H NMR (500 MHz, CDCI3) δ 8.25 (d, J = 3.5 Hz, IH), 8.14-8.11 (m, 2H), 7.20-7.16 (m, 2H), 5.41 (br s, IH), 4.84-4.81 (m, 2H), 3.02-2.78 (m, 8H), 2.38-2.33 (m, IH), 2.18-2.16 (m, IH), 1.95-1.92 (m, 2H), 1.80-1.70 (m, 4H), 1.561.46 (m, 5H) ppm. ¹³C NMR (125 MHz, CDCI3) δ 174.2, 165.1, 163.1, 158.3, 158.2,

150.5, 150.2, 150.1, 148.5, 146.8, 146.6, 131.12, 131.05, 131.0, 130.3, 130.25, 130.23, 130.21, 115.6, 115.4, 63.4, 52.9, 46.6, 46.4, 44.14, 44.09, 30.3, 28.7, 28.6, 24.4, 23.1,

22.5 ppm. Purity: >99% LCMS (214 nm & 254 nm); rétention time 1.50 min; (M+H⁴)

442.2.

Example 55 l-(5-Fluoro-4-(4-fIuorophenyl)pyrimidin-2-yl)-7V-(4-methyl-lazabicyclo|3.2.2|nonan-4-yl)piperjdiiie-4-carboxamide

Exchanging 2,4-dichloropyrimidine for 2,4-dichloro-5-fluoropyrimidine, the same reaction sequence outlined in Example 41 was used to generate the title compound. ‘H

NMR (500 MHz, CDClj) δ 8.25 (d, J = 3.0 Hz, IH), 8.14-8.11 (m, 2H), 7.18 (t, J = 8.5

196

Hz, 2H), 5.36 (s, IH), 4.85-4.82 (m, 2H), 3.04-2.83 (m, 8H), 2.39-2.34 (m, 2H), 1.96-1.92 (m, 3H), 1.82-1.53 (m, 10H) ppm. ¹³C NMR (125 MHz, CDClj) δ 174.0, 165.1, 163.1, 158.27, 158.25, 150.5, 150.23, 150.16, 148.5, 146.8, 146.6, 131.1, 131.04, 130.99, 130.3, 130.25, 130.23, 130.20, 115.6, 115.4, 59.5, 53.1, 47.6, 46.1, 44.4, 44.12, 44.09, 39.3,

36.1, 28.8, 28.5, 25.1, 24.3, 24.2 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.52 min; (M+H⁴) 456.2.

Example 56 l-(5-Fluoro-4-(4-(2-methoxyethoxy)phenyl)pyrimîdin-2-yl)-/V-(4-methyI-lazabicycIo[3.2.2|nonan-4-yl)piperidine-4-carboxamide

Exchanging 2,4-dichloropyrimidine for 2,4-dichloro-5-fluoropyrimidine and 4fluorophcnylboronic acid for (4-(2-methoxycthoxy)phenyl)boronic acid, the same reaction sequence outlincd in Example 41 was used to générale the title compound. 'H NMR (500 MHz, CDC1₃) δ 8.21 (d, ./=4.0 Hz, JH), 8.10 (d, J = 8.5 Hz, 2H), 7.03 (dd, J = 7.0 Hz & 2.0 Hz, 2H), 5.37 (s, IH), 4.85-4.82 (m, 2H), 4.21 (t, J= 4.5 Hz, 2H), 3.80 (t, J= 4.5 Hz, 2H), 3.49 (s, 3H), 3.06-2.83 (m, 8H), 2.38-2.31 (m, 2H), 1.95-1.92 (m, 3H), 1.77-1.51 (m, 10H) ppm. ^,3C NMR (125 MHz, CDCh) δ 174.1, 160.7, 158.3, 150.9, 150.8, 150.7, 148.5, 146.3, 146.1, 130.6, 130.5, 126.8, 114.5, 70.9, 67.3, 59.4, 59.2, 53.1,

47.6, 46.1, 44.5, 44.2, 44.1, 39.3, 36.1, 28.9, 28.6, 25.1, 24.3, 24.2 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.33 min; (M+H⁴) 512.3.

Example 57 l-(5-Fluoro-4-(4-(2-methoxyethoxy)plienyl)pyrimidin-2-yl)-/V-(3-methylquinuclidïn-

3-yl)piperidine-4-carboxamide

Exchanging 2,4-dichloropyrimidine for 2,4-dichloro-5-fluoropyrimidine, 4fluorophenylboronic acid for (4-(2-methoxyethoxy)phenyl)boronic acid and Intermediate 5 for Intermediate 1, the same réaction sequence outlined in Ex amp le 41 was used to generate the title compound. *H NMR (400 MHz, CDCI3) Ô 8.09 (d, J= 2.4 Hz, IH), 7.53 (dd, J= 8.8 Hz & 1.6 Hz, 2H), 7.02 (dd, J = 7.2 Hz & 2.0 Hz, 2H), 6.68 (d, J= 5.2 Hz, IH), 5.61 (br s, IH), 4.30-4.17 (m, 4H), 3.80-3.78 (m, 2H), 3.48 (s, 3H), 3.07-2.83 (m, 8H), 2.32-2.18 (m, 2H), 1.94-1.50 (m, 11 H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ 174.3,

159.3, 156.7, 152.2, 137.8, 137.6, 135.5, 135.3, 130.0, 126.8, 114.7, 107.4, 70.9, 67.4, 63.0, 59.2, 52.9, 46.6, 46.4, 46.0, 43.9, 30.9, 30.1, 28.5, 28.4, 24.3, 22.8, 22.3 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.27 min; (M+H⁴) 497.3.

Example 58 l-(5-Fluoro-4-(4~((2-methoxyethoxy)methyl)phenyl)pyrimidin-2-yl)-/V-(4-methyl-lazabicyclo|3.2.2|nonan-4-vl)piperidine-4~carboxamide

Exchanging 2,4-dichloropyrimidine for 2,4-dichloro-5-fluoropyrimidinc and 4fluorophenylboronic acid for 2-(4-((2-mcthoxycthoxy)methyl)phcnyl)-4,4,5,5tetramethyl-l,3,2-dioxaborolanc, the same reaction sequence outlined in Example 41 was used to generate the title compound. ‘H NMR (400 MHz, CDCI3) 6 8.23 (d, J = 3.6 Hz, IH), 8.06 (d, J= 8.3 Hz, 2H), 7.46 (d, ./= 8.3 Hz, 2H), 5.49 (s, IH), 4.87-4.77 (m, 2H), 4.64 (s, 2H), 3.67-3.62 (m, 2H), 3.62-3.57 (m, 2H), 3.41 (s, 3H), 3.10-2.80 (m, 8H), 2.442.30 (m, 2I-I), 1.97-1.45 (m, 13H) ppm. Purity: 99.1% (214 & 254 nm) UPLCMS; rétention time: 0.89 min; (M+H⁴) 526.4.

197

Example 59 l-(5“Fluoro-4-(4-((2-methoxyethoxy)methyl)phenyI)pyrimidin-2-yl)-/V-(3methylquinucIidÎn-3-yl)piperidine-4-carboxainide

Exchanging 2,4-dichloropyrimidinc for 2,4-dichloro-5-fluoropyrimidine, 4fluorophcnylboronic acid for 2-(4-((2-methoxycthoxy)methyl)phcnyl)-4,4,5,5tetramethyl-l,3,2-dioxaborolane and Intermediate 5 for Intermediate 1, the same reaction sequence outlined in Example 41 was used to generate the title compound. *H NMR (400 MHz, CDCh) Ô 8.23 (d, 3.6 Hz, IH), 8.06 (d, .7 = 8.3 Hz, 2H), 7.46 (d, .7= 8.3 Hz,

2H), 5.43 (s, IH), 4.86-4.78 (m, 2H), 4.64 (s, 2H), 3.67-3.62 (m, 2H), 3.62-3.57 (m, 2H), 3.41 (s, 3H), 3.00-2.88 (m, 4H), 2.88-2.71 (m, 4H), 2.38-2.28 (m, IH), 2.16-2.11 (m, IH), 1.96-1.86 (m, 2H), 1.82-1.66 (m, 2H), 1.57-1.38 (m, 5H) ppm. Purity: >99.9% (214 & 254 nm) UPLCMS; rétention time: 0.87 min; (M+H*) 512.4.

Example 60 l-(5-Fluoro-4-(4-(methoxymetliyl)phenyl)pyrimidin-2-yl)-7V-(4-metliyl-lazabicyclo[3.2.2|nonan-4-yl)piperidine-4-carboxamide

Exchanging 2,4-dichloropyrimidine for 2,4-dichloro-5-fluoropyrimidine and 4fluorophenylboronic acid for 2-(4-(methoxymcthyl)phcnyl)-4,4,5,5-tetramethyl-l,3,2dioxaborolane, the same réaction sequence outlined in Example 41 was used to generate the title compound. ^lH NMR (500 MHz, CDC1₃) δ 8.26 (d, J= 3.5 Hz, IH), 8.09 (d, J =

7.5 Hz, 2H), 7.48 (d, .7= 8.5 Hz, 2H), 5.44 (s, IH), 4.86-4.83 (m, 2H), 4.55 (s, 2H), 3.44 (s, 3H), 3.09-2.83 (m, 8H), 2.42-2.18 (m, 2H), 1.98-1.93 (m, 3H), 1.83-1.51 (m, 10H) ppm. '³C NMR (100 MHz, CDC1₃) δ 174.1, 158.4, 151.2, 151.1, 150.9, 148.4, 146.7,

146.4, 140.9, 133.5, 133.4, 129.0, 127.5, 74.2, 59.4, 58.2, 53.1, 47.7, 46.0, 44.5, 44.1, 39.0, 36.0, 30.9, 28.8, 28.6, 25.1, 24.1, 23.9 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.40 min; (M+H*) 482.2.

Example 61 l-(5-Fluoro-4-(4-(metlioxymethyI)phenyl)pyrimidin-2-yl)-/V-(3-methylquinuclidin-3yl)piperidine-4-carboxamide

Exchanging 2,4-dichloropyrimidine for 2,4-dichloro-5-fluoropyrimidine, 4fluorophenylboronic acid for 2-(4-(methoxymcthyl)phcnyl)-4,4₎5,5-tetramcthyl-l,3,2dioxaborolane and Intermediate 5 for Intermediate 1, the same reaction sequence outlined in Example 41 was used to generate the title compound. ‘H NMR (500 MHz, CDCI3) δ 8.26 (d, J = 3.5 Hz, IH), 8.09 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 5.58 (br s, IH), 4.86-4.83 (m, 2H), 4.55 (s, 2H), 3.44 (s, 3H), 3.01-2.84 (m, 8H), 2.40-2.22 (m, 2H), 1.94-1.92 (m, 2H), 1.80-1.48 (m, 9H) ppm. ¹³C NMR (100 MHz, CDCh) δ 174.3, 158.3,

151.2, 151.1, 150.9, 148.4, 146.7, 146.4, 140.9, 133.4, 129.0, 128.9, 127.5, 74.2, 63.2,

58.2, 52.9, 46.6, 46.4, 44.2, 44.1, 30.9, 30.1, 28.7, 28.6, 24.3, 22.9, 22.4 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.38 min; (M+H*) 468.3.

Example 62 l-(5-FIuoro-4-(4-(3-methoxypropoxy)phenyl)pyrimidin-2-yl)-jV-(4-metliyl-lazabicyc!o[3.2.2]nonan-4-yl)piperidine-4-carboxamide

Exchanging 2,4-dichloropyrimidinc for 2,4-dichloro-5-fluoropyrimidine and 4fluorophcnylboronic acid for 2-(4-(3-methoxypropoxy)phenyl)-4,4,5,5-tetramethyl-l,3,2

198 dioxaborolane, the same réaction sequence outlined in Example 41 was used to generate the title compound. *H NMR (400 MHz, CDCI3) δ 8,17 (d, J= 3.8 Hz, IH), 8.06 (d, J = 9.0 Hz, 2H), 6.97 (d, J= 9.0 Hz, 2H), 5.65 (s, IH), 4.85-4.75 (m, 2H), 4.12 (t, J = 6.3 Hz, 2H), 3.57 (t, J= 6.3 Hz, 2H), 3.36 (s, 3H), 3.18-2.89 (m, 8H), 2.52-2.46 (m, IH), 2.452.35 (m, IH), 2.12-2.01 (m, 2H), 2.01-1.53 (m, 10H), 1.47 (s, 3H) ppm. Purity: >99.9% (214 & 254 nm) UPLCMS; rétention time: 0.96 min; (M+H⁺) 526.3.

Example 63 l-(5-Fluoro-4-(4-(3-methoxypropoxy)phenyl)pyrimidîn-2-yl)-A^r-(3methylq u in uclidin-3~yl)piperidine-4-carboxa mi de

Exchanging 2,4-dichloropyrimidinc for 2,4-dichloro-5-fluoropyrimidinc, 4fluorophcnylboronic acid for 2-(4-(3-methoxypropoxy)phcnyl)-4,4,5,5-tctramcthyl-1,3,2dioxaborolane and Intermediate 5 for Intermediate 1, the same reaction sequence outlined in Example 41 was used to generate the title compound. *H NMR (400 MHz, CDCI3) δ 8.19 (d, ./= 3.8 Hz, IH), 8.07 (d, J= 8.9 Hz, 2H), 6.98 (d, J= 8.9 Hz, 2H), 5.38 (s, IH), 4.85-4.77 (m, 2H), 4.13 (t, J = 6.3 Hz, 2H), 3.57 (t, J = 6.3 Hz, 2H), 3.36 (s, 3H), 3.002.88 (m, 4H), 2.88-2.71 (m, 4H), 2.37-2.27 (m, IH), 2.16-2.04 (m, 3H), 1.96-1.86 (m, 2H), 1.82-1.65 (m, 4H), 1.56-1.38 (m, 5H) ppm. Purity: >99.9% (214 & 254 nm) UPLCMS; rétention time: 0.95 min; (M+H⁴) 512.3.

Example 64

1-(4-(3,4-Difluorophenyl)pyrimidin-2-yl)-7V-(4-methyI-l-azabicyclo[3.2.2]nonan-4y!)piperidine-4-carboxamide

Exchanging 4-fluorophenylboronic acid for 3,4-difluorophenylboronic acid, the same reaction sequence outlined in Example 41 was used to generate the title compound. *H NMR (500 MHz, CDCI3) δ 8.39 (d, J = 5.0 Hz, IH), 7.94-7.93 (m, IH), 7.78-7.77 (m, IH), 7.27-7.24 (m, IH), 6.87 (d, J = 5.0 Hz, III), 5.44 (br, IH), 4.96-4.93 (m, 211), 3.062.87 (m, 8H), 2.41-2.39 (m, 2H), 1.97-1.52 (m, 13H) ppm. ¹³C NMR (125 MHz, CDCL3) Ô 174.1, 162.1, 161.7, 158.9, 152.9, 152.8, 151.6, 151.5, 150.9, 150.8, 149.7, 149.6,

134.9, 123.2, 123.1, 117.4, 117.3, 117.1, 116.2, 116.0, 105.0, 59.4, 53.0,47.6,46.0,44.5,

43.7, 43.5, 39.0, 36.0, 28.9, 28.7, 25.1, 24.1, 23.9 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.23 min; (M+H⁺) 456.2.

Example 65

1-(4-(3,5-Dinuorophenyl)pyrimidin-2-yl)-JV-(4-mcthyl-l-azabicycIo[3.2.2]nonan-4yl)piperidine-4-carboxamide

Exchanging 4-fluorophenylboronic acid for 3,5-difluorophcnylboronic acid, the same reaction sequence outlined in Example 41 was used to generate the title compound. *H NMR (500 MHz, CDCI3) δ 8.42 (d, J = 5.5 Hz, IH), 7.60-7.57 (m, 2H), 6.95-6.90 (m, IH), 6.87 (d, 5.5 Hz, IH), 5.49 (s, IH), 4.96-4.93 (m, 2H), 3.06-2.87 (m, 8 H), 2.442.37 (m, 2H), 1.99-1.93 (m, 3H), 1.94-1.52 (m, 10H) ppm. ¹³C NMR (125 MHz, CDCI3) δ 174.1, 164.3, 164.2, 162.3, 162.2, 161.8, 161.7, 158.9, 141.3, 141.2, 109.9, 109.7,

105.7, 105.5, 105.3, 59.4, 53.0, 47.6, 46.0, 44.4, 43.5, 39.0, 36.0, 28.9, 28.6, 25.1, 24.1, 23.9 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 2.00 min; (M+H⁴)

456.3.

Example 66

199 l-(4-(4-(2-Methoxvethoxy)phenyl)pyrimidiri-2-vl)-/V-(4-methyl-lazabicycIo[3.2.2]nonan-4-yl)piperidine-4-carboxamide

Exchanging 4-fluorophenylboronic acid for (4-(2-methoxyethoxy)phcnyl)boronic, the same reaction sequence outlined in Example 41 was used to generate the title compound. 'H NMR (500 MHz, CDCl₃) δ 8.33-8.32 (d, J = 5.0 Hz, IH), 8.02 (d, J = 9.0 Hz, 2H), 7.01 (d, J= 8.5 Hz, 2H), 6.88 (d, J = 5.0 Hz, IH), 5.37 (s, IH), 4.98-4.95 (m, 2H),4.20 (t, J = 5.0 Hz, 2H), 3.79 (t, ./=5.0 Hz, 2H), 3.48 (s, 3H), 3.0I-2.83 (m, 8H), 2.38-2.36 (m, 2H), l.96-1.93 (m, 3H), 1.78-1.50 (m, 10H) ppm. ^I3C NMR (125 MHz, CDCh) δ 174.1,

163.8, 161.8, 160.8, 158.0, 130.3, 128.4, 114.6, 104.9, 70.9, 67.4, 59.4, 59.2, 53.1, 47.6,

46.1, 44.7, 43.5, 39.3, 36.1, 28.9, 28.7, 25.1, 24.3, 24.2 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.13 min; (M+H ) 494.3.

Example 67 l-(4-(4-(3-Methoxypropoxy)phenyl)pyrimidin-2-yl)-lV-(4-methyl-lazabicyclo[3.2.2|nonan-4-y))piperidine-4-carboxamide

Exchanging 4-fluorophenylboronic acid for 2-(4-(3-methoxypropoxy)phenyl)-4,4,5,5tetramethyl-l,3,2-dioxaborolane, the same réaction sequence outlined in Example 41 was used to generate the title compound. *H NMR (500 MHz, CDCl₃) δ 8.34 (d, ,/=5.0 Hz, IH), 8.03 (d, J = 9.0 Hz, 2H), 7.00 (d, J= 9.0 Hz, 2H), 6.89 (d, J= 5.0 Hz, IH), 5.38 (s, IH), 4.99-4.96 (m, 2H), 4.14 (t, J = 6.0 Hz, 2H), 3.60 (t, J= 5.0 Hz, 2H), 3.39 (s, 3H), 3.02-2.83 (m, 8H), 2.39-2.36 (m, 2H), 2.11-2.08 (m, 2H), 1.98-1.52 (m, 13H) ppm. ¹³C NMR (125 MHz, CDC1₃) δ 174.1, 163.9, 161.8, 161.0, 158.0, 130.1, 128.5, 114.5,104.9,

69.1, 65.0, 59.4, 58.7, 53.1,47.6,46.1, 44.7,43.5, 39.2, 36.1, 29.6, 29.0, 28.8, 25.1, 24.3, 24.1 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.28 min; (M+H⁺)

508.3.

Example 68 l-(4'-(2-Methoxyethoxy)-[l,r-biphenyl|-3-yl)-7V-(4-niethyl-I-azabicyclo|3.2.2]nonan-

4-yl)piperidine-4-carboxamide

Exchanging 4-fluorophenylboronic acid for (4-(2-methoxyethoxy)phenyl)boronic acid and Intermediate 1 for Intermediate 5, the same reaction sequence outlined in Example 33 was used to generate the title compound. ’H NMR (500 MHz, CDCI3) δ 7.52 (d, J = 8.5 Hz, 2H), 7.31 (t, J =8.0 Hz, IH), 7.12 (t, J =2.0 Hz, IH), 7.05 (d,J=7.5Hz, 1 H), 7.01 (d, J= 8.5 Hz, 2H), 6.92 (dd, J= 8.0 Hz & 2.0 Hz, IH), 5.38 (s, IH), 4.20-4.17 (m, 2H), 3.81-3.79 (m, 4H), 3.49 (s. 3H), 3.01-2.79 (m, 8H), 2.40 (m, IH), 2.25-2.20 (m, IH), 1.97-1.53 (m, 13H) ppm. ^Î3C NMR (125 MHz, CDCI3) δ 174.2, 158.3, 151.9, 141.8,

134.5, 129,4, 128.2, 118.5, 115.3, 115.1, 114.8, 71.1, 67.4, 59.4, 59.2, 53.1, 49.6, 49.5, 47.6, 46.1, 44.1, 39.2, 36.1, 29.1,28.9, 25.1, 24.3, 24.2 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.19 min; (M+H⁺) 492.3.

Example 69 l-(4’-((2-Methoxyethoxy)methyl)-[l,r-biphenyl]-3-yl)-7V-(4-inethyl-lazabicycIo[3.2.2]nonan-4-yl)piperidine-4-carboxamïde

Exchanging 4-fluorophenylboronic acid for 2-(4-((2-methoxycthoxy)mcthyl)phenyl)4,4,5,5-tetramethyl-l,3,2-dioxaborolane and Intermediate 1 for Intermediate 5, the same reaction sequence outlined in Example 33 was used to generate the title compound. ’H

200

NMR (500 MHz, CDCh) δ 8.38 (d, .7 = 5.5 Hz, IH), 8.04 (d, .7 = 8.0 Hz, 2H), 7.47 (d,J = 8.0 Hz, 2H), 6.95 (d, J= 5.5 Hz, IH), 5.46 (s, IH), 4.99-4.96 (m, 2H), 4.66 (s, 2H), 3.663.60 (m, 4H), 3.43 (s, 3H), 3.05-2.84 (m, 8H), 2.42-2.37 (m, 2H), 1.97-1.95 (m, 3H), 1.94-1.51 (m, 10H) ppm. ^I3C NMR (125 MHz, CDCh) δ 174.2, 164.1, 161.8, 158.3,

140.7, 137.1, 127.9, 127.1, 105.5, 72.9, 72.0, 69.4, 59.4, 59.1, 53.1, 47.7,46.0,44.6, 43.5,

38.9, 36.0, 31.0, 29.0, 28.7, 25.1, 24.0, 23.9 ppm. Purity: > 98% LCMS (214 nm & 254 nm); rétention time 1.29 min; (M+H⁺) 508.3. Ή NMR (400 MHz, CDCh) 6 7.60-7.58 (d, J= 8.0 Hz, 2H), 7.44 (t, J= 7.6 Hz, 2H), 7.37-7.32 (m, 2H), 7.15 (s, IH), 7.10-7.08 (d, J = 7.2 Hz, IH), 6.96-6.94 (d, J = 8.0 Hz, IH), 5.46 (s, IH), 3.83-3.80 (m, 2H), 3.08-2.78 (m, 8H), 2.41 (m, IH), 2.24-2.21 (m, IH), 2.01-1.52 (m, 13H) ppm. Purity: >95% (214 & 254 nm) LCMS; rétention time: 1.38 min; (M+H*) 418.3.

Example 70 l-(4-(4-(Methoxymetliyl)phenyI)pyrimidin-2-yl)-/V-(4-methyl-lazabicyclo[3.2.2|nonan-4-yl)piperîdme-4-carboxamide

Exchanging 4-fluorophenylboronic acid for 2-(4-(methoxymethyl)phcnyl)-4,4,5,5tetramcthyl-l,3,2-dioxaborolane, the same reaction sequence outlined in Example 41 was used to generate the title compound. *H NMR (500 MHz, CDCh) δ 8.37 (d,.7 = 5.0 Hz, IH), 8.04 (d,.7 = 8.0 Hz, 2H), 7.44 (d, J= 8.0 Hz, 2H), 6.94 (d, J= 5.0 Hz, IH), 5.39 (s, IH), 4.99-4.96 (m, 2H), 4.54 (s, 2H), 3.43 (s, 3H), 3.02-2.85 (m, 8H), 2.39-2.37 (m, 2H), 1.96-1.51 (m, 13H) ppm. ^I3C NMR (125 MHz, CDCh) Ô 174.1, 164.1, 161.8, 158.3,

140.7.137.1, 127.7, 127.0, 105.5, 74.2, 59.4, 58.2, 53.1, 47.6, 46.1, 44.6, 43.5, 39.2, 36.1, 29.0, 28.7, 25.1, 24.2, 24.1 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.82 min; (M+H*) 464.4.

Example 71 l-(4-(4-(2-Fluoroethoxy)phenyl)pyrimidîn-2-yl)-7V-(4-methyl-lazabicyclo[3.2.2|nonan-4-yl)piperidine-4-carboxamide

Exchanging 4-fluorophcnylboronic acid for 2-(4-(2-fluoroethoxy)phenyl)-4,4,5,5tetramethyl-l,3,2-dioxaborolane, the same réaction sequence outlined in Example 41 was used to generate the title compound. *H NMR (500 MHz, CDCI3) δ 8.34 (d, J = 5.0 Hz, IH), 8.04 (d, J= 9.0 Hz, 2H), 7.02 (d, J = 9.0 Hz, 2H), 6.89 (d, J = 5.5 Hz, 1 H), 5.36 (s, IH), 4.98-4.95 (m, 2H), 4.86-4.74 (dt, J= 48 Hz & 4.0 Hz, IH), 4.33-4.26 (dt, J=27 Hz & 4.0 Hz, IH), 3.03-2.83 (m, 8H), 2.39-2.36 (m, 2H), 1.97-1.51 (m, 13H) ppm. ¹³C NMR (125 MHz, CDCh) δ 174.1, 163.7, 161.8, 160.4, 158.1, 130.8, 128.5, 114.6, 104.9, 82.5,

81.1, 67.2, 67.1, 59.4, 53.1, 47.6, 46.1, 44.7, 43.5, 39.3, 36.1, 29.0, 28.7, 25.1, 24.3, 24.2 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.47 min; (M+H¹) 482.2.

Example 72 l-(4-(4-(3~Methoxypropoxy)phenyl)pyrimidin-2-yl)-A^r-(quinuclidin-3-yl)piperidine4-carboxamide

Exchanging 4-fluorophenylboronic acid for 2-(4-(3-methoxypropoxy)phenyl)-4,4,5,5tetramethyl-l,3,2-dioxaborolane and Intermediate 5 for quinuclidin-3-amine, the same reaction sequence outlined in Ex amp le 41 was used to generate the title compound. 'H

NMR (500 MHz, CDCh) δ 8.34 (d, J= 5.0 Hz, IH), 8.03 (d, J= 9.0 Hz, 2H), 7.00 (d, J =

9.0 Hz, 2H), 6.89 (d, J = 5.0 Hz, IH), 6.14 (br s, IH), 4.99 (d, .7= 13.0 Hz, 2H), 4.16 (t, J = 6.5 Hz, 2H), 4.07 (m, IH), 3.61 (t, J= 6.0 Hz, 2H), 3.40-3.37 (m, 4H), 3.08-2.71 (m,

201

7H), 2.50-2.46 (m, IH), 2.H-1.56 (m, 11H) ppm. ^l3C NMR (100 MHz, CDCl₃) δ 174.8,

163.8, 161.7, 161.1, 158.0, 130.0, 128.4, 114.5, 104.8, 69.1, 64.9, 58.7, 55.3, 47.3, 46.6, 46.0, 43.8, 43.5, 30.9, 29.6, 28.9, 28.6, 25,4, 25.1, 19.7 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.26 min; (M+H⁺) 480.3.

Exampie 73 l-(4-(4-(Methoxvmethyl)phenyl)pvrimidin-2-yl)-jV-(3-methylquinuclidin-3yl)piperidine-4-carboxamide

Exchanging 4-fluorophenylboronic acid for 2-(4-(methoxymcthyl)phenyl)-4,4,5,5tetramethyl-l,3,2-dioxaborolanc and Intermediate 5 for Intermediate 1, the same reaction sequence outlined in Example 41 was used to generate the title compound. *H NMR (400 MHz, CDC1₃) δ 8.36-8.34 (d, J= 5.2 Hz, IH), 8.02 (d, J = 8.4 Hz, 2H), 7.43 (d, J= 8.0 Hz, 2H), 6.92 (d, J= 5.2 Hz, IH), 5.45 (s, IH), 4,95 (d, 13.2 Hz, 2H), 4.52 (s, 2H),

3.41(s, 3H), 3.00-2.76 (m, 8H), 2.40-2.35 (m, IH), 2.15-2.13 (m, IH), 1.95-1.47(m, 11H) ppm. ¹³C NMR (100 MHz, CDC1₃) δ 174.3, 164.1, 161.8, 158.3, 140.7, 137.1, 127.8,

127.1, 105.5, 74.3, 63.4, 58.2, 52.9, 46.6, 46.4, 44.4, 43.5, 30.3, 28.8, 28.7, 24.4, 23,1,

22.5 ppm. Purity: > 96% LCMS (214 nm & 254 nm); rétention time 1.25 min; (M+H*)

450.3.

Example 74 I-(4-(4-((2-Methoxyeihoxy)methyl)phenyl)pyrimidm-2-yl)-7V-(4-methyl-lazabicyclo[3.2.2]nonan-4-yl)piperidine-4-carboxamide

Exchanging 4-fluorophenylboronic acid for 2-(4-((2-methoxyethoxy)methyl)phenyl)-

4,4,5,5-tctramethyl-l,3,2-dioxaborolane, the same réaction sequence outlined in Example 41 was used to generate the title compound. ’H NMR (500 MHz, CDCI3) ô 8.38 (d, J =

5.5 Hz, IH), 8.04 (d, J= 8.0 Hz, 2H), 7.47 (d, J= 8.0 Hz, 2H), 6.95 (d, .7= 5.5 Hz, IH), 5.46 (s, IH), 4.99-4.96 (m, 2H), 4.66 (s, 2H), 3.66-3.60 (m, 4H), 3.43 (s, 311), 3.05-2.84 (m, 8H), 2.42-2.37 (m, 2H), 1.97-1.95 (m, 3H), 1.94-1.51 (m, 10H) ppm. ^I3C NMR (125 MHz, CDC1₃)ô 174.2, 164.1, 161.8, 158.3, 140.7, 137.1, 127.9, 127.1, 105.5, 72.9, 72.0,

69.4, 59.4, 59.1, 53.1, 47.7, 46.0, 44.6, 43.5, 38.9, 36.0, 31.0, 29.0, 28.7, 25.1, 24.0, 23.9 ppm. Purity; > 98% LCMS (214 nm & 254 nm); rétention time 1.29 min; (M+H*) 508.3.

Example 75 4-Fluoro-l-(4-(4-(methoxymethyl)phenyl)pyrimidin-2-yl)-JV-(4-methyl-lazabicyclo[3.2.2|nonan-4-yl)piperidine-4-carboxamidc

Exchanging 4-fluorophcnylboronic acid for 2-(4-(methoxymethyl)phcnyl)-4,4,5,5tetramethyl-l,3,2-dioxaborolane and ethyl piperidine-4-carboxylate for ethyl 4fluoropiperidine-4-carboxylate hydrochloride, the same réaction sequence outlined in Example 41 was used to generate the title compound. ^lH NMR (400 MHz, CDCI3) δ 8.36 (d, J= 5.6 Hz, IH), 8.01 (d, J= 8.0 Hz, 2H), 7.42 (d, J= 8.0 Hz, 2H), 6.94 (d, J= 5.6 Hz, IH), 6.35 (m, IH), 4.89-4.85 (m, 2H), 4.51 (s, 2H), 3.40 (s, 3H), 3.31-3.25 (m, 2H), 3.042.83 (m, 6H), 2.34-2.21 (m, 4H), 1.95-1.61 (m, 10H) ppm. ^,3C NMR (100 MHz, CDCI3) δ 171.1, 170.9, 164.1, 161.7, 158.3, 140.7, 140.0, 127.8, 127.1, 105.8, 96.2 (d,./= 185.6 Hz), 74.2, 59.3, 58.2, 53.1, 47.6, 46.0, 39.2, 39.0, 36.2, 32.2, 32.0, 31.7, 25.0, 24.3, 24.1 ppm. Purity: > 97% LCMS (214 nm & 254 nm); rétention time 1.37 min; (M+H¹) 482.2.

Example 76

202

4-Fluoro-l-(4-(4-(3-methoxypropoxy)phenyl)pyrimidin-2-yi)-A^r-(3methylquinuclidin-3-yl)piperidine-4-carboxamide

Exchanging 4-fluoroplienylboronic acid for 2-(4-(3-methoxypropoxy)phenyl)-4,4,5,5tetramethyl-l,3,2-dioxaborolane, ethyl piperidine-4-carboxylatc for ethyl 4fluoropiperidinc-4-carboxylatc hydrochloride and Intermediate 5 for Intermediate l, the same reaction sequence outlined in Example 41 was used to generate the title compound. 'H NMR (400 MHz, CDCl₃) δ 8.33 (d, J= 5.2 Hz, IH), 8.01 (d, J= 8.8 Hz, 2H), 6.98 (d, J = 9.2 Hz, 2H), 6.91 (d, J = 5.2 Hz, IH), 6.39 (d, J= 6.4 Hz, IH), 4.89-4.85 (m, 2H), 4.13 (t, J= 6.4 Hz, 2H), 3.59 (t, 7= 6.4 Hz, 2H), 3.38 (s, 3H), 3.01-3.26 (m, 2H), 3.052.82 (m, 6H), 2.31-2.05 (m, 6H), 1.86-1.51 (m, 8H) ppm. ^l3C NMR (100 MHz, CDC1₃) δ

171.4, 171.2, 163.9, 161.7, 161.1, 158.0, 130.0, 128.5, 114.5, 105.2, 97.1, 69.1, 64.9, 63.0, 58.7, 52.7, 46.5, 46.4, 39.3, 32.1, 32.0, 31.9, 31.8, 30.1, 29.6, 24.2, 22.8, 22.3 ppm. Purity: > 96% LCMS (214 nm & 254 nm); rétention time 1.54 min; (M+H*) 512.3.

Example 77 4-Fluoro-l-(5-fluoro-4-(4-((2-metlioxyethoxy)niethyl)phenyl)pyriïnidin-2-yl)-A^r-(4methyl-l-azabicyclo[3.2.2]nonan-4-yl)piperidine-4-carboxamide

Exchanging 4-fluorophenylboronic acid for 2-(4-((2-methoxyethoxy)mcthyl)phcnyl)-

4.4.5.5- tetramethyl-l,3,2-dioxaborolane, ethyl piperidin.e-4-carboxylate for ethyl 4fluoropiperidine-4-carboxyiate hydrochloride, and 2,4-dichloropyrimidine for 2,4dichloro-5-fluoropyrimidine, the same reaction sequence outlined in Example 41 was used to generate the title compound. ^[H NMR (400 MHz, CDC13) δ 8.24 (d, 7 = 3.6 Hz, IH), 8.05 (d, 7= 8.2 Hz, 2H), 7.46 (d, 7= 8.2 Hz, 2H), 6.34 (d, 7= 7.2 Hz, IH), 4.75-4.72 (m, 2H), 4.65 (s, 2H), 3.66-3.58 (m, 4H), 3.41 (s, 3H), 3.31-3.24 (m, 2H), 3.05-2.85 (m, 6H), 2.35-2.17 (m, 3H), 1.96-1.50 (m, 11 H) ppm. ¹³C NMR (100 MHz, CDCI3) δ 171.1,

170.9, 158.2, 151.3, 146.8, 140.9, 133.3, 129.0, 127.6, 97.0, 72.8, 72.0, 69.5, 59.3, 59.1, 53.0, 47.6, 46.0, 39.9, 38.8, 36.2, 35.1, 31.8, 31.7, 25.0, 24.2, 24.0 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.57 min; (M+H*) 544.3.

Example 78 4-Fluoro-l-(5-fluoro-4-(4-((2-methoxyethoxy)methyl)plienyl)pyrimidin-2-yl)-/V-(4methyl-l~azabicyclo[3.2.2]nonan-4-yl)piperidine-4-carboxamide (single enantiomer A)

Exchanging 4-fluorophcnylboronic acid for 2-(4-((2-methoxyethoxy)methyl)phenyl)-

4.4.5.5- tctramethyl-l,3,2-dioxaborolane, ethyl piperidine-4-carboxylate for ethyl 4fluoropiperidine-4-carboxylate hydrochloride, 2,4-dichloropyrimidmc for 2,4-dichloro-5fluoropyrimidinc and Intermediate 5 for Intermediate 9, tlie same reaction sequence outlined in Example 41 was used to generate the title compound. *H NMR (400 MHz, CDCh) δ 8.24 (d,7 = 3.5 Hz, IH), 8.05 (d,7= 8.4 Hz, 2H), 7.46 (d,7= 8.4 Hz, 2H), 6.34 (d, 7 = 7.3 Hz, IH), 4.78-4.70 (m, 2H), 4.65 (s, 2H), 3.67-3.63 (m, 2H), 3.62-3.57 (m, 2H), 3,41 (s, 3H), 3.33-3.22 (m, 2H), 3.09-2.78 (m, 6H), 2.36-2.10 (m, 3H), 2.00-1.70 (m, 6H), 1.67-1.46 (m, 5H) ppm. Purity: >99.9% (214 & 254 nm) UPLCMS; rétention time: 0.92 min; (M+H*) 544.5.

Example 79 4-Fluoro-l-(5-fluoro-4-(4-((2-methoxyethoxy)methyl)phenyl)pyrimidin-2-yl)-A^r-(4methyl-l-azabicvclo|3.2.2]nonan-4-yl)piperidine-4-carboxainide

203 (single enantiomer B)

4,4,5,5-tctramethyl-l,3,2-dioxaborolanc, ethyl pipcridine-4-carboxylatc for ethyl 4fluoropiperidine-4-carboxylatc hydrochloride, 2,4-dichloropyrimidinc for 2,4-dichloro-5fluoropyrimidinc and Intermediate 5 for Intermediate 10, the same réaction sequence outlined în Exampie 41 was used to generate the title compound. 'H NMR (400 MHz, CDCl₃) δ 8.24 (d, J = 3.5 Hz, l H), 8.05 (d, J « 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 6.34 (d, J = 7.3 Hz, IH), 4.78-4.70 (m, 2H), 4.65 (s, 2H), 3.67-3.63 (m, 2H), 3.62-3.57 (m, 2H), 3.41 (s, 3H), 3.33-3.22 (m, 2H), 3.09-2.78 (m, 6H), 2.36-2.10 (m, 3H), 2.00-1.70 (m, 6H), 1.67-1.46 (m, 5H) ppm. Purity: >99.9% (214 & 254 nm) UPLCMS; rétention time: 0.92 min; (M+H*) 544.5.

Exampie 80 4-Fluoro-l-(4-(4-(methoxymethyl)phenyl)pyrimidin-2-yI)“/V-(3-methyiquiiHiclidin-3yl)piperidine-4-carboxamide

Exchanging 4-fluorophenylboronic acid for 2-(4-(methoxymethyl)phenyl)-4,4,5,5tetramethyl-l,3,2-dioxaborolane, ethyl piperidine-4-carboxylatc for ethyl 4fluoropipcridine-4-carboxylatc hydrochloride and Intermediate 5 for Intermediate 1, the same réaction sequence outlined in Example 41 was used to generate the title compound. 'H NMR (500 MHz, CDClj) δ 8.40 (d, J= 5.5 Hz, IH), 8.05 (d, J= 8.0 Hz, 2H), 7.45 (d, J= 8.0 Hz, 2H), 6.98 (d, J = 4.5 Hz, IH), 6.44 (d, J = 7.0 Ηζ,ΙΗ), 4.90 (d, J = 13.5 Hz, 2H), 4.55 (s, 2H), 3.44 (s, 3H), 3.31 (t, J = 13.0 Hz,, 2H), 3.08-2.88 (m, 6H), 2.34-2.20 (m, 5H), 1.91-1.53 (m, 7H) ppm. ^I3C NMR (125 MHz, CDCI3) δ 171.4, 171.3, 164.2,

161.7, 158.4, 140.7, 137.0, 127.8, 127.1, 105.9, 96.9, 95.4, 74.2, 62.6, 58.2, 52.7, 46.4,

46.2, 39.3, 32.1, 31.9, 31.8, 31.0, 30.1, 24.2, 22.6, 22.0 ppm. Purity: > 97% LCMS (214 nm & 254 nm); rétention time 1.50min; (M+H*) 468.3.

Example 81 (5)-4-Fluoro-l-(4-(4-(methoxymethyl)phenyl)pyrimidin-2-yl)-jV-(3methylquinuclidin-3-yl)piperidine-4-carboxamide

Exchanging 4-fluorophenylboronic acid for 2-(4-(methoxymethyl)phenyl)-4,4,5,5tetramcthyl-l,3,2-dioxaborolane, ethyl piperidine-4-carboxylate for ethyl 4fluoropiperidine-4-carboxyIatc hydrochloride and Intermediate 5 for Intermediate 11, the same reaction sequence outlined in Example 41 was used to generate the title compound. 'H NMR (500 MHz, CDCh) Ô 8.39 (d, J= 5.5 Hz, IH), 8.04 (d, J= 8.5 Hz, 2H), 7.45 (d, J= 8.5 Hz, 2H), 6.97 (d, J =5.5 Hz, IH), 6.40 (d, J = 6.5 Ηζ,ΙΗ), 4.90-4.87 (m, 2H), 4.54 (s, 2H), 3.43 (s, 3H), 3.34-3.28 (m, 2H), 3.02-2.82 (m, 6H), 2.34-2.20 (m, 5H), 1.91-1.51 (m, 7H) ppm. ^l3C NMR (125 MHz, CDC1₃) δ 171.3, 171.2, 164.2, 161.7, 158.3, 140.7, 137.0, 127.8, 127.1, 105.9, 96.9, 95.4, 74.2, 63.2, 58.2, 52.8, 46.6, 46.4, 39.3, 32.1, 32.0,

31.9, 31.8, 30.1, 24.2, 23.0, 22.4 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.38 min; (M+H⁴) 468.2.

Example 82 4-Fluoro-l-(4-(4-(3-mcthoxypropoxy)phenyl)pyrimidin-2-yl)-/V-(4-methyl-lazabicyclo|3.2.2]nonan-4-yl)piperidine-4-carboxamide

Exchanging 4-fluorophenylboronic acid for 2-(4-(3 - methoxypropoxy)p heny 1)-4,4,5,5tetramethyl-l,3,2-dioxaborolane and ethyl pipcridinc-4-carboxylate for ethyl 4fluoropiperidine-4-carboxylate hydrochloride, the same reaction sequence outlined in Example 41 was used to generatc the title compound. *H NMR (400 MHz, CDCI3) ô 8.33 (d, J= 5.2 Hz, IH), 8.01 (d, 8.8 Hz, 2H), 6.98 (d, J= 8.4 Hz, 2H), 6.91 (d, J= 5.2 Hz,

IH), 6.36 (d, J= 7.6 Hz, IH), 4.89-4.86 (m, 2H), 4.13 (t, J = 6.4 Hz, 2H), 3.59 (t, .7 = 6.4 Hz, 2H), 3.38 (s, 3H), 3.32-3.26 (m, 2H), 3.05-2.91 (m, 6H), 2.41-1.59 (m, 16H) ppm. ¹³C NMR (100 MHz, CDCI3) δ 171.3, 171.1, 163.9, 161.7, 161.1, 158.0, 129.9, 128.5, 114.5,

105.2, 97.2, 69.1, 64.9, 59.2, 58.7, 52.8, 47.5, 45.9, 39.3, 38,2, 36.0, 32.2, 32.0, 31.9,

31.7, 29.6, 25.0, 23.6, 23.4, 23.3 ppm. Purity: > 96% LCMS (214 nm & 254 nm); rétention time 1.57 min; (M+H⁺) 526.4.

Exampie 83 4-Fluoro-l-(4-(4-((2-methoxyethoxy)methyl)phenyl)pyrimidin-2-yl)-JV-(3n)CtIiylquinuclidin-3-yl)piperidine-4-carboxamide

4.4.5.5- tctramcthyl-l,3,2-dioxaborolane, ethyl piperidine-4-carboxylate for ethyl 4fluoropiperidine-4-carboxylate hydrochloride and Intermediate 5 for Intermediate 1, the same reaction sequence outlined in Example 41 was used to gcncrate the title compound. ‘H NMR (500 MHz, CDCI3) δ 8.39 (d, J= 5.5 Hz, IH), 8.04 (d, J= 8.0 Hz, 2H), 7.47 (d, J= 8.0 Hz, 2H), 6.97 (d, J= 5.0 Hz, IH), 6.39 (d, J= 7.5 Hz, IH), 4.89 (d, J= 13.0 Hz, 2H), 4.66 (s, 2H), 3.67-3.60 (m, 4H), 3.43 (s, 3H), 3.30 (t, ./= 12.0 Hz, 2H), 2.97-2.83 (m, 6H), 2.35-2.19 (m, 3H), 1.91-1.51 (m, 9H) ppm. ¹³C NMR (125 MHz, CDCh) Ô

171.3, 171.2, 164.2, 161.7, 158.4, 140.7, 137.0, 127.9, 127.1, 105.9, 96.9, 95.4, 72.9, 72.0, 69.4, 63.2, 59,1, 52.8, 46.5, 46.4, 39.3, 32.1, 32.0, 31.9, 31.8, 31.0, 30.1, 24.2, 23.0, 22.4 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.34 min; (M+H⁴)

512.3,

Exampie 84 (5)-4-Fluoro-l-(4-(4-((2-methoxyethoxy)methyl)phenyl)pyrimidin-2-yl)-A^r-(3methyIquinucIidin-3-yl)piperidine-4-carboxamide

4.4.5.5- tetramcthyl-l,3,2-dioxaborolanc, ethyl piperidinc-4-carboxylate for ethyl 4- fluoropipcridine-4-carboxylate hydrochloride and Intermediate 5 for Intermediate 11, the same reaction sequence outlined in Example 41 was used to generate the title compound. *H NMR (500 MHz, CDCh) δ 8.38 (d, 5.0 Hz, IH), 8.03 (d, J= 8.0 Hz, 2H), 7.46 (d,

J= 8.0 Hz, 2H), 6.96 (d, J= 5.5 Hz, IH), 6.41 (d, J= 7.0 Hz, IH), 4.88 (m, 2H), 4.65 (s, 2H), 3.67-3.59 (m, 4H), 3.42 (s, 3H), 3.33-3.27 (m, 2H), 3.03-2.81 (m, 6H), 2.33-2.20 (m, 4H), 1.92-1.85 (m, 3H), 1.59-1.49 (m, 5H) ppm. ^I3C NMR (100 MHz, CDCh) δ 171.4,

171.2, 164.2, 161.7, 158.3, 140.8, 137.0, 127.8, 127.1, 105.9, 96.9, 95.4, 72.9, 72.0, 69.4,

63.1, 59.1, 52.8, 46.5, 46.4, 39.3, 32.1, 32.0, 31.9, 31.8, 30.1, 24.2, 22.9, 22.3 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.34 min; (M+H⁴) 512.3.

Exampie 85

4-Fluoro-l-(4-(4-(2-methoxyethoxy)phenyl)pyrimidin-2-yl)-A^r-(3-methylquinuclidin3-yl)piperidine-4-carboxamidc

205

Exchanging 4-fluorophcnylboronic acid for (4-(2-methoxyethoxy)phenyl)boronic acid, ethyl pipcridinc-4-carboxylate for ethyl 4-fluoropiperidme-4-carboxylate hydrochloride and Intermediate 5 for Intermediate l, the same reaction sequence outlincd in Example 41 was used to generate the title compound. *H NMR (500 MHz, CDCI3) δ 8.35 (d, J= 5.0 Hz, IH), 8.03 (d, J= 9.0 Hz, 2H), 7.02 (d, ./ = 9.0 Hz, 2H), 6.92 (d, J= 5.5 Hz, IH), 6.58 (d, J = 6.5 Hz, l H), 4.89-4.86 (m, 2H), 4.21 (t, J = 5.0 Hz, 2H), 3.81 (t, J = 5.0 Hz, 2H), 3.49 (s, 3H), 3.35-3.27 (m, 2H), 3.07-2.98 (m, 6H), 2.38-2.20 (m, 3H), 1.94-1.56 (m, 9H) ppm. ¹³C NMR (125 MHz, CDCh) δ 171.7, 171.5, 163.9, 161.7, 160.8, 158.1, 130.2,

128.5, 114.6, 105.3, 96.9, 95.4, 70.9, 67.3, 61.4, 59.3, 54.8, 52.5, 46.2, 45.9, 39.2, 32.1,

31.9, 31.8, 31.7, 30.9, 29.8, 24.2, 24.1, 21.8, 21.3 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.32 min; (M+H⁺) 497.9.

Example 86 (5)-4-Fluoro-l-(4-(4-(2-methoxyethoxy)phenyl)pyrÎmidin-2-yl)-7V-(3methylquinuclidm-3-yl)piperÎdine-4-carboxamide

Exchanging 4-fluorophenylboronic acid for (4-(2-methoxyethoxy)phenyl)boronic acid, ethyl piperidine-4-carboxylate for ethyl 4-fluoropiperidine-4-carboxylate hydrochloride and Intermediate 5 for Intermediate 11, the same reaction sequence outlïned in Example 41 was used to generate the title compound. *H NMR (500 MHz, CDCI3) δ 8.34 (d,./ -

4.5 Hz, IH), 8.02 (dd, J= 11.0 Hz & 2.5 Hz, 2H), 7.02 (dd, J= 11.0 Hz & 2.5 Hz, 2H), 6.91 (d, J = 5.5 Hz, 1 H), 6.38 (d, J = 7.0 Hz, 1 H), 4.89-4.86 (m, 2H), 4.20 (t, J = 5.0 Hz, 2H), 3.80 (t, ./= 5.0 Hz, 2H), 3.48 (s, 3H), 3.32-3.26 (m, 2H), 2.95-2.74 (m, 6H), 2.332.18 (m, 3H), 1.92-1.75 (m, 4H), 1.58-1.43 (m, 5H) ppm. ¹³C NMR (125 MHz, CDCI3) δ

171.3, 171.2, 163.9, 161.7, 160.8, 158.1, 130.3, 128.5, 114.6, 105.2, 96.9, 95.4, 70.9,

67.3, 63.3, 59.2, 52.8, 46.5, 46.4, 39.3, 32.1, 32.0, 31.9, 31.8, 30.1, 24.2, 23.0, 22.4 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.35 min; (M+H*) 498.2.

Example 87 4-Fluoro-l-(4-(4-(2-fluoroethoxy)phcnyl)pyrimidin-2-yl)-jV-(quinuclidin-3yl)piperidine-4-carboxamide

Exchanging 4-fluorophenylboronic acid for 2-(4-(2-fluoroethoxy)phenyl)-4,4,5,5tctramcthyl-l,3,2-dioxaborolane, ethyl piperidine~4-carboxylate for ethyl 4fluoropiperidine-4-carboxylatc hydrochloride and Intermediate 5 for quinuclidin-3-amine, the same réaction sequence outlined in Example 41 was used to generate the title compound. ^lH NMR (500 MHz, CDCI3) δ 8.36 (d, J = 4.5 Hz, IH), 8.05 (d, J= 9.0 Hz, 2H), 7.03 (d, J = 8.5 Hz, 2H), 6.93 (d, J = 5.5 Hz, IH), 6.85 (m, IH), 4.91-4.76 (m, 4H), 4.32-4.06 (dt, ./= 19.5 Hz & 4.5 Hz, 2H), 4.07-4.06 (m, IH), 3.47-3.30 (m, 3H), 3.122.80 (m, 5H), 2.32-1.62 (m, 9H) ppm. '³C NMR (125 MHz, CDCI3) δ 171.9, 171.7, 163.8, 161.6, 160.4, 158.2, 130.7, 128.6, 114.6, 105.2, 96.8, 82.5, 81.1, 67.2, 67.0, 55.1,

47.1, 46.5, 45.8, 39.2, 32.2, 32.1, 31.9, 25.4, 24.9, 19.5 ppm. Purity: > 95% LCMS (214 nm & 254 nm); rétention time 1.31min; (M+H⁴) 472.0.

Example 88 (S)-4-Fluoro-l-(4-(4-(2-nuoroetlioxy)phenyl)pyrimidin-2-yl)-7V-(quinuclidin-3yl)piperidine-4-carboxamide

Exchanging 4-fluorophcnylboronic acid for 2-(4-(2-fluoroethoxy)phenyl)-4,4,5,5tctramethyl-l,3,2-dioxaborolanc, ethyl piperidine-4-carboxylate for ethyl 4206 fluoropipcridine-4-carboxylate hydrochloride and Intermediate 5 for (S)-quinuclidin-3amine, the same reaction sequence outlined in Example 41 was used to generate the title compound. ^[H NMR (500 MHz, CDC1₃) δ 8.36 (d, J= 5.5 Hz, IH), 8.04 (dd, J = 7.0 Hz &2.0 Hz, 2H), 7.03 (d, J= 8.5 Hz, 2H), 6.93 (d,7=5.0 Hz, IH), 6.65 (t,7=6.5 Hz, IH), 4.91-4.86 (m, 3H), 4.77 (t, 7= 4.0 Hz, IH), 4.34-4.26 (m, 2H), 4.00 (m, IH), 3.45-3.34 (m, IH), 3.35-3.30 (m, 2H), 2.89-2.83 (m, 4H), 2.61-2.58 (m, IH), 2.35-2.20 (m, 2H), 2.00-1.87 (m, 3H), 1.75- 1.70 (m, 3H), 1.58-1.55 (m, IH) ppm. ^l3C NMR (100 MHz, CDClj) δ 171.8,171.6, 163.8, 161.6, 160.4, 158.2, 130.6, 128.6, H4.6, 105.2,97.1,95.2,

82.7, 81.0, 67.2, 67.0, 55.7, 47.3, 46.6, 46.0, 39.2, 32.2, 32.1, 32.0, 31.9, 25.5, 25.4, 19.8 ppm. Purity: > 95% LCMS (214 nm & 254 nm); rétention time 1.35 min; (M+H⁺) 472.2.

Exampie 89 4-Fluoro-l-(4-(4-((2-methoxyethoxy)methyl)phenyl)pyrimidin-2-yl)-7V-(4-methyl-lazabkycIo[3.2.2]nonan~4-yl)piperidine-4-carboxamide

4,4,5,5-tetramethyl-l,3,2-dioxaborolane and ethyl pipcridinc-4-carboxylate for ethyl 4fluoropipcridine-4-carboxylate hydrochloride, the same réaction sequence outlined in Exampie 41 was used to generate the title compound. *H NMR (500 MHz, CDCI3) δ 8.39 (d, 7=5.5 Hz, IH), 8.04 (d,7= 8.5 Hz, 2H), 7.47 (d,7=8.0 Hz, 2H), 6.95 (d,7=5.0 Hz, IH), 6.67 (d, 7 = 7.5 Hz, IH), 4.90-4.87 (m, 2H), 4.66 (s, 2H), 3.67-3.61 (m, 4H), 3.43 (s, 3I-I), 3.33-3.27 (m, 2H), 3.04-2.87 (m, 6H), 2.38-2.24 (m, 3H), 1.89-1.52 (m, 11H) ppm. ¹³C NMR (125 MHz, CDCI3) Ô 171.1, 171.0, 164.2, 161.7, 158.4, 140.7, 137.0, 127.9,

127.1, 124.8, 105.9, 96.9, 95.5, 72.9, 72.0, 69.4, 59.3, 59.1, 53.0, 47.5, 46.0, 39.3, 38.9,

36.2, 32.2, 32.0, 31.9, 31.7, 31.0, 25.0, 24.2, 24.0 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.36 min; (M+H'j 526.3.

Exampie 90 4-FIuoro-l-(4-(4-(2-fluoroethoxy)phenyl)pyrimidm-2-yl)-/V-(4-metliyl-lazabicyclo[3.2.2]nonan-4-yl)piperidinc-4-carboxamidc

Exchanging 4-fluorophenylboronic acid for 2-(4-(2-fluoroethoxy)phenyl)-4,4,5,5tetramethyl-l,3,2-dîoxaborolane and ethyl pipcridine-4-carboxylate for ethyl 4fluoropipcridinc-4-carboxylatc hydrochloride, the same réaction sequence outlined in Example 41 was used to generate the title compound. ^JH NMR (500 MHz, CDCI3) Ô 8.36 (d,7= 5.5 Hz, IH), 8.04 (d,7= 9.0 Hz, 2H), 7.03 (d, 7= 8.5 Hz, 2H), 6.93 (d,7= 5.0 Hz, IH), 6.38 (d, 7 = 7.0 Hz, IH), 4.90-4.76 (m, 4H), 4.34-4.27 (m, 2H), 3.33-3.27 (m, 2H), 3.11-2.88 (m, 6H), 2.40-2.21 (m, 3H), 2.04-1.53 (m, 11H) ppm. ^ljC NMR (125 MHz, CDC1₃)ô 171.2, 171.1, 163.8, 161.7, 160.4, 158.2, 130.7, 128.6, 114.6, 105.3,97.0,95.5,

82.5, 81.1, 67.2, 67.1, 59.2, 52.8, 47.5, 45.9, 39.3, 38.4, 36.1, 32.2, 32.0, 31.9, 31.7, 25.0,

23.8, 23.6 ppm. Purity: > 96% LCMS (214 nm & 254 nm); rétention time 1.33min; (M+H) 500.0.

Example 91 4-FIuoro-l~(5-nuoro-4-(4-(2-iTicthoxyethoxy)phenyl)pyriinidin-2-yl)-/V-(4-methvl-lazabicyclo[3.2.2Jnonan-4-yl)piperidine-4-carboxamide

Exchanging 4-fluorophenylboronic acid for (4-(2-methoxyethoxy)phcnyl)boronic acid, ethyl piperidine-4-carboxylate for ethyl 4-fluoropipcridine-4-carboxylatc hydrochloride and 2,4-dichloropyrimidinc for 2,4-dichloro-5-fluoropyrimidine, the same reaction

207 sequence outlincd in Example 41 was used to gencrate the title compound. *H NMR (500 MHz, CDCh) Ô 8.22 (d, J= 3.5 Hz, IH), 8.10 (d, J= 9.0 Hz, 2H), 7.03 (d, J= 8.0 Hz, 2H), 6.37 (d, J = 7.5 Hz, 1 H), 4.75 (m, 2H), 4.21 (t, J « 4.5 Hz, 2H), 3.80 (t, J = 4.5 Hz, 2H), 3.49 (s, 3H), 3.31-3.26(m, 2H), 3.10-2.91 (m, 6H), 2.41-2.22(m, 3H), 2.01-1.53 (m, 11H) ppm. ¹³C NMR (125 MHz, CDCh) ô 171.4, 171.2, 160.8, 158.1, 151.0, 150.9,

150.7, 148.7, 146.4, 146.2, 130.6, 130.5, 126.7, 114.5, 96.8, 95.3, 70.9, 67.3, 63.7, 59.3,

59.1, 52.2, 47.1, 45.4, 39.9, 37.3, 35.7, 32.0, 31.8, 31.7, 31.5, 25.0, 22.8, 22.6 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.44 min; (M+H¹) 530.2.

Example 92 4-Fluoro-l-(4-(4-(2-fluoroetlioxy)phenyl)pyrimidin-2-yl)-jV-(3-methylquinuclidin-3yl)piperidine-4-carboxamide

Exchanging 4-fluorophenylboronic acid for 2-(4-(2-fluoroethoxy)phcnyl)-4,4,5,5tetramethyl-l,3,2-dioxaborolane, ethyl pipcridinc-4-carboxylate for ethyl 4fluoropipcridine-4-carboxylate hydrochloride and Intermediate 5 for Intermediate 1, the same reaction sequence outlincd in Example 41 was used to generate the title compound. 'H NMR (400 MHz, CDCh) δ 8.35 (d, J = 5.2 Hz, IH), 8.04 (d, J=8.8 Hz, 2H), 7.02 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 5.6 Hz, IH), 6.41 (d, J = 6.8 Hz, IH), 4.88-4.74 (m, 4H), 4.35-4.26 (m, 2H), 3.31-3.29 (m, 2H), 3.00-2.85 (m, 6H), 2.41-2.19 (m, 3H), 1.96-1.52 (m, 9H) ppm. ¹³C NMR (100 MHz, CDCh) δ 171.4, 171.2, 163.8, 161.7, 160.4, 158.1,

130.7, 128.6, 114.6, 105.3, 97.1, 95.2, 82.6, 80.9, 67.3, 67.1, 63.0, 52.8, 46.5, 46.3, 39.3,

32.1, 32.0, 31.9, 31.8, 30.9, 30.1, 24.2, 22.8, 22.3 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.32 min; (M+H¹) 486.0.

Example 93 4-Fluoro-l-(4-(4-(2-methoxyetlioxy)phenyl)pyrirmdin-2-yl)-7V-(4-methyl-lazabicyclo[3.2.2]nonan-4-yl)piperidine-4-carboxamide

Exchanging 4-fluorophenylboronic acid for (4-(2-mcthoxyethoxy)phenyl)boronic acid and ethyl piperidine-4-carboxylate for ethyl 4-fluoropiperidine-4-carboxylatc hydrochloride, the same reaction sequence outlincd in Example 41 was used to generate the title compound. ’H NMR (500 MHz, CDCh) δ 8.35 (d, J= 5.0 Hz, IH), 8.03 (d, J = 9.0 Hz, 2H), 7.02 (d, J = 9.0 Hz, 2H), 6.92 (d, J = 5.5 Hz, 1 H), 6.37 (d, J = 7.0 Hz, 1 H), 4.88 (m, 2H), 4.21 (t, J= 4.5 Hz, 2H), 3.81 (t, J = 4.5 Hz, 2H), 3.49 (s, 3H), 3.32-3.27 (m, 2H), 3.09-2.89 (m, 6H), 2.40-2.21 (m, 3H), 2.01-1.53 (m, 11H) ppm. ¹³C NMR (100 MHz, CDCh) δ 171.2, 171.0, 163.9, 161.7, 160.8,158.1, 130.3,128.5,114.6, 105.2, 97.2,

95.3, 70.9, 67.3, 59.3, 53.0, 47.5, 46.0, 39.3, 38.7, 36.2, 32.2, 32.0,31.9, 31.7, 25.0, 24.1, 23.8 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.33 min; (M+H¹) 512.0.

Example 94 4-Fluoro-l-(4-(4-fluorophenyl)pyrimidÎn-2-yl)-A^r-(4-methyl-lazabicyclo[3.2.2]nonan-4-yl)piperidine-4-carboxamide

Exchanging ethyl piperidine-4-carboxylate for ethyl 4-fIuoropiperidine-4-carboxylatc hydrochloride, the same réaction sequence outlined in Example 41 was used to generate the title compound. NMR (400 MHz, CDCh) δ 8.36 (d, J= 5.2 Hz, IH), 8.07-7.96 (m,

2H), 7.14 (t, ./= 8.7 Hz, 2H), 6.89 (d, J = 5.2 Hz, IH), 6.35 (d, J= 7.2 Hz, IH), 4.92-4.76 (m, 2H), 3.36-3.19 (m, 2H), 3.10-2.73 (m, 6H), 2.38-2.12 (m, 3H), 2.02-1.68 (m, 6H),

208

1.67-1.40 (m, 5H) ppm. Purity: 99.7% (214 & 254 nm) UPLCMS; rétention time: 0.87 min; (M+H⁴) 456.5.

Example 95 4-Fhioro-l-(4-(4-fluorophenyl)pyrimidm-2-yl)-/V-(3-metliylquinuclidin-3yl)piperidine-4-carboxainide

Exchanging ethyl piperidine-4-carboxylate for ethyl 4-fluoropipcridine-4-carboxylate hydrochloridc and Intermediate 5 for Intermediate 1, the same reaction sequence outiined in Example 41 was used to generate the title compound. ’H NMR (400 MHz, CDCI3) δ

8.36 (d, J = 5.1 Hz, 1 H), 8.07-7.97 (m, 2H), 7.18-7.06 (m, 2H), 6.89 (d, J = 5.1 Hz, 1 H),

6.37 (d, J= 6.9 Hz, IH), 4.93-4.75 (m, 2H), 3.37-3.18 (m, 2H), 2.99-2.67 (m, 6H), 2.372.09 (m, 3H), 1.95-1.67 (m, 4H), 1.60-1.34 (m, 5H) ppm. Purity: 99.7% (214 & 254 nm) UPLCMS; rétention time: 0.92 min; (M+H¹) 442.5,

Example 96

-(4-(4~(M eth oxy met hy l)ph eny l)py r i midin-2-y l)-4-methy l-7V-(4-methy I-1 azabicyclo[3.2.2]nonan-4-yI)piperidine-4-carboxamide

Exchanging 4-fluorophcnylboronic acid for 2-(4-(methoxymethyl)phcnyl)-4,4,5,5tetramethyl-l,3,2-dioxaborolanc and ethyl 4-piperidine-4-carboxylate for ethyl 4methylpiperidine-4-carboxylatc hydrochloride, the same reaction sequence outiined in Example 41 was used to generate the title compound. *H NMR (400 MHz, CDClj) δ 8.35 (d, J= 5.1 Hz, IH), 8.03 (d, J= 8.2 Hz, 2H), 7.43 (d, .7 = 8.2 Hz, 2H), 6.92 (d, ./ = 5.1 Hz, IH), 5.48 (s, IH), 4.52 (s, 2H), 4.27-4.16 (m, 2H), 3.75-3.64 (m, 2H), 3.41 (s, 3H), 3.092.74 (m, 6H), 2.44-2.32 (m, IH), 2.11-2.01 (m, 2H), 2.00-1.89 (m, IH), 1.87-1.45 (m, 10H), 1.27 (s, 3H) ppm. Purity: >99.9% (214 & 254 nm) UPLCMS; rétention time: 0.83 min; (M+H⁺) 478.4.

Example 97 l-(4-(4-((2-Methoxyethoxy)methyl)phenyl)pyrimidin-2-yl)-4-ineihy]-7V-(4-methyl-lazabicyclo[3.2.2]nonan-4-yl)piperidine-4-carboxamide

4.4.5.5- tetramcthyl-l,3,2-dioxaborolane and ethyl 4-pipcridine-4-carboxylate for ethyl 4methylpiperidine-4-carboxylate hydrochloride, the same réaction sequence outiined in Example 41 was used to generate the title compound. *H NMR (400 MHz, CDCI3) δ 8.368.35 (d, J = 5.2 Hz, 1 H), 8.03 (d, J = 8.0 Hz, 2H), 7.45 (d, .7=8.0 Hz, 2H), 6.92 (d, J = 4.8 Hz, IH), 5.50 (s, IH), 4.64 (s, 2H), 4.23-4.19 (m, 2H), 3.72-3.58 (m, 6H), 3.41 (s, 3H), 3.08-2.84 (m, 6H), 2.42 (m, IH), 2.07-1.50 (m, 13H), 1.27 (s, 3H) ppm. ^l3C NMR (100 MHz, CDChjÔ 175.9, 164.0, 161.8, 158.3, 140.7, 137.0, 127.8, 127.0, 105.4, 72.9, 72.0, 69.4, 59.3, 59.1, 53.2, 47.8, 45.9, 41.9, 40.9, 39.2, 36.2, 34.9, 25.8, 25.1, 24.3, 24.2 ppm. Purity: > 95% LCMS (214 nm & 254 nm); rétention time 1.35 min; (M+H¹) 522.3.

Example 98 l-(4-(4-((2-Methoxyethoxy)methyl)phenyl)pyrimidin-2-yl)-4-methyl-jV-(3methylquinuclidin-3-yl)piperitline-4-carboxamide

Exchanging 4-fluorophcnylboronic acid for 2-(4-((2-methoxyethoxy)methyl)phenyI)-

4.4.5.5- tetramethyl-l,3,2-dioxaborolane, ethyl 4-piperidine-4-carboxylate for ethyl 417263

209 methylpipcridine-4-carboxylatc hydrochloride and intermediate 5 for Intermediate 1, the same reaction sequence outlined in Example 41 was used to gcncrate the title compound. ’H NMR (500 MHz, CDC1₃) δ 8.37 (d, J= 4.5 Hz, I H), 8.04 (d, J = 8.0 Hz, 2H), 7.46 (d, J= 8.5 Hz, 2H), 6.93 (d, J= 5.5 Hz, IH), 5.62 (s, IH), 4.66 (s, 2H), 4.26-4.23 (m, 2H), 3.71-3.60 (m, 6H), 3.43 (s, 3H), 3.04-2.82 (m, 6H), 2.20 (m, IH), 2.10-2.07 (m, 2H), 1.82-1.49 (m, 9H), 1.29 (s, 3H) ppm. ¹³C NMR (125 MHz, CDCI3) Ô 176.0, 164.0, 161.8,

158.3, 140.7, 137.1, 127.8, 127.1, 105.4, 72.9, 72.0, 69.4, 63.2, 59.1, 52.8, 48.8, 46.6,

46.5, 41.8, 41.0, 34.9, 30.6, 25.8, 24.2, 23.0, 22.6 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.33 min; (M+H⁺) 508.3.

Example 99 l-(4-(4-Fluoroplienyl)pyrimidin-2-yl)-4-hy(lroxy-jV-(4-methyl-lazabicycIo[3.2.2]nonan-4-yl)pïperidme-4-carboxamtde

To a stirred solution of 2,4-dichloropyrimîdine (3.00 g, 20.1 mmol) in toluene (25 mL) was added 4-fluorophenylboronic acid (2.82 g, 20.1 mmol), potassium carbonate (8.32 g, 60.3 mmol), tctrakis(triphenylphosphine)palladium(0) (0.630 g, 0.545 mmol) and 1:1 (v/v) ethanol/water (36 mL). The mixture was heated at 55 °C for 12 hours and then concentrated. The residue was diluted with water and extracted with ethyl acetate. The combined cxtracts were washed with brine, dried (NujSO;) and concentrated. The crude material was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford 2-chloro-4-(4-fluorophenyl)pyrimidine as a yellow solid (2.50 g, 61%). To a stirred solution of this compound (1.04 g, 5,00 mmol) in N,/^-dimethylformamide (15 mL) was added 4-hydroxypiperidinc-4-carboxylic acid (0.910 g, 5.00 mmol) and césium carbonate (3.43 g, 10.5 mmol). The mixture was heated ovemight at 100 °C and then concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford l-(4-(4-fluorophenyl)pyrimidin-2-yl)-4hydroxypipcridine-4-carboxylic acid as a yellow solid (1.02 g, 64%). Using General Procedure D and Intermediate 5, this carboxylic acid was subjected to amidc coupling to generate the title compound as a white solid (0.071 g, 39%).^lH NMR (500 MHz, CDCI3) δ 8.37 (d, J= 5.0 Hz, IH), 8.07-8.04 (m, 2H), 7.15 (t, J= 8.5 Hz, 2H), 6.89 (d, J= 5.0 Hz, IH), 6.74 (s, IH), 4.82 (d,./ = 12.5 Hz, 2H), 3.99 (brs, IH), 3.34-3.30 (m, 2H), 3.012.84 (m, 6H), 2.39 (m, IH), 2.17-2.14 (m, 2H), 1.95-1.49 (m, 1 IH) ppm. ^lâC NMR (125 MHz, CDCI3) δ 175.3, 165.3, 163.3, 163.2, 161.7, 158.4, 133.8, 129.0, 128.9, 115.7,

115.5, 105.2, 73.5, 59.0, 53.0, 47.8, 45.8, 39.5, 38.7, 36.1, 34.3, 34.1, 25.1, 24.1, 23.9 ppm. Purity: > 98% LCMS (214 nm & 254 nm); rétention time 1.52 min; (M+H'} 454.3.

Example 100 l-(4-(4-FIuorophenyl)pyrimidiii-2-yl)-4-me(lioxy-/V-(4-mcthyl-lazabicyclo[3.2.2|nonan-4-yl)piperidine-4-carboxamide

To a stirred solution of 2,4-dichloropyrimidîne (3.00 g, 20.1 mmol) in toluene (25 mL) was added 4-fluorophenylboronic acid (2.82 g, 20.1 mmol), potassium carbonate (8.32 g, 60.3 mmol), tetrakis(lriphenylphosphine)palladium(0) (0.630 g, 0.545 mmol) and 1:1 (v/v) ethanol/water (36 mL). The mixture was heated at 55 °C for 12 hours and then concentrated. The residue was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried (NajSCL) and concentrated. The crude material was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford 2-chloro-4-(4-fluorophenyl)pyrimidine as a yellow solid (2.50 g, 61%). To a stirred and cooled solution of this compound (0.317 g, 1.00 mmol) in N,N

210 dimethylformamide (15 mL) was added sodium hydride (60% dispersion in minerai oil; 0,120 g, 3.00 mmol). The mixture was stirred for 30 minutes before adding iodomethane (0.187 mL, 3.00 mmol) and then allowed to slowly warm to room température and stirred overnight. The reaction was concentrated and the residue was partitioned between water and ethyl acetate. The organic layer was combined with an additional ethyl acetate extract, dried (NaîSO₄) and concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford methyl 1-(4-(4fluorophcnyl)pyrimidin-2-yl)-4-methoxypiperidine-4-carboxylate as a yellow oil (0.210 g, 61%). To a stirred solution of this compound (0.165 g, 0.500 mmol) in methanol (3 mL) and water (1 mL) was added sodium hydroxide (0.100 g, 2.50 mmol). After ovemight stirring, the solution was acidifïed with 2.0 M hydrochloric acid and extracted with ethyl acetate. The combined extracts were dried (Na2SO₄) and concentrated to afford l-(4-(4-fluorophcnyl)pyrimidin-2-yl)-4-methoxypiperidinc~4-carboxylic acid as a white solid (0.157 g, 95%). Using General Procedure D and Intermediate 5, this carboxylic acid was subjected to amide coupling to generate the title compound as a white solid (0.061 g, 44%).‘H NMR (500 MHz, CDCh) δ 8.37 (d, J =5.5 Hz, IH), 8.07-8.05 (m, 2H), 7.16 (t, J = 8.5 Hz, 2H), 6.90 (d, J = 5.5 Hz, IH), 6.46 (s, IH), 4.70-4.67 (m, 2H), 3.36-3.29 (m, 5H), 3.08-2.87 (m, 6H), 2.39 (m, IH), 2.13-1.51 (m, 13H) ppm. ¹³C NMR (100 MHz, CDCI3) ô 173.5, 165.6, 163.2, 163.1, 161.8, 158.4, 133.9, 133.8, 129.0, 128.9, 115.7, 115.5, 105.2, 79.3, 59.0, 53.1,51.7,47.6, 46.1,39.6, 38.8, 36.4,31.4, 30.4, 25.0, 24.1, 24.0 ppm. Purity: > 98% LCMS (214 nm & 254 nm); rétention time 1.38 min; (M+H^f) 468.3.

Example 101 4-Methoxy-l-(4-(4-(3-mcthoxypropoxy)plienyl)pyrimidin-2-yl)-/V-(4-methyl-lazabicyclo [3.2.21 no nan-4-yl)piperidine-4-carboxamide

Exchanging 4-fluorophenylboronic acid for 2-(4-(3-methoxypropoxy)phenyl)-4,4,5,5tctramethyl-l,3,2-dioxaborolane, the same reaction sequence outlincd in Example 100 was used to generate the title compound. *H NMR (500 MHz, CDCh) ô 8.34 (d, J = 5.0 Hz, IH), 8.02 (d, J = 8.5 Hz, 2H), 6.99 (d, J = 9.0 Hz, 2H), 6.89 (d, J = 5.0 Hz, IH), 6.46 (s, IH), 4.69 (s, 2H), 4.14 (t, J= 6.5 Hz, 2H), 3.60 (t, J = 6.0 Hz, 2H), 3.39-3.31 (m, 8H), 3.12-2.91 (m, 6H), 2.43 (m, IH), 2.12-1.52 (m, 15H) ppm. ^I3CNMR (125 MHz, CDC1₃) δ 173.7, 163.9, 161.8, 161.0, 158.0, 130.1, 128.5, 114.5, 104.9, 79.4, 69.1, 64.9, 58.9,

58.8, 53.0, 51.8, 47.6, 46.0, 39.6, 38.3, 36.2, 31.5, 30.4, 29.6, 25.0, 23.7, 23.6 ppm. Purity: > 96% LCMS (214 nm & 254 nm); rétention time 1.36 min; (M+H⁺) 538.3.

Example 102 l-(5-Fluoro-4-(4-(2-fluoroethoxy)phenyl)pyrimidin-2-yl)-4-methoxy-N-(4-methyl-lazabicyclo[3.2.2[nonan-4-yl)piperidlne-4-carboxamide

Exchanging 4-fluorophenylboronic acid for 2-(4-(2-fluoroethoxy)phenyi)-4,4,5,5tetramethyl-l, 3,2-dioxaborolane and 2,4-dichloropyrimidine for 2,4-dichloro-5fluoropyrimidine, the same réaction sequence outlined in Example 100 was used to generate the title compound. ’H NMR (500 MHz, CDCh) ô 8.22 (d, J = 4.0 Hz, IH), 8.11 (d, J= 8.5 Hz, 2H), 7.03 (d, J = 8.5 Hz, 2H), 6.45 (s, IH), 4.87-4.75 (dt, ./=47,5 Hz & 4.0 Hz, 2H), 4.58-4.56 (m, 2H), 4.33-4.27 (dt, J = 27.5 Hz & 4.0 Hz, 2H), 3.34 (s, 3H), 3.31-3.27 (m, 2H), 3.03-2.87 (m, 6H), 2.37 (m, IH), 2.09-1.50 (m, 13H) ppm. ^l3C NMR (125 MHz, CDCh) δ 173.5, 160.3, 158.3,150.8, 150.7, 150.5, 148.5, 146.4, 146.2, 130.7,

130.6, 127.3, 127.2, 114.4, 82.5, 81.1, 79.2, 67.2, 67.0, 59.0, 53.2, 51.7, 47.6, 46.1,40.2,

211

39.0, 36.4, 31.3, 30.3, 25.0, 24.3, 24.1 ppm. Purity: > 97% LCMS (214 nm & 254 nm); rétention time l .49 min; (M+H) 530.3.

Example 103 I-(4-(4-(2-Fluoroethoxy)phcnyl)pyrimidin-2-yl)-4-metlioxy-/V-(4-niethyl-lazabicyclo[3.2.2]nonan-4-yi)piperidine-4-carboxamide

Exchanging 4-fluorophenylboronic acid for 2-(4-(2-fluoroethoxy)phcnyl)-4,4,5,5tetramethyl-I,3,2-dioxaborolane, the same reaction séquence outlined in Example 100 was used to generate the title compound. *H NMR (500 MHz, CDCI3) δ 8.33 (d, J- 5.0 Hz, 1 H), 8.03 (d, J= 9.0 Hz, 2H), 7.01 (d,./ = 9.0 Hz, 2H), 6.88 (d, J= 4.5 Hz, IH), 6.44 (s, IH), 4.85-4.73 (dt, J = 47.5 Hz & 4.0 Hz, 2H), 4.68-4.66 (m, 2H), 4.32-4.24 (dt, J = 27.5 Hz & 4.0 Hz, 2H), 3.33-3.27 (m, 5H), 3.07-2.84 (m, 6H), 2.37 (s, IH), 2.12-1.49 (m, 13H) ppm. ^l3C NMR (125 MHz, CDCh) δ 173.6, 163.7, 161.8, 160,4, 158.1, 130.8,

128.6, 114.6, 105.0, 82.5, 81.2, 79.4, 67.2, 67.1, 59.0, 53.2, 51.8, 47.6, 46.1, 39.6, 38.8,

36.4, 31.5, 30.4, 25.0, 24.1, 24.0 ppm. Purity: > 96% LCMS (214 nm & 254 nm); rétention time 1.35 min; (M+H) 512.3.

Example 104 1-(4-(4-FluorophenyI)-5-(2-methoxyethoxy)pyrimidin-2-y!)-/V-(4-methyl-lazabicyclo[3.2.2]nonan-4-yl)piperidine-4-carboxamide

Exchanging 2,4-dichIoropyrimidine for 2,4-dichloro-5-methoxypyrimidine, the first two steps of the réaction sequence outlined in Example 41 were used to generate the intermediate, ethyl 1 -(4-(4-fluorophenyl)-5-methoxypyrimidin-2-yl)piperidinc-4carboxylate. To a stirred and cooled (-70 °C ) solution of this compound (2.20 g, 6.13 mmol) in dichloromethane (30 mL) was added a 4.0 M solution of boron tribromide in dichloromethane (6.13 mL, 24.5 mmol). The reaction was stirred at -70 °C for 1 hour, warmed to 0 °C, and then stirred for another 2 hours. After quenching with added methanol, the reaction mixture was partitioncd between water and dichloromethane. The aqueous phase was extracted again with dichloromethane and the combined organic layers were dried (Na₂SÛ4) and concentrated. The residue was purified by flash chromatography over silica using a dichloromethane/methanol eluant to afford ethyl l-(4(4-fluorophcnyl)-5-hydroxypyrimidin-2-yl)piperidine-4-carboxylate as a brown oil (1.50 g, 71%). To a stirred solution of this compound (0.900 g, 2.61 mmol) in N,/Vdimethylformamide (10 mL) was added 1 -bromo-2-methoxyethane (0.725 g, 5.22 mmol) and césium carbonate (2.55 g, 7.83 mmol). The reaction was stirred at 60 °C for 4 hours before diluting with water and extracting with ethyl acetate. The combined organic layers were washed with water and aqueous sodium chloride solution, dried (Na₂SO4) and concentrated. The residue was purified by flash chromatography over silica using a hexanc/cthyl acetate eluant to afford ethyl l-(4-(4-fluorophenyl)-5-(2methoxyethoxy)pyrimidin-2-yl)piperidine-4-carboxylate as a brown oil (0.550 g, 52%). To a stirred solution of this ester (0.550 g, 1.36 mmol) in 1:1:1 tetrahydrofuran/water/methanol (9 mL) was added sodium hydroxide (0.273 g, 6.82 mmol). After 3 hours, the reaction was concentrated and the residue was taken up in water. The solution was made acidic (~pH 3) with the addition of 1.0 N hydrochloric acid and then extracted with ethyl acetate. The combined extracts were dried (Na₂SC>4) and concentrated to afford l-(4-(4-fIuorophenyl)-5-(2-methoxyethoxy)pyrimidin-2yl)piperidinc-4-carboxylic acid as a light yellow solid (0.450 g, 88%). Using General Procedure D and Intermediate 5, this carboxylic acid was subjected to amide coupling to

212 generate the title compound as a light yellow solid (0.090 g, 44%).^lH NMR (500 MHz, CDCb) δ 8.22-8.19 (m, 3H), 7.15-7.11 (m, 2H), 5.37 (s, IH), 4.82 (d, J= 13.5 Hz, 2H), 4.03 (t, J = 4.5 Hz, 2H), 3.66 (t, J= 5.0 Hz, 2H), 3.41 (s, 3H), 3.07-2.81 (m, 8H), 2.38-

2.30 (m, 2H), 1.97-1.51 (m, 13H) ppm. ^I3C NMR (125 MHz, CDClj) δ 174.2, 164.7,

162.7, 157.7, 154.1, 148.0, 143.2, 132.2, 131.6, 131.5, 115.1, 114.9, 71.1, 71.0, 59.4, 59.1, 53.1, 47.6, 46.1, 44.6, 44.1, 39.3, 36.1, 28.9, 28.6, 25.1, 24.3, 24.2 ppm. Purity: > 98% LCMS (214 nm & 254 nm); rétention time 1.55 min; (M+H⁴) 512.3.

Example 105 l-(4-(4-Fluorophenyl)-6-(2-mcthoxyethoxy)pyrimÎdin-2-yl)-A^r-(4-methyl-lazabicyclo[3.2.2Jnonari-4-yl)pipcridine-4-carboxamide

Exchanging 2,4-dichloropyrimidine for 2,4,6-trichloropyrimidinc, the first step of the reaction sequence outlined in Example 41 was used to generate the intermediate 2,4dichloro-6-(4-fluorophcnyl)pyrimidine. To a stirred solution of this compound (0.800 g,

3.30 mmol) in acetonitrile (20 mL) was added césium carbonate (3.23 g, 9.90 mmol). The suspension was stirred at 0 °C for 30 minutes before adding 2-methoxycthanol (0.201 g, 2.64 mmol), dropwise over 2-3 minutes. The mixture was allowed to slowly warm to room température, stirred for two more hours and then concentrated. The residue was purified by flash chromatography over silica using a hcxane/ethyl acetate eluant to afford 2-chloro-4-(4-fluorophenyl)-6-(2-mcthoxyethoxy)pyrimidine as a colorless oil (0.470 g, 51%). To a stirred solution of this compound (0.300 g, 1.06 mmol) in éthanol (5 mL) was added trifluoroacetic acid (0.081 mL, 1.06 mmol) and ethyl piperidine-4-carboxylate (0.200 g, 1.28 mmol). The reaction was heated overnight at 80 °C, cooied and concentrated. The residue was purified by flash chromatography over silica using a hcxane/ethyl acetate eluant to afford ethyl l-(4-(4-fluorophenyl)-6-(2mcthoxycthoxy)pyrimidin-2-yl)pipcridine-4-carboxylate as a colorless oil (0.400 g, 94%). To a stirred solution of this intermediate (0.400 g, 0.990 mmol) in methanol (2 mL), tetrahydrofuran (1 mL) and water (1 mL) was added sodium hydroxide (0.199 g, 4.96 mmol). After overnight stirring, the reaction was concentrated. The residue was taken up in water and the solution was made acidic (-pH 3) with 1.0 N hydrochloric acid. The resulting suspension was extracted with ethyl acetate. The combined extracts were dried (Na₂SO4) and concentrated to afford l-(4-(4-fluoropheny 1)-6-(2mcthoxycthoxy)pyrimidin-2-yl)pipcridine-4-carboxylic acid as a white solid (0.320 g, 86%). Using General Procedure D and Intermediate 5, this carboxylic acid was subjected to amide coupling to generate the title compound as a white solid (0.100 g, 49%).^lH NMR (500 MHz, CDClj) δ 8.02-7.98 (m, 2H), 7.15-7.11 (m, 2H), 6.44 (s, IH), 5.37 (s, IH), 4.95 (d, J= 12.5 Hz, 2H), 4.52 (t, J= 4.5 Hz, 2H), 3.77 (t, J= 4.5 Hz, 2H), 3.47 (s, 3H), 3.07-2.94 (m, 6H), 2.88-2.84 (m, 2H), 2.40-2.33 (m, 2H), 1.95-1.51 (m, 13H) ppm. ^,3C NMR (125 MHz, CDC1₃) Ô 174.1, 170.6, 165.0, 164.2, 163.1, 161.4, 134.2, 134.1,

128.8, 115.5, 115.3, 92.0, 70.8, 64.8, 59.4, 59.1, 53.1, 47.7, 46.1, 44.7, 43.6, 39.2, 36.1,

30.9, 28.9, 28.7, 25.1, 24.3, 24.1 ppm. Purity: > 97% LCMS (214 nm & 254 nm); rétention time 1.40 min; (M+H⁴) 512.4.

Example 106

1-(4-(4-FIuorophenyl)pyriilin-2-yl)-jV-(4-methyl-l-azabicyclo[3.2.2]nonan-4yl)piperidine-4-carboxamide

To a stirred solution of 4-bromo-2-fluoropyridine (1.76 g, 10.0 mmol) in acetonitrile (10 mL) was added ethyl piperidine-4-carboxylatc (2.36 g, 15.0 mmol) and potassium

213 carbonate (2.76 g, 20.0 mmol). The reaction was heated at 60 °C ovemight and then concentrated. The residue was purified by flash chromatography over silica using a hexanc/ethyl acetate cluant to afford ethyl l-(4-bromopyridin-2-yl)pipcridine-4carboxylatc as a colorless oil (2.40 g, 76%). To a stirred solution of this compound in 10:1 1,4-dioxane/water (20 mL) was added 4-fluorophenylboronic acid (0.536 g, 3.83 mmol) potassium carbonate (1.10 g, 7.98 mmol) and [1,1*bis(diphenylphosphino)fcrrocenc]dichloropalladium(II) (0.117 g, 0.160 mmol). The reaction was heated ovemight at 95 °C. After diluting with water, the reaction mixture extracted with ethyl acetate. The combined extracts were dried (Na₂SO4) and concentrated. The residue was purified by flash cliromatography over silica using a hexane/ethyl acetate cluant to afford ethyl l-(4-(4-fluorophenyl)pyridin-2-yl)piperidine-4carboxylate as a white solid (1.00 g, 95%). Using the final two steps described in Exampie 41, this intermediate was used to prépare the title compound. *H NMR (500 MHz, CDCk) δ 8.23 (d, J= 5.0 Hz, IH), 7.60-7.55 (m, 2H), 7.18-7.14 (m, 2H), 6.80-6.78 (m, 2H), 5.37 (s, IH), 4.45-4.42 (m, 2H), 3.07-2.80 (m, 8H), 2.39-2.30 (m, 2H), 1.98-1.50 (m, 13H) ppm. ¹³C NMR (125 MHz, CDCb) δ 174.0, 164.1, 162.2, 159.9, 149.1, 148.4,

135.7, 128.7, 115.9, 115.7, 111.7, 105.1, 59.5, 53.1, 47.6, 46.1, 45.2, 44.4, 39.2, 36.1,

28.7, 28.4, 25.1, 24.3, 24.2 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.04 min; (M+H⁴) 437.2.

Exampie 107 l-(5-(4-Fluorophenyl)pyridin-3-yl)-JV-(4-niethyl-l-azabicyclo[3.2.2]nonan-4yl)piperi(line-4-carboxamide

A stirred mixture of 3,5-dibromopyridine (0.500 g, 2.11 mmol), ethyl pipcridinc-4carboxylate (1.60 g, 10.2 mmol) and césium carbonate (0.729 g, 2.24 mmol) was heated in a microwave reactor at 150 °C for 1 hour. The reaction was cooled and concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford ethyl l-(5-bromopyridin-3-yl)piperidine-4-carboxylate as a yellow oil (0.078 g, 12%). Using the final three steps described in Example 106, this intermediate was used to préparé the title compound. H NMR (500 MHz, CDC1₃) δ 8.30 (d, J- 2.0 Hz, IH), 8.27 (s, IH), 7.55-7.52 (m, 2H), 7.30 (s, IH), 7.16 (t, J= 8.5 Hz, 2H), 5.43 (s, IH), 3.85-3.82 (m, 2H), 3.06-2.85 (m, 8H), 2.40-2.23 (m, 2H), 1.99-1.54 (m, 13H) ppm. ¹³C NMR (125 MHz, CDCI3) δ 173.8, 163.8, 161.8, 146.9, 139.0, 137.6, 135.8, 134.5,

128.9, 121.1, 116.0, 115.8, 59.5, 53.1,48.6, 47.6, 46.1,43.7,39.2, 36.1, 28.8, 28.5, 25.1,

24.3, 24.2 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.19 min; (M+H⁴) 437.3.

Exampie 108 l-(2-(4-Fluorophenyl)pyridin-4~yl)-7V-(4-methyl-l-azabicyclo[3.2.2]nonan~4yl)piperidine-4-carboxamide

To a stirred solution of 2,4-dichloropyridine (4.00g, 27.0 mmol) in a mixture of N_tNdimethylformamide (50 mL) and water (25 mL) was added 4-fluorophenylboronic acid (3.78 g, 27.0 mmol), sodium bicarbonate (2.27 g, 27.03 mmol) and bis(triphenylphosphinc)palladium(n) dichloride (0.948 g, 1.35 mmol). The reaction was heated ovemight at 80 °C and then concentrated. The residue was taken up in ethyl acetate, washed with water and aqueous sodium chloride solution, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford 4-chloro-2-(4-fluorophenyl)pyridinc as a colorless

214 solid (2.21 g, 39%). This intermediate (2.18 g, 10.5 mmol) was combined with ethyl piperidinc-4-carboxylate (3.30 g, 21.0 mmol), N,N-diisopropylethylamine (4.4 mL, 25 mmol) and acetonitrile (12 mL) in a sealcd microwave reaction vessei. With stirring, the mixture was heated in a microwave reactor for 5 hours at 180 °C. The reaction was then concentrated and the residue was taken up in ethyl acetate and washed with an aqueous sodium bicarbonate solution. The aqueous layer was back-cxtractcd with ethyl acetate and the combined organic layers were dried (Na₂SO^) and concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford ethyl 1 -(2-(4-fluorophcnyl)pyridin-4-yl)pipcridine-4-carboxylate as a pale amber oil (2.88 g, 84%). Using the final two steps described in Example 41, this intermediate was used to préparé the title compound. 'H NMR (400 MHz, CDC1₃) δ 8.22 (d, J= 6.0 Hz, IH), 8.158.09 (m, 2H), 7.42 (s, IH), 7.33-7.22 (m, 3H), 6.79 (dd, ./=6.0, 2.5 Hz, IH), 4.15-4.05 (m, 2H), 3.03-2.69 (m, 8H), 2.55-2.43 (m, IH), 2.34-2.27 (m, IH), 1.82-1.44 (m, 9H), 1.41-1.27 (m, 4H) ppm. Purity: 95% (214 & 254 nm) UPLCMS; rétention time: 0.46 min; (M+H⁴) 437.4.

Exampie 109 l-(4-(4-Fluorophcnyl)pyrimidin-2-yl)-/V-mcthyI-A^r-(quinuclidin-3-yl)piperidinc-4carboxamide

Using General Procedure D and the reaction inputs l-(4-(4-fluorophcnyl)pyrimidin-2yl)piperidine-4-carboxylic acid (prepared as described in Example 41) and Nmethylquinuclidin-3-amine, the title compound was prepared. ’H NMR (500 MHz, CDCI3) δ 8.39 (d, J= 5.5 Hz, IH), 8.08-8.05 (m, 2H), 7.17 (t, J= 8.5 Hz, 2H), 6.90 (d, J = 5.0 Hz, IH), 4.99-4.96 (m, 2H), 4.58-4.54 (m, IH), 3.33-2.83 (m, 12H), 2.08-1.55 (m, 9H) ppm. ^,3C NMR (125 MHz, CDCI3) δ 175.6, 165.3, 163.3, 163.2,161.8, 158.4, 133.9, 129.0, 128.9, 115.7, 115.5, 105.2, 51.1, 47.5, 46.8, 43.5, 28.4, 21.8 ppm. Purity: > 96% LCMS (214 nm & 254 nm); rétention time 1.24 min; (M+H ) 424.2.

Example 110 l-Azabicyclo[3.2.2]nonan-4-yl l-(4-(4-fluorophenyl)pyrimidin-2-yl)piperidine-4carboxylatc

To a stirred solution of ethyl l-(4-(4-fluorophenyl)pyrimidin-2-yl)piperidine-4carboxylate (prepared as described in Example 41; 0.200 g, 0.607 mmol) and Intermediate 3 (0.094 g, 0.666 mmol) in toluene (10 mL) was added a 60% dispersion of sodium hydride in minerai oil (0.097 g, 2.43 mmol) and 4Â molecular sieves. The mixture was heated at reflux for two nights before filtering off the solids and conccntrating. The residue was purified by reverse phase préparative HPLC to afford the title compound as yellow oil (0.066 g, 27%).‘h NMR (500 MHz, CDC1₃) ô 8.38 (d, J = 5.0 Hz, IH), 8.09-8.05 (m, 2H), 7.17 (t, J= 8.5 Hz, 2H), 6. 90 (d, J = 5.0 Hz, IH), 5.055.00 (m, 111), 4,83-4.80 (m, 2H), 3.22-2.85 (m, 8H), 2.66-2.59 (m, IH), 2.06-1.56 (m, 11H) ppm. *³C NMR (125 MHz, CDCI3) δ 174.0, 165.3, 163.3, 163.2, 161.7, 158.4, 133.8, 129.0, 128.9, 115.7, 115.5, 105.1, 78.1, 51.8, 47.9, 45.2, 43.2, 41.8, 33.4, 30.3, 28.0, 24.9, 22.3 ppm. Purity: > 98% LCMS (214 nm & 254 nm); rétention timel.47 min; (M+H⁴) 425.2.

Example 111 l-(5-Fluoro-4-(4-(3-inethoxypropoxy)phenyl)pyrimidin-2-yl)-yV-(4-methyl-lazabicyclo[3.2.2]nonan-4-yl)azetidine-3-carboxamide

215

Exchanging 4-fluorophenylboronic acid for 2-(4-(3-mcthoxypropoxy)phenyl)-4,4,5,5tetramethyl-l,3,2-dioxaborolane, ethyl piperidinc-4-carboxylate for methyl azetidine-3carboxylate hydrochloride and 2,4-dichloropyrimidine for 2,4-dichloro-5fluoropyrimidinc, the same reaction sequence outlined in Example 41 was used to generate the title compound. *H NMR (500 MHz, CDC1₃) δ 8.23 (d, J = 4.5 Hz, 1 H), 8.10 (d, J= 8.5 Hz, 2H), 7.00 (d, J= 9.0 Hz, 2H), 5.55 (s, IH), 4.33-4.30 (m, 4H), 4.15 (t, J = 6.0 Hz, 2H), 3.59 (t, J= 6.0 Hz, 2H), 3.39-3.36 (m, 4H), 3.07-2.99 (m, 4H), 2.89-2.86 (m, 2H), 2.43 (s, IH), 2.12-2.07 (m, 2H), 1.99-1.54 (m, 9H) ppm. ¹³C NMR (125 MHz, CDCI3) Ô 171.5, 161.1, 160.0, 151.5, 151.4, 149.5, 146.4, 146.2, 130.7, 130.6, 126.1,

114.4, 69.1, 64.9, 59.9, 58.8, 53.3, 53.0, 47.2,46.4, 39.0, 36.1, 35.2, 30.9, 29.5, 24.9, 24.0 ppm. Purity: > 98% LCMS (214 nm & 254 nm); rétention time 1.41 min; (M+H⁴) 498.3.

Example 112 l-(5-Fluoro-4-(4-fluorophenyl)pyrimidin-2-yl)-A^r-(4-methyl-lazablcyclo[3.2.2]nonan-4-yl)azetidme-3-carboxamide

Exchanging ethyl pipcridinc-4-carboxyîate for methyl azetidine-3-cafboxylatc hydrochloride and 2,4-dichloropyrimidine for 2,4-dichloro-5-fluoropyrimidine, the same reaction sequence outlined in Example 41 was used to generate the title compound. *H NMR (500 MHz, CDCI3) δ 8.25 (d, J = 3.0 Hz, IH), 8.12-8.09 (m, 2H), 7.17-7.13 (m, 2H), 5.42 (s, IH), 4.32-4.27 (m, 4H), 3.36-3.33 (m, IH), 3.01-2.80 (m, 6H), 2.38 (m, IH), 1.97-1.52 (m,9H) ppm. ^BC NMR (125 MHz, CDCI3) ô 171.3, 165.3, 163.3,160.0, 159.9,

151.4, 150.7, 149.4, 146.9, 146.7, 131.2, 131.1, 129.9, 129.8, 115.7, 115.5, 59.9, 53.2, 53.0, 47.1, 46.5, 39.2, 36.2, 35.1, 24.8, 24.2, 24.1 ppm. Purity: > 98% LCMS (214 nm & 254 nm); rétention time 1.34 min; (M+H⁴) 428.2.

Example 113 l-(4-(4-Fluorophenyl)pyrimidin-2-yl)-A^r-(4-methyl-l-azabicyclo[3.2.2|nonan-4yl)azctidine-3-carboxamide

Exchanging ethyl piperidinc-4-carboxylate for methyl azetidine-3-carboxylate, the same réaction sequence outlined in Example 41 was used to generate the title compound. ’H NMR (500 MHz, CDC1₃) δ 8.36 (d, ./=5,5 Hz, 111), 8.06-8.03 (m, 2H), 7.14 (t, J= 8.5 Hz, 2H), 6.96 (d, J= 4.5 Hz, IH), 5.44 (s, IH), 4.35-4.33 (m, 4H), 3.38-3.35 (m, IH), 3.00-2.81 (m, 6H), 2.38 (m, IH), 1.97-1.52 (m, 9H) ppm. ¹³C NMR (125 MHz, CDCI3) δ 171.2, 163.5, 163.4, 163.2, 158.4, 133.5, 129.1, 115.8, 115.6, 106.3, 60.0, 53.0, 52.9,

52.8, 47.2, 46.5, 39.2, 36.2, 35.4, 24.9, 24.2, 24.1 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.26 min; (M+H⁴) 410.2.

Example 114 l-(4^,-Fluoro-[l,r-biphenyl]-3-yl)-/V-(4-methyl-l-azabicyclo[3.2.2]nonan-4yl)azetidine-3-carboxamide

Exchanging ethyl piperidine-4-carboxylate for methyl azetidine-3-carboxylate, the same reaction sequence outlined in Example 33 was used to generate the title compound. *H

NMR (500 MHz, CDCI3) δ 7.55-7.52 (m, 2H), 7.30 (t, J= 8.0 Hz, IH), 7.12 (t, J= 8.5

Hz, 2H), 6.96 (d, J= 7.5 Hz, IH), 6.63 (s, IH), 6.50 (d, J = 8.0 Hz, IH), 5.75 (s, IH),

4.12-4.02 (m, 4H), 3.39-3.35 (m, IH), 3.03-2.84 (m, 6H), 2.40 (s, IH), 1.98-1.55 (m, 9H) ppm. ¹³C NMR (125 MHz, CDCI3) δ 171.6, 163.4, 161.4, 151.9, 141.2, 137.7, 129.4,

216

128.8, 128.7, 117.2, 115.5, 115.4, 110.8, 110.4, 59.8, 55.1, 55.0, 53.1, 47.3, 46.4, 39.1, 36.3,36.2, 24.9,24.2 ppm. Purity: > 98% LCMS (214 nm & 254 nm); rétention time 1.42 min; (M+H¹) 408.3.

Example 115 l-(4-(4-Fluorophenoxy)pyrimidin-2-yI)-7V-(4-methyl-l-azabicycIo[3.2.2]nonan-4yl)piperidine-4-carboxamide

To a stirred solution of 4-fluorophcnol (0.448 g, 4.00 mmol) in tetrahydrofuran (35 mL) was added potassium Zer/-butoxide (0.493 g, 4.40 mmol). After 30 minutes, 2,4dicliloropyrimidine (0.596 g, 4.00 mmol) was added and the reaction was left to stir for another 6 hours. At this time, the reaction was fïltered to remove the suspended solids and the filtrate was concentrated to afford crude 2-chloro-4-(4-fluorophenoxy)pyrimidine as a white solid (0.827 g, 92%). This intermediate (0.548 g, 2.40 mmol), which was clean enough to use without purification, was combined with ethyl piperidine-4-carboxylate (0.452 g, 2.88 mmol) and triethylamine (1.0 mL, 7.2 mL) in éthanol (10 mL). The stirred mixture was heated ovemight at 80 °C and then concentrated. The residue was purified by flash chromatography over silica using a hexane/cthyl acetate cluant to afford ethyl l-(4(4-fl·uoroρhenoxy)pyrimidin-2-yl)piperidίne-4-carboxylate as a light ycllow oil (0.639 g, 76%). To a stimed solution of this intermediate (0.330 g, 0.960 mmol) in 1:1 (v/v) methanol/water (4 mL) was added solid sodium hydroxide (0.192 g, 4.80 mmol). After ovemight stirring, the reaction was concentrated. The residue was dissolved in water, made acidic (pH ~3) with the addition of IN hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na₂SÛ4) and concentrated to afford l-(4-(4-fluorophenoxy)pyrimidin-2-yI)piperidine-4-carboxylic acid as a white solid (0.288 g, 95%). Using General Procedure D and Intermediate 5, this carboxylic acid was subjccted to amide coupling to generate the title compound as a white solid (0.019 g, 7%). *H NMR. (500 MHz, CDC1₃) δ 8.16 (d, J= 5.5 Hz, IH), 7.12-7.05 (m, 4H, ), 5.99 (d, J= 5.5 Hz, IH), 5.28(s, IH), 4.62-4.60 (m, 2H), 3.01-2.80 (m, 8H), 2.34-2.26 (m, 2H), 1.91-1.47 (m, 13H) ppm. ^t3C NMR (125 MHz, CDCI3) δ 173.9,169.9,

161.5, 160.9, 159.5, 158.9, 148.5, 123.2, 116.1, 115.9, 95.5, 59.5, 53.2, 47.6, 46.2, 44.5,

43.4, 39.4, 36.1, 28.8, 28.5, 25.1, 24.4, 24.2 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.32 min; (M+H') 454.3.

Example 116 4-Fluoro-l-(4-(4-fluorophenoxy)pyrimidin-2-y])-7V-(4-methyl-lazabicyclo[3.2.2]nonan-4-yl)piperidinc-4-carboxamide

Exchanging ethyl pipcridinc-4-carboxylate for ethyl 4-fluoropiperidinc-4-carboxylatc hydrochloride, the same reaction sequence outlined in Example 115 was used to generate the title compound. ’H NMR (400 MHz, CDCI3) δ 8.17 (d, J = 5.5 Hz, IH), 7.15-7.02 (m, 4H), 6.31 (d, J= 7.3 Hz, IH), 6.03 (d, J= 5.5 Hz, 2H), 4.62-4,41 (m, 2H), 3.22-2.76 (m, 8H), 2.36-2.28 (m, IH), 2.26-2.02 (m, 2H), 2.00-1.89 (m, IH), 1.87-1.67 (m, 5H), 1.671.42 (m, 5H) ppm. Purity: >99.9% (214 & 254 nm) UPLCMS; rétention time: 0.82 min; (M+H⁺) 472.4.

Example 117 4-FIuoro-l-(4-(4-fluorophenoxy)-13i5-triazin-2-yI)-/V-(4-methyl-lazabicyclo[3.2.2|nonan-4-yl)piperidinc-4-carboxamide

217

Exchanging 2,4-dichloropyrimidinc for 2,4-dichlorotriazinc and ethyl piperidinc-4carboxylate for ethyl 4-fluoropîperidine-4-carboxylatc hydrochloride, the same réaction sequence outlined in Example 115 was used to generate the title compound. ’H NMR (400 MHz, CDClj) δ 8.37 (s, lH), 7.20-7.03 (m, 4H), 6.32 (d, J= ΊΛ Hz, IH), 4.85-4.72 (m, IH), 4.60-4.47 (m, IH), 3.34-3.11 (m, 2H), 3.10-2.74 (m, 6H), 2.37-2.05 (m, 3H), 2.02-1.43 (m, i IH) ppm. Purity: >99.9% (214 & 254 nm) UPLCMS; rétention time: 0.74 min; (M+H⁴) 473.5.

Example 118 4-Eluoro-l-(5-fluoro-4-(4-(2-methoxyetlioxy)phenoxy)pyrimidin-2-yl)-jV-(3mcthyIquinuclidin-3-yl)piperidinc-4-carboxamide

Exchanging 4-fluorophcnol for 4-(2-mcthoxycthoxy)phcnol, ethyl pipcridinc-4carboxylate for ethyl 4-fluoropiperidine-4-carboxylate hydrochloride and Intermediate 5 for Intermediate 1, the same réaction sequence outlined in Example 115 was used to generate the title compound. ’H NMR (500 MHz, CDCI3) δ 8.08 (d, J = 3.0 Hz, IH), 7.11-7.08 (m, 2H), 6.96-6.93 (m, 2H), 6.32 (d, J= 7.0 Hz, IH), 4.34-4.32 (m, 2H), 4.14 (t, J = 4.5 Hz, 2H), 3.79 (t, J= 4.5 Hz, 2H), 3.49 (s, 3H), 3.09-2.75 (m, 8H), 2.18-2.02 (m, 3H), 1.87-1.27 (m, 9H) ppm. ¹³C NMR (100 MHz, CDCI3) ô 171.2, 171.0, 157.8,

157.7, 156.8, 156.1, 145.6, 144.7, 144.5, 140.8, 138.3, 122.5, 114.9, 96.7, 94.8, 71.0,

67.6, 63.2, 59.3, 52.8, 46.5, 46.3, 39.6, 31.7, 31.6, 31.5, 31.4, 30.1, 24.1, 23.0, 22.4 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.44 min; (M+H⁴) 532.2.

Example 119 l-(4-(4-Cyanoplienoxy)pyrimidin-2-yl)-4-fluoro-/V-(3-methylquinucIidm-3yI)piperidine-4-carboxamlde

Exchanging 4-fluorophenol for 4-cyanophenol, ethyl piperidine-4-carboxylate for ethyl 4fluoropiperidine-4-carboxylatc hydrochloride and Intermediate 5 for Intermediate 1, the same reaction sequence outlined in Example 115 was used to generate the title compound. *H NMR (500 MHz, CDCI3) δ 8.24 (d, J= 6.5 Hz, IH), 7.71 (d, J= 8.5 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 6.35 (d, J = 6.5 Hz, IH), 6.17 (d, J= 6.0 Hz, IH), 4.52-4.46 (m, 2H), 3.14-3.12 (m, 2H), 2.93-2.77 (m, 6H), 2.18-2.02 (m, 3H), 1.79-1.47 (m, 9H) ppm. ^I3C NMR (125 MHz, CDCI3) δ 171.1, 168.8, 161.1, 160.1, 156.2, 133.5, 122.7, 118.5, 108.7,

96.5, 63.2, 52.9, 46.5, 46.4, 39.2, 31.9, 31.8, 31.7, 31.6, 30.1, 24.1, 23.0, 22.4 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.39 min; (M+H⁴) 465.2.

Example 120

1-(4-(4-Cyanopli en oxy)pyrimidi n-2-y 1)-4-0 uoro-7V-(4-m et hyl-1azabicyclo[3.2.2|nonan-4-yl)piperidine-4-carboxamidc

Exchanging 4-fluorophcnol for 4-cyanophcnol and ethyl piperidine-4-carboxylatc for ethyl 4-fluoropipcridinc-4-carboxylate, the same reaction sequence outlined in Example 115 was used to generate the title compound. ³H NMR (500 MHz, CDCI3) δ 8.24 (d, J = 5.0 Hz, IH), 7.70 (d, J= 9.0 Hz, 2H), 7.29 (d, J= 8.5 Hz, 2H), 6.33 (d, J= 7.5 Hz, IH), 6.16 (d, 5.5 Hz, IH), 4.47 (m, 2H), 3.15-2.82 (m, 8H), 2.34-2.31 (m, IH), 2.17-1.49 (m, 13H) ppm. ^I3CNMR(125 MHz, CDClj) Ô 170.9, 170.7, 168.8, 161.1, 160.1, 156.2,

133.5, 122.7, 118.5, 108.7, 96.8, 96.4, 94.9, 59.4, 53.0, 47.5, 45.9, 39.2, 38.8, 36.2, 32.0,

31.7, 31.5, 24.9, 24.2, 24.0 ppm. Purity; > 99% LCMS (214 nm & 254 nm); rétention time 1.43 min; (M+H⁴) 478.9.

218

Example 121 l-(4-(4-Fluorophenoxy)pyrimîdin-2-yl)-A^r-(3-methylquinuclîdin-3-yl)pipendine-4carboxamidc

Exchanging 2,4-dichloropyrimidinc for 2,4-dichloro-5-fluoropyrimidinc and Intermediate 5 for Intermediate 1, the same reaction sequence outlined in Example 115 was used to generate the title compound. *H NMR (500 MHz, CDCh) δ 8.10 (d, J = 2.5 Hz, IH), 7.17-7.07 (m, 4H), 5.36 (s, IH), 4.41 (d,./ = 13.0 Hz, 2H), 2.90-2.74 (m, 8H), 2.27-2.13 (m, 2H), 1.79-1.71 (m, 3H), 1.64-1.42 (m, 8H) ppm. ^I3C NMR (125 MHz, CDCh) ô 174.0, 160.9, 160.0, 157.3, 157.3, 156.9, 147.8, 145.0, 144.9, 140.3, 138.3, 123.2, 123.1,

115.9, 115.7, 63.4, 52.9, 46.6, 46.4, 44.0, 43.8, 30.3, 28.4, 28.3, 24.4, 23.0, 22.5 ppm. Purity: > 97% LCMS (214 nm & 254 nm); rétention time 1.40min; (M+H*) 458.0.

Example 122 l-(5-Cyano-4-(4-nuorophenoxy)pyrimidin-2-yl)-4-nuoro-A^r-(3-methylquinuclidin-3y))piperidine-4-carboxamide

Exchanging 2,4-dichloropyrimidine for 2,4-dichloro-5-cyanopyrimidine, ethyl piperidine4-carboxylatc for ethyl 4-fluoropiperidme-4-carboxylate and Intermediate 5 for Intermediate 1, the same reaction sequence outlined in Example 115 was used to generate the title compound. *H NMR (500 MHz, CDCh) δ 8.45 (s, IH), 7.15-7.08 (m, 4H), 6.34 (d, J=6.5 Hz, IH), 4.80 (d, J= 12.5 Hz, IH), 4.18 (d, J = 12.0 Hz, 1H),3.25 (t, ./= 12.5 Hz, IH), 3.07 (t, J= 12.5 Hz, IH), 2.94-2.79 (m, 6H), 2.18-1.72 (m, 7H), 1.58-1.49 (m, 5H)ppm. ¹³C NMR (100 MHz, CDCh) δ 170.6, 170.4, 169.0, 163.3, 161.4, 160.5, 159.0,

147.3, 123.3, 123.2, 116.1, 115.8, 115.0, 96.1, 94.3, 83.3, 63.0, 52.9, 46.5, 46.3, 39.5,

39.3, 32.1, 32.0, 31.9, 31.8, 31.7, 30.1, 24.1, 22.9, 22.3 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.89 min; (M+H*) 483.1.

Example 123 4-Fluoro-A^r-(4-methyl-l-azabicyclo[3.2.2]nonan-4-yl)-l-(4-((tetrahydro-2H-pyran-4yl)oxy)pyrimidïn-2-yl)piperidine-4-carboxamide

To a stirred and cooled (0 °C) solution of tetrahydro-2/7-pyran-4-ol (1.12 g, 11.0 mmol) in /V,?/-dirncthylformamÎdc (20 mL) was added a 60% dispersion of sodium hydride in minerai oil (660 mg, 16.5 mmol). The mixture was stirred at 0 C for 20 minutes before adding 2,4-dichloropyrimidine (1.98 g, 13.2 mmol) in one portion. The reaction was then left to slowly warm to room température and stir ovemight. After this time, the reaction was quenched with water (~80 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (NaîSOj and concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford 2-chloro-4-((tctrahydro-2H-pyran-4-yl)oxy)pyrimidine as a light yellow oil (1.13 g, 53%). Exchanging 2-chloro-4-(4-fluorophcnyl)pyrimidine for the présent intermediate, the final three steps of Example 41 were used to préparé the title compound. *H NMR (500 MHz, CDCh) δ 8.08 (d, J= 6.0 Hz, IH), 6.35 (d,./ = 7.5 Hz, IH), 6.00 (d, J= 5.5 Hz, IH), 5.25-5.20 (m, IH), 4.68-4.65 (m, 2H), 4.00-3.96 (m, 2H), 3.63-3.59 (m, 2H), 3.25-3.20 (m, 2H), 3.00-2.81 (m, 6H), 2.40-2.39 (m, IH), 2.25-2.14 (m, 2H), 2.07-1.51 (m, 15H) ppm. ¹³C NMR (100 MHz, CDCh) δ 171.1, 170.9, 168.8, 161.3, 158.2, 97.4, 97.0,95.2, 69.6, 65.3, 59.3, 52.8, 47.5, 45.9, 39.3, 38.4, 36.1, 32.0, 31.8, 31.7, 31.6, 25.0,

219

23.9, 23.6 ppm. Purity; > 99% LCMS (214 nm & 254 nm); rétention time 1J3 min; (M+H*) 462.0.

Exampie 124

4-Fluoro-l-(4-((4-nuorobenzyl)oxy)pyrimidiii-2-yl)-/V-(4-methyl-lazabicyclo|3.2.2|nonan-4-yl)piperidine-4-carboxamide

Exchanging tetrahydro-4-pyranol for 4-fluorobenzyl alcohol, the same réaction sequence outlined in Example 123 was used to generate the title compound. ^]H NMR (400 MHz, 10 CDCI3) δ 8.07 (d, J= 5.6 Hz, IH), 7.42-7.34 (m, 2H), 7.09-7.01 (m, 2H), 6.33 (d, J = 7.4

Hz, IH), 6.03 (d, J = 5.6 Hz, IH), 5.29 (s, 2H), 4.73-4.63 (m, 2H), 3.28-3.16 (m, 2H), 3.09-2.78 (m, 6H), 2.37-2.30 (m, IH), 2.30-2.08 (m, 2H), 2.01-1.90 (m, IH), 1.89-1.69 (m, 5H), 1.67-1.45 (m, 5H) ppm. Purity; >99.9% (214 & 254 nm) UPLCMS; rétention time: 0.75 min; (M+H*) 486.3,

Example 125 4-Fluoro-l-(4-((4-fluorobenzyl)oxy)pyrimidm-2-yl)-A^,“(3-methylqiimuclidin-3yl)piperidine-4-carboxainide

Exchanging tctrahydro-4-pyranol for 4-fluorobcnzyl alcohol and Intermediate 5 for Intermediate 1, the same reaction sequence outlined in Example 123 was used to generate the title compound. *H NMR (400 MHz, CDCI3) δ 8.07 (d, J = 5.6 Hz, IH), 7.42-7.35 (m, 2H), 7.09-7.01 (m, 2H), 6.34 (d, J= 6.8 Hz, IH), 6.03 (d, J= 5.6 Hz, IH), 5.29 (s, 2H), 4.73-4.63 (m, 2H), 3.27-3.17 (m, 2H), 2.93 (s, 2H), 3.09-2.78 (m, 4H), 2,30-2.07 (m, 3H), 25 1.89-1.68 (m, 4H), 1.59-1.40 (m, 5H) ppm, Purity: >99,9% (214 & 254 nm) UPLCMS;

rétention time: 0.73 min; (M+H*) 472.3.

Exampie 126

4-Fluoro-l-(6-(4-fluorophenoxy)pyrazÎn-2-yl)-7V-(4-metliyl-l-azabicyclo|3.2.2]nonan30 4-yl)pipcridine-4-carboxamide

To a stirred solution of 2,6-dichloropyrazinc (4.44 g, 29.8 mmol) and 4-fluorophenol (3.00 g, 26.8 mmol) in M/V-dimcthylformamide (100 mL) was added potassium tertbutoxidc (6.01 g, 53.6), portion wise over ~5 minutes. The reaction was heated ovemight 35 at 90 °C and then concentrated. Tlic residue was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford 2-chloro-6-(4-fluorophcnoxy)pyrazine as a white solid (5.70 g, 95%). To a stirred solution of this product (0.850 g, 3.78 mmol) in jV./'Z-dimethyiformamide (15 mL) was added ethyl 4-fluoropiperidine-4-carboxylate (0.960 g, 4.54 mmol) and césium carbonate (2.46 g, 7.55 mmol). The mixture was heated 40 ovemight at 60 °C and then concentrated. The residue was purified by flash chromatography over silica usîng a hexane/ethyl acetate eluant to afford ethyl 4-fluoro-l(6-(4-fluorophenoxy)pyrazin-2-yl)pipcridine-4-carboxylate as a yellow solid (0.190 g, 14%). To a stirred solution of this intermediate (0.300 g, 0.826 mmol) in 2:1:1 mcthanol/tctrahydrofuran/watcr (8 mL) was added solid sodium hydroxide (0.165 g, 4.13 45 mmol). The mixture was stirred ovemight and then concentrated. The residue was dissolved in water, made acidic (pH ~3) with the addition of IN hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to afford 4-fluoro-l-(6-(4-fluorophenoxy)pyrazin-2yl)piperidine-4-carboxylic acid as a yellow solid (0.176 g, 64%). Exchanging ethyl l-(450 (4-fluorophenyi)pyrimidin-2-yl)pipcridine-4-carboxylate for the présent intermediate, the

220 final two steps of Example 41 were used to prépare the title compound. *H NMR (500 MHz, CDCl₃) δ 7.85 (s, IH), 7.58 (s, IH), 7.14-7.07 (m, 4H), 6.32 (d, J= 7.0 Hz, IH), 4.12 (d, J = 13.5 Hz, 2H), 3.19 (t, J = 11.0 Hz, 2H), 3.17-2.83 (m, 6H), 2.35 (m, IH), 2.24-1.97 (m, 3H), 1.85-1.51 (m, 10H) ppm. ¹³C NMR (125 MHz, CDCh) δ 170.7,170.5,

160.6, 158.7, 158.3, 152.6, 149.2, 123.5, 122.8, 122.7, 120.5, 116.1, 115.9, 96.3, 94.8,

59.4, 53.0, 47.5, 46.0, 40.1, 38.8, 36.2, 31.6, 31.4, 31.2, 24.9, 24.2, 24.0 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.36 min; (M+H⁺) 472.0.

Example 127

4-Fluoro-l-(5-(4-nuorophenoxy)pyridin-3-yl)-/V-(4-methyl-l-azabicyclo|3.2.2]nonan4-yl)pipcridine-4-carboxamide

To a stirred and cooled (0 °C) suspension of a 60% dispersion of sodium hydride in minerai oil (1.30 g, 32.5 mmol) in V./V-dimcthylfonnamide (20 mL) was added 4fluorophcnol (2.00 g, 17.8 mmol). After 1 hour at 0 °C, 3,5-dibromopyridine (4.00 g, 16.9 mmol) was added. The mixture was heated ovemight at 90 °C and then diluted with water (100 mL) and extracted with ethyl acetate. The combined extracts were dried (Na₂SO4) and concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford 3-bromo-5-(4-fluorophenoxy)pyridinc as a light yellow oil (0.660 g, 13%). To a stirred mixture of this intermediate (600 mg, 2.24 mmol) and ethyl 4-fluoropipcridine-4-carboxylate hydrochloride (0.566 g, 2.68 mmol) in toluene (15 mL) was added tris(dibenzylideneacetone)dipalladium(0)(0.204 g, 0.223 mmol), 2,2bis(diphcnylphosphino)-l,l'-binaphthalene (0.278 g, 0.446 mmol) and potassium tertbutoxïdc (0.860 g, 4.48 mmol). The reaction was heated ovemight at 90 °C, cooled and filtered through Celite. The filtrate was concentrated to afford a residue which was diluted with 2.0 N hydrochloric acid (40 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na₂SO/|) and concentrated to afford 4fluoro-l-(5-(4-fluorophenoxy)pyridin-3-yl)piperidine-4-carboxylic acid (expected ester product hydrolyzed in the course of the catalytic amination reaction/workup) as a white solid (420 mg, 57%). Using General Procedure E and Intermediate 5, this carboxylic acid was subjected to amide coupling to generate the title compound as a brown solid (0.031 g, 16%). ’H NMR (500 MHz. CDCI3) δ 8.10 (d, J= 2.0 Hz, IH), 7.81 (d, J= 2.0 Hz, IH), 7.10-7.02 (m, 4H), 6.82-6.81 (m, IH), 6.34 (d, J= 7.5 Hz, IH), 3.64-3.62 (m, 2H), 3.162.82 (m, 811), 2.40-2.32 (m, 311), 1.99-1.52 (m, 1 IH) ppm. ¹³C NMR (125 MHz, CDCI3) Ô 170.8, 170.6, 160.0, 158.1, 154.6, 152.2, 147.5, 133.4, 131.0, 120.5, 120.4, 116.6,

116.4, 112.1, 95.8, 94.3, 59.4, 53.1, 47.5, 46.0, 44.1, 38.9, 36.3, 31.8, 31.6, 31.5, 31.4, 25.0, 24.3, 24.1 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.22 min; (M+H⁴) 471.3.

Example 128

4-Fluoro-l-(4-((4-fl uo robenzyl)oxy)-13,5-t riazln-2-yl)-iV-(4-methyl-lazabicyclo[3.2.2]nonan-4-yl)piperidine-4-carboxamide

To a stirred solution of 2,4-dichloro-l,3,5-triazine (1.00 g, 6.71 mmol) in 1,4-dioxane (10 mL) was added JV,7V-diisopropylethylamine (2.50 mL, 14.4 mmol) and ethyl 4fluoropipcridine-4-carboxylate hydrochloride (1.14 g, 5.37 mmol). The réaction was stirred at 55 °C for 1 hour and then concentrated. The residue was purified by flash chromatography over silica gel using a hexane/ethyl acetate eluant to afford ethyl l-(4chloro-l,3,5-triazin-2-yl)-4-fluoropiperidine-4-carboxylate as a colorless oil (1.40 g,

72%). To a stirred and cooled (0 °C) solution of (4-fluorophenyl)methanol (0.131 g, 1.04

221 mmol) in anhydrous tctrahydrofuran (l mL) was added a 60% dispersion of sodium hydride in minerai oil (0.046 g, l.l5 mmol). After I hour at the same température, the product of step l (0.300 g, l .04 mmol) was added in a single portion. The réaction was then stirred at room température for 2 hours bcforc diluting with water (10 mL) and cxtracting with ethyl acetate. The combined organic layers were dried (Na₂SO4) and concentrated to afford crude product which was purified by revcrscd-phasc flash chromatography over C-18 silica using an acetonitrile/water/trifluoroacetic acid eluant to afford ethyl 4-fluoro-1 -(4-((4-fluorobcnzyl)oxy)-1,3,5-triazin-2-yl)piperidine-4carboxylatc (0.120 g, 30%) as a colorless oil. Exchanging ethyl 1-(4-(4fluorophenyl)pyrimidin-2-yl)piperidine-4-carboxylatc for the présent intermediate, the final two steps of Example 41 were used to préparé the title compound. *H NMR (500 MHz, CDCIj) δ 8.38 (s, IH), 7.45-7.42 (m, 2H), 7.07 (t, 8.5 Hz, 2H), 6.35 (d, J = 6.5

Hz, IH), 5.37 (s, 2H), 4.81-4.73 (m, 2H), 3.30-2.94 (m, 8H), 2.47 (m, IH), 2.24-2.03 (m, 6H), 1.87-1.53 (m, 7H) ppm. ^I3C NMR (100 MHz, CDClj) δ 170.5, 170.0, 167.5, 165.2,

131.8, 130.2, 130.1, 129.5, 115.5, 115.3, 68.1, 59.3, 52.5, 47.3, 45.9, 39.0, 38.5, 37.6,

35.8, 32.1, 24.9, 23.1, 22.9 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.36min; (M+H⁴) 487.2.

Example 129 4-Fluoro-l-(5-(4-nuorophenoxy)pyrimÎdin-2-yl)-/V-(3-methylquinuclidin-3yl)piperidine-4-carboxamide

To a stirred solution of 2-chloropyrimidin-5-ol (1.50 g, 11.6 mmol) in dichioromethane (20 mL) was added 4-fluorophenylboronic acid (3.30 g, 23.2 mmol), copper(Il) acetate (2.49 g, 13.9 mmol) and triethylamine (8.0 mL, 57 mmol). The mixture was left open to the air and stirred ovemight. The suspension was then filtered through a pad of Celitc and concentrated. The residue was purified by flash chromatography over silica using a hexanc/cthyl acetate eluant to afford 2-chloro-5-(4-fluorophenoxy)pyrimidinc as a lîght yellow solid (0.400 g, 17%). Exchanging 2-chloro-4-(4-fluorophcnyl)pyrimidine for this intermediate, ethyl pipcridinc-4-carboxylatc for ethyl 4-fluoropiperidine-4-carboxylate hydrochloride and Intermediate 5 for Intermediate 1, the final three steps of Example 41 were used to préparé the title compound. *H NMR (400 MHz, CD3OD) δ 8.20 (s, 2H), 7.09-6.99 (m, 4H), 4.70-4.66 (m, 2H), 3.33-3.16 (m, 3H), 2.90-2.83 (m, 5H), 2.30-2.01 (m, 311), 1.92-1.89 (m, 4H), 1.70-1.50 (m, 5H) ppm. ^I3C NMR (100 MHz, CD₃OD) δ

172.4, 172.2, 159.8, 158.5, 157.4, 154.4, 150.0, 143.3, 118,2, 118.1, 116,1, 115.8, 95.7,

93.8, 60.7, 52.8, 45.6, 45.5, 39.6, 31.5, 31.4, 31.3, 31.2, 29.3, 23.0, 21.8, 21.3 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.39 min; (M+H⁴) 458.0.

Example 130 l-(5-(4-Fluorophenoxy)pyrimidin-2-yl)-A^r-(4-methyl-l-azabicyclo[3.2.2]nonan-4yl)piperidine-4-carboxamide

Exchanging 2-ch!oro-4-(4-fluorophcnyl)pyrimidine for 2-chloro-5-(4fluorophenoxy)pyrimidine (prepared as described in Example 129), the final three steps of Example 41 were used to préparé the title compound. *H NMR (500 MHz, CDCI3) δ 8.14 (s, 2H), 7.02-6.98 (m, 2H), 6.91-6.88 (m, 2H), 5.44 (s, IH), 4.76-4.73 (m, 2H), 3.062.84 (m, 8H), 2.41-2.34 (m, 2H), 1.95-1.49 (m, 13H) ppm. ¹³C NMR (125 MHz, CDCI3) δ 174.1, 159.4, 158.8, 157.5, 154.3, 150.3, 142.6, 118.0, 117.9, 116.4, 116.2, 59.4, 53.1,

47.6, 46.1, 44.4, 44.0, 39.2, 36.1, 31.0, 28.8, 28.5, 25.1, 24.2, 24.1 ppm. Purity: > 99% LCMS (214 11m & 254 nm); rétention time 1.38 min; (M+H⁴) 454.2.

222

Example 131

4-Fluoro-l-(5-(4-(2-metlioxyethoxy)plienoxy)pyiïmidin-2~yl)-7V-(3methylquinuclidin-3-yl)pipcridine-4-carboxamide

Exchanging 4-fluorophenylboronic acid for (4-(2-mcthoxycthoxy)phcnyl)boronic acid, the first step of Example 129 was used to préparé 2-chloro-5-(4-(2mcthoxyethoxy)phenoxy)pyrimidine. Exchanging 2-chloro-4-(4-fluorophenyl)pyrimidinc for this intermediate, ethyl pipcridine-4-carboxylate for ethyl 4-fluoropipcridine-4carboxylate hydrochloride and Intermediate 5 for Intermediate 1, the final three steps of Example 41 were used to préparé the title compound. *H NMR (500 MHz, CDCI3) δ 8.16 (s, 2H), 6.91 (m, 4H), 6.38 (d, J =7.0 Hz, 1 H), 4.67 (d,J = 13.5 Hz, IH), 4.11 (t, J =5.0 Hz, 2H), 3.76 (t, J = 4.5 Hz, 2H), 3.48 (s, 3H), 3.25 (t, J = 13.5 Hz, 2H), 3.01-2.83 (m, 6H), 2.31-2.20 (m, 3H), 1.87-1.80 (m, 5H), 1.61-1.52 (m, 5H) ppm. ¹³CNMR(100 MHz, CDC1₃)Ô 171.3, 171.1, 158.4, 154.7, 151.9, 149.8, 143.6, 118.2, 115.8, 96.9, 95.0,71.1,

67.8, 63,1, 59.2, 52.8, 46.5, 46.4, 39.8, 31.9, 31.8, 31.7, 31.6, 30.1, 24.2, 23.0, 22.3 ppm. Purity; > 99% LCMS (214 nm & 254 nm); rétention time 1.39 min; (M+H‘) 514.0.

Example 132 4-Fluoro-l-(5-((4-iluorobenzyl)oxy)pyrimidin-2-yl)-jV-(4-methyl-lazabicyclo|3.2.2|nonan-4-yl)piperidine-4-carboxamide

To a stirred solution of 5-bromo-2-chloropyrimidine (2.00 g, 10.3 mmol) in 7V,2Vdimethylformamide (30 mL) was added ethyl 4-fluoropiperidine-4-carboxylate hydrochloride (2.63 g, 12.4 mmol) and césium carbonate (3.37 g, 10.3 mmol). The suspension was heated ovemight at 50 °C and then concentrated. The residue was taken up in ethyl acetate and washed with scveral portions of water. The organic layer was dried (Na2SC>4) and concentrated. The crude product was purified by flash chromatography over silica using a hexane/cthyl acetate eluant to afford ethyl 1-(5-bromopyrimidin-2-yl)4-fluoropipcridine-4-carboxylate as a white solid (2.93 g, 85%), To a stirred solution this intermediate (2.89 g, 8.70 mmol) in A',V-dimcthylformamidc (32 mL) was added bis(pinacolato)diboron (2.65 g, 10.4 mmol), potassium acetate (4.27 g, 43.5 mmol) and [l,T-bis(diphenylphosphino)fenOccne]dichloropalladium(II) (318 mg, 435 gmol). The mixture was heated ovemight at 90 °C and then cooled and concentrated, The residue taken up in water and ethyl acetate, resulting in an unresolved émulsion. After suction filtering the mixture through a plug of Celite, the organic layer was separated and washed with additional portions of water. The solution was then dried (NaîSO^ and concentrated to afford ethyl 4-fluoro-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2yl)piperidinc-4-carboxyiate as a dark brown solid (3.32 g, 101%). The crude product was used without purification in the next step. To a stirred solution of the boronate (3.31 g, 8.73 mmol) in 1:1 tetrahydrofuran/water (80 mL) was added sodium perborate monohydrate (2.21 g, 21.0 mmol). The reaction was stirred ovemight and then diluted with aqueous ammonium chloride solution (—100 mL). The mixture was extracted with ethyl acetate. The combined extracts were then washed with aqueous sodium chloride solution, dried (NaîSOi) and concentrated. The crude product was purified by flash chromatography over silica using an ethyl acetate/chloroform eluant to afford ethyl 4fluoro-l-(5-hydroxypyrimidin-2-yl)piperidine-4-carboxylate as a gray-green solid (1.64 g, 70%). To a stirred solution of this intermediate (0.828 g, 3.07 mmol) in N,Ndi methyl formamide (15 mL) was added l-(bromomcthyl)-4-fluorobenzene (0,639 g, 3.38 mmol) and césium carbonate (2.00 g, 6.15 mmol). The mixture was heated ovemight at

223 °C and then concentrated. The residue was taken up in ethyl acetate and washed with sevcral portions of water. The organic layer was then dried (Na₂SÛ4) and concentrated. The crude product was purified by flash chromatography over silica using a hcxane/ethyl acetate cluant to afford ethyl 4-fluoro-l-(5-((4-fluorobcnzyl)oxy)pyrimidin-2yl)piperidine-4-carboxylate as white solid (0.909 g, 78%). To a stirred solution of this ester (880 mg, 2.33 mmol) in l:l:l tctrahydrofuran/cthanol/water (21 mL) was added lithium hydroxide monohydrate (0.294 g, 7.01 mmol). The réaction was stirred ovemight and then concentrated. The residue was taken up in water. The resultîng suspension was treated with 1.0 N aqueous HCl (7.0 mL) and then extracted with chloroform. The combined extracts were dried (Na₂SO4) and concentrated to afford 4-fluoro-1-(5-((4fluorobenzyl)oxy)pyrÎmidin-2-yl)piperidine-4-carboxylic acid as a white solid (0.736 g, 90%). Using General Procedure E and Intermediate 5, this carboxylic acid was subjected to amide coupling to generate the title compound as a yellow solid (0.395 g, 81%). ^lH NMR (400 MHz, CDClj) δ 8.09 (s, 2H), 7.42-7.33 (m, 2H), 7.11-7.03 (m, 2H), 6.33 (d,./ = 7.2 Hz, IH), 4.98 (s, 2H), 4.63-4.53 (m, 2H), 3.25-3.15 (m, 2H), 3.08-2.90 (m, 4H), 2.89-2.78 (m, 2H), 2.36-2.30 (m, IH), 2.30-2.09 (m, IH), 2.00-1.89 (m, IH), 1.88-1.68 (m, 5H), 1.67-1.44 (m, 5H) ppm. Purity: >99.9% UPLCMS (214 nm & 254 nm); rétention time 0.73 min; (Μ+Ι-Γ) 472.3.

Exampie 133 4-Fluoro-l-(5-(4-fluorophenoxy)pyrazÎn-2-yl)-A^r-(3-methylquinuclidîn-3yl)piperidine-4-carboxamide

To a stirred solution of 2,5-dibromopyrazine (0.500 g, 2.10 mmol) in N,Ndimethylformamide (15 mL) was added ethyl 4-fluoropiperidine-4-carboxylatc (0.444 g, 2.10 mmol) and césium carbonate (1.37 g, 4.20 mmol). The mixture was heated ovemight at 60 °C and then concentrated. The residue was purified by flash chromatography over silica using a hexanc/ethyl acetate cluant to afford ethyl l-(5-bromopyrazin-2-yl)-4fluoropipcridine-4-carboxylatc as a yellow solid (0.330 g, 47%). This intermediate (0.400 g, 1.20 mmol) was combined with 4-fluorophcnoI (0.175 g, 1.56 mmol), copper oxide (0.052 g, 0.363 mmol) imidazole-4-carboxylic acid (0.081 g, 0.723 mmol), césium carbonate (1.17 g, 3.59 mmol) and acctonitrile (12 mL) in a sealed microwavc reaction vessel. The stirred mixture was heated in a microwave reactor at 120 °C for 6 hours. The reaction was then cooled and filtered to remove the solids. The filtrate was concentrated and the residue was purified by flash chromatography over silica using a hexane/ethyl acetate cluant to afford ethyl 4-fluoro-l-(5-(4-fluorophenoxy)pyrazin-2-yl)piperidinc-4carboxylate as a yellow oil (0.120 g, 28%). To a stirred solution of this intermediate (0.120 g, 0.330 mmol) in 1:1 (v/v) methanol/water (4 mL) was added solid sodium hydroxide (0.066 g, 1.65 mmol). After ovemight stirring, the réaction was concentrated. The residue was dissolved in water, made acidic (pH ~3) with the addition of IN hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na₂SO4) and concentrated to afford 4-fluoro-1-(5-(4fluorophenoxy)pyrazin-2-yl)piperidine-4-carboxylic acid as a white solid (0.090 g, 81%). Using General Procedure E and Intermediate 5, this carboxylic acid was subjected to amide coupling to generate the title compound as a yellow solid (0.019 g, 36%). *H NMR (500 MHz, CDClj) δ 7.99 (d, J = 1.0 Hz, IH), 7.76 (d,./ = 1.5 Hz, IH), 7.07-7.06 (m, 4H), 6.37 (d, J = 6.5 Hz, IH), 4.17-4.15 (m, 2H), 3.27-3.20 (m, 2H), 2.88-2.83 (m, 6H), 2.37-2.20 (m, 3H), 1.90-1.52 (m, 9H) ppm. ¹³C NMR (100 MHz, CDClj) δ 158.0, 152.6, 152.0, 151.1, 148.0, 131.9, 126.6, 121.2, 121.1, 116.3, 116.1,96.4,94.6, 63.1,52.9,46.5,

224

46.4, 41.2, 31.5, 31.4, 31.3, 31.2, 30.1, 24.2, 22.9, 22.3 ppm. Purity: > 98% LCMS (214 nm & 254 nm); rétention time 1.41 min; (M+H) 458.2.

Example 134 4-Fluoro-l-(6-(4-nuorophenoxy)pyridazÎn-3-yl)-/V-(4-methyl-lazabicyclo[3.2.2]nonan-4-yl)piperidine-4-carboxamide

To a stirred solution of 3,6-dicliloropyridazine (0.400 g, 2.68 mmol) in N,Ndimethylformamide (15 mL) was added ethyl 4-fluoropiperidine-4-carboxylate (0.567 g, 2.68 mmol) and césium carbonate (2.62 g, 8.04 mmol). The mixture was heated ovemight at 60 °C and then concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford ethyl l-(6-chloropyridazin-3-yl)-4fluoropiperidine-4-carboxylate as a white solid (0.400 g, 52%). This intermediate (0.400 g, 1.39 mmol) was combined with 4-fluorophenol (0.203 g, 1.81 mmol), copper iodide (0.026 g, 0.137 mmol), V.Mdimcthylglycinc (0.029 g, 0.281 mmol), potassium carbonate (0.576 g, 4.17 mmol) and l-methyl-2-pyrrolidinone (8 mL) in a scalcd microwave reaction vessel. The stirred mixture was heated in a microwave reactor at 160 °C for 6 hours. The reaction was then cooled and filtered to remove the soiids. The filtrate was concentrated and the residue was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford ethyl 4-fluoro-l-(6-(4-fluorophenoxy)pyridazin-3yl)pipcridine-4-carboxylate as a white solid (0.120 g, 24%). Exchanging ethyl 4-fluoro-l(6-(4-fluorophenoxy)pyrazin-2-yl)piperidine-4-carboxylate for the présent intermediate, the final two steps of Example 133 were used to prépare the title compound. ’ll NMR (500 MHz, CDC1₃) Ô 7.17-7.05 (m, 6H), 6.36 (d, J = 7.5 Hz, IH), 4.21-4.18 (m, 2H), 3.31-3.26 (m, 2H), 3.10-3.03 (m, 4H), 2.94-2.90 (m, 2H), 2.41-2.22 (m, 3H), 1.99-1.51 (m, 1 IH) ppm. ^l3C NMR (125 MHz, CDCI3) δ 171.0, 170.8, 160.5, 160.4, 158.6, 157.7, 149.9, 122.4, 119.7, 118.5, 116.2, 116.0, 96.4, 94.9, 59.3, 52.7, 47.4, 45.9, 41.6, 38.1, 36.0, 31.6, 31.5, 31.4, 31.2, 31.2, 25.0, 23.5, 23.3 ppm. Purity: > 96% LCMS (214 nm & 254 nm); rétention time 1.84 min; (M+H⁴) 472.2.

Example 135 4-FIuoro-l-(4-((4-fluorophenoxy)methyl)pyrimidin-2-yl)-7V-(3-methylquinuclÎdÎn-3yl)piperidine-4-carboxamide

To a stirred solution of (2-chloropyrimidin-4-yl)mcthanol (0.600 g, 4.14 mmol) in dichloromethane (10 mL) was added thionyl chloride (0.488 g, 4.14 mmol). The mixture was stirred at room température ovemight and then concentrated to afford 2-chloro-4(chloromethyl)pyrimidine as a yellow oil (0.500 g, 74%). To a stirred solution of this intermediate (0.500 g, 3.07 mmol) and 4-fluorophenol (0.378 g, 3.37 mmol) in acetonitrile (10 mL) was added potassium carbonate (0.847 g, 6.14 mmol). The reaction was heated at reflux for 1.5 hours and then concentrated. The residue was purified by flash chromatography over silica gel using a hexane/ethyl acetate eluant to afford 2chloro-4-((4-fluorophenoxy)methyl)pyrimidinc as a white solid (0.300 g, 41%). To a stirred solution of this compound (0.490 g, 2.06 mmol) in acetonitrile (15 mL) was added ethyl 4-fluoropiperidine-4-carboxylate hydrochloride (0.480 g, 2.26 mmol) and potassium carbonate (0.569 g, 4.12 mmol). The réaction was heated at reflux ovemight, diluted with water (20 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (NajSCL) and concentrated. The residue was purified by flash chromatography over silica gel using a hexane/ethyl acetate eluant to afford ethyl 4fluoro-l-(4-((4-fluorophenoxy)mcthyl)pyrimidin-2-yl)piperidinc-4-carboxylatc as a white

225 solid (0.400 g, 53%). Exchanging ethyl l-(4-(4-fluorophenyl)pyrimÎdin-2-yl)piperidine-4carboxylatc for the présent intermediate, the final two steps of Example 41 were used to préparé the title compound. ^lH NMR(400 MHz, CDC1₃) Ô 8.30 (d, J= 4.8 Hz, IH), 7.01 6.97 (m, 2H), 6.90-6.87 (m, 2H), 6.69 (d, J= 4.8 Hz, IH), 6.38 (d, J= 6.8 Hz, IH), 4.93 (s, 2H), 4.75 (d, J = 12.8 Hz, 2H), 3.26-3.20 (m, 2H), 3.00-2.80 (m, 6H), 2.32-2.12 (m, 3H), 1.88-1.77 (m, 4H ), 1.59-1.50 (m, 5H) ppm. ^l3CNMR(100 MHz, CDCh) δ 171.3, 171.1, 166.7, 161.1, 158.6, 158.4, 156.3, 154.3, 154.3, 116.0, 115.8, 115.7, 115.6, 106.5,

96.9, 95.1, 70.3, 63.0, 52.8, 46.5, 46.3, 39.1, 32.0, 31.9, 31.8, 31.7, 30.1, 24.2, 22.9, 22.3 ppm. Purity: > 95% LCMS (214 nm & 254 nm); rétention time 1.42 min; (M+H’) 472.2.

Example 136 4-Fluoro-l-(5-(4-fluorobenzyl)pyrîmidin-2-yl)-jV-(3-methylquinuclidin-3yl)piperidïne-4-carboxamide

To a stirred solution of 4-hydroxybenzaldehyde (6.00 g, 49.1 mmol) în acetonitrile (200 mL) was added césium carbonate (40.0 g, 123 mmol) and l-chloro-2-mcthoxyethane (6.90 g, 73.7 mmol). The solution was heated at reflux ovemight and then diluted with water (100 mL). The mixture was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried (NajSC^) and concentrated. The residue was purified by flash chromatography over silica gel using a hexane/ethyl acetate eluant to afford 4-(2-mcthoxyethoxy)bcnzaldchyde as a light yellow oil (6.00 g, 67%). To a stirred solution of this compound (2.70 g, 15.0 mmol) in 1,4-dioxane (50 mL) was added 4-methylbenzenesulfonohydrazide (2.79 g, 15.0 mmol). The solution was heated at 90 °C for 1 hour and then concentrated to afford crude N'-(4-(2-methoxyethoxy)benzylidene)-4methylbenzcnesuifonohydrazide as a yellow solid (5.22 g, 99%). This material was used without purification in the next step. To a stirred solution of the hydrazone (5.22 g, 15.0 mmol) in 1,4-dioxane (50 mL) was added potassium carbonate (6.20 g, 44.9 mmol) and

2-chloropyrimidin-5-ylboronic acid (2.37 g, 15.0 mmol). Mixture was heated at 90 °C for 3 hours, diluted with water (100 mL) and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (NaîSCL) and concentrated. The residue was purified by flash chromatography over silica gel using a hexane/ethyl acetate eluant to afford 2-chloro-5-(4-(2-mcthoxycthoxy)benzyl)pyrimidine as a light yellow oil (0.700 g , 17%). To a stirred solution of this intermediate (0.700 g, 2.52 mmol) in acetonitrile (15 mL) was added ethyl 4-fluoropiperidinc-4-carboxylatc hydrochloride (0.453 g, 2.59 mmol) and césium carbonate (2.46 g, 7.55 mmol). The mixture was heated at 80 °C ovemight, diluted with water (50 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO₄) and concentrated. The residue purified by flash chromatography over silica gel using a dichloromethanc/mcthanol eluant to afford ethyl 4-fluoro-1-(5-(4-(2mcthoxyethoxy)benzyl)pyrimidin-2-yl)piperidine-4-carboxylatc as a light yellow solid (0.667 g, 74%). Exchanging ethyl 1-(4-(4-0 uorophenyl)pyrimidin-2-yl)piperidine-4carboxylatc for the présent intermediate, the final two steps of Example 41 were used to préparé the title compound. ^lH NMR (400 MHz, CDCI3) δ 8.16 (s, 2H), 7.08 (d, J= 8.8 Hz, 2H), 6.87 (d, J= 8.8 Hz, 2H), 6.37 (d, J= 7.2 Hz, IH), 4.70-4.66 (m, 2H), 4.11 (t, ./ = 4.4 Hz, 2H), 3.76-3.74 (m, 4H), 3.46 (s, 3H), 3.26-3.19 (m, 2H), 2.96-2.79 (m, 6H), 2.282.15 (m, 3H), 1.87-1.77 (m, 4H), 1.58-1.50 (m, 5H) ppm. ¹³CNMR (100 MHz, CDCh) δ

171.3, 171.1, 160.5, 157.9, 157.4, 132.4, 129.5, 122.4, 114.8, 97.0,95.1, 71.0,67.3, 63.0,

59.2, 52.8, 46.5, 46.3, 39.3, 34.7, 31.9, 31.8, 31.7, 31.6, 30.1, 24.2, 22.9, 22.3 ppm. Purity: > 93% LCMS (214 nm & 254 nm); rétention time 1.36 min; (M+H⁴) 512.3.

226

Example 137 (3Æ)-3-Metliyl-/V-(4-metliyl-l-azabicyclo[3.2.2]nonan-4-yl)-4-(4-plienylpyrimidin-2yl)piperazine-l-carboxamide (single enantiomer B)

To a stirred solution of 2,4-dichloropyrimidinc (3.00 g, 20.1 mmol) in toluene (25 mL) was added phcnylboronic acid (2.47 g, 20.3 mmol), potassium carbonate (8.40 g, 60.9 mmol), tetrakis(triphcnylphosphine)palladium(0) (1.26 g, 1.02 mmol) and 1:1 (v/v) cthanol/watcr (36 mL). The mixture was heated ovemight at 55 °C and then concentrated. The residue was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na₂SO4) and concentrated. The crude material was purified by flash chromatography over silica using a hexanc/cthyl acetate eluant to afford 2-chloro-4-phcnylpyrimidinc as a yellow solid (3.20 g, 83%). To a stirred solution of this intermediate (1.10g, 5.77 mmol) in butyrontrile (20 mL) was added (R)-tert-butyl

3-mcthylpipcrazine-l-carboxylate (2.31 g, 11.5 mmol) and potassium carbonate (2.07 g, 15.0 mmol). The mixture was heated at reflux for 48 hours and then concentrated. The residue was taken up in ethyl acetate and washed with water. The aqueous layer was back-cxtracted with ethyl acetate and the combined organic layers were dried (Na₂SO4) and concentrated. The crude product was purified by flash chromatography over silica using a mcthanol/dichloromcthanc eluant to afford (R)-tert-butyl 3-methyl-4-(4phcnylpyrimidin-2-yl)pipcrazinc-l -carboxylate as amber solid (1.72 g, 84%). The tbutoxycarbonyl protecting group was removed from this compound using General Procedure G to afford (/î)-2-(2-methylpiperazin-l-yl)-4-phcnylpyrimidine. The intermediate was, in tum, reacted with Intermediate 10 using General Procedure A to generate the title compound. ‘H NMR (400 MHz, DMSO-cfc) δ 8.46 (d, J= 5.1 Hz, IH), 8.18-8.10 (m, 2H), 7.57-7.48 (m, 3H), 7.22 (d, J= 5.1 Hz, IH), 5.72 (s, IH), 4.93-4.82 (m, IH), 4.54-4.42 (m, IH), 4.13-4.02 (m, IH), 3.94-3.84 (m, IH), 3.27-3.06 (m, 2H), 2.98-2.64 (m, 7H), 2.43-2.33 (m, IH), 1.83-1.63 (m, 4H), 1.57-1.24 (m, 5H), 1.16 (d, J = 6.6 Hz, 3H) ppm. Purity: 99.7% (214 & 254 nm) UPLCMS; rétention time: 0.82 min; (M+H*) 435.5.

Exampie 138 (3/î)-3-Methyl-/V-(4-methyl-1 -azabicyclo[3.2.2] nonan-4-yl)-4-(4-phenylpy ri mid i n-2yl)piperazine-l-carboxamide (single enantiomer A)

Exchanging Intermediate 10 for Intermediate 9, the same reaction sequence outlined in Example 137 was used to generate the title compound. *H NMR (400 MHz, DMSO-t/e) δ 8.46 (d, J = 5.2 Hz, 1 H), 8.19-8.09 (m, 2H), 7.58-7.47 (m, 3H), 7.22 (d, J = 5.2 Hz, 1 H), 5.70 (s, IH), 4.91-4.80 (m, IH), 4.54-4.42 (m, IH), 4.07-3.88 (m, 2H), 3.27-3.14 (m, IH), 3.14-3.04 (m, IH), 3.00-2.67 (m, 7H), 2.40-2.31 (m, IH), 1.87-1.64 (m, 4H), 1.57-1.43 (m, IH), 1.42-1.26 (m, 4H), 1.15 (d, J =6.6 Hz, 3H)ppm. Purity: 99.4% (214 & 254 nm) UPLCMS; rétention time: 0.83 min; (M+H*) 435.5.

Example 139 (35)-3-lVIethyl-JV-(4-methyl-l-azabicyclo[3.2.2|nonan-4-yl)-4-(4-phenyIpyrimidin-2yl)piperazine-l-carboxamide (single enantiomer B)

227

Exchanging (Æ)-tert-butyl 3-mcthylpipcrazine-l-carboxylate for (S)-tert-butyl 3methylpiperazinc-l-carboxylate, the same reaction sequence outlined in Example 137 was used to generate the title compound. ’H NMR (400 MHz, DMSO-Js) δ 8.46 (d, J = 5.2 Hz, IH), 8.18-8.09 (m, 2H), 7.57-7.47 (m, 3H), 7.22 (d, J = 5.2 Hz, IH), 5.70 (s, IH), 4.91-4.80 (m, IH), 4.53-4.42 (m, IH), 4.05-3.87 (m, 2H), 3.26-3.14 (m, 1H),3.O9 (dd,J =

13.4, 3.8 Hz, IH), 2.99-2.67 (m, 7H), 2.40-2.31 (m, IH), 1.87-1.63 (m, 4H), 1.56-1.43 (m, IH), 1.42-1.26 (m, 4H), 1.15 (d, J = 6.6 Hz, 3H) ppm. Purity: >99.9% (214 & 254 nm) UPLCMS; rétention time: 0.83 min; (M+H⁴) 435.5.

Example 140 (35)-3-Methyl-7V-(4-mcthyl-l-azabicyclo[3.2.2]nonan-4-yl)-4-(4-phenylpyrimidin-2y))piperazine-l-carboxamide (single enantiomer Λ)

Exchanging (Æ)-tert-butyl 3-mcthylpiperazine-l -carboxylate for (S)-Ze/t-butyl 3mcthylpiperazine-1-carboxylate and Intermediate 10 for Intermediate 9, the same reaction sequence outlined in Example 137 was used to generate the title compound. *H NMR (400 MHz, DMSO-î/₆) δ 8.46 (d, J= 5.2 Hz, IH), 8.18-8.10 (m, 2H), 7.56-7.48 (m, 3H), 7.22 (d, J= 5.2 Hz, IH), 5.73 (s, IH), 4.93-4.81 (m, IH), 4.54-4.43 (m, IH), 4.12-4.02 (m, IH), 3.94-3.84 (m, IH), 3.26-3.07 (m, IH), 3.00-2.69 (m, 7H), 2.43-2.35 (m, IH), 1.84-1.64 (m, 4H), 1.57-1.44 (m, IH), 1.43-1.26 (m, 4H), 1.16 (d, J= 6.5 Hz, 3H) ppm. Purity: 99.6% (214 & 254 nm) UPLCMS; rétention time: 0.82 min; (M+H⁴) 435.5.

Example 141 3-Methyl-A^r-(4-methyl-l-azabicyclo[3.2.2]nonan-4-yl)-4-(4-phenylpyrimidin-2y l)pl perazin e-1-car boxa mide

Exchanging (Jî)-tert-butyl 3-mcthylpipcrazine-l-carboxylate for racemic tert-butyl 3mcthylpipcrazinc-1-carboxylate and Intermediate 10 for Intermediate 5, the same reaction sequence outlined in Example 137 was used to generate the title compound. *H NMR (500 MHz, CDCI3) Ô 8.41 (d, J= 5.5 Hz, IH), 8.08-8.06 (m, 2H), 7.50-7.49 (m, 3H), 7.00 (d, J= 5.5 Hz, IH), 5.06-4.98 (m, IH), 4.66-4.58 (m, IH), 4.37-4.35 (m, IH), 4.00-3.89 (m, IH), 3.78-3.66 (m, IH), 3.50-3.37 (m, 2H), 3.116-3.01 (m, 5H), 2.85-2.82 (m, 2H), 2.47-2.39 (m, IH), 2.00-1.96 (m, 3H), 1.75-1.52 (m, 6H), 1.31 (d, J = 6.5 Hz, 3H) ppm. ^,3C NMR (125 MHz, CDC1₃) δ 164.3, 161.4, 158.3, 157.2, 137.5, 130.5, 128.7, 127.0,

105.9, 59.0, 53.24, 53.21,47.9, 47.7, 47.6,47.4,47.2, 46.22, 46.18, 43.9,43.6, 39.8, 39.6,

38.4, 36.7, 36.5, 25.9, 25.8, 24.44, 24.42, 24.2, 24.1, 15.2, 15.1 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.32 min; (M+H⁴) 435.3.

Example 142 3-Ethyl-JV-(4-methyl-l-azabicyclo[3.2.2]nonan-4-yl)-4-(4-phenylpyrimidin-2yl)piperazine-l-carboxaniide

Exchanging (Æ)-tert-butyl 3-mcthylpïperazine-l-carboxylate for tert-butyl 3ethylpiperazinc-1-carboxylate and Intermediate 10 for Intermediate 5, the same reaction sequence outlined in Example 137 was used to generate the title compound. *H NMR (400 MHz, CDClj) δ 7.60-7.58 (d, J= 8.0 Hz, 2H), 7.44 (t, J= 7.6 Hz, 2H), 7.37-7.32 (m,

2H), 7.15 (s, IH), 7.10-7.08 (d, 7.2 Hz, IH), 6.96-6.94 (d, J = 8.0 Hz, IH), 5.46 (s,

IH), 3.83-3.80 (m, 2H), 3.08-2.78 (m, 8H), 2.41 (m, IH), 2.24-2.21 (m, IH), 2.01-1.52

228 (m, 13H) ppm. Purity: 97.7% (214 & 254 nm) UPLCMS; rétention time: 0.89 min; (M+H⁴) 449.5.

Exampie 143 3-Ethyl-W-(4-methyl-l-azabicyclo[3.2.2)nonan-4-yl)-4-(4-plienylpyrimidin-2yl)piperazine-1 -carboxamide

Exchanging 2,4-dichloropyrimidine for 2,4-dichloro-5-fluoropyrimidine, (Æ)-tert-butyl 3methylpiperazinc-l-carboxylate for racemic tert-butyl 3-methylpiperazine-l-carboxylate and Intermediate 10 for Intermediate 5, the same reaction sequence outlined in Example 137 was used to gencrate the title compound. '11 NMR (500 MHz, CDC1₃) δ 8.29 (d, J = 3.5 Hz, IH), 8.12-8.09 (m, 2H), 7.53-7.50 (m, 3H), 4.91-4.87 (m, IH), 4.53-4.48 (m, IH), 4.36-4.34 (m, IH), 4.00-3.90 (m, IH), 3.75-3.66 (m, IH), 3.45-3.35 (m, 2H), 3.15-2.84 (m, 7H), 2.44-2.39 (m, IH), 1.99-1.85 (m, 3H), 1.74-1.52 (m, 6H), 1.29 (dd, J= 6.5 Hz & 2.0Hz, 3H) ppm. ^l3C NMR (125 MHz, CDCI₃) δ 157.8,157.1, 151.5, 151.4, 150.9, 148.9,

146,8, 146.6, 134.0, 130.6, 128.9, 128.5, 59.0, 53.3, 47.9, 47.7, 47.6, 46.3, 46.2, 43.8,

43.6, 39.9, 39.7, 38.9, 36.7, 36.5, 25.9, 25.8, 24.5, 24.3, 24.2, 15.0, 14.9 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.37 min; (M+H⁴) 453.3.

Example 144 3-(Methoxymetliyl)-7V-(4-methyl-l-azabicyclol3.2.2|nonan-4-yl)-4-(4phenylpyrimidin-2-yl)piperazine-l-carboxamîde

2-Chloro-4-phenylpyrimidinc (prepared as described in Example 137; 0.332 g, 1.74 mmol), tert-butyl 3-(methoxymcthyl)piperazine-l-carboxylate (0.400 g, 1.74 mmol), Λζ/V-diisopropylethylamine (0.61 mL, 3.49 mmol) and acetonitrile (8 mL) were loaded into a sealed microwave reaction vial. The mixture was heated with stiiring in a microwave reactor for 36 hours at 140 °C. The reaction was then concentrated and the residue was partitioned between water and ethyl acetate. The organic layer was combined with a second ethyl acetate extract, dried (Na₂SO4) and concentrated. The crude product was purified by flash chromatography over silica using a dichloromethane/methanol eluant to afford tert-butyl 3-(mcthoxymethyl)-4-(4-phcnylpyrimidin-2-yl)piperazine-lcarboxylate as a glassy, faint amber solid (0.397 g, 60%). The t-butoxycarbonyl protccting group was removed from this compound using General Procedure G to afford 2-(2-(methoxymethyl)pipcrazin-l-yl)-4-phenylpyrimidine. The intermediate was, in tum, reacted with Intermediate 5 using General Procedure A to generate the title compound. ^lH NMR (400 MHz, DMSO-î/₆) δ 8.47 (d, J= 5.1 Hz, IH), 8.18-8.09 (m, 2H), 7.57-7.47 (m, 3H), 7.24 (d,5.1 Hz, IH), 5.65 (s, 0.5H), 5.61 (s, 0.5H), 4.99-4.84 (m, IH), 4.58-4.42 (m, IH), 4.13-3.93 (m, 2H), 3.56-3.35 (m, 2H), 3.29 (s, 1.5H), 3,28 (s, 1.5H), 3.25-3.03 (m, 2H), 3.01-2.65 (m, 7H), 2.37-2.28 (m, IH), 1.86-1.61 (m, 4H), 1.55-1.21 (m, 5H) ppm. Purity: 99.4% (214 & 254 nm) UPLCMS; rétention time: 0.83 min; (M+H⁴) 465.4.

Example 145

4-(4-(4-Fluorophenyl)pyrimidin-2-yl)-3-methyl“A^r-(4-methyl-lazabicyclo|3.2.2]nonan-4-yl)piperazine-l-carboxamide

Exchanging 2-chloro-4-phcnylpyrimidine for 2-chloro-4-(4-fluorophcnyl)pyrimidinc, (Λ)tert-butyl 3-mcthylpiperazine-l-carboxylate for racemic tert-butyl 3-methylpiperazine-l carboxylate and Intermediate 10 for Intermediate 5, the final three steps of Example 137 were used to generate the title compound. *H NMR (500 MHz, CDCh) δ 8.38 (d, ./= 5.5

229

Hz, IH), 8.06-8.03 (m, 2H), 7.15 (t, J= 8.5 Hz, 2H), 6.92 (d, J =5.5 Hz, IH), 4.99-4.96 (m, IH), 4.60-4.56 (m, IH), 4.34 (d, J= 6.0 Hz, IH), 3.98-3.88 (m, IH), 3.73-3.64 (m, IH), 3.45-3.34 (m, 2H), 3.13-2.84 (m, 7H), 2.40-2.37 (m, III), l.96-1.53 (m, 9H), 1.29 (dd, J= 7.0 Hz & 2.5 Hz, 3H) ppm. ^I3C NMR (125 MHz, CDClj) δ 165.4, 163.4, 163.2,

161.3, 158.4, 157.2, 133.7, 139.0, 128.9, 115.7, 115.6, 105.5, 59.1, 53.3,47.9,47.7,47.6,

47.4.47.2, 46.3, 43.9, 43.6, 40.0, 39.8, 38.4, 36.8, 36.6, 25.9, 25.8, 24.5, 24.3, 24.2, 15.3. 15.1 ppm. Purity: > 97% LCMS (214 nm & 254 nm); rétention time J.37 min; (M+H⁴)

453.3.

Exampie 146 4-(4-(4-Fluoroplienyl)pyrimidin-2-yl)-3-methyl-/V-(4-inetliyl-lazabicyclo[3.2.2]nonan-4-yl)piperazine-l-carboxainide

Exchanging phenylboronic acid for (4-(2-methoxycthoxy)phenyl)boronic acid, 2,4dichloropyrimidine for 2,4-dichloro-5-fluoropyrimidinc, (Æ)-tert-butyl 3mcthylpipcrazine-1-carboxylate for racemic ieri-butyl 3-methylpiperazine-l-carboxylate and Intermediate 10 for Intermediate 5, the same réaction sequence outlined in Example 137 was used to generate the title compound. *H NMR (400 MHz, CDCh) δ 8.21 (d, J = 3.8 Hz, IH), 8.09 (d, J= 8.9 Hz, 2H), 7.02 (d, J= 8.9 Hz, 2H), 4.91-4.81 (m, IH), 4.504.36 (m, 2H), 4.22-4.16 (m, 2H), 4.01-3.87 (m, IH), 3.82-3.63 (m, 3H), 3.47 (s, 3H), 3.43-3.30 (m, 2H), 3.14-2.80 (m, 7H), 2.47-2.38 (m, IH), 1.99-1.78 (m, 3H), 1.78-1.48 (m, 6H), 1.26 (d, J= 2.2 Hz, 1.5H), 1.25 (d, J = 2.2 Hz, 1.5H) ppm. Purity: 98.7% (214 & 254 nm) UPLCMS; rétention time: 0.91 min; (M+H⁴) 527.5.

Example 147 <.7s-3,5-DimethyI-/V-(4-niethyl-l-azabicyclo[3.2.2|nonan-4-yI)-4-(4-phenylpyriinidin2-yl)piperazine-l-carboxamide

A stirred mixture of 2-chloro-4-phenylpyrimidine (prepared as described in Exampie 137; 0.190 g, 0.999 mmol), 2,2,6,6-tetramethylpiperidine and ieri-butyl eis-3,5dimethylpipcrazine-1-carboxylate was heated at 140 ⁰ for 48 hours and then concentrated. The residue was purified by flash chromatography over silica using a hexanc/ethyl acetate eluant to afford fôrt-butyl m-3,5-dimethyl-4-(4-phenylpyrimidin-2-yl)piperazine-lcarboxylatc as a white solid (0.094 g, 26%). To a stirred and cooled (0 °C) solution of this intermediate (0.185 g, 0.500 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (4 mL). The reaction was allowed to warm to room température and stirred for an additional 2 hours. At this time, the mixture was diluted with a saturated aqueous sodium carbonate solution (enough to make the solution basic) and extracted with dichloromethane. The combined cxtracts wcrc dried (Na₂SO4) and concentrated to afford 2-(cis-2,6-dimethylpiperazin-l-yl)-4-phenylpyrimidine as a yellow oil (0.136 g, 100%). Using General Procedure A and Intermediate 5, this intermediate was used to generate the title compound as a white solid (0.068 g, 31%). *H NMR (500 MHz, CDCI3) δ 8.43 (d, J = 5.0 Hz, IH), 8.09-8.06 (m, 2H), 7.51-7.49 (m, 3H), 7.01 (d, J = 5.5 Hz, IH), 4.98-4.96 (m, 2H), 4.44 (s, IH), 3.97 (d, J= 12.0 Hz, IH), 3.78 (d, J= 12.0 Hz, IH), 3.28-2.90 (m, 8H), 2.48 (m, IH), 1.98-1.57 (m, 9H), 1.38 (t, J= 7.5 Hz, 6H) ppm. ^]3CNMR (125 MHz, CDCh) δ 164.2, 160.8, 158.3, 157.2, 137.7, 130.5, 128.7, 126.9, 105.7, 59.0, 53.3, 48.8,

48.2, 48.0, 46.4, 46.3, 46.0, 39.6, 36.6, 26.0, 24.3, 24.0, 19.4 ppm. Purity: > 95% LCMS (214 nm & 254 nm); rétention time 1.99 min; (M+H⁴) 449.4.

Example 148

230

4-(5-Fluoro-4-(4-(methoxymctliyl)plicnyl)pyrimidin-2-yl)-3-ïsopropyl-A^|f-(4-nictliyl-lazabicyclo[3.2.2]nonaii-4-yl)piperazine-l-carl)oxami(Ie

Exchanging 2,4-dichloropyrimidinc for 2,4-dichloro-5-fluoropyrimidinc and phcnylboronîc acid for 2-(4-(mcthoxymcthyl)phenyl)-4,4,5,5-tetramethyl-l,3,2dioxaborolanc, the first step of Example 137 was used to prépare 2-chloro-5-fluoro-4-(4(methoxymethyl)phenyl)pyrimidine. To a stirred solution of this intermediate (0.400 g, 1.58 mol) in toluene (8 mL) was added tert-butyl 3-isopropylpiperazine-l-carboxylate (0.434 g, 1.90 mmol), bis(tri-zert-butylphosphine)palladium(0) (0.081 g, 0.158 mmol), trimethylhexadecylammonium chloride (0.101 g, 0.316 mmol) and a 50% aqueous sodium hydroxide solution (0.25 mL, 4.73 mmol). The mixture was heated at 100 °C ovemight and concentrated. The residue was purified by flash chromatography over silica using a hcxanc/cthyl acetate cluant to afford partially purified tert-butyl 4-(5-fluoro-4-(4(methoxymethyl)ph cnyl)pyrim idi n-2-y l)-3 -isopropy Ipip erazinc-1 -carboxylate as 1 ight yellow oil (0.500 g). This material was taken up in dichloromethane (5 mL), stirred and treated with trifluoroacetic acid (3.0 mL). After 3 hours, the reaction was concentrated and the residue was purified by reversed-phase flash chromatography over Cl8 silica using a acctonitrilc/water/trifluoroacetic acid cluant. 5-Fluoro-2-(2-isopropylpiperazin-lyl)-4-(4-(methoxymethyl)phcnyl)pyrimidine was affordcd as a light yellow oil (0.200 g, 36% for two steps). Using General Procedure A and Intermediate 5, this intermediate was used to generate the title compound as a white solid (0.105 g, 63%). ’H NMR (500 MHz, CDClj) δ 8.24 (d, J = 3.5 Hz, IH), 8.08 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H), 4.75-4.72 (m, IH), 4.59-4.55 (m, 3H), 4.33-4.31 (m, IH), 3.94-3.86 (m, 2H), 3.45 (s, 3H),

3.28-3.19 (m, 2H), 3.07-2.85 (m, 7H), 2.43-2.40 (m, IH), 2.26-2.19 (m, IH), 1.94-1.50 (m, 9H), 1.13 (t, J = 7.5 Hz, 3H), 0,87 (d, J = 7.5 Hz, 3H) ppm. ^I3C NMR (125 MHz, CDClj) δ 158.4, 157.0, 151.1, 151.0, 150.4, 148.4, 146.7, 146.4, 140.9, 133.4, 129.0,

128.9, 127.5, 74.2, 59.0, 58.3, 57.5, 57.3, 53.2, 47.8, 47.6, 46.4, 46.1, 44.0, 43.9, 43.5,

43.3, 39.9, 39.7, 39.1, 36.7, 36.4, 27.1, 27.0, 25.9, 25.7, 24.4, 24.1, 20.4, 20.2, 19.1, 19.0 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.54 min; (M+H*) 525.3.

Example 149 4-(4-(4-(Methoxymetliyl)phenyl)pyrimidin-2-yl)-jV-(4-methyl-lazabicyclo[3.2.2|noiiaii-4-yl)-3-(triiluoromethyl)piperazine-l-carboxamide

Exchanging phcnylboronîc acid for 2-(4-(mcthoxymcthyl)phenyI)-4,4,5,S-tétraméthylia ,2-dioxaborolanc, the first step of Example 137 was used to préparé 2-chloro-4-(4(methoxymethyl)phenyl)pyrimidine. To a stirred solution of this intermediate (880 mg, 3.75 mmol) in toluene (30 mL) was added tert-butyl 3-(trifluoromethyl)piperazine-lcarboxylatc (1.10 g, 4.33 mmol), césium carbonate (6.11 g, 18.75 mmol), 2,2'bis(diphenylphosphino)-l,r-binaphthalene (700 mg, 1.12 mmol and palladium(II) acetate (0.168 g, 0.748 mmol). The mixture was heated at reflux ovemight, cooled and diluted with water (-100 mL). The mixture was extracted with ethyl acetate and the combined organic layers were dried (Na₂SÛ4) and concentrated. The crude product was purified by flash chromatography over silica using a hcxane/ethyl acetate cluant to afford tert-butyl 4-(4-(4-(mcthoxymethyl)phcnyl)pyrimidin-2-yl)-3-(trifluoromethyl)piperazine-lcarboxylate as a colorless gum (0.179 g, 11%). The t-butoxycarbonyl protecting group was removed from this compound using General Procedure G to afford 4-(4(mcthoxymethyl)phenyl)-2-(2-(trifluoromcthyl)piperazin-l-yl)pyrimidine. This intermediate was, in tum, reacted with Intermediate 5 using General Procedure A to generate the title compound. ’H NMR (400 MHz, CDClj) δ 8.42 (dd, J - 5.2,1.4 Hz, IH),

231

8.02 (d, ./= 7.8 Hz, 2H), 7.45 (d, ./ = 7.8 Hz, 2H), 7.27 (s, IH), 7.09 (dd, ./= 5.2, 1.4 Hz, IH), 5.72-5.58 (m, IH), 4.93-4.79 (m, IH), 4.53 (s, IH), 4.43-4.36 (m, IH), 4.26-4.18 (m, 0.5H), 4.16-4.08 (m, 0.5H), 4.05-3.89 (m, 11-1), 3.59-3.40 (m, 5H), 3.15-2.75 (m, 7II), 2.44-2.35 (m, IH), 1.98-1.41 (m, 9H) ppm. Purity: >99.9% (214 & 254 nm) UPLCMS; rétention time: 0.90 min; (M+H⁺) 533.3.

Example 150 3-(Dinuoromethyl)-4-(4-(4-(melhoxymethyl)phenyl)pynmidin-2-yl)-7V-(4-methyl-lazabicyclo[3.2.2|nonan-4-yl)pipcrazine-l-carboxamide

Exchanging tert-butyl 3-isopropylpiperazine-l-carboxyiate for Ze/7-butyl 3(difluoromethyl)pipcrazine-l -carboxyiate, the final three steps of Example 148 were used to generate the title compound. ’H NMR (500 MHz, CDClj) δ 8.43 (d, J = 5.5 Hz, IH), 8.04 (d, J= 8.0 Hz, 2H), 7.476 (d, J = 8.0 Hz, 2H), 7.09 (d, J= 5.0 Hz, IH), 6.17 (t, J = 56 Hz, IH), 5.14-5.10 (m, IH), 4.79 (m, IH), 4.55 (s, 2H), 4.41-4.39 (m, IH), 4.05-3.95 (m, 2H), 3.58-3.45 (m, 5H), 3.18-2.84 (m, 7H), 2.41-2.38 (m, IH), 1.95-1.50 (m, 9H) ppm. ¹³C NMR (100 MHz, CDC1₃) Ô 164.3, 161.5, 158.4, 156.4, 141.2, 136.4, 132.1,

131.9, 128.5, 128.4, 114.7 (td,./= 246 Hz & 7.4 Hz), 107.0, 74.2, 59.1, 58.3, 53.2, 52.9,

52.6, 52.4, 52.1,47.7, 47.5, 46.3,46.1, 43.4, 43.2, 39.7, 39.6, 39.5, 39.4, 36.7, 36.5, 30.9,

25.8.25.6, 24.4, 24.0 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.29 min; (M+H⁺) 515.3.

Example 151 3-Isopropyl-4-(4-(4-(methoxymethyl)phenyl)-13»S-triazin-2-yl)-A^r-(4-metliyl-lazabicyclo[3.2.2]nonan-4-yl)piperazine-l-carboxanude

To a stirred and cooled (0 °C) suspension of 2,4-dichloro-l,3,5-triazine (0.800 g, 5.33 mmol) and potassium carbonate (1.47 g, 10.7 mmol)in tetrahydrofuran (20 mL) was added, dropwisc over 30 minutes, a solution of tert-butyl 3-isopropylpiperazine-lcarboxylatc (1.22 mg, 5.33 mmol) in tetrahydrofuran (10 mL). The mixture was stirred at 0 °C for 2 hours and then at room température ovemight. The reaction was then concentrated and the residue was purified by column chromatography over neutral alumina using a hexane/ethyl acetate eluant to afford tert-butyl 4-(4-chloro-l,3,5-triazin2-yl)-3-isopropylpipcrazine-l-carboxyiate as a white solid (1.10 g, 60%). To a stirred solution of this intermediate a (0.450 g, 1.32 mmol) in 1,4-dioxane was added 2-(4-((2methoxyethoxy)methyl)phenyl)-4,4,5,5-tetramcthyl-l,3,2-dioxaborolane (0.391 g, 1.58 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.119 g, 0.130 mmol), 2dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.124 g, 0.260 mmol) and césium carbonate (1.08 g, 3.31 mmol). The mixture was heated ovemight at 140 °C for 16 hours, fïltered through Celite, and concentrated. The residue was purified by flash chromatography over silica gel using a dichloromcthane/methanol eluant to afford tertbutyl 3-isopropyl-4-(4-(4-(methoxymethyl)phenyl)-1,3,5-triazin-2-yl)piperazine-1 carboxyiate as a white solid (200 mg, 35%). To a stirred and cooled (0 °C) solution of this intermediate (200 mg, 0.470 mmol) in dichloromethane (10 mL) was added trifluoracetic acid (10 mL). The reaction was stirred for another 3 hours at 0 °C beforc diluting with 2.0 N aqueous potassium carbonate solution (cnough to render the mixture basic) and extracting with dichloromethane. The combined organic phases were washed with brine, dried (Na₂SO4) and concentrated to afford 2-(2-isopropylpiperazin-l-yl)-4-(4(methoxymethyi)phenyl)-l,3,5-triazine as a white solid (150 mg, crude). Using General Procedure A and Intermediate 5, this intermediate was used to generate the title

232 compound as a light yellow solid (0.040 g, 15%). *H NMR (500 MHz, CDCI3) ô 8.65 (d, J= 3.0 Hz, IH), 8.41-8.37 (m, 2H), 7.47-7.45 (m, 2H), 4.99 (m, 0.5H), 4.80 (m, IH), 4.63 (m, 0.5H), 4.56 (s, 2H), 4.35 (d, J= 12.5 Hz, IH), 4.08-3.89 (m, 2H), 3.44 (s, 3H), 3.192.84 (m, 9H), 2.42-2.40 (m, IH), 2.24 (m, IH), 1.98-1.56 (m, 9H), 1.19-1.13 (m, 3H), 0.89-0.85 (m, 3H) ppm. ^,3C NMR (125 MHz, CDC1₃) δ 170.5, 170.2, 166.2, 166.0, 164.5,

156.8, 142.5, 135.6, 135.5, 128.6, 128.5, 127.5, 74.2, 59.2, 59.1, 58.3, 56.8, 56.7, 56.6,

53.1.47.6, 47.5,46.4, 46.2, 44.5,44.1, 44.0, 43.6, 43.5, 43.4,43.3, 39.8, 39.6, 38.6, 38.4,

36.6, 36.4, 27.0, 26.6, 26.5, 25.8, 25.6, 24.3, 24.0, 20.5, 20.4, 20.3, 20.2, 19.0, 18.7 ppm. Purity: > 95% LCMS (214 nm & 254 nm); rétention time 1.90 min; (M+H⁴) 508.3.

Example 152 (3/ï)-4-(5-(4-Fluoroplienoxy)pyrimidin-2-yl)-3-methyl-A^r-(4-methyl-lazabicyclo[3.2.2|nonan-4-yl)piperazine-l-carboxamide

Exchangïng 2-chloro-5-fluoro-4-(4-(methoxymethyl)phenyl)pyrimidine for 2-chloro-5(4-fluorophenoxy)pyrimidinc (prepared as described in Example 129) and ferf-butyl 3isopropylpipcrazine-1-carboxylate for (fï)-ferf-butyl 3-methylpiperazine-1 -carboxylate, the final three steps of Example 148 were used to générale the title compound. *H NMR (500 MHz, CDCI3) δ 8.17 (s, 2H), 7.02-6.99 (m, 2H), 6.92-6.89 (m, 2H), 4.85-4.73 (m, IH), 4.45-4.32 (m, 2H), 3.97-3.88 (m, IH), 3.73-3.62 (m, IH), 3.37-3.32 (m, 2H), 3.102.79 (m, 7H), 2.43-2.38 (m, IH), 1.99-1.48 (m, 9H), 1.25-1.23 (m, 3H) ppm. ^I3C NMR (100 MHz, CDîOD) δ 160.2, 159.3, 158.5, 158.4, 157.8, 155.7, 152.0, 143.5, 119.4,

119.3, 117.8, 117.6, 59.6, 54.4, 54.3, 49.4, 49.0, 48.7, 48.5, 48.4, 48.2, 46.8, 46.5, 44.7, 44.4, 39.9, 39.8, 37.1, 36.9, 27.3, 27.1, 25.8, 25.7, 25.4, 25.3, 15.5, 15.4 ppm. Purity: > 96% LCMS (214 nm & 254 nm); rétention time 1.37 min; (M+H⁴) 469.2.

Exampie 153 3-Ethynyl-4-(4-(4-(methoxymethyl)phenyl)pyrimidm-2-yl)-A^,-(4-methyl-lazabicyclo[3.2.2]nonan-4-yl)piperazine-l-carboxamide

To a stirred solution of 2-chloro-4-(4-(methoxymcthyl)phenyl)pyrimidine (prepared as described in Exampie 149; 0.936 g, 4.00 mmol) in V.V-dimcthylformamidc (10 mL) was added ferf-butyl 3-(hydroxymcthyl)piperazine-l-carboxylate (1.73 g, 8.00 mmol). The réaction was heated at 90 °C for 5 days and then concentrated. The residue was purified by flash chromatography over silica gel using a hexane/cthyl acetate eluant to afford fertbutyl 3-(hydroxymethyl)-4-(4-(4-(mcthoxymethyl)phenyl)pyrimidin-2-yl)piperazine-1 carboxylate as a white solid (1.066 g, 65%). To a stirred solution of this intermediate (0.543 g, 1.32 mmol) in ethyl acetate (10 mL) was added 2-iodoxybenzoic acid (1.10 g, 3.93 mmol.). The réaction was heated at 80 °C for 3 hours and then concentrated. The residue was purified by flash chromatography over silica gel using a hexane/cthyl acetate eluant to afford ferf-butyl 3-ethynyl-4-(4-(4-(methoxymethyI)phcnyl)pyrimidîn-2yl)pipcrazine-l-carboxylate as a yellow oil (0.480 g, 89%). The f-butoxycarbonyl protecting group was removed firom this compound using General Procedure G to afford 2-(2-ethynylpiperazin-l -yl)-4-(4-(methoxymethyl)phenyl)pyrimidine. This intermediate was, in tum, reacted with Intermediate 5 using General Procedure A to generate the title compound. *H NMR (500 MHz, CDC1₃) δ 8.46 (d, J= 5.5 Hz, IH), 8.07 (d, J = 8.0 Hz, 2H), 7.47 (d, J= 8.0 Hz, 2H), 7.10 (d, J = 5.0 Hz, IH), 5.78 (s, IH), 4.67-4.50 (m, 4H),

4.29-3.99 (m, 2H), 3.44 (s, 311), 3.42-3.30 (m, 2H), 3.09-2.84 (m, 7H), 2.47-2.41 (m, IH), 2.23-2.22 (m, IH), 1.99-1.55 (m, 9H) ppm. ¹³C NMR (125 MHz, CDCI3) δ 164.3, 161.3,

158.5, 156.8, 156.7, 141.1, 136.5, 127.8, 127.2, 107.2, 81.2, 81.1, 74.2, 71.8, 71.7, 59.1,

233

59.0, 53.3, 53.2, 48.9, 48.5, 47.9, 47.8, 46.2, 46.1, 44.0, 39.7, 39.6, 36.7, 36.6, 25.8, 24.4,

24.1 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.35 min; (M+H⁴)

489.3,

Exampie 154 l-AzabicycIo[3.2.2|nonan-4-yl 3-methyl-4-(4-plienylpyrimidin-2-yl)piperazine-lcarboxylate

Exchanging (/?)-Zeri-butyl 3-methylpiperazine-l -carboxylate for racemic ieri-butyl 310 mcthylpipcrazine-1 -carboxylate, the first three steps of Example 137 were used to préparé 2-(2-methylpipcrazin-l-yl)-4-phenylpyrimidine. The intermediate was, in tum, reacted with Intermediate 3 using General Procedure C to generate the title compound. *H NMR (500 MHz, CDC1₃) δ 8.40 (d, J= 5.5 Hz, IH), 8.07-8.04 (m, 2H), 7.49-7.47 (m, 3H), 6.99 (d, J = 5.5 Hz, IH), 5.08 (m, IH), 4.98 (m, IH), 4.67 (m, IH), 4.25-4.02 (m, 15 2H), 3.30-2.82 (m, 9H), 2.36-1.57 (m, 7H), 1.26 (d,./ = 7.0 Hz, 3H) ppm. ¹³C NMR (125

MHz, CDC1₃)ô 164.3, 161.5, 158.4, 155.4, 137.6, 130.5, 128.7, 126.9, 105.9, 79.2. 79.1,

51.8.48.3, 48.0, 47.9,47.6, 46.6, 46.3, 45.4, 45.3, 43,8, 43.6, 38.2, 33.5, 30.8, 30.7, 24.8,

22.4.22.3, 14.5, 14.2 ppm. Purity: > 99% LCMS (214 nm & 254 nm); rétention time 1.48 min; (M+H⁴) 422.2.

Exampie 155 Qulnuclidin-3-yl (2-(4'-(2-πιεί1ιοχγεί1ιοχγ)-[1,Γ-ΝρΗ€ηγ1|-4-γ1)ρπ)ρ3η-2yl)carbamate

Using General Procedure F and the réaction inputs ethyl 2-(4-bromophenyl)-2methylpropanoatc and 4-(2-methoxyethoxy)phcnylboronic acid, ethyl 2-(4'-(2methoxycthoxy)-[l,r-biphcnyl]-4-yl)-2-methylpropanoatc was prepared as an off-white solid. To a stirred solution of this compound (3.01 g, 8.78 mmoi) in 1:1:1 (v/v/v) tetrahydrofuran/cthanoi/water (45 mL) was added lithium hydroxide monohydrate (1.47 30 g, 61.4 mmol). The mixture was heated at reflux ovemight and then concentrated. The residue was dissolved in water, treated with IN hydrochloric acid (65 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na₂SC>4) and concentrated to afford 2-(4'-(2-mcthoxycthoxy)-[l,r-biphenyl]-4-yl)-2methylpropanoic acid as a white solid (2.75 g, 100%). This intermediate and quinuclidin35 3-ol were reacted according to General Procedure H to generate the title compound as a colorless, glassy solid (23%). ^lH NMR (400 MHz, DMSO-î/6) δ 7.62-7.29 (m, 7H), 7.01 (d, J = 8.9 Hz, 2H), 4.47-4.37 (m, IH), 4.17^1.08 (m, 2H), 3.72-3.62 (m, 2H), 3.32 (s, 3H), 3.09-2.25 (m, 6H), 2.05-1.18 (m, UH) ppm. ^I3C NMR (100 MHz, DMSO-î/6) δ

157.9, 154.5, 146.7, 137.4, 132.5, 127.5, 125.7, 125.2, 114.8, 70.4, 70.0, 66.9, 58.2, 55.4, 40 54.2, 46.9, 45.9, 29.4, 25.3, 24.2, 19.2 ppm. Purity: 100%, 99.1% (210 & 254 nm)

UPLCMS; rétention time: 0.87 min; (M+H⁴) 439.0.

Example 156 (5}-Qumuclidin-3-yl (2-(4'-(2-metlioxyethoxy)-[l,l’-biphenyl]-4-yI)propan-245 yl)carbamate

Using General Procedure H and the reaction inputs 2-(4'-(2-methoxyethoxy)-[ 1, Γbiphenyl]-4-yl)-2-methylpropanoic (prepared as described in Example 1) and (5)quinuclidin-3-ol, the title compound was prepared as a colorless, glassy solid. NMR data

234 matchcd that of Example 1. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.87 min; (M+H¹) 439.5.

Example 157 (R) -l-(2-(4'-(2-Metlioxyethoxy)-[l,r-biplienyl]-4-yl)propan-2-yl)-3-(3metliylquinuclidin-3-yl)urea

Using General Procedure H and the reaction inputs 2-(4^,-(2-methoxycthoxy)-[l,rbiphenyl]-4-yl)-2-methylpropanoic (prepared as described in Example 155) and Intermediate 12, the title compound was prepared as a white solid. ^lH NMR (400 MHz, DMSO-î/c) δ 7.57 (d, J= 8.8 Hz, 2H), 7.51 (d, J= 8.4 Hz, 2H), 7.38 (d, J= 8.4 Hz, 2H), 7.01 (d, J= 8.8 Hz, 2H), 6.15 (s, IH), 5.76 (s, IH), 4.15-4.08 (m, 2H), 3.74-3.64 (m, 2H),

3.32 (s, 3H), 2.74-2.44 (m, 6H), 1.93-1.85 (m, IH), 1.85-1.73 (m, IH), 1.67-1.56 (m, IH), 1.53 (d, J= 11.9 Hz, 6H), 1.42-1.31 (m, IH), 1.29 (s, 2H), 1.29-1.20 (m, IH) ppm. ^,3C NMR (100 MHz, DMSCMs) Ô 157.9, 156.9, 147.8, 137.2, 132.5, 127.5, 125.6, 125.3,

114.8, 70.4, 66.9, 63.6, 58.2, 53.8, 50.7, 46.2, 46.1, 30.4, 30.3, 29.9, 25.1, 23.0, 22.3 ppm. Purity: 100%, 99.9% (210 & 254 nm) UPLCMS; rétention time: 0.97 min; (M+H⁴) 452.4.

Example 158 (S) -l-(2-(4^l-(2-Metlioxyethoxy)-(l,l’-biphenyl|-4-yl)propan-2-yl)-3-(3methylquinuclldin-3-yI)urea

Using General Procedure H and the réaction inputs 2-(4'-(2-methoxyethoxy)-[l,l·biphenyl]-4-yl)-2-methylpropanoic (prepared as described in Example 155) and Intermediate 11, the title compound was prepared as a white solid. NMR data matchcd that of Example 3. Purity: 100%, 99.9% (210 & 254 nm) UPLCMS; rétention time: 0.97 min; (M+H⁴) 452.4.

Example 159 l-(3-EthyIquinuclidin-3-yl)-3-(2-(4'-(2-methoxyethoxy)-fl,l'-biphenyl]-4-yl)propan2-yI)urea

Using General Procedure H and the reaction inputs 2-(4'-(2-methoxyethoxy)-[l,rbiphenyl]-4-yl)-2-mcthylpropanoic (prepared as described in Example 155) and Intermediate 2, the title compound was prepared as a white solid. *H NMR (400 MHz, DMSO-i/s) δ 7.56 (d, J= 8.8 Hz, 2H), 7.50 (d, J= 8.5 Hz, 2H), 7.39 (d, J= 8.5 Hz, 2H), 7.01 (d,./ = 8.8 Hz, 2H), 6.18 (s, IH), 5.73 (s, IH), 4.32-3.96 (m, 2H), 3.87-3.63 (m, 2H),

3.32 (s, 3H), 2.75-2.45 (m, 6H), 1.93-1.58 (m, 4H), 1.53 (d, J= 16.2 Hz, 7H), 1.42-1.13 (m, 2H), 0.75 (t, J = 7.3 Hz, 3H) ppm. ¹³C NMR (100 MHz, DMSO-r/_e) ô 157.9, 156.8,

147.8, 137.2, 132.5, 127.5, 125.6, 125.3, 114.8, 70.4, 66.9, 62.9, 58.1, 53.7, 53.2, 46.5,

46.3, 30.4, 29.8, 27.8, 27.7, 22.6, 22.3, 8.0 ppm. Purity: 100%, 99.9% (210 & 254 nm) UPLCMS; rétention time: 1.00 min; (M+H⁴) 466.4.

Example 160

-(2-(4 '-(2-Meth oxy et h oxy)- [ 1,1 '-b ipheny I] -4-y l)p ro p a n-2-yI)-3 -(4-m ethy I-1 azabicyclo|3.2.2]nonan-4-yl)urea

Using General Procedure H and the réaction inputs 2-(4'-(2-methoxyethoxy)-[l,rbiphenyl]-4-yl)-2-methylpropanoic (prepared as described in Example 155) and

Intermediate 5, the title compound was prepared as a white solid. ⁽H NMR (400 MHz,

235

DMSO-î/₆) δ 7.56 (d, ./ = 8.8 Hz, 2H), 7.50 (d, J= 8.5 Hz, 2H), 7.39 (d, J =8.5 Hz, 2H), 7.01 (d, J= 8.8 Hz, 2H), 6.22 (br s, IH), 5.72 (br s, 1 H), 4.20-4.07 (m, 2H), 3.85-3.60 (m, 2H), 3.32 (s, 3H), 2.93-2.66 (m, 6H), 2.11-2.05 (m, IH), 1.83-1.36 (m, 10H), 1.33-1.19 (m,4H) ppm. ^l3CNMR(100 MHz, DMSO-</₆) δ 157.9, 156.8, 147.8,137.2, 132.5, 127.5,

125.6, 125.3, 114.8, 70.4, 66.9, 58.2, 57.2, 53.7, 52.8, 48.1, 45.0, 36.2, 30.4, 29.8, 26.2,

24.4, 23.9 ppm. Purity: 100%, 99.0% (210 & 254 nm) UPLCMS; rétention time: 0.98 min; (M+H*) 466,4.

Exampie 161 /V-(2-(4*-(2-Methoxyethoxy)-[l,r-biphenyl]-4-yi)propan-2-y))“l_J4diazabicyclo[3.2.2|nonane-4-carboxamide

Using General Procedure H and the réaction inputs 2-(4'-(2-mcthoxyethoxy)-[l,rbiphcnyl]-4-yl)-2-methylpropanoic (prepared as described in Example 155) and Intermediate 6, the title compound was prepared as a white solid. *H NMR (400 MHz, DMSO-r/e) δ 7.56 (d, J= 8.8 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.36 (d, J= 8.4 Hz, 2H), 7.01 (d, J= 8.8 Hz, 2H), 6.12 (s, IH), 4.19 (s, IH), 4.12 (dd, J= 5.4, 3.8 Hz, 2H), 3.753.62 (m, 2H), 3.48 (t, J= 5.6 Hz, 2H), 3.32 (s, 3H), 2.96-2.70 (m, 6H), 1.93-1.83 (m, 2H), 1.68-1.40 (m, 8H) ppm. ^I3C NMR (100 MHz, DMSO-î/₆) δ 157.8, 155.4, 148.1, 136.9,

132.7, 127.5, 125.5, 125.2, 114.8, 70.4, 66.9, 58.1, 57.5, 54.5, 46.6, 46.0, 41.4, 30.2, 27.0 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.85 min; (M+H*)

438.5.

Example 162 l-(l-(4'-(2-Mcthoxycthoxy)-[l,l'-biphenyl]-4-yl)cycIopropyl)-3-(quinuclidin-3yl)urea

Exchanging ethyl 2-(4-bromophenyl)-2-methylpropanoate for ethyl l-(4bromophenyl)cyclopropanecarboxylatc, the reaction sequence outlined in Example 155 was used to préparé l-(4'-(2-mcthoxyethoxy)-[l,r-biphenyl]-4yl)cyclopropanccarboxylic acid. This intermediate and qutnuclidin-3-amine were reacted according to General Procedure H to generate the title compound as a white solid. Il NMR (400 MHz, DMSO-î/₆) δ 7.55 (d, J= 8.8 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 7,18 (d, J= 8.4 Hz, 2H), 7.01 (d, J= 8.8 Hz, 2H), 6.68 (br s, IH), 5.99 (br s, IH), 4.15-4.09 (m, 2H), 3.75-3.63 (m, 2H), 3.61-3.50 (m, IH), 3.32 (s, 3H), 3.06 (dd, J= 13.6, 9.5 Hz, IH), 2.73-2.54 (m, 4H), 2.35-2.22 (m, IH), 1.71-1.40 (m, 4H), 1.36-1.24 (m, IH), 1.21-1.08 (m, 4H) ppm. ¹³CNMR(100 MHz, DMSO-i/₆) Ô 157.9,157.5,143.4, 136.9,132.4,127.5,

125.7, 125.0, 114.8, 70.4, 66.9, 58.2, 56.1, 46.9, 46.3, 46.1, 33.9, 26.1, 25.6, 19.8, 18.6 ppm. Purity: 100%, 99.9% (210 & 254 nm) UPLCMS; rétention time: 0.82 min; (M+H*)

436.3.

Example 163

1-(1-(4'-(2-Methoxyeth oxy)- [1,1 '-biphenyl] -4-yl)cyclopropyl)-3-(3methylquinucIidin-3-yl)urea

Using General Procedure H and the réaction inputs 1-(4'-(2-mc thoxy et box y )-[!,]'biphenyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 162) and

Intermediate 1, the title compound was prepared as a white solid. *H NMR (400 MHz,

DMSO-i/û) Ô 7.56 (d, J= 8.8 Hz, 2H), 7.51 (d, J= 8.4 Hz, 2H), 7.18 (d, J= 8.4 Hz, 2H),

7.00 (d, J= 8.8 Hz, 2H), 6.63 (s, IH), 5.61 (s, IH), 4,17-4.06 (m, 2H), 3.80-3.61 (m, 2H),

236

3.32 (s, 3H), 2.82-2.52 (m, 6H), 1.99-1.82 (m, IH), 1.78-1.54 (m, 2H), 1.46-1.30 (m, 4H),

1.29- 1.19 (m, IH), 1.19-1.11 (m, 4H) ppm. ¹³C NMR (100 MHz, DMSO-rf₆) δ 157.9,

157.3, 143.5, 136.9, 132.4, 127.5, 125.7, 124.8, 114.8, 70.4, 66.9, 63.4, 58.2, 50.9, 46.2, 46.0, 33.8, 30.4, 25.0, 23.0, 22.3, 18.8 ppm. Purity; 100%, 99.9% (210 & 254 nm) UPLCMS; rétention time: 0.85 min; (M+H⁴) 450.4.

Example 164 l-(3-Ethylquinuclidin-3-yl)-3-(l-(4*-(2-methoxyetlioxy)-[l,r-biplienyl]-4y 1) cy cl opro py 1) u r ea

Using General Procedure H and the reaction inputs l-(4'-(2-methoxyethoxy)-[l,l'biphenyl]-4-yl)cyclopropanccarboxylic acid (prepared as described in Example 162) and Intermediate 2, the title compound was prepared as a white solid. *H NMR (400 MHz, DMSO-î/₆) δ 7.56 (d, J= 8.8 Hz, 2H), 7.50 (d, J= 8.4 Hz, 2H), 7.19 (d, J = 8.3 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 6.65 (s, IH), 5.57 (s, IH), 4.17-4.03 (m, 2H), 3.77-3.61 (m, 2H),

3.32 (s, 3H), 2.77-2.51 (m, 6H), 1.97-1.83 (m, 2H), 1.78-1.49 (m, 3H), 1.43-1.30 (m, IH),

1.30- 1.20 (m, IH), 1.20-1.04 (m, 4H), 0.73 (t, J= 7.2 Hz, 3H) ppm. ’³C NMR (100 MHz, DMSO-i/e) δ 157.9, 157.1, 143.4, 136.9, 132.4, 127.5, 125.7, 124.7, 114.8, 70.4, 66.9,

62.8, 58.2, 53.4, 46.4, 46.3, 33.8, 27.8, 27.7, 22.6, 22.3, 18.9, 7.9 ppm. Purity: 99.9%, 99.5% (210 & 254 nm) UPLCMS; rétention time: 0.89 min; (M+H⁺) 464.4.

Example 165 l-(l-(4'-(2-Methoxyethoxy)-|l,l'-biphenyl]-4-yl)cyclopropyl)-3-(4-methyl-lazabicyclo[3.2.2|nonan-4-yl)urea

Using General Procedure H and the réaction inputs l-(4'-(2-methoxycthoxy)-[l,rbiphcnyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 162) and Intermediate 5, the title compound was prepared as a white solid. ^JH NMR (400 MHz, DMSO-î/û) δ 7.55 (d, J= 8.6 Hz, 2H), 7.50 (d, J= 8.2 Hz, 2H), 7.20 (d, J= 8.1 Hz, 2H), 7.00 (d, J= 8.6 Hz, 2H), 6.70 (s, IH), 5.56 (s, IH), 4.20-4.05 (m, 2H), 3.72-3.62 (m, 2H),

3.32 (s, 3H), 2.94-2.54 (m, 6H), 2.18-2.06 (m, IH), 1.83-1.57 (m, 3H), 1.57-1.00 (m, 10H) ppm. ¹³C NMR (100 MHz, DMSO-î/₆) δ 157.9, 157.2, 143.5, 136.9, 132.4, 127.5,

125.7, 124.8, 114.8, 70.4, 66.9, 58.2, 57.4, 52.7, 47.9, 45.0, 39.1, 36.4, 33.8, 26.1, 24.4, 24.0, 18.9, 18.7 ppm. Purity: 100%, 99.3% (210 & 254 nm) UPLCMS; rétention time: 0.85 min; (M+H⁴) 464.4.

Example 166 Quinuclidïn-3-yl (l-(4'-(2-mcthoxyethoxy)-[l,l^,-biphenyl]-4yl)cyclopropyl)carbamate

Using General Procedure H and the réaction inputs l-(4’-(2-methoxyethoxy)-[l,rbiphenyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 162) and quinuclidin-3-ol, the title compound was prepared as a glassy, purple solid. *H NMR (400 MHz, DMSO-i/e) δ 8.02 (brs, IH), 7.60-7.46 (m, 4H), 7.29-7.13 (m, 2H), 7.01 (d, J= 8.7 Hz, 2H), 4.58-4.46 (m, IH), 4.17-4.07 (m, 2H), 3.72-3.61 (m, 2H), 3.32 (s, 3H), 3.13-2.89 (m, IH), 2.83-2.24 (m, 5H), 1.84-1.01 (m, 9H) ppm. ^I3C NMR (100 MHz, DMSO-J_fl) δ

157.9, 156.0, 142.4, 137.1, 132.4, 127.5, 125.8, 125.1, 114.8, 70.4, 70.4, 66.9, 58.1, 55.5,

46.9, 46.0, 34.3, 25.3, 24.2, 19.2, 18.1 ppm. Purity: 100%, 99.9% (210 & 254 nm) UPLCMS; rétention time: 0.83 min; (M+H⁴) 437.0.

237

Example 107

Quinuclidin-3-yl (2-(3'-(2-methoxyethoxy)-[l,r-biphenyl|-4-yI)propan-2yl)carbamate

Exchanging 4-(2-mcthoxyethoxy)phenylboronic acid for 3-(2mcthoxycthoxy)phcnylboronic acid for, the reaction sequence outlined in Example 155 was used to préparé 2-(3'-(2-methoxyethoxy)-[l,l'-biphenyl]-4-yl)-2-methylpropanoic acid. This intermediate and quinuclidin-3-ol were reacted according to General Procedure H to generate the title compound as a glassy, colorless solid. ^lH NMR (400 MHz, DMSOJ6) δ 7.63-7.31 (m, 6H), 7.24-7.10 (m, 2H), 6.92 (dd, ./=8.2, 1.9 Hz, IH), 4.51-4.34 (m, IH), 4.21-4.08 (m, 2H), 3.72-3.64 (m, 2H), 3.32 (s, 3H), 3.09-2.26 (m, 5H), 2.04-1.22 (m, 9H) ppm. ¹³C NMR (100 MHz, DMSO-J6) Ô 158.9, 154.6, 147.6, 141,5, 137.6, 129.9,

126.3, 125.2, 118.9, 113.2, 112.5, 70.4, 70.0, 66.9, 58.2, 55.4, 54.2, 46.9, 45.9, 29.4,25.3,

24.2, 19.2 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.91 min; (M+H*) 439.4.

Example 168 l-Azabicyclo[3.2.2]nonan-4-yl (2-(3*-(2-methoxycthoxy)-[l,l'-biphcnyl|-4-yI)propan2-yl)carbamate

Using General Procedure H and the reaction inputs 2-(3'-(2-mcthoxycthoxy)-[l,rbiphcnyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 167) and Intermediate 3, the title compound was prepared as a glassy, amber solid. ’H NMR (400 MHz, DMSO-c/s) δ 7.58 (d, J= 8.5 Hz, 2H), 7.53-7.31 (m, 4H), 7.24-7.12 (m, 2H), 6.92 (dd, J= 8.2, 1.8 Hz, IH), 4.65-4.55 (m, IH), 4.26-4.08 (m, 2H), 3.83-3.60 (m, 2H), 3.32 (s, 3H), 3.00-2.45 (m, 6H), 1.97-1.34 (m, 13H) ppm. ^l3C NMR (100 MHz, DMSO-î/û) δ

158.9, 154.2, 147.7, 141.5, 137.6, 129.9, 126.3, 125.2, 118.9, 113.2, 112.5, 77.1, 70.4,

66.8, 58.2, 54.1, 51.4, 47.7, 44.6, 33.5, 30.6, 29.6, 24.7, 22.2 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.92 min; (M+H*) 453.4.

Example 169 jV-(2-(3'-(2-Mcthoxyetlioxy)-[l,r-biphenyi]-4-yl)propan-2-yI)-l,4diazabicyclo[3.2.2]nonane-4-carboxamide

Using General Procedure H and the reaction inputs 2-(3'-(2-mcthoxyethoxy)-[l,l'biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 167) and Intermediate 6, the title compound was prepared as an off-white solid. *H NMR (400 MHz, DMSO-î/g) δ 7.55 (d, J= 8.5 Hz, 2H), 7.44-7.28 (m, 3H), 7.25-7.09 (m, 2H), 6.14 (br s, IH), 4.22-4.12 (m, 3H), 3.70-3.65 (m, 2H), 3.52-3.45 (m, 2H), 3.32 (s, 3H), 2.952.75 (m, 6H), 1.93-1.82 (m, 2H), 1.64-1.52 (m, 8H) ppm. ^,3C NMR (100 MHz, DMSOd₆) δ 158.9, 155.4, 149.0, 141.7, 137.1, 129.9, 126.1, 125.2, 118.9, 113.1, 112.5, 70.4,

66.8, 58.2, 57.5, 54.5, 46.6, 46.0, 41.5, 30.2, 27.0 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.86 min; (M+H*) 438.4.

Example 170

Quinuclidm-3-yl (2-(4'-(2-methoxyethoxy)-[I,r-biphenyl|-3-yl)propan-2yl)carbamate

Exchanging ethyl 2-(4-bromophenyl)-2-methylpropanoate for ethyl 2-(3-bromophenyl)-2methylpropanoatc, the réaction sequence outlined in Example 155 was used to préparé 2238 (4'-(2-methoxyethoxy)-[l,r-biphenyl]-3-yl)-2-mcthylpropanoic acid. This intermediate and quinuclidin-3-ol were reacted according to General Procedure H to generate the title compound as a yellow solid. *H NMR (400 MHz, DMS(W_fl) δ 7.62-7.20 (m, 7H), 7.03 (d,J = 8.7 Hz, 2H), 4.48-4.35 (m, 2H), 4.18-4.08 (m, 2H), 3.72-3.62 (m, 2H), 3.32 (s, 3H), 3.10-2.19 (m, 6H), 2.10-1.10 (m, HH) ppm. ^I3C NMR (100 MHz, DMSO-i/j δ 158.0, 154.6, 148.8, 139.5, 133.1, 128.5, 127.7, 123.8, 123.2, 122.7, 114.8, 70.4, 69.9, 67.0, 58.2, 55.3, 54.5, 47.0, 45.9, 29.4, 25.3, 24.2, 19.2 ppm. Purity: 97.4%, 94.6% (210 & 254 nm) UPLCMS; rétention time: 0.88 min; (M+H⁺) 439.3.

Example 171 l-Azabicyclo[3.2.2|nonan-4-yl (2-(4'-(2-methoxyethoxy)-[l,r-biphenyl]-3-yl)propan2-yl)carbamate

Using General Procedure H and the reaction inputs 2-(4'-(2-mcthoxyethoxy)-[l,l'biphenyl]-3-yl)-2-methylpropanoic acid (prepared as described in Example 170) and Intermediate 3, the title compound was prepared as a tan solid. 'H NMR (400 MHz, DMSO-Jj δ 7.60-7.19 (m, 7H), 7.03 (d, J = 8.8 Hz, 2H), 4.66-4.55 (m, IH), 4.17-4.09 (m, 2H), 3.72-3.63 (m, 2H), 3.32 (s, 3H), 3.02-2.40 (m, 5H), 1.98-1.30 (m, 3H) ppm. ^I3C NMR (100 MHz, DMSO-J₆) δ 158.0, 154.3, 148.9, 139.4, 133.1, 128.5, 127.7, 123.8,

123.2, 122.7, 114.8, 77.0, 70.4, 67.0, 58.2, 54.5, 51.4, 47.6, 44.7, 30.6, 29.9, 24.7, 22.1, 18.6 ppm. Purity; 97.0%, 93.9% (210 & 254 nm) UPLCMS; rétention time: 0.89 min; (M+H') 453.3.

Example 172

Quinuclidin-3-yl (2-(4'-(3-methoxypropoxy)-|l,l'-biphenyI]-4-yl)propan-2yl)carbamate

To a stirred solution of 4-iodophenol (10.05 g, 45.68 mmol) in acetonitrile (100 mL) was added potassium carbonate (6.95 g, 50.2 mmol) and 1 -chloro-3-methoxypropane (6.4 mL, 57.1 mmol). The mixture was heated at reflux ovemight and then concentrated. The residue was taken up in water and extracted with ethyl acetate. The combined cxtracts were washed with aqueous sodium bicarbonate solution, dried (NaîSOj and concentrated. The crude material was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford l-iodo-4-(3-methoxypropoxy)benzenc as a colorless oil (4.39 g, 33%), This intermediate and ethyl 2-mcthyl-2-(4-(4,4,5,5tctramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propanoatc were reacted according to General Procedure F to generate ethyl 2-(4'-(3-methoxypropoxy)-[l,r-biphenyl]-4-yl)-2methylpropanoate. To a stirred solution of this compound (0.693 g, 1.94 mmol) in 1:1:1 (v/v/v) tctrahydrofiiran/cthanol/water (10 mL) was added lithium hydroxide monohydratc (0.326 g, 7.77 mmol). The mixture was heated at reflux ovemight and then concentrated. The residue was dissolved in water, treated with IN hydrochloric acid (10 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (NaîSOj and concentrated to afford 2-(4'-(3-mcthoxypropoxy)-[l,r-biphcnyl]-4-yl)-2methylpropanoic acid as a waxy, off-white solid (0.630 g, 99%). This intermediate and qumuclidin-3-ol were reacted according to General Procedure H to generate the title compound as a glassy, colorless solid (62%). *H NMR (400 MHz, DMSO-i/j δ 7.61-7.29 (m, 7H), 7.00 (d, J= 8.8 Hz, 2H), 4.47-4.36 (m, IH), 4.05 (t, J = 6.4 Hz, 2H), 3.48 (t, J= 6.3 Hz, 2H), 3.26 (s, 3H), 3.10-2.25 (m, 6H), 2.04-1.74 (m, 4H), 1.65-1.23 (m, 9H) ppm. ^I3CNMR(100MHz,DMSO-î/6)ô 158.0, 154.5, 146.7, 137.4, 132.4, 127.5, 125.7, 125.2,

114.8, 69.9, 68.5, 64.6, 57.9, 55.4, 54.2, 46.9, 46.0, 29.4, 29.0, 25.2, 24.1, 19.2 ppm.

239

Purity: 97.7%, 98.2% (210 & 254 nm) UPLCMS; rétention time: 0.96 min; (M+H⁴)

453.5.

Example 173 l-(2-(4'-(3-Methoxypropoxy)-[l,r-biphenyI]-4-yl)propan-2-yl)-3-(3metliylquinuclidin-3-yl)urea

Using General Procedure H and the reaction inputs 2-(4'-(3-methoxypropoxy)-[l,rbiphcnyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 172) and Intermediate 1, the title compound was prepared as a white solid. ’H NMR. (400 MHz, DMSO-ί/ό) δ 7.56 (d, J= 8.8 Hz, 2H), 7.51 (d, J= 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.00 (d, ./ = 8.8 Hz, 2H), 6.17 (br s, IH), 5.79 (brs, IH), 4.05 (t, J = 6.4 Hz, 2H), 3.48 (t, J = 6.3 Hz, 2H), 3.26 (s, 3H), 2.74-2.51 (m, 6H), 2.01-1.74 (m, 4H), 1.68-1.45 (m, 7H), 1.44-1.21 (m, 5H) ppm. ^,3C NMR (100 MHz, DMSO-O δ 158.0, 156.9, 147.7, 137.2,

132.4.127.5, 125.6, 125.3, 114.8, 68.5, 64.6, 63.4, 57.9, 53.8, 50.7, 46.1,46.0,30.3, 29.9, 29.0, 25.1, 22.8, 22.2 ppm. Purity: 98.0%, 98.1% (210 & 254 nm) UPLCMS; rétention time: 0.94 min; (M+H⁴) 466.5.

Example 174 /V-(2-(4*-(3-Methoxypropoxy)-[l,l'-biphenyl]-4-yl)propan-2-yl)-l,4diazabicycIo[3.2.2]nonane-4-carboxamide

Using General Procedure H and the réaction inputs 2-(4-(3-methoxypropoxy)-[Ι,Γbiphenyl]-4-yl)-2-mcthylpropanoic acid (prepared as described in Example 172) and Intermediate 6, the title compound was prepared as a white solid. ’H NMR (400 MHz, DMSO-Jû) Ô 7.56 (d, J= 8.8 Hz, 2H), 7.49 (d, J= 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 6.11 (s, IH), 4.22-4.16 (m, IH), 4.05 (t, J= 6.4 Hz, 2H), 3.523.44 (m, 6H), 3.26 (s, 3H), 2.96-2.73 (m, 6H), 2.01-1.81 (m, 4H), 1.65-1.48 (d, 8H) ppm. ^I3C NMR (100 MHz, DMSO-<7₆) δ 157.9, 155.4, 148.1,136.9, 132.6, 127.5, 125.5, 125.2,

114.8, 68.5, 64.6, 57.9, 57.5, 54.5, 46.6, 46.0, 41.5, 30.2, 29.0, 27.0 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.88 min; (M+H⁴) 452.5.

Example 175 Quinuclidin-3-yl (2-(4'-(2-methoxyethoxy)-[l,l*-biphenylj-3-yI)propan-2yl)carbamate

Exchanging ethyl 2-(4-bromophenyl)-2-methylpropanoate for ethyl l-(4bromophcnyl)cyclopropanecarboxylate, the reaction sequence outlined in Example 18 was used to prépare l-(4'-(3-mcthoxypropoxy)-[l,T-biphenyl]-4yl)cyclopropanecarboxylic acid. This intermediate and quinuclidin-3-ol were reacted according to General Procedure H to generate the title compound as a glassy, colorless solid. ‘H NMR (7:3 rotomer mixture) (400 MHz, DMSO-cfc) Ô 8.01 (br s, 0.7H), 7.77 (br s, 0.3H), 7.59-7.47 (m, 4H), 7.28-7.16 (m, 2H), 6.99 (d, J= 8.8 Hz, 2H), 4.57-4.47 (m, IH), 4.05 (t, J= 6.4 Hz, 2H), 3.48 (t, J= 6.4 Hz, 2H), 3.25 (s, 3H), 3.18-2.89 (m, IH), 2.81-2.25 (m, 6H), 2.00-1.03 (m, 7H) ppm. ¹³C NMR (major rotomer) (100 MHz, DMSO-Jô) δ 158.0, 156.0, 142.4, 137.2, 132.3, 127.5, 125.8, 125.1, 114.8, 70.4, 68.5, 64.6, 57.9, 55.4, 46.9, 45.9, 34.3, 28.9, 25.3, 24.2, 19.2, 18.0 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.91 min; (M+H⁴) 451.6.

Example 176

240 l-(l-(4'-(3-Methoxypropoxy)-[l,r-biphenyl|-4-yl)cyclopropyl)-3-(3methylquinucIidin-3-yl)urea

Using General Procedure H and the réaction inputs l-(4'-(3-methoxypropoxy)-[l,l'biphenyl]-4-yl)cyclopropanccarboxylic acid (prepared as described in Example 175) and Intermediate 1, the title compound was prepared as an off-whitc solid. 'H NMR (400 MHz, DMSO-rfe) δ 7.55 (d, J= 8.8 Hz, 2H), 7.50 (d, J= 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 6.99 (d, J= 8.8 Hz, 2H), 6.63 (br s, IH), 5.62 (br s, IH), 4.05 (t, J = 6.3 Hz, 2H),

3.48 (t, J = 6.3 Hz, 2H), 3.25 (s, 3H), 2.77-2.52 (m, 6H), 2.00-1.88 (m, 3H), 1.76-1.55 (m, 2H), 1.43-1.07 (m, 9H) ppm. ^l3C NMR (100 MHz, DMSO-î/₆) δ 158.0, 157.3, 143.5,

136.9, 132.3, 127.4, 125.7, 124.8, 114.8, 68.5, 64.6, 63.4, 57.9, 50.9, 46.2, 46.0, 33.8, 30.4, 29.0, 25.0, 22.9, 22.3, 18.8 ppm. Purity; 97.6%, 98.2% (210 & 254 nm) UPLCMS; rétention time: 0.87 min; (M+H) 464.6.

Exampie 177 l-(l-(4'-(3-Methoxypropoxy)-[ l,r-biphenylj-4-yl)cycIopropyl)-3-(4-methyl-lazabicyclo [3.2.2 ) nonan-4-yl)urea

Using General Procedure H and the reaction inputs l-(4’-(3-mcthoxypropoxy)-[l,rbiphenyl]-4-yl)cyclopropanccarboxylic acid (prepared as described in Example 175) and Intermediate 5, the title compound was prepared as an off-whitc solid. ’H NMR (400 MHz, DMSO-</₆) δ 7.55 (d, ./= 8.6 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.20 (d, J= 8.3 Hz, 2H), 6.99 (d, J= 8.6 Hz, 2H), 6.69 (br s, IH), 5.56 (br s, IH), 4.05 (t, J= 6.3 Hz, 2H),

3.48 (t, J= 6.3 Hz, 2H), 3.25 (s, 3H), 2.87-2.52 (m, 6H), 2.16-2.09 (m, IH), 2.0-1.91 (m, 2H), 1.80-1.60 (m, 3H), 1.55-1.88 (m, 10H) ppm. ¹³C NMR (100 MHz, DMSO-O δ 158.0, 157.2, 143.4, 136.9, 132.3,127.5, 125.7, 124.8, 114.8, 68.5, 64.6, 57.9, 57.4, 52.8,

47.8, 45.0, 36.3, 33.9, 29.0, 26.1, 24.4, 23.9, 18.9, 18.7 ppm. Purity: 98.0%, 98.3% (210 & 254 nm) UPLCMS; rétention time: 0.87 min; (M+H⁺) 478.6.

Example 178 l-Azabicycio[3.2.2|nonan-4-yl (l-(4'-(3-methoxypropoxy)-[l,l'-biphenyl|-4yl)cyclopropyl)carbamate

Using General Procedure H and the reaction inputs l-(4'-(3-mcthoxypropoxy)-[l,rbiphenyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 175) and Intermediate 3, the title compound was prepared as a glassy, colorless solid. *H NMR (3:1 rotomer mixture) (400 MHz, DMSO-t/g) ô 7.96 (br s, 0.75H), 7.71 (br s, 0.25H), 7.277.15 (m, 2H), 6.99 (d, J = 8.4 Hz, IH), 4.75-4.68 (m, IH), 4.05 (t, J= 6.3 Hz, 2H), 3.48 (t, J =6.3 Hz, 2H), 3.25 (s, 3H), 3.00-2.58 (m, 6H), 2.01-1.39 (m, 9H), 1.20-1.08 (m, 4H) ppm. ¹³C NMR (major rotomer) (100 MHz, DMSO-î/₆) δ 158.0, 155.6, 142.4, 137.2,

132.3,127.5, 125.8, 125.2, 114.8, 77.4, 68.5, 64.6, 57.9, 51.4, 47.7, 44.5, 34.3, 33.5, 30.5,

28.9, 24.6, 22.0, 18.0 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; retention time: 0.92 min; (M+H ) 465.6.

Example 179

Quinuclidin-3-yl (2-(4^,-(2-(l_JH^r-pyrazol-l-yl)ethoxy)-[l,l'-biphenyIJ-4-yl)propan-2yl)carbamate

Using General Procedure F and the reaction inputs ethyl 2-mcthyl-2-(4-(4,4,5,5telramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate and 1 -(2-(417263

241 bromophenoxy)cthyl)pyrazolc, ethyl 2-(4'-(2-(l/y-pyrazol-l-yl)ethoxy)-[l,r-biphenyl]-4yl)-2-methylpropanoate was prepared as a yellow oil. To a stirred solution of this compound (3.09 g, 8.16 mmol) in l:l:1 (v/v/v) tetrahydrofuran/ethanol/water (40 mL) was added lithium hydroxide monohydrate (l .37 g, 57.1 mmol). The mixture was left for 6 days and then concentrated. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was then treated with IN hydrochloric acid (57 mL) and extracted with ethyl acetate. The combined organic layers were dried (Na₂SO₄) and concentrated. The resulting solid was triturated with diethyl ether to afford 2-(4'-(2-( l Hpyrazol-l-yl)ethoxy)-[l,r-biphenyl]-4-yl)-2-methylpropanoic acid as a tan solid (Ll8 g, 41%). This intermediate and quinuclidin-3-ol were reacted according to General Procedure H to generate the title compound as a white solid. ³H NMR (400 MHz, DMSOc/₆) δ 7.79 (d, J= 2.1 Hz, IH), 7.62-7.27 (m, 8H), 6.98 (d, J= 8.7 Hz, 2H), 6.25 (t, J= 2.1 Hz, IH), 4.51 (t, J= 5.3 Hz, 2H), 4.46-4.31 (m, 3H), 3.10-2.20 (m, 6H), 2.14-1.11 (m, 11H) ppm. ^I3C NMR (100 MHz, DMSO-^) δ 157.5, 154.5, 146.8, 138.8, 137.3, 132.8,

130.5, 127.6, 125.7, 125.2, 115.0, 105.1, 70.0, 66.6, 55.4, 54.2, 50.6, 46.9, 45.9, 29.4,

25.2, 24.2, 19.2 ppm. Purity: 100%, 99.5% (210 & 254 nm) UPLCMS; rétention time: 1.00 min; (M+H⁺) 475.4.

Example 180 l-(2-(4'-(2-(Liï-Pyrazol-l~yl)ethoxy)-[l,l’-biphenyl]-4-yl)propan-2-yl)-3-(3mettiylquinuclidin-3-yl)urea

Using General Procedure H and the reaction ïnputs 2-(4'-(2-(l/7-pyrazol-l-yl)ethoxy)[l,r-biphcnyl]-4-yl)-2-mcthylpropanoic acid (prepared as described in Example 179) and Intermediate 1, the title compound was prepared as a white solid. ’H NMR (400 MHz, DMSO-î/s) δ 7.79 (dd, ./ = 2.2, 0.5 Hz, IH), 7.55 (d, J= 8.9 Hz, 2H), 7.50 (d, ./ = 8.6 Hz, 2H), 7.38 (d, 8.5 Hz, 2H), 6.98 (d, ./= 8.9 Hz, 2H), 6.25 (t, J= 2.2 Hz, IH), 6.15 (s,

IH), 5.76 (s, IH), 4.51 (t, J= 5.3 Hz, 2H), 4.37 (t, J= 5.3 Hz, 2H), 2.71-2.46 (m, 6H), 1.91-1.84 (m, IH), 1.84-1.72 (m, IH), 1.65-1.45 (m, 7H), 1.43-1.19 (m, 5H) ppm. ^,3C NMR (100 MHz, DMSO-t/₆) δ 157.5, 156.9, 147.8, 138.8, 137.1, 132.8, 130.5, 127.5,

125.6, 125.3, 115.0, 105.1,66.6, 63.5, 53.8,50.7,50.6, 46.2,46.1,30.4, 30.3, 29.9, 25.1, 23.0, 22.3 ppm. Purity: 100%, 99.9% (210 & 254 nm) UPLCMS; rétention time: 0.99 min; (M+H⁺) 488.4.

Example 181 l-(2-(4'-(2-(lJÏ-Pyrazol-l-yl)ethoxy)-|l₉l'biplienyl]-4-yl)propan-2-yl)-3-(4-meihyl-lazabicyclo [3.2.2] nonan-4-y))u rea

Using General Procedure H and the reaction inputs 2-(4'-(2-(l£f-pyrazol-l-yl)cthoxy)[l,r-biphcnyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 179) and Intermediate 5, the title compound was prepared as a white solid. *H NMR (400 MHz, DMSO-t/ή) δ 7.79 (dd, J= 2.2, 0.5 Hz, IH), 7.58-7.33 (m, 6H), 6.98 (d, J= 8.8 Hz, 2H), 6.25 (t, J= 2.2 Hz, IH), 6.21 (s, IH), 5.72 (br s, IH), 4.51 (t, J= 5.3 Hz, 2H), 4.37 (t, J = 5.3 Hz, 2H), 2.91-2.58 (m, 6H), 2.11-2.01 (s, IH), 1.83-1.14 (m, 15H) ppm. ¹³C NMR (100 MHz, DMSO-ί/ή) δ 157.5, 156.8, 147.9, 138.8, 137.1, 132.9, 130.5, 127.6, 125.6,

125.3, 115.0, 105.1, 66.6, 57.2, 53.7, 52.8, 50.6, 48.1, 45.0, 36.2, 30.4, 29.7, 26.2, 24.5, 24.0 ppm. Purity: 100%, 98.8% (210 & 254 nm) UPLCMS; rétention time: 0.99 min; (M+H⁴) 502.4.

Example 182

242

Quinuclidin-3-yl (2-(4-(2-(1/7-1,2,3-triazol-l-yl)ethoxy)-[l,r-l)iphenyl]-4-yl)propan2-yl)carbamate

To a stirred and cooled (0 °C) solution of 2-(4-bromophenoxy)ethanol (10.60 g, 48.8 mmol) and triethylamine (10.2 mL, 73.2 mmol) in méthylène chloride (100 mL) was added, dropwise, mcthancsulfonyl chloride (5.7 mL, 73.2 mmol). The mixture was allowcd to warm to room température and then stirred ovemight. The réaction solution was diluted with methylenc chloride and washed with aqueous sodium bicarbonate. The organic layer was dried (Na₂SC>4) and concentrated to afford crude 2-(4bromophcnoxy)ethyl methanesulfonate as a yellow solid. To a stirred solution of this material in dîmcthylsulfoxidc (50 mL) was added sodium azidc (3.81 g, 58.6 mmol). The mixture was left for 3 days and then diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried (Na₂SO4) and then concentrated. The crude material was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford l-(2-azidocthoxy)-4-bromobcnzcne as a colorless oil (8.66 g, 73% overall). This intermediate (2.24 g, 9.25 mmol) was combined with ethynyltrimethylsilane (6.4 mL, 46 mmol), copper(II) sulfate pentahydrate (0.232 g, 0.929 mmol), sodium ascorbate (0.735 g, 3.71 mmol), A'./V'-dimcthylfonnamidc (30 mL) and water (3 mL). The mixture was heated in a microwave reactor (110 °C) with stirrîng for 90 minutes. The reaction was filtered through a plug of Celite, which was subsequently washed with ethyl acetate. The combined fîltrate was washed with water, aqueous sodium bicarbonate solution and brine and then dried (Na₂SÜ4) and concentrated. The crude was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford a mixture of l-(2-(4-bromophenoxy)ethyl)-17ï-l,2,3-triazole and 1-(2-(4bromophenoxy)cthyl)-4-(trimcthylsilyl)-l/f-l,2,3-triazole (--70/30 ratio). This material was dissolved in tetrahydrofuran (25 mL) and treated with a IM solution of tetrabutylammonium fluoridc in tetrahydrofuran (3.1 mL). The réaction was stirred ovemight, concentrated and purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford clcan l-(2-(4-bromophenoxy)ethyl)-l/f-l,2,3triazolc as white solid (1.81 g, 73% overall). This product and ethyl 2-mcthyl-2-(4(4,4,5,5-tctramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propanoate were reacted according to General Procedure F to generatc ethyl 2-(4'-(2-(l/f-l,2,3-triazol-l-yl)ethoxy)-[l,rbiphenyl]-4-yl)-2-methylpropanoate. To a stirred solution of this compound (1.83 g, 4.83 mmol) in 1:1:1 (v/v/v) tetrahydrofuran/ethanol/water (20 mL) was added lithium hydroxide (0.809 g, 33.8 mmol). After heating at reflux ovemight, the reaction was diluted with water, washed with dicthyl ether and treated with 1 N hydrochloric acid (33 mL). The mixture was then extracted with 5:1 (v/v) chloroform/isopropanol and the combined organic layers were dried (Na₂SO4) and concentrated. The resulted solid was triturated with dicthyl ether to afford 2-(4^,-(2-(l//-l,2,3-triazol-l-yl)ethoxy)-[l,rbiphenyl]-4-yl)-2-methylpropanoic acid as an off-white solid (1.16 g, 69%). This intermediate and quinuclidin-3-ol were reacted according to General Procedure H to gcncrate the title compound as a white solid. NMR (400 MHz, DMSO-rff,) δ 8.21 (d, J = 0.9 Hz, IH), 7.75 (d, J= 0.8 Hz, IH), 7.63-7.26 (m, 7H), 7.00 (d, J= 8.8 Hz, 2H), 4.81 (t, J= 5.1 Hz, 2H), 4.49-4.35 (m, 3H), 3.31 (s, 3H), 3.10-2.19 (m, 6H), 2.10-1.12 (m, 11H) ppm. ^I3C NMR (100 MHz, DMSO-</_f>) δ 157.3, 154.5, 146.8, 137.3, 133.3, 133.0,

127.6, 125.8,125.3, 125.2,115.0, 69.9,66.3, 55.4, 54.2, 48.8, 46.9, 45.9, 29.4, 25.3, 24.2,

19.2. ppm. Purity: 100%, 98.9% (210 & 254 nm) UPLCMS; rétention time: 0.97 min; (M+H⁴) 476.4.

Example 183

243 l-(2-(4'-(2-(Lff-l,23-rriazol-l-yl)ethoxy)-[l,l'-biphenyl]-4-yl)propan-2-yl)-3-(3metiiylquinuclidm-3-yl)urea

Using General Procedure H and the réaction inputs 2-(4'-(2-(l/7-l,2,3-triazol-lyl)ethoxy)-[l,r-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 182) and Intermediate 1, the title compound was prepared as a white solid. *H NMR (400 MHz, DMSO-î/₆) δ 8.21 (d, J= 0.9 Hz, IH), 7.75 (d, ./ = 0.8 Hz, IH), 7.56 (d, .7 = 8.8 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 7.38 (d, J= 8.5 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 6.16 (br s, IH), 5.77 (br s, IH), 4.80 (t, J= 5.1 Hz, 2H), 4.45 (t, J= 5.2 Hz, 2H), 2.72-2.47 (m, 6H), 1.91-1.73 (m, 2H), 1.66-1.44 (m, 7H), 1.43-1.20 (m, 5H) ppm. ^l3C NMR (100 MHz, DMSO-î/₆) δ 157.3, 156.9, 147.9, 137.0, 133.3, 133.0, 127.6, 125.6,

125.3, 115.0, 66.3, 63.5, 53.8, 50.7, 48.8, 46.2, 46.0, 30.4, 30.3, 29.9, 25.1, 22.9, 22.2 ppm, Purity: 100%, 99.9% (210 & 254 nm) UPLCMS; rétention time: 0.95 min; (M+H¹)

489.4.

Example 184 l-(2-(4'-(2-(lff-l,23-Triazol-l-yl)ethoxy)-|l,r-biphenyl]-4-yl)propan-2-yl)-3-(3cthylquinuclidin-3-yl)urca

Using General Procedure H and the réaction inputs 2-(4-(2-(1/7-1,2,3-triazol-lyl)cthoxy)-[l,r-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 182) and Intermediate 2, the title compound was prepared as a white solid. ’H NMR (400 MHz, DMSO-î/₆) δ 8.21 (d, ./=0.8 Hz, IH), 7.75 (d, J= 0.7 Hz, IH), 7.56 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.39 (d, J= 8.4 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 6.19 (br s, IH), 5.73 (br s, IH), 4.81 (t, J= 5.1 Hz, 2H), 4.45 (t, J= 5.1 Hz, 2H), 2.83-2.42 (m, 6H), 1.91-1.41 (m, 11H), 1.41-1.20 (m, 2H), 0,74 (t, J= 7.3 Hz, 3H) ppm. ¹³CNMR(100 MHz, DMSO-î/₆)ô 157.3, 156.8, 147.9, 137.1, 133.3, 133.0, 127.6, 125.6,

125.3, 115.0, 66.3, 62.8,53.7, 53.2,48.8,46.4, 46.3, 30.4, 29.8, 27.8, 27.7, 22.6,22.3, 8.0 ppm. Purity: 100%, 99.9% (210 & 254 nm) UPLCMS; rétention time: 0.99 min; (M+H¹)

503.4,

Example 185 l-(2-(4'-(2-(LH-l,2,3-TriazoLl-yl)ethoxy)-[l,r-biphenyI]-4-yl)propan-2-yl)-3-(4mcthyl-l-azabicyclo[3.2.2]nonan-4-yl)urca

Using General Procedure H and the reaction inputs 2-(4-(2-(177-1,2,3-triazol-lyl)cthoxy)-[l,l’-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 182) and Intermediate 5, the title compound was prepared as a white solid. ’H NMR (400 MHz, DMSO-J₆) δ 8.21 (d, J= 0.9 Hz, IH), 7.75 (d, J= 0.9 Hz, IH), 7.56 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 6.23 (br s, IH), 5.74 (br s, IH), 4.80 (t, .7 = 5.1 Hz, 2H), 4.45 (t, J= 5.2 Hz, 2H), 2.90-2.61 (m, 6H), 2.11-2.03 (s, IH), 1.83-1.35 (m, 11H), 1.33-1.16 (m, 4H) ppm. ¹³C NMR (100 MHz, DMSO-</₆) δ 157.3, 156.8, 147.9, 137.1, 133.3, 133.1, 127.6, 125.6,

125.4, 125.3, 115.0, 66.3, 57.2, 53.7, 52.8, 48.8, 48.1, 45.0, 36.2, 30.4, 29.8, 26.2, 24.5, 24.0 ppm. Purity: 100%, 99.9 % (210 & 254 nm) UPLCMS; rétention time: 0.96 min; (M+H¹) 503.4.

Example 186

Q uin u cli din -3-yl (2-(4 '-(2-methoxyethoxy)- [ 1,1 *-bi pheny 1 ]-3-yi)p ro p a n-2yl)carbamate

244

Exchanging 3-(4-bromophenoxy)propan-l-ol for 2-(4-bromophcnoxy)ethanol, the reactionsequence outlined in Example 182 was used to préparé2-(4-(3-(1/7-1,2,3-triazoll-yl)propoxy)-[l,r-biphenyl]-4-yl)-2-mcthylpropanoic acid. This intermediate and quinuclidin-3-ol were reacted according to General Procedure H to generate the title compound as a glassy, colorless solid. H NMR (400 MHz, IDMSO-Jc,) Ô 8.17 (s, IH), 7.73 (s, IH), 7,64-7.24 (m, 7H), 6.99 (d, J= 8.7 Hz, 2H), 4.57 (t, J= 7.0 Hz, 2H), 4.484.32 (m, 1 H), 4.01 (t, J = 6.0 Hz, 2H), 3.12-2.19 (m, 8H), 2.08-1.13 (m, 11H) ppm. ^,3C NMR (100 MHz, DMSO-O δ 157.8, 137.4, 133.2, 132.6, 127.6, 125.7, 125.2, 124.8,

114.9, 70.0, 64.5, 55.4, 54.2, 46.9, 46.3, 45.9, 29.5, 29.4, 25.2, 24.2, 19.2 ppm. Purity: 98.5%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.81 min; (M+H⁴) 490.5.

Example 187 l-Azabïcyclo[3.2.2|nonan-4-yl (2-(4'-(3-(177-l,2,3-triazol-l-yl)prüpoxy)-[l J'biplienyl]-4-yl)propan-2-yi)carbamate

Using General Procedure H and the reaction inputs 2-(4'-(3-(l/7-l,2,3-triazol-lyl)propoxy)-[l,r-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 186) and Intermediate 3, the title compound was prepared as a pale yellow solid. *H NMR (400 MHz, DMSO-</₆) δ 8.17 (s, IH), 7.74 (s, IH), 7.64-7.26 (m, 7H), 6.99 (d, J = 8.6 Hz, 2H), 4.67-4.50 (m, 3H), 4.01 (t, J= 6.0 Hz, 2H), 3.03-2.18 (m, 8H), 2.00-1.28 (m, 13H) ppm. ¹³C NMR (100 MHz, DMSO-î/₆) δ 157.8, 154.2, 146.8, 137.4, 133.2,

132.6, 127.6, 125.7, 125.2, 124.8, 114.9, 77.1, 64.5, 54.1, 51.5, 47.7, 46.3, 44.6, 33.5,

30.6, 29.6, 29.5, 24.7, 22.2 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.82 min; (M+H ) 504.5.

Example 188 #-(2-(4'-(3-(Lï/-l,2,3-Triazol-l-yl)propoxy)-[l,r-biphenyl]-4-yl)propan-2-yl)-l, 4diazabicyclo[3.2.2|nonane-4-carboxanude

Using General Procedure H and the réaction inputs 2-(4^(3-(1/7-1,2,3-^18201-1yl)propoxy)-[l,r-biphenyi]-4-yl)-2-methylpropanoic acid (prepared as described in Example 186) and Intermediate 6, the title compound was prepared as a white solid. *H NMR (400 MHz, DMSO-</₆) δ 8.17 (d, .7= 0.9 Hz, IH), 7.73 (d, J= 0.9 Hz, IH), 7.56 (d, J= 8.8 Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 6.11 (s, IH), 4.57 (t, J = 7.0 Hz, 2H), 4.22-4.16 (m, IH), 4.01 (t, J= 6.0 Hz, 2H),

3.48 (t, J= 5.6 Hz, 2H), 3.02-2.71 (m, 6H), 2.30 (quin, J= 6.5 Hz, 2H), 1.94-1.82 (m, 2H), 1.64-1.50 (m, 8H) ppm. ¹³C NMR (100 MHz, DMSO-4») δ 157.7, 155.4, 148.1,

136.8, 133.2, 132.8, 127.5, 125.5, 125.2, 124.8, 114.9, 64.5, 57.5, 54.5, 46.6, 46.3, 46.0,

41.4, 30.2, 29.5, 27.0 ppm. Purity: 97.4%, 99.3% (210 & 254 nm) UPLCMS; rétention time: 0.75 min; (M+H⁴} 489.5.

Example 189

Quinuclidin-3-yl (2-(4'-(3-cyanopropoxy)-[l,l'-biphcnyll-4-yl)propan-2yl)carbamate

To a stirred solution of 4-bromophcnol (17.1 g, 98.8 mmol) in acetonitrile (150 mL) was added 1-bromobutylnitrilc (12.3 mL, 124 mmol) and potassium carbonate (15.0 g, 109 mmol). The mixture was heated to reflux ovemight, cooled and concentrated. The residue was taken up in water and extracted with ethyl acetate. The combined extracts were dried

245 (Na₂SO4) and concentrated and the crude material was purified by flash chromatography over silica using a hexanc/cthyl acetate eluant to afford 4-(4-bromophenoxy)butanenitrile as a white solid (20.8 g, 88%). To a stirred solution of this product in N,Ndimethylformamide (100 mL), was added bis(pinacolato)diboron (4.60 g, I8.l mmol), potassium acétate (7.41 g, 75.5 mmol) and [l,T-bis(diphenylphosphino)ferroccnc]dichloropalladium(II) complcx with dichloromethane (0.616 g, 1.04 mmol). The mixture was heated to reflux ovemight and then concentrated. The residue was taken up in ethyl acetate and washed with water and brine. The organic layer was dried (Na₂SO-i) and concentrated and the crude product was purified by flash chromatography over silica using a hcxanc/ethyl acetate eluant to afford 4-(4-(4,4,5,5-tetramcthyl-l,3,2dioxaboroian-2-yl)phenoxy)butanenitrile as a white solid (3.43 g, 79%). This product and quinuclidin-3-yl (2-(4-bromophcnyl)propan-2-yl)carbamate (prepared by reacting quinuclidin-3-ol and 2-(4-bromophcnyl)propan-2-aminc using General Procedure H) were reacted according to General Procedure F to generate the title compound as a white solid. 'H NMR (400 MHz, DMSO-rf₆) δ 7.67-7.26 (m, 7H), 7.02 (d, J = 8.8 Hz, 2H), 4.50-4.33 (m, IH), 4.08 (t, J = 6.0 Hz, 2H), 3.14-2.18 (m, 8H), 2.04 (quin, J= 6.7 Hz, 2H), 1.94-1.70 (m, 1IH) ppm. ¹³C NMR (100 MHz, DMSO-î/₆) Ô 157.7, 154.5, 146.8,

137.4, 132.7, 127.6, 125.7, 125.2, 120.2, 114.9, 70.0, 65.8, 55.4, 54.2, 46.9, 45.9, 29.4,

25.3, 24.7, 24.2, 19.2, 13.4 ppm. Purity: 100%, 98.9% (210 & 254 nm) UPLCMS; rétention time: 0.88 min; (M+H⁺) 448.6.

Example 190

QuinucIidin-3-yl (2-(4'-(cyanomethoxy)-| l,T-biplienyl]-4-yl)propan-2-yl)carbamate

Using General Procedure F and the reaction inputs quinuclidin-3-yl (2-(4bromophenyl)propan-2-yI)carbamate (prepared by reacting quinuclidin-3-ol and 2-(4bromophenyl)propan-2-aminc using General Procedure H) and 4(cyanomethoxy)phenylboronic acid, the title compound was prepared as a pale amber solid. ‘H NMR (400 MHz, DMSO-J₆) S 7.65 (d, J= 8.2 Hz, 2H), 7.60-7.31 (m, 5H), 7.15 (d, J = 8.9 Hz, 2H), 5.21 (s, 2H), 4.53-4.30 (m, IH), 3.18-2.19 (m, 6H), 2.05-1.18 (m, 11H) ppm. ^,3C NMR (100 MHz, DMSO-î/₆) δ 155.8, 154.6, 147.2, 137.2, 134.4, 127.8, 126.0, 125.3, 116.7, 115.3, 70.0, 55.4, 54.2, 53.5, 46.9, 45.9, 29.4, 25.2, 24.2, 19.2 ppm. Purity; 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.85 min; (M+H⁴) 420.3.

Example 191

Quinuclidin-3-yl (2-(4’-((3-methyloxetaii-3-yl)inethoxy)-[l,l'-biphenyl|-4-yl)propan2-yl)carbamate

To a stirred solution of 4-bromophcnol (3.61 g, 20.8 mmol) in A./V-di methyl formant idc (100 mL) was added sodium hydride (60% dispersion in minerai oil; 0.917 g, 22.9 mmol). After 30 minutes 3-(chloromcthyl)-3-mcthyloxetane was added. The reaction heated to 80 °C ovemight and then concentrated. The residue was taken up in ethyl acetate and washed with water and brine. The organic layer was dried (Na₂SC>4) and concentrated and the crude product was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford 3-((4-bromophenoxy)mcthyl)-3-methyloxetane as a colorless oil (4.64 g, 87%). This product and ethyl 2-methyl-2-(4-(4,4,5,5-tctramethyl-1,3,2dioxaborolan-2-yl)phcnyl)propanoatc were reacted according to General Procedure F to generate ethyl 2-methyl-2-(4'-((3-methyloxetan-3-yl)methoxy)-[ 1, r-bîphcnyl]-4yl)propanoate. To a stirred solution of this compound (1.37 g, 3.72 mmol) in 1:1:1 (v/v/v) tctrahydrofuran/ethanol/watcr (20 mL) was added lithium hydroxide monohydrate (0.780

246 g, 18.6 mmol). After heating at reflux ovemight, the réaction was diluted with water, washed with diethyl ether and treated with 1 N hydrochloric acid (20 mL). The mixture was then extracted with ethyl acetate and the combined organic layers were dried (NaîSCh) and concentrated to afford 2-methyl-2-(4'-((3-mclhyloxctan-3-yl)methoxy)[l,l'-biphenyl]-4-yl)propanoic acid as an off-white solid (1.20 g, 95%). This intermediate and quinuclidin-3-ol were reacted according to General Procedure H to generate the title compound as a white solid. 'H NMR (400 MHz, DMSO-î/₆) δ 7.64-7.29 (m, 7H), 7.06 (d, J = 8.9 Hz, 2H), 4.51 (d, J = 5.7 Hz, 2H), 4.46-4.35 (m, IH), 4.32 (d, J = 5.8 Hz, 2H), 4.09 (s, 2H), 3.15-2.35 (m, 6H), 2.06-1.21 (s, 14H) ppm. ¹³C NMR (100 MHz, DMSO-rf₆) δ 158.3, 154.6, 146.6, 137.4, 132.6, 127.5, 125,7, 125.2, 115.0, 78.6, 72.6, 70.0, 55.4,

54.2, 46.9, 45.9, 39.0, 29.4, 25.3, 24.2, 21.0, 19.2 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.93 min; (M+H⁴) 465.4.

Exampie 192 l-Azabicyclo[3.2.2)nonan-4-yl (2-(4’-((3-mcthyloxetan-3-yl)methoxy)-[l,r-biphenyl[4-yl)propan-2-yl)carbamate

Using General Procedure H and the reaction inputs 2-mcthyl-2-(4'-((3-methyloxetan-3yl)methoxy)-[l,l'-biphenyl]-4-yl)propanoic acid (prepared as described in Example 191) and Intermediate 3, the title compound was prepared as a pale amber solid. ’H NMR (400 MHz, DMS(W₆) Ô 7.58 (d, J = 8.4 Hz, 2H), 7.53 (d, J= 8.5 Hz, 2H), 7.47 (br s, IH), 7.37 (d, J= 8.1 Hz, 2H), 7.06 (d, J= 8.8 Hz, 2H), 4.66-4.54 (m, IH), 4.51 (d, J= 5.7 Hz, 2H), 4.32 (d, ,/=5.8 Hz, 2H), 4.09 (s, 2H), 3.09-2.55 (m, 6H), 1.98-1.28 (m, 16H) ppm. ^l3CNMR(100 MHz, DMSO-rfû) δ 158.3, 154.1, 146.8, 137.3, 132.7, 127.5, 125.7, 125.2, 115.0, 78.6, 77.1, 72.6, 54.1, 51.4, 47.7, 44.6, 39.0, 33.5, 30.6, 29.6, 24.7, 22.2, 21.0 pm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.94 min; (M+H⁴) 479.4.

Exampie 193 W-(2-(4^,-((3-Methyloxetan-3-yI)methoxy)-|l,l^,-biphenyl]-4-yl)propan-2-yl)-l,4diazabîcyclo [3.2.2 |nonane-4-carboxamide

Using General Procedure H and the reaction inputs 2-methyl-2-(4'-((3-methyloxetan-3yl)methoxy)-[l,r-biphenyi]-4-yl)propanoic acid (prepared as described in Example 191) and Intermediate 6, the title compound was prepared as a pale amber solid. *H NMR (400 MHz, DMSO-ί/β) ô 7.58 (d, J= 8.7 Hz, 2H), 7.50 (d, J= 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 6.12 (s, 1 H), 4.51 (d, J = 5.7 Hz, 2H), 4.32 (d, J = 5.8 Hz, 2H), 4.23-4.15 (m, IH), 4.08 (s, 2H), 3.49 (t, J= 5.5 Hz, 2H), 3.01-2.60 (m, 6H), 1.941.80 (m, 2H), 1.66-1.47 (m, 8H), 1.38 (s, 3H) ppm. ¹³C NMR (100 MHz, DMSO-î7₆) δ

158.2, 155.4, 148.1, 136.8, 132.8, 127.5, 125.5, 125.2, 115.0, 78.6, 72.6, 57.5,54.5,46.6, 46.0, 41.5, 39.0, 30.2, 27.0, 21.0 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.88 min; (M+H⁴) 464.4.

Example 194

Qulnuclidm-3-yI (2-i4'-(2-(oxetan-3-yl)ethoxy)-[l,l'-biptienyl]-4-yl)propan-2yl)carbamate

To a stirred solution of 2-(oxetan-3-yl)ethanol (4.07 g, 39.9 mmol) in methylene chloride (200 mL) was added triethylaminc (5.8 mL, 41.6 mmol) and p-toluenesulfonyl chloride (8.36 g, 43.8 mmol). The reaction was stirred ovemight and then washed with 0.2 N hydrochloric acid and aqueous sodium bicarbonate solution. The organic layer was dried

247 (Na₂SO4) and concentrated and the resulting crude product was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford 2-(oxetan-3yl)ethyl 4-mcthylbenzcnesulfonate as a colorless oil (6.65 g, 65% overall). To a stirred solution of this product (3.00 g, 11.7 mmol) in acetone (45 mL) was added 4bromophenol (1.69 g, 9.77 mmol) and potassium carbonate (1.69 g, 12.2 mmol). The réaction was heated to reflux overnight, coolcd and filtered. The fîltrate was concentrated onto silica and subjccted to flash chromatography over silica using a hexane/ethyl acetate eluant to afford 3-(2-(4-bromophenoxy)ethyl)oxctane as a white solid (2.43 g, 97%). This product and ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)phenyl)propanoate were reacted according to General Procedure F to generate ethyl 2methyl-2-(4'-(2-(oxetan-3-yl)ethoxy)-[l,r-biphenyl]-4-yl)propanoate. To a stirred solution of this compound (1.32 g, 3.58 mmol) in 1:1:1 (v/v/v) tctrahydrofuran/cthanol/watcr (25 mL) was added lithium hydroxide monohydrate (0.752 g, 17.9 mmol). After stirring at room température overnight, the réaction heated at reflux for 4 hours. At this time, the mixture concentrated and the residue was dissolved in water. The solution was washed with dicthyl ether and then treated with 1 N hydrochloric acid (20 mL). The mixture was extracted with ethyl acetate and the combined organic layers were dried (Na^SCL) and concentrated to afford 2-methyl-2-(4'-(2-(oxetan-3-yl)ethoxy)[l,l'-biphenyl]-4-yl)propanoic acid as an off-white solid (1.18 g, 97%). This intermediate and quinuclidin-3-ol were reacted according to General Procedure H to generate the title compound as a pale amber solid. *H NMR (400 MHz, DMSO-î/s) 5 7.63-7.28 (m, 7H), 6.97 (d, J = 8.9 Hz, 2H), 4.67 (dd, J= 7.9, 5.9 Hz, 2H), 4.47-4.32 (m, 3H), 3.97 (t, J = 6.3 Hz, 2H), 3.21-3.07 (m, IH), 3.07-2.18 (m, 6H), 2.15-1.12 (m, 13H) ppm. ^I3C NMR (100 MHz, DMSO-J₆) δ 157.9, 154.5, 146.7, 137.4, 132.4, 127.5, 125.7, 125.2, 114.8, 76.2, 70.0, 65.9, 55.4, 54.2, 46.9, 45.9, 32.6, 32.4, 29.4, 25.3, 24.2, 19.2 ppm. Purity: 100%, 99.6% (210 & 254 nm) UPLCMS; rétention time: 0.93 min; (M+H*) 465.

Example 195 l-Azabicyclo|3.2.2|nonan-4-yl (2-(4'-(2-(oxetan-3“yl)ethoxy)-Il,l^,-biphenyl]-4yl)propan-2-yl)carbamate

Using General Procedure H and the réaction inputs 2-melhyl-2-(4'-(2-(oxetan-3yl)cthoxy)-[l,T-biphcnyl]-4-yl)propanoic acid (prepared as described in Example 194) and Intermediate 3, the title compound was prepared as a pale amber solid. *H NMR (400 MHz, DMSO-Js) δ 7.61-7.26 (m, 7H), 6.97 (d, J= 8.7 Hz, 2H), 4.67 (dd, ./= 7.9, 5.9 Hz, 2H), 4.64-4.56 (m, IH), 4.37 (t, ./=6.1 Hz, 2H), 3.98 (t, J = 6.2 Hz, 2H), 3.21-3.07 (m, IH), 3.03-2.33 (m, 6H), 2.13-2.03 (m, 2H), 2.00-1.31 (m, 13H) ppm. ⁱ³C NMR (100 MHz, DMSO-i/s) δ 157.9, 154.2, 146.8, 137.4, 132.4, 127.5, 125.7, 125.2, 114.8, 77.1,

76.2, 65.9, 54.1, 51.5, 47.7, 44.6, 33.5, 32.5, 32.4, 30.6, 29.6, 24.7, 22.2 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.94 min; (M+H⁺) 479.

Example 196 2V’-(2-(4'-(2-(Oxetan-3-yl)ethoxy)-[l,l'-biphenylj-4-yl)propan-2-yl)-l,4diazabicyclo[3.2.2|nonanc-4-carboxamide

Using General Procedure H and the réaction inputs 2-mcthyl-2-(4'-(2-(oxetan-3yl)ethoxy)-[l,r-biphenyl]-4-yl)propanoic acid (prepared as described in Example 194) and Intermediate 6, the title compound was prepared as a tan solid. ’H NMR (400 MHz,

DMSO-i/e) δ 7.55 (d, .7= 8.7 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H),

6.97 (d, J= 8.7 Hz, 2H), 6.12 (s, IH), 4.67 (dd, J=7.8, 5.9 Hz, 2H), 4.36 (t, J= 6.1 Hz,

248

2H), 4.24-4.14 (m, IH), 3.97 (t, ./=6.1 Hz, 2H), 3.56-3.40 (m, 2H), 3.21-3.06 (m, IH), 2.98-2.71 (m, 6H), 2.14-2.02 (m, 2H), 1.95-1.81 (m, 2H), 1.66-1.50 (m, 8H) ppm. ¹³C NMR (100 MHz, DMSO-î/o) δ 157.8, 155.4, 148.1, 136.9, 132.6, 127.5, 125.5, 125.2,

114.8, 76.2, 65.8, 57.5, 54.5, 46.6, 46.0, 41.4, 32.6, 32.4, 30.2, 27.0 ppm. Purity: 100%, 100% (2 i 0 & 254 nm) UPLCMS; rétention time: 0.87 min; (M+H) 464.

Exampie 197

QuinucIidin-3-yl (2-(4'-((2-methoxyethoxy)methyl)-[l,l’-biphenyl]-4-yl)propan-2yl)carbamate

To a stirred solution of 2-methoxyethanoi (2.60 mL, 32.9 mmol) in tetrahydrofuran (160 mL) was added sodium hydride (60% dispersion in minerai oil; 1.50 g, 36.2 mmol). The mixture was stirred for 30 minutes before adding 4-bromobenzyl bromide (8.64 g, 34.6 mmol). After ovemight stirring, the réaction was concentrated. The residue was taken up in ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dried (Na₂SO4) and concentrated. The resulting yellow oil was purified by flash chromatography over silica using a hcxanc/ethyl acetate cluant to afford 1-bromo-4-((2methoxyethoxy)methyl)benzcne as a colorless oil (6.43 g, 80%). This product and ethyl 2-mcthy 1-2-(4-(4,4,5,5-tctramcthyl -1,3,2-dioxaborolan-2-yl)phenyl)propanoatc were reacted according to General Procedure F to generate ethyl 2-(4'-((2methoxyethoxy)mcthyl)-[l,r-biphenyl]-4-yl)-2-mcthylpropanoate. To a stirred solution of this compound (0.759 g, 2.13 mmol) in 1:1:1 (v/v/v) tetrahydrofuran/ethanol/water(25 mL) was added lithium hydroxide (0.255 g, 10.6 mmol). After heating at reflux ovemight, the reaction was concentrated and the residue was dissolved in water. The solution was washed with diethyl ether and then treated with 1 N hydrochloric acid (20 mL). The mixture was extracted with ethyl acetate and the combined organic layers were dried (Na₂SÛ4) and concentrated to afford 2-(4'-((2-mcthoxyethoxy)mcthyl)-[l,l’-biphenyl]-4yl)-2-methylpropanoic acid as an off-white solid (0.657 g, 93%). This intermediate and quinuclidin-3-ol were reacted according to General Procedure H to generate the title compound as a soft, pale beige solid. ^lH NMR (400 MHz, DMSO-r/β) δ 7.68-7.52 (m, 5H), 7.48-7.34 (m, 4H), 4.52 (s, IH), 4.46-4.37 (m, IH), 3.63-3.53 (m, 2H), 3.53-3.48 (m, 2H), 3.27 (s, 3H), 3.08-2.29 (m, 6H), 2.03-1.20 (m, UH) ppm. ¹³C NMR (100 MHz, DMSO-i/fi) δ 154.4, 147.4, 139.1, 137.5, 132.4, 128.1, 126.3, 126.2, 125.3, 71.7, 71.3,

69.2, 69.0, 58.1, 54.9, 54.2, 46.7, 45.7, 29.4, 25.0, 23.3, 18.7 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.91 min; (M+H⁴) 453.5.

Exampie 198 l-(2-(4’-((2-Methoxyethoxy)methyl)-[l,l'-biphenyl]-4-yl)propan-2-yl)-3-(3methylquinuclidin-3-yl)urea

Using General Procedure H and the reaction inputs 2-(4'-((2-methoxyethoxy)methyl)~ [l.l'-bÎphcnylj-d-yO^-mcthylpropanoic acid (prepared as described in Example 197) and Intermediate 1, the title compound was prepared as a white solid. *H NMR (400 MHz, DMSO-t/e) δ 7.63 (d, J =8.2 Hz, 2H), 7.57 (d, ./ = 8.5 Hz, 2H), 7.40 (dd, J= 10.3, 8.4 Hz, 4H), 6.17 (s, IH), 5.77 (s, IH), 4.52 (s, 2H), 3.61-3.55 (m, 2H), 3.53-2.48 (m, 2H), 3.27 (s, 3H), 2.71-2.48 (m, 6H), 1.91-1.85 (m, IH), 1.84-1.73 (m, IH), 1.66-1.46 (m, 7H), 1.43-1.20 (m, 5H) ppm. ¹³C NMR (100 MHz, DMSO-î/₆) δ 156.9, 148.5, 139.2, 137.4,

137.2, 128.0, 126.3, 126.0,125.4, 71.7, 71.3, 69.0, 63.5, 58.1, 53.8, 50.7, 46.2, 46.1, 30.4,

30.3, 29.9, 25.1, 23.0, 22.3 ppm. Purity: 100%, 99.5% (210 & 254 nm) UPLCMS; rétention time: 0.89 min; (M+H⁴) 466.6.

249

Example 199 l-(3-Ethylquinuclidïn-3-yl)-3-(2-(4^,-((2-mcthoxyethoxy)methyl)-[l,r-biphenyl]-4yl)propan-2-yl)urca

Using General Procedure H and the réaction inputs 2-(4'-((2-methoxyethoxy)methyl)[l,r-biphenyl]-4-yl)-2-mcthylpropanoic acid (prepared as described in Example 197) and Intermediate 2, the title compound was prepared as a white solid. *H NMR (400 MHz, DMSO-rffi) δ 7.62 (d, J= 8.2 Hz, 2H), 7.56 (d, J= 8.5 Hz, 2H), 7.42 (d, J = 8.5 Hz, 2H), 7.39 (d, J= 8.2 Hz, 2H), 6.20 (s, IH), 5.73 (s, IH), 4.52 (s, 2H), 3.64-3.55 (m, 2H), 3.553.45 (m, 2H), 3.27 (s, 3H), 2.78-2.52 (m, 6H), 1.90-1.71 (m, 3H), 1.71-1.45 (m, 8H), 1.39-1.21 (m, 2H), 0.75 (t, J = 7.3 Hz, 3H) ppm. ^I3C NMR (100 MHz, DMSO-î/₆) δ

156.7, 148.5, 139.2, 137.4, 137.3, 128.0, 126.3, 126.0, 125.4, 71.7, 71.3, 69.0, 62.9, 58.1,

53.8, 53.2, 46,5, 46.3, 30.4, 29.8, 27.8, 27.7, 22,6, 22.3, 8.0 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.88 min; (M+H⁺) 480.6.

Example 200 l-Azabicyclo[3.2.2|nonan-4-yl (2-(4'-((2-methoxyethoxy)methyl)-[l,r-biphenyl]-4yl)propa n-2-yl)carbamate

Using General Procedure H and the réaction inputs 2-(4^l-((2-mcthoxycthoxy)mcthyl)[l,r-biphcnyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 197) and Intermediate 3, the title compound was prepared as a soft amber solid. *H NMR (400 MHz, DMSO-Je) Ô 7.62 (d, J= 8.0 Hz, 2H), 7.57 (d, J= 8.4 Hz, 2H), 7.49 (br s, IH), 7.45-7.35 (m, 4H), 4.65-4.56 (m, IH), 4.52 (s, 2H), 3,61-3.55 (m, 2H), 3.53-3.47 (m, 2H), 3.27 (s, 3H), 2.99-2.45 (m, 6H), 1.96-1.34 (m, 13H) ppm. ¹³C NMR (100 MHz, DMSOί/₆) δ 154.2, 139.1, 137.5, 137.4, 128.0, 126.3, 126.1, 125.3, 77.1, 71.7, 71.3, 69.0, 58.1,

54.1, 51.4, 47.6, 44.6, 33.5, 30.6, 29.6, 24.7, 22.2 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.87 min; (M+H⁺) 467.6.

Example 201 l-(2-(4’-((2-Methoxyethoxy)methyI)-[l,r-biphenyIl-4-yl)propan-2-yI)-3-(4-methyl-lazabicycIo[3.2.2]nonan-4-yl)urea

Using General Procedure H and the reaction inputs 2-(4’-((2-methoxyethoxy)mcthyl)[l,r-biphenyl]-4-yl)-2-mcthylpropanoic acid (prepared as described in Example 197) and Intermediate 5, the title compound was prepared as a glassy, colorless solid. *H NMR (400 MHz, DMSO-i/e) δ 7.62 (d, 8.2 Hz, 2H), 7.56 (d, J= 8.4 Hz, 2H), 7.43 (d, J =

8.6 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 6.24 (br s, IH), 5.74 (br s, IH), 4.52 (s, 2H), 3.65-

3.55 (m, 2H), 3.55-3.47 (m, 2H), 3.27 (s, 3H), 2.93-2.62 (m, 6H), 2.12-2.04 (m, IH), 1.84-1.35 (m, 11H), 1.35-1.17 (m, 4H) ppm. ¹³C NMR (100 MHz, DMSO-î/₆) δ 156.8, 148.6, 139.2, 137.4, 137.3, 128.0, 126.3, 126.0, 125.4, 71.7, 71.3, 69.0, 58.1, 57.2, 53.7,

52.8, 48.1, 45.0, 36.2, 30.4, 29.8, 26.2, 24,4, 23.9 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.86 min; (M+H⁺) 480.6.

Example 202 N-(2-(4'-((2-Methoxyethoxy)methyl)-[l,l’-biphenyl]-4-yl)propan-2-yl)-l,4diazabicyclo|3.2.2|nonane-4-carboxamide

250

Using General Procedure H and the reaction inputs 2-(4'-((2-mcthoxycthoxy)methyl)[l,r-biphcnyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 197) and Intermediate 6, the title compound was prepared as an off-white solid. *H NMR (400 MHz, DMSO-i/e) δ 7.62 (d, J= 8.2 Hz, 2H), 7.55 (d, J= 8.4 Hz, 2H), 7.39 (d, J= 8.3 Hz, 4H), 6.14 (s, IH), 4.52 (s, 2H), 4.22-4.16 (m, IH), 3.65-3.54 (m, 2H), 3.54-3.44 (m, 4H), 3.27 (s, 3H), 3.00-2.67 (m, 6H), 1.94-1.82 (m, 2H), 1.65-1.50 (m, 8H) ppm. ¹³C NMR (100 MHz, DMSO-O δ 155.4, 148.9, 139.3, 137.3, 136.9, 128.0, 126.3, 125.9, 125.3,

71.7, 71.3, 69.0, 58.1, 57.5, 54.5, 46.6, 46.0, 41.4, 30.2, 27.0 ppm. Purity: 90.8%, 91.5% (210 & 254 nm) UPLCMS; rétention time: 0.80 min; (M+H⁴) 452.5.

Exampie 203

Quinuclidm-3-yl (2-(4’-((2-methoxyethoxy)methyl)-|l,l’-biphenyl]-3-yl)propan-2yl)carbamate

Exchanging ethyl 2-mcthyl-2-(4-(4,4,5,5-tetramcthyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate for ethyl 1-(4-(4,4,5,5-tctramcthyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxylate, the reaction sequence outlined in Example 197 was used to préparé l-(4^,-((2-methoxyethoxy)mcthyl)-[l,r-biphcnyl]-4-yl)cyclopropanccarboxylic acid. This intermediate and quinuclidm-3-ol were reacted according to General Procedure H to generate the title compound as a glassy, colories» solid. ’H NMR (7:3 rotomer mixture) (400 MHz, DMSO-O δ 8.03 (br s, 0.7H), 7.79 (br s, 0.3H), 7.68-7.49 (m, 4H), 7.39 (d, 8.0 Hz, 2H), 7.34-7.15 (m, 2H), 7.32 - 7.08 (m, 2H), 4.52 (br s, 3H), 3.62 -

3.54 (m, 2H), 3.54-3.45 (m, 2H), 3.26 (s, 3H), 3.14-2.87 (m, IH), 2.83-2.24 (m, 6H), 1.95-1.00 (m, 9H) ppm. ¹³C NMR major rotomer (100 MHz, DMSO-r/s) δ 157.9, 154.5,

146.8, 137.4, 132.5, 127.5, 125.7, 125.2, 114.8, 70.4, 69.9, 66.9, 58.1, 55.4, 54.2, 46.9,

45.9, 29.4, 25.3, 24.2, 19.2 ppm. Purity: 100%, 99.0% (210 & 254 nm) UPLCMS; rétention time: 0.83 min; (M+H⁴) 451.6.

Example 204 l-Azabicyclo[3.2.2|nonan-4-yl (l-(4'-((2-niethoxyethoxy)inethyI)-[l,r-biphenyl]-4yl)cyclopropyl)carbamate

Using General Procedure H and the reaction inputs l-(4'-((2-methoxyethoxy)methyl)[l,l'-biphenyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 203) and Intermediate 3, the title compound was prepared as a glassy, colorless solid. *H NMR (7:3 rotomer mixture) (400 MHz, DMSO-î/û) ô 7.97 (br s, 0.7H), 7.72 (br s, 0.3H), 7.62 (d, J= 8.3 Hz, 2H), 7.57 (d, J= 8.2 Hz, 2H), 7.39 (d, J= 8.3 Hz, 2H), 7.30-7.18 (m, 2H), 4.75-4.67 (m, IH), 4.52 (s, 2H), 3.64-3.54 (m, 2H), 3.54-3.43 (m, 2H), 3.26 (s, 3H), 3.02-

2.55 (m, 6H), 1.99-1.37 (m, 7H), 1.25-1.09 (m, 4H) ppm. ^I3C NMR (major rotomer) (100 MHz, DMSO-</û) δ 155.7, 143.3, 139.0, 137.4, 137.2, 128.0, 126.3, 126.2, 125.2, 77.5,

71.7, 71.3, 69.0, 58.1, 51.4, 47.7, 44.5, 34.3, 33.5, 30.6, 24.7, 22.2, 18.1 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.84 min; (M+H⁴) 465.5,

Example 205 l-(l-(4'-((2-Methoxyethoxy)methyl)-[l,r-bîphenyl] -4-y l)cyclop ro py 1)-3-(3methylquinuclidin-3-yl)urea

Using General Procedure H and the reaction inputs l-(4'-((2-methoxyethoxy)methyl)[l,r-biphcnyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 203) and Intermediate 1, the title compound was prepared as a white solid. *H NMR (400

251

MHz, DMSO-î/₆) Ô 7.62 (d, J= 8.3 Hz, 2H), 7.56 (d, .7= 8.5 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 7.21 (d, J= 8.4 Hz, 2H), 6.64 (br s, IH), 5.63 (br s, IH), 4.51 (s, 2H), 3.66-3.54 (m, 2H), 3.54-3.45 (m, 2H), 3.26 (s, 3H), 2.80-2.53 (m, 6H), 1.95-1.89 (m, IH), 1.76-1.56 (m, 2H), 1.44-1.08 (m, 9H) ppm. ¹³C NMR (100 MHz, DMSO-J₆) δ 157.3, 144.3, 139.0,

137.4, 136.9, 128.0, 126.2, 126.1, 124.8, 71.7, 71.3, 68.9, 63.4, 58.1, 50.9, 46.2, 46.0,

33.9, 30.4, 25.0, 22.9, 22.3, 19.0 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.80 min; (M+H⁴) 464.6.

Example 206 l-(3-Etliylquinuclidin-3-yl)-3-(l-(4*-((2-nietlioxyethoxy)methyl)-ll,r-bÎphenyl]-4yl)cyclopropyl)urea

Using General Procedure H and the réaction inputs l-(4'-((2-mcthoxyethoxy)mcthyl)[l,r-biphcnyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 203) and Intermediate 2, the title compound was prepared as an ofî-white solid. ^lH NMR (400 MHz, DMSO-i/e) δ 7.62 (d, J= 8.2 Hz, 2H), 7.56 (d, J= 8.4 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.22 (d, J= 8.4 Hz, 2H), 6.66 (br s, IH), 5.58 (br s, IH), 4.51 (s, 2H), 3.66-3.54 (m, 2H), 3.54-3.46 (m, 2H), 3.26 (s, 3H), 2.83-2.53 (m, 6H), 1.97-1.84 (m, 2H), 1.77-1.50 (m, 3H), 1.40-1.05 (m, 6H), 0.73 (t, J = 7.2 Hz, 3H) ppm. ^I3C NMR (100 MHz, DMSO-J₆) δ

157.1, 144.3, 139.0, 137.4, 136.9, 128.0, 126.2, 126.1, 124.8, 71.7, 71.3, 68.9, 62.8, 58.1, 53.5, 46.4, 46.2, 33.9, 27.8, 27.7, 22.6, 22.2, 19.0, 7.9 ppm. Purity: 100%, 99.6% (210 & 254 nm) UPLCMS; rétention time: 0.83 min; (M+H⁴) 478.6.

Example 207 l-(l-(4'-((2-Methoxyethoxy)methyl)-(l,l ’-biphcnyl]-4-yl)cycIopropyl)-3-(4-mcthyl-lazabicyclo[3.2.2]nonan-4-yl)urea

Using General Procedure H and the réaction inputs l-(4'-((2-methoxyethoxy)methyl)[l,l'-biphcnyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 203) and Intermediate 5, the title compound was prepared as a glassy, colorless solid. 'H NMR (400 MHz, DMSO-J₆) δ 7.62 (d, ./= 8.3 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 7.23 (d, J= 8.3 Hz, 2H), 6.70 (br s, IH), 5.57 (br s, IH), 4.51 (s, 2H), 3.62-

3.55 (m, 2H), 3.55-3.44 (m, 2H), 3.26 (s, 3H), 2.95-2.56 (m, 6H), 2.17-2.08 (m, IH), 1.81-1.60 (m, 3H), 1.55-1.38 (m, 211), 1.38-1.07 (m, 8H) ppm. ^I3C NMR (100 MHz, DMSO-î/₆) Ô 157.2, 144.5, 139.0, 137.4, 137.0, 128.0, 126.2, 126.1, 124.9, 71.7, 71.3,

68.9, 58.1, 57.4, 52.8, 47.9, 45.1, 39.2, 36.4, 33.9, 26.1, 24.4, 24.0, 19.0, 18.8 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.79 min; (M+H⁴) 478.6 (M+l).

Example 208 l-(3-Ethylquinuclidin-3-yl)-3-(l-(4'-((2-metlioxyethoxy)methyl)-[l_>l'-biphenylJ-4yl)cyclopropyl)urea (single enantiomer A)

Using General Procedure H and the réaction inputs l-(4'-((2-methoxyethoxy)mcthyl)[l,r-biphenyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 203) and Intermediate 13, the title compound was prepared as an off-white solid. NMR data matchcd that of Example 52. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.84 min; (M+H⁴) 478.4.

Example 209

252 l-(3-Ethylqiiinuclidin-3-yl)-3-(l-(4'-((2-methoxyetlioxy)methyl)-[l,r-biphcnyl|-4yl)cyclopropyl)urea (single enantiomer B)

Using General Procedure H and the reaction inputs l-(4'-((2-methoxyethoxy)methyl)[l,l'-biphenyl]-4-yl)cyclopropanccarboxylic acid (prepared as described in Example 203) and Intermediate 14, the title compound was prepared as an off-white solid. NMR data matched that of Exampie 52. Purity: 100%, 99.7% (210 & 254 nm) UPLCMS; rétention time: 0.84 min; (M+H') 478.4.

Exampie 210 (iS)-l-(l-(4'-((2-Methoxyethoxy)methyl)-[l,l'-biphenyl|-4-yl)cyclopropyl)-3-(3metliylquinuclidin-3-yl)urea

Using General Procedure H and the réaction inputs l-(4'-((2-methoxyethoxy)methyl)[l,l'-biphenyl]-4-y!)cyclopropanccarboxylic acid (prepared as described in Exampie 203) and Intermediate 11, the title compound was prepared as an off-white solid. NMR data matched that of Example 51. Purity: 100%, 99.4% (210 & 254 nm) UPLCMS; rétention time: 0.79 min; (M+H⁺) 464.4.

Exampie 211 (lî)-l-(l-(4^,-((2-Methoxyethoxy)methyl)-[l,l*-biphenyl]-4-y])cyclopropyl)-3-(3methylq u in ucl i d i n-3-yl)u rea

Using General Procedure H and the reaction inputs l-(4'-((2-methoxycthoxy)methyl)[l,r-biphenyI]-4-yl)cyclopropanccarboxylic acid (prepared as described in Example 203) and Intermediate 12, the title compound was prepared as an off-white solid. NMR data matched that of Example 51. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.79 min; (M+H) 464.3.

Example 212

1-Azabîcyclo [3.2.2] nonan-4-yl (l-(4'-(3-methoxypropyl)-[l,l '-bi phenyl]-4yl)cyclopropyl)carbamate

Using General Procedure F and the reaction inputs ethyl 1-(4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phcnyl)-cyclopropanecarboxylate and 1 -bromo-4-(3methoxypropyl)benzene, ethyl 1 -(4'-(3-methoxypropyI)-[l, 1 '-biphenyl]-4yl)cyclopropanecarboxylate was prepared as a pale yellow oil. To a stirred solution of this compound (1.99 g, 5.88 mmol) in 1:1:1 (v/v/v) tetrahydrofuran/cthanol/water (30 mL) was added lithium hydroxidc (0.704 g, 29.4 mmol). The mixture was heated at reflux overnight and then concentrated. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was then treated with IN hydrochloric acid (30 mL) and extracted with ethyl acetate. The combined organic layers were dried (NaîSCU) and concentrated to afford l-(4'-(3-methoxypropyl)-[l,l'-biphenyl]-4yl)cyclopropanccarboxylic acid as a white solid (1.53 g, 84%). This intermediate and

Intermediate 3 were reacted according to General Procedure H to generate the title compound as a white solid. *H NMR (7:3 rotomer mixture) (400 MHz, DMSO-î/g) δ 7.96 (br s, 0.75H), 7.72 (br s, 0.25H), 7.54 (d, J= 8.2 Hz, 4H), 7.26 (d, J= 8.1 Hz, 2H), 7.20 (d, J= 8.2 Hz, 2H), 4.76-4.67 (m, IH), 3.34 (t, J= 6.4 Hz, 3H), 3.24 (s, 3H), 3.00-2.56 (m, 8H), 1.99-1.39 (m, 9H), 1.27-1.08 (m, 4H) ppm. ^I3C NMR (major rotomer) (100

MHz, DMSO-i/e) Ô 155.6, 143.0, 140.8, 137.4, 128.8, 126.3, 126.1, 125.2, 77.5, 71.1,

253

57.8, 51.4, 47.7, 44.5, 34.3, 33.5, 31.3, 30.7, 30.5, 24.6, 22.1, I8.1 ppm. Purity: 97.5%,

98.0% (210 & 254 nm) UPLCMS; rétention time: 0.95 min; (M+H⁴) 449.5.

Example 213 l-(l-(4'-(3-Mellioxypropyl)-ll,l'-biphenyl|-4-yl)cyclopropyl)-3-(4-methyl-lazabicycIo[3.2.2]nonan-4-yl)urea

Using General Procedure H and the reaction inputs l-(4'-(3-mcthoxypropyl)-[l,rbiphenyl]-4-yl)cyclopropanccarboxylic acid (prepared as described in Example 212) and Intermediate 5, the title compound was prepared as a white solid. ^!H NMR. (400 MHz, DMSO-</_G) δ 7.54 (dd, J= 8.2, 2.5 Hz, 4H), 7.26 (d, 8.0 Hz, 2H), 7.22 (d, J= 8.2 Hz,

2H), 6.71 (br s, IH), 5.57 (br s, IH), 3.33 (t, J= 6.4 Hz, 3H), 3.24 (s, 3H), 2.89-2.48 (m, 8H), 2.18-2.08 (m, IH), 1.88-1.58 (m, 5H), 1.56-1.04 (m, 10H) ppm. ^I3C NMR. (100 MHz, DMSO-t/e) ô 157.2, 144.0, 140.7, 137.4, 137.2, 128.8, 126.3, 126.0, 124.8, 71.1,

57.8, 57.4, 52.8, 47.9, 45.0, 39.2, 36.4, 33.9, 31.3, 30.8, 26.1, 24.5, 24.1, 19.0, 18.8 ppm. Purity: 100%, 99.5% (210 & 254 nm) UPLCMS; rétention time: 0.90 min; (M+H⁺) 462.6.

Example 214

-( 1 -(4 '-(3-M ethoxy propyl)-( 1,1 -biphenyl ] -4-y IJcyclopropy 1)-3-(3methylq u in uclidin-3-y l)u rea

Using General Procedure H and the réaction inputs l-(4'-(3-methoxypropyl)-[l,rbiphenyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 212) and Intermediate I, the title compound was prepared as a white solid. *H NMR (400 MHz, DMSO-i/e) Ô 7.54 (dd, J = 8.4, 2.2 Hz, 4H), 7.26 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 6.64 (br s, IH), 5.63 (br s, IH), 3.34 (t, J= 6.4 Hz, 3H), 3.24 (s, 3H), 2.77-2.52 (m, 8H), 1.95-1.89 (m, IH), 1.86-1.76 (m, 2H), 1.76-1.56 (m, 2H), 1.44-1.08 (m, 9H) ppm. ¹³C NMR (100 MHz, DMSO-<7₆) δ 157.3, 144.0, 140.7, 137.4,137.1, 128.8, 126.3, 126.0,

124.8, 71.1, 63.4, 57.8, 50.9, 46.2, 46.0, 33.9, 31.3, 30.8, 30.4, 25.0, 22.9, 22.2, 18.9 ppm. Purity: LCMS 100%, 99.6% (210 & 254 nm) UPLCMS; rétention time: 0.91 min; (M+H⁺) 448.6.

Example 215 l-(3-Ethylquinuclidin-3-yl)-3-(l-(4^,-(3-methoxypropyl)-{l,l’-biphenyl]-4yl)cyclopropyl)urea

Using General Procedure H and the réaction inputs l-(4'-(3-methoxypropyl)-[l,rbiphenyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 212) and Intermediate 2, the title compound was prepared as a white solid. *H NMR (400 MHz, DMSO-t/c) ô 7.58-7.50 (m, 4H), 7.26 (d, J = 8.2 Hz, 2H), 7.21 (d, J= 8.4 Hz, 2H), 6.66 (br s, IH), 5.58 (br s, IH), 3.34 (t, J= 6.4 Hz, 3H), 3.24 (s, 3H), 2.72-2.52 (m, 8H), 1.981.49 (m, 7H), 1.41-1.07 (m, 6H), 0.73 (t, J = 7.2 Hz, 3H) ppm. ^,3C NMR (100 MHz, DMSO-Je) δ 157.1, 144.0, 140.7, 137.4, 137.1, 128.8, 126.3, 126.0, 124.7, 71.1, 62.8,

57.8, 53.4, 46.4, 46.2, 33.8, 31.3, 30.8, 27.8, 27.7, 22.6, 22.2, 18.9, 7.9 ppm. Purity: 100%, 99.9% (210 & 254 nm) UPLCMS; rétention time: 0.95 min; (M+H⁴) 462.6.

Example 216

Quinuclidin-3-yl (l-(4'-((pyndin-3-ylmethoxy)methyl)-[l,l’-biphenyl]-4yl)cyclopropyl)carbamate

254

To a stirred solution of 3-pyridinemethanol (2.00 g, 18.3 mmol) in tetrahydrofuran (80 mL) was added sodium hydridc (60% dispersion; 0.806 g, 20.2 mmol). After 2 hours, 4bromobcnzylbromide (4.80 g, 19.2 mmol) was added and the mixture was stirred ovemight. The reaction was then concentrated and partitioncd between water and ethyl acetate. The organic layer was combined with a second ethyl acetate extract, dried (Na₂SO4) and concentrated. The crude product was purified by flash chromatography over silica using a hexane/cthyl acetate eluant to afford 3-(((4bromobenzyl)oxy)methyl)pyridine as an amber oil (3.67 g, 72%). This product and ethyl 1 -(4-(4,4,5,5-tetramcthyl-l ,3,2-dioxaborolan-2-yl)phenyl)-cyclopropanecarboxylate were reacted according to General Procedure F to generate ethyl l-(4'-((pyridin-3ylmethoxy)methyl)-[l,l’-biphenyl]-4-yl)cyclopropanecarboxylate. To a stirred solution of this compound (1.81 g, 4.67 mmol) in 1:1:1 (v/v/v) tetrahydrofuran/ethanol/water (30 mL) was added lithium hydroxidc monohydratc (0.980 g, 23.4 mmol). After stirring at room température ovemight, the reaction was concentrated and the residue was dissolved in water. The solution was washed with dicthyl ether and then treated with 1 N hydrochloric acid (23.4 mL). The mixture was extracted with 4:1 (v/v) chloroform/isopropanol and the combined organic layers were dried (Na₂SÜ4) and concentrated to afford l-(4^,-((pyridin-3-ylmetlioxy)mcthyl)-[l,r-biphenyl]-4yl)cyclopropanecarboxylic acid as a beige solid (1.68 g, 100%). This intermediate and quinuclidin-3-ol were reacted according to General Procedure H to generate the title compound as an off-white solid. ’H NMR (400 MHz, DMSO-î/g) δ 8.59 (br s, IH), 8.548.49 (m, IH), 8.05 (br s, IH), 7.84-7.74 (m, IH), 7.68-7.52 (m, 4H), 7.48-7.35 (m, 3H), 7.34-7.17 (m, 2H), 4.64-4.47 (m, 5H), 3.14-2.89 (m, IH), 2.82-2.24 (m, 5H), 1.94-1,67 (m, 2H), 1.65-1.04 (m, 7H) ppm. ^I3C NMR (100 MHz, DMSO-e/₆) δ 156.0, 148.9, 148.8,

143.3, 139.2, 137.2, 137.1, 135.4, 133.8, 128.2, 126.4, 126.3, 125.2, 123.5, 71.4, 70.4, 69.0, 55.5, 46.9, 46.0, 34.3, 25.3, 24.3, 19.3, 18.2 ppm. Purity: 100%, 100% (210 nm & 254 nm) UPLCMS; rétention time: 0.65 min; (M+H¹) 484,

Example 217 l-(3-Ethylquinuclidin-3-yl)-3-(l-(4'-((pyrid!n-3-ylmethoxy)methyl)-{l,l^,-biphenyl]-4yl)cyclopropyl)urea

Using General Procedure H and the reaction inputs l-(4'-((pyridin-3-ylmcthoxy)methyl)[l,r-biphenyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 216) and Intermediate 2, the title compound was prepared as a pale amber solid. *H NMR (400 MHz, DMSO-J₆) δ 8.62-8.56 (m, IH), 8.54-8.49 (m, IH), 7.82-7.75 (m, IH), 7.64 (d, J = 8.1 Hz, 2H), 7.57 (d, J= 8.4 Hz, 2H), 7.43 (d, J= 8.1 Hz, 2H), 7.39 (dd, J= 7.8, 4.8 Hz, IH), 7.23 (d,./=8.4 Hz, 2H), 4.59 (br s, 4H), 2.80-2.50 (m, 6H), 1.98-1.84 (m, 2H), 1.791.48 (m, 3H), 1.41-1.07 (m, 6H), 0.74 (t, J = 7.0 Hz, 3H) ppm. ^l3C NMR (100 MHz, DMSO-î/g) S 157.1, 148.9, 148.8, 139.2, 137.0, 136.9, 135.4, 133.8, 128.2, 126.3, 126.1,

124.8, 123.5, 71.4, 69.0, 62.8, 53.5, 46.4, 46.3, 33.9, 27.8, 27.7, 22.3, 19.0, 8.0 ppm. Purity: 100%, 99.6% (210 & 254 nm) UPLCMS; rétention time: 0.66 min; (M+H*) 511.

Example 218 I-(3-Propylquînuclidin-3-yl)-3-(l-(4’-((pyridin-3-ylmetlioxy)methyl)-[l,r-bÎphenyl]4-y l)cyclopr o pyl)urea

Using General Procedure H and the reaction inputs l-(4'-((pyridin-3-ylmethoxy)mcthyl)[l,r-biphenyi]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 216) and Intcimediate 17, the title compound was prepared as a pale amber solid. ’H NMR

255 (400 MHz, DMSO-rfe) 5 8,59 (d, J = 2.0 Hz, 1Η), 8.52 (dd, J= 4.8, 1.6 Hz, IH), 7.817.76 (m, IH), 7.63 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.2 Hz, 2H), 7.41-7.37 (m, IH), 7.22 (d, J= 8.4 Hz, 2H), 6.67 (br s, IH), 5.61 (br s, IH), 4.59 (s, 4H), 2.81-2.70 (m, IH), 2.70-2.51 (m, 5H), 1.95-1.78 (m, 2H), 1.77-1.49 (m, 3H), 1.41-1.06 (m, 8H), 0.87 (t, J= 7.2 Hz, 3H) ppm. ^I3C NMR (100 MHz, DMSO-î/₆) δ 157.2, 148.8,

148.8, 139.2, 137.1, 136.9, 135.4, 133.8, 128.2, 126.1, 124.8, 123.5, 71.4, 69.0, 63.1,

53.4, 46.4, 46.3, 37.8, 33.9, 28.2, 22.7, 22.3, 19.0, 18.9, 16.7, 14.5 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.70 min; (M+H*) 525.

Example 219 Quinuclîdin-3-yl (l-(4'-((pyrimidiii-5-ylmetlioxy)inetliyl)-[l,l'-bipIienyl|-4yl)cycl op ropy l)ca r b amate

Exchanging 3-pyridincmcthanol for 5-pyrimidinemcthanol, the reaction sequence outlined in Example 216 was used to préparé l-(4^,-((pyrimidin-5-ylmcthoxy)mcthyl)[l,l'-biphenyl]-4-yl)cyclopropanecarboxylic acid. This compound and quinuclidin-3-ol were reacted according to General Procedure H to generate the title compound as an offwhite solid. 'H NMR (400 MHz, DMSO-<7₆) δ 9.14 (s, IH), 8.82 (s, 2H), 8.05 (br s, IH), 7.64 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 7.9 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 7.33-7.17 (m, 2H), 4.63 (s, 2H), 4.62 (s, 2H), 4.58-4.48 (m, IH), 3.15-2.89 (m, IH), 2.81-2.25 (m, 5H), 1.95-1.02 (m, 9H) ppm. ¹³C NMR (100 MHz, DMSO-Jj Ô 157.7, 156.2, 156.0, 143.3,

139.2, 137.1, 136.9, 131.8, 128.2, 126.4, 126.3, 125.2, 71.7, 70.4, 66.8, 55.5, 46.9, 46.0,

34.3, 25.3, 24.2, 19.2, 18.2 ppm. Purity: 100%, 99.3% (210 & 254 nm) UPLCMS; rétention time: 0.78 min; (M+H⁺) 485.

Example 220 l-(3-Ethylquinuclidin-3-yl)-3-(l-(4'-((pyrimidin-5-ylmethoxy)methyl)-[l,rbiphenyl|-4-yl)cyclopropyl)urea

Using General Procedure H and the reaction inputs l-(4'-((pyrimidin-5ylmethoxy)mcthyl)-[l,r-biphenyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 219) and Intermediate 2, the title compound was prepared as an offwhite solid. 'H NMR (400 MHz, DMSO-j-,) δ 9.14 (s, IH), 8.82 (s, 2H), 7.64 (d, J= 8.2 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.23 (d, J= 8.4 Hz, 2H), 6.68 (br s, IH), 5.60 (br s, IH), 6.63 (s, 2H), 4.62 (s, 2H), 2.79-2.51 (m, 6H), 1.97-1.84 (m, 2H), 1.78-1.50 (m, 3H), 1.41-1.07 (m, 6H), 0.74 (t, J = 7.0 Hz, 3H) ppm. ^l3C NMR (100 MHz, DMSO-î/₆) δ 157.7, 157.1, 156.2, 144.3, 139.2, 136.9, 136.8, 131.8, 128.2, 126.4,

126.1, 124.8, 71.7, 66.8, 62.8, 53.5, 46.4, 46.2, 33.9, 27.8, 27.7, 22.6, 22.2, 19.0 ppm. Purity: 100%, 98.7% (210 & 254 nm) UPLCMS; rétention time: 0.78 min; (M+H*) 512.

Example 221 l-AzabicycIo[3.2.2]nonan-4-yl (l-(4'-((pyrimidin-5-ylmethoxy)methyl)-[l,rbiphenyl]-4-yl)cyclopropyI)carbamate

Using General Procedure H and the reaction inputs l-(4'-((pyrimidin-5ylmethoxy)methyl)-[l,r-biphenyl]-4-yl)cyclopropanccarboxylic acid (prepared as described in Example 219) and Intermediate 3, the title compound was prepared as an offwhite solid. *H NMR (400 MHz, DMSO-J₆) δ 9.14 (s, IH), 8.82 (s, 2H), 7.99 (br s, IH),

7.64 (d, J= 8.2 Hz, 2H), 7.58 (d, J =8.2 Hz, 2H), 7.45 (d, J= 8.2 Hz, 2H), 7.31-7.17 (m,

2H), 4.77-4.68 (m, IH), 4,63 (s, 2H), 4.62 (s, 2H), 3.00-2.55 (m, 6H), 2.00-1.35 (m, 7H),

256

I.17(brs, 4H) ppm. ^l3CNMR (100 MHz, DMSO-î/₆) δ 157.7, 156.2, 155.7,143.3, 139.2,

137.1, 136.9, 131.8, 128.2, 126.4, 126.2, 125.2, 77.5, 71.7, 66.8, 51.4, 47.7, 44.5, 34.4,

33.5, 30.6, 24.7, 22.2, 18.2 ppm. Purity: 100%, 99.2% (210 & 254 nm) UPLCMS; rétention time: 0.79 min; (M+H⁺) 499.

Exampie 222 l-(2-(4’-(3-Methoxypropyl)-[l,r-biphenyl]-4-yl)propan-2-yl)-3-(3methylquînudidin-3-yl)urea

Exchanging ethyl 1-(4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxylate for ethyl 2-methyl-2 -(4-(4,4,5,5-tetramethyl-l, 3,2dioxaborolan-2-yl)phcnyl)-propanoate, the réaction sequence outlined in Example 212 was used to prépare 2-(4'-(3-methoxypropyl)-[l,r-biphcnyl]-4-yl)-2-mcthylpropanoic acid. This compound and Intermediate 1 were reacted according to General Procedure H to generate the title compound as a white solid. *H NMR (400 MHz, DMSO-ifc) δ 7.63-

7.47 (m, 4H), 7.41 (d, J= 8.5 Hz, 2H), 7.27 (d, J = 8.2 Hz, 2H), 6.18 (br s, IH), 5.79 (br s, IH), 3.34 (t, J = 6.4 Hz, 2H), 3.24 (s, 3H), 2.74-2.52 (m, 8H), 1.91-1.74 (m, 4H), 1.67-

1.47 (m, 7H), 1.44-1.20 (m, 5H) ppm. ¹³C NMR (100 MHz, DMSCW₆) δ 156.9, 148.2,

140.7, 137.6, 137.5, 128.8, 126.4, 125.9, 125.3, 71.2, 63.4, 57.8, 53.8, 50.7, 46.1, 46.0,

31.3, 30.8, 30.3, 29.9, 25.1, 22.9, 22.2 ppm. Purity: 99.9%, 98.1% (210 & 254 nm) UPLCMS; rétention time: 0.97 min; (M+H*) 450.5.

Example 223

Qulnuclidin-3-yl (2-(4'-(hydroxymethyl)-[l,r-biphenyl]-4-yl)propan-2-yl)carbamate

Using General Procedure F and the reaction inputs ethyl 2-(4-bromophenyl)-2methylpropanoate and 4-formylphenylboronic acid, ethyl 2-(4’-formyl-[l,l'-biphenyl]-4yl)-2-methylpropanoatc was prepared as a pale amber solid. Thîs intermediate and quinuclidin-3-ol were reacted according to General Procedure H to generate quinuclidin3-yl (2-(4'-formyl-[l,r-biphcnyl]-4-yl)propan-2-yl)carbamate as foamy, yellow solid. To a stirred solution of this material (0.755 g, 1.92 mmol) in 2:1 (v/v) tetrahydrofuran/ethanol (15 mL) was added sodium borohydride (0.073 g, 1.93 mmol). After 45 minutes, the reaction was diluted with water and extracted with chloroform, The combined extracts were dried (Na2SO4) and concentrated onto silica. Flash chromatography over silica using a chloroform/methanol/ammonia eluant provided the title compound as a white solid (0.323 g, 43%). *H NMR (400 MHz, DMS(W_fi) δ 7.667.29 (m, 9H), 5.18 (t, J = 5.7 Hz, IH), 4.53 (d, J= 5.7 Hz, 2H), 4.46-4.37 (m, IH), 3.112.19 (m, 6H), 2,11-1.10 (m, 11 H) ppm. ^l3CNMR(100 MHz, DMSO-i/₆) δ 154.7, 147.3,

141.5, 138.4, 137.7, 127.0, 126.2, 126.1, 125.3, 70.0, 62.6, 55.4, 54.2, 46.9, 45.9, 29.4,

25.3, 24.2, 19.2 ppm. Purity: 97.5%, 99.1% (210 & 254 nm) UPLCMS; rétention time: 0.73 min; (M+H J 395.

Example 224 l-(2-(4'-(2-HydroxyetliyI)-[l,l^,-biphenyl]-4-yl)propan-2-yl)-3-(3-propylquinuclldin3-yl)urea

Using General Procedure F and the reaction inputs l-(2-(benzyloxy)ethyl)-4bromobenzene and ethyl 2-mcthyl-2-(4-(4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2yl)phenyl)propanoate, ethyl 2-(4'-(2-(bcnzyloxy)ethyl)-[l,r-biphenyl]-4-yl)-2mcthylpropanoatc was prepared as a colorlcss gum. To a stirred solution of this

257 compound (1.34 g, 3.33 mmol) in l:l:l (v/v/v) tetrahydrofuran/ethanol/water (18 mL) was added lithium hydroxide monohydrate (0.698 g, 16.6 mmol). After heating at reflux ovemight, the reaction was concentrated and partitioncd between water and diethyl ether. The resulting émulsion was extracted repeatedly with 0.2 N aqueous sodium hydroxide solution (5 x 50 mL). The clear portion of the aqueous layer was removed each time. The combined aqueous layers were then treated with 1.0 N hydrochloric acid (80 mL) and the resulting suspension of white solid was extracted with ethyl acetate. The combined organic layers were dried (Na₂SÛ4) and concentrated to afford 2-(4'-(2-(benzyloxy)ethyl)[l,r-biphenyl]-4-yl)-2-methylpropanoic acid as a white solid (1.20 g, 96%). This compound and Intermediate 17 were reacted according to General Procedure H to generate l-(2-(4'-(2-(benzyloxy)cthyl)-[l,r-biphcnyl]M-yl)propan-2-yl)-3-(3propyIquinuclidin-3-yl)urca as a colorless, foamy solid. To a stirred solution of this material (0.435 g, 0.806 mmol) in methanol was added 1.0 N hydrochloric acid (1 mL) and 10% palladium on carbon (50% water; 0.087 g). The mixture was cycled between vacuum and a nitrogen purge several times, refilling with hydrogen after the last évacuation. After 1.25 hours the reaction was filtered through Celite and concentrated. The residue was taken up în aqueous sodium carbonate solution and extracted with 4:1 (v/v) chlorofbrm/isopropanol. The combined extracts were dried (Na₂SO<i) and concentrated onto silica. Flash chromatography over silica using a chloroform/methanol/ammonia gradient provided the purified title compound as foamy, colorless solid (0.296 g, 82%). *H NMR (400 MHz, DMSO-î/₆) δ 7.56-7.47 (m, 4H), 7.44-7.37 (m,2H), 7.33-7.26 (m,2H), 6.19 (s, lH),5.74(s, 1H),4.65 (brs, lH),3.63(t,J = 7.0 Hz, 2H), 2.79-2.46 (m, 8H), 1.89-1.82 (m, IH), 1.82-1.68 (m, 2H), 1.67-1.42 (m, 8H), 1.40-1.14 (m, 4H), 0.86 (t, J= 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, DMSO-î/₆) δ

156.8, 148.3, 138.5, 137.8, 137.5, 129.4, 126.2, 125.9, 125.3,63.1,62.1,53.7, 53.1,46.4,

46.3, 38.6, 37.8, 30.6, 29.6, 28.2, 22.6, 22.2, 16.7,14.5 ppm. Purity: 100%, 99.0% (210 & 254 nm) UPLCMS; rétention time: 0.83 min; (M+H⁴) 450.

Example 225 l-(3-Ethylquinuclidin-3-yl)-3-(2-(4'-(2-hydroxyethyl)-|l,r-biphenyl]-4-yl)propan-2yl)urca

Exchanging Intermediate 17 for Intermediate 2, the réaction scqucncc outlined in Example 224 was used to préparé the title compound as an off-whitc solid. ^lH NMR (400 MHz, DMSO-î/g) δ 7.62-7.36 (m, 6H), 7.34-7.21 (m, 2H), 6.22 (br s, IH), 5.78 (br s, 1 H), 4.66 (brs, IH), 3.63 (t, J= 7.0 Hz, 2H), 2.83-2.43 (m, 8H), 1.93-1.18 (m, 13H), 0.75 (t, J = 7.4 Hz, 3H) ppm. ^l3CNMR (100 MHz, DMSO-ùfe) δ 156.8,148.2, 138.5, 137.7, 137.5, 129.4, 126.2, 125.9, 125.3, 62.7, 62.1, 53.8, 53.2, 46.4, 46.2, 38.6, 30.4, 29.8, 27.7, 22.4,

22.1, 8.0 ppm. Purity: 100%, 98.0% (210 & 254 nm) UPLCMS; rétention time: 0.79 min; (M+H⁴) 436.

Example 226

Quinuclidîn-3-yl (2-(4'-(2-liydroxyethyI)-[l,I’-biphenyI]-4-yI)propan-2-yl)carbamate

Exchanging Intermediate 17 for quinuclidin-3-ol, the reaction sequence outlined in

Example 224 was used to prépare the title compound as a colorless solid. *H NMR (400

MHz, DMSO-Jg) δ 7.85-7.63 (m, IH), 7.63-7.19 (m, 8H), 4.78-4.62 (m, 2H), 3.71-2.78 (m, 8H), 2.76 (t, J= 6.8 Hz, 2H), 2.26-1.96 (m, 2H), 1.96-1.40 (m, 9H) ppm. ^I3C NMR (100 MHz, DMSO-î/g) δ 153.8, 146.8, 138,7, 137.9, 137.6, 129.4, 126.3, 126.1, 125.3,

258

66.2, 62.1, 54.4, 52.8, 45.4, 44.5, 38.6, 29.5, 29.2, 24.0, 19.9, 16.6 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.75 min; (M+H) 409.

Exampie 227

Quïnuclitlin-3-yl (2-(4'-(2-(lZf-l,2,3-triazoI-4-yl)ethyl)-[l,r-biphenyl]-4-yl)propan-2yl)carbamate

To a stirred solution of l-bromo-4-(but-3-yn-l-yl)benzene (1.73 g, 8.27 mmol) in a mixture of reri-butanol (76 mL) and water (24 mL) was added benzyl azide (1.14 g, 9.13 mmol), L-sodium ascorbate (0.164 g, 0.828 mmol) and copper(II) sulfate pentahydrate (0.103 g, 0.413 mmol). After 2 days, more benzyl azide was added (0.25 mL, 2.00 mmol) and the reaction was stirred for another night. The reaction was then concentrated and the residue was taken up in aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined extracts were dried (Na₂SO₄) and concentrated onto silica. Flash chromatography over silica using a hexane/ethyl acetate eluant provided 1 -benzyl-4-(4bromophcncthyl)-l//-l,2,3-triazole as white solid (1.17 g, 41%). This compound and ethyl 2-mcthyl-2-(4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenyl)propanoate were reacted according to General Procedure F to generate ethyl 2-(4'-(2-(l-benzyl-l/f-1,2,3triazol-4-yl)ethyl)-[l,l'-biphenyl]-4-yl)-2-methylpropanoate as a white solid. To a stirred solution of this compound (1.22 g, 2.69 mmol) in 2:3:3 (v/v/v) watcr/tctrahydrofuran/ethanol (32 mL) was added lithium hydroxide monohydratc (0.564 g, 13.4 mmol). After heating at reflux ovemight, the reaction was concentrated and the residue was dissolved in water. The solution was washed with diethyl ether and then treated with 1 N hydrochloric acid (13.4 mL). The resultîng milky suspension was extracted with ethyl acetate and the combined organic layers were dried (Na₂SO₄) and concentrated to afford 2-(4^,-(2-(l-bcnzyl-l/f-l,2,3-triazol-4-yl)cthyl)-[l,l'-biphenyl]-4yl)-2-methylpropanoic acid as a white solid (1.16 g, 100%). This compound and quinuclidin-3-ol were reacted according to General Procedure H to generate quinuclidin3-yl (2-(4'-(2-( 1 -benzyl-1 H-1,2,3 -triazol-4-yl)ethyl)-[ 1,1 ’-biphenyl] -4-y l)propan-2yl)carbamate as a foamy, colorless solid. To a stirred solution of this intermediate (0.450 g, 0,819 mmol) in methanol (20 mL) was added 1.0 N hydrochloric acid (1 mL) and 10% palladium on carbon (50% water; 0.225 g). The mixture was cycled between vacuum and a nitrogen purge several times, refilling with hydrogen after the last évacuation. After 7 hours, the reaction filtered through Celite and concentrated. The residue was purified by flash chromatography over silica using a chloroform/methanol/ammonia gradient to afford the title compound as a foamy, colorless solid (0.332 g, 88%). ^]H NMR (400 MHz, DMSO-i/e) δ 7.63-7.25 (m, 10H), 4.48-4.35 (m, IH), 3.09-2.19 (m, 10H), 2.10-1.02 (m, 11H) ppm. ^I3C NMR (100 MHz, DMSO-î/₆) δ 154.5, 147.2, 144.0, 140.1, 137.7, 137.6,

129.3, 128.9, 126.4, 126.1, 125.3, 70.0, 55.4, 54.2, 46.9, 45.9,34.2, 29.4, 26.0,25.3, 24.2, 19.2 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.83 min; (M+H⁴) 460.

Exampie 228 l-Azabicyclo[3.2.2]nonan-4-yl (2-(4'-(2-(lÆ-l,2,3-triazol-4-vl)cthyl)-[l,r-biphenyl|4-y l)propa n-2-y l)ca r ba m a te

Exchanging quinuclidin-3-ol for Intermediate 3, the reaction sequence outlined in

Example 227 was used to préparé the title compound as a colorless solid. NMR (400

MHz, DM 50¾) δ 14.69 (br s, IH), 7.59 (s, IH), 7.55 (d, J = 8.4 Hz, 4H), 7.48 (br s,

IH), 7.39 (d, J= 8.1 Hz, 2H), 7.30 (d, J= 8.3 Hz, 2H), 4.65-4.55 (m, IH), 3.04-2.42 (m,

259

ΙΟΗ), 2.01-1.31 (m, 13H) ppm. ¹³C NMR (100 MHz, DMSO-J₆) δ 154.2, 147.3, 144.1,

140.1, 137.8, 137.6, 129.3, 128.9, 126.4, 126.0, 125.3, 77.0, 54.1, 51.4, 47.7, 44.6, 34.2,

33.4, 30.5, 26.0, 24.5, 22.0 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.83 min; (M+H ) 474.

Example 229

Quinuclidin-3-yl (2-(4'-(morpholinomethyl)-[l,r-biphenyl]-4-yl)propan-2yl)carbamate

Using General Procedure F and the reaction inputs ethyl 2-(4-bromophenyl)-2mcthylpropanoate and 4-(4-morpholinomethyl)phcnylboronic acid, ethyl 2-mcthyI-2-(4'(morpholinomethyl)-[l,r-biphenyl]-4-yl)propanoate was prepared as an amber oil. To a stirred solution of this compound (2.86 g, 7.79 mmol) in 1:1:1 (v/v/v) tetrahydrofuran/cthanol/water (40 mL) was added lithium hydroxide (1.31 g, 54.5 mmol). After heating at reflux ovemight, the reaction was diluted with water and washed with diethyl ether. The aqueous layer was treated with 1.0 N hydrochloric acid (56 mL) and extracted with 4:1 (v/v) chloroform/isopropanol. The combined extracts were dried (Na₂SO4) and concentrated. The residue was trîturated with diethyl ether to afford 2methyl-2-(4'-(morpholinomethyl)-[l,r-biphcnyl]-4-yl)propanoic acid as a tan solid (2.50 g, 95%). This compound and quinuclidin-3-ol were reacted according to General Procedure H to generate the title compound as an off-white solid. *H NMR (400 MHz, DMSO-t/e) δ 7.67-7.26 (m, 9H), 4.50-4.34 (m, 1 H), 3.58 (t, J= 4.6 Hz, 4H), 3.49 (s, 2H), 3.10-2.22 (m, 8H), 2.07-1.18 (m, 11H) ppm. ¹³C NMR (100 MHz, DMSO-O δ 154.6,

147.4, 138.7, 137.6, 136.8, 129.4, 126.3, 126.1, 125.3, 70.0, 66.2, 62.1, 55.4, 54.2, 53.2, 46.9, 46.0, 29.4, 25.2, 24.2, 19.2 ppm. Purity: 96.5%, 98.9% (210 & 254 nm) UPLCMS; rétention time: 0.50 min; ((M+H*)/2) 232.9.

Example 230 7V-(2-(4^,-(MorphoIinomethyl)-[l,l '-biphenyl]-4-yl)propan-2-yl)-l,4diazabicyclo[3.2.2|nonane-4-carboxamide

Using General Procedure H and the reaction inputs 2-methyl-2-(4’-(morpholinomethyl)[l,l'-biphenyl]-4-yl)propanoic acid (prepared as described in Example 229) and Intermediate 6, the title compound was prepared as a colorless solid. ^JH NMR (400 MHz, DMSO-i/s) Ô 7.59 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.3 Hz, 2H), 7.44-7.32 (m, 4H), 6.16 (br s, IH), 4.24-4.16 (m, IH), 3.62-3.54 (m, 2H), 3.54-3.43 (m, 4H), 3.00-2.72 (m, 6H), 2.44-2.29 (m, 4H), 1.95-1.82 (m, 2H), 1.66-1.49 (m, 8H) ppm. ¹³C NMR (100 MHz, DMSO-î/ô) δ 155.4, 148.7, 138.9, 137.0, 136.7, 129.4, 126.3, 125.9, 125.3, 66.2, 62.1,

57.4, 54.6, 53.2, 46.5, 45.9, 41.2, 30.2, 26.8 ppm. Purity: 97.2%, 99.9% (210 & 254 nm) UPLCMS; rétention time: 0.44 min; ((M+l)/2) 232.4.

Example 231

Quinuclidin-3-yl (2-(4’-morpholino-[l,l '-biplienyl|-4-yl)propan-2-yl)carbamate

Using General Procedure F and the reaction inputs ethyl 2-(4-bromophenyl)-2methylpropanoate and 4-(4-(4,4,5,5-tctramcthyl-1,3,2-dioxaborolan-2-yl)phcnyl)morpholine, ethyl 2-mcthyl-2-(4'-morpholino-[l,r-biphenyl]-4-yl)propanoatc was prepared as a white solid. To a stirred solution of this compound (3.32 g, 9.39 mmol) in

1:1:1 (v/v/v) tetrahydrofuran/cthanol/water (50 mL) was added lithium hydroxide (1.57 g,

65.6 mmol). After heating at reflux for 3 hours, the reaction was diluted with water and

260 washed with diethyl ether. The aqueous layer was acidified to pH -5 with 1.0 N hydrochloric acid and extracted with ethyl acetate. The combined extracts were filtered free of solid and concentrated to afford 2-methyl-2-(4'-morpholino-(l,r-biphenyl]-4yl)propanoic acid (2.62 g, 86%). This compound and quinuclidin-3-ol were reacted according to General Procedure H to generate the title compound as an off-whitc solid. *H NMR. (400 MHz, DMSO-J₆) δ 7.56-7.40 (m, 6H), 6.96 (d, J = 8.8 Hz, 2H), 5.19 (br s, IH), 4.70-4.54 (m, IH), 3.92-3.83 (m, 4H), 3.27-2.41 (m, 10H), 2.09-1.28 (m, l IH) ppm. ¹³CNMR (100 MHz, DMSO-i/fi) δ 155.2,151.0, 147.1, 138.3, 131.3, 127.6, 126.1, 125.9, 116.0, 70.6, 66,8, 56.0, 54.7, 48.9, 46.6, 30.1, 30.0, 25.9, 24.8, 19.8 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 1.02 min; (M+H⁴) 450.4.

Example 232 l-(3-Methylqiiinuclidin-3-yl)-3-(2-(4'-morpholino-[l,r-biphenyl]-4-yl)propan-2yl)urea

Using General Procedure H and the réaction inputs 2-methyl-2-(4'-morpholino-[l,rbîphenyl]-4-yl)propanoic acid (prepared as described in Example 231) and Intermediate

1, the title compound was prepared as a white solid. *H NMR (400 MHz, CDC1₃) δ 7.577.40 (m, 6H), 6.96 (d, J= 8.8 Hz, 2H), 5.19 (br s, IH), 4.71-4.53 (m, IH), 3.93-3.82 (m, 4H), 3.27-2.11 (m, 10H), 2.09-1.25 (m, 11H) ppm. ¹³C NMR (100 MHz, DMSO-cM δ

156.9, 150.2, 147.4, 137.4, 130.7, 126.9, 125.3, 115.3, 66.1, 63.6, 53.8, 50.7, 48.3, 46.2,

46.1, 30.4, 30.3, 29.9, 25.1, 23.0, 22.3 ppm. Purity: 100%, 99.9% (210 & 254 nm) UPLCMS; rétention time: 0.82 min; 463.1 (M+l).

Example 233 l-(4-Methyl-l-azabicyclo[3.2.2|nonan-4-yl)-3-(2-(4^,-morpholino-[l,l'-biphenyl]-4yl)propan-2-yl)urea

Using General Procedure H and the réaction inputs 2-methyl-2-(4'-morpholino-[l,rbiphenyl]-4-yl)propanoic acid (prepared as described in Example 231) and Intermediate 5, the title compound was prepared as an off-white solid. *H NMR (400 MHz, DMSO-i/e) δ 7.58-7.44 (m, 4H), 7.38 (d, ./=8.4 Hz, 2H), 7.01 (d, J= 8.6 Hz, 2H), 6.21 (br s, IH), 5.72 (br s, IH), 3.85-3.63 (m, 4H), 3.23-3.02 (m, 4H), 2.94-2.63 (m, 6H), 2.12-2.03 (m, IH), 1.84-1.35 (m, 11H), 1.35-1.17 (m, 4H) ppm. ^I3C NMR (100 MHz, DMSO-î/₆) δ

156.8, 150.2, 147.5, 137.4, 130.7, 126.9, 125.3, 125.3, 115.3, 66.1, 57.2, 53.7, 52.8, 48.3,

48.1, 45.0, 36.2, 30.4, 29.8, 26.2, 24.5, 24.0 ppm. Purity: 100%, 98.8% (210 & 254 nm) UPLCMS; rétention time: 0.83 min; (M+H⁺) 477.1.

Example 234 l-(3-Ethylquînuclidln-3-yl)-3-(2-(4'-morpliolino-[l,l'-biphenyl]-4-yl)propan-2vl)urca

Using General Procedure H and the reaction inputs 2-methyl-2-(4'-morpholino-[l,rbiphcnyl]-4-yl)propanoic acid (prepared as described in Example 231) and Intermediate

2, tlie title compound was prepared as a foamy, colorless solid. *H NMR (400 MHz, DMSO-Jo) δ 7.52 (d, ./= 8.9 Hz, 2H), 7.49 (d, ./= 8.5 Hz, 2H), 7.38 (d, J= 8.5 Hz, 2H), 7.01 (d, J= 8.9 Hz, 2H), 6.17 (br s, IH), 5.71 (br s, IH), 3.80-3.69 (m, 4H), 3.20-3.08 (m, 4H), 2.84-2.53 (m, 6H), 1.92-1.41 (m, HH), 1.41-1.19 (m, 2H), 0.74 (t, J= 7.3 Hz, 3H) ppm. ¹³CNMR (100 MHz, DMSO-ifc) δ 156.8, 150.2, 147.4, 137.4, 130.7, 126.9, 125.3,

261

115.3, 66.1, 62.9, 53.7, 53.2, 48.3, 46.5, 46.3, 30.4, 29.8, 27.8, 27.7, 22.6, 22.3, 8.0 ppm. Purity: 100%, 99.9% (210 & 254 nm) UPLCMS; rétention time: 1.03 min; (M+H) 477.4.

Example 235

Quiniiclidiiï-3-yl (2-(4-(me(liylsulfonyl)-[I,l*-biphenyl)-4-yl)propan-2-yl)carbamate

Using General Procedure F and the réaction inputs ethyl 2-methyl-2-(4-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)phcnyl)propanoate and 4-bromophenyl methyl sulfone, ethyl 2-mcthyl-2-(4'-(methylsulfonyl)-[l,r-biphenyl]-4-yl)piOpanoate was prepared as a white solid. To a stirred solution of this compound (1.03 g, 2.97 mmol) in 1:1:1 (v/v/v) tetrahydrofuran/ethanol/water (18 mL) was added lithium hydroxide monohydrate (0.624 g, 14.9 mmol). After stirrîng at room température ovemight, the réaction was heated at reflux for 3 hours, cooled and concentrated. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was treated with 1.0 N hydrochloric acid (20 mL) and extracted with 4:1 (v/v) chloroform/isopropanol. The combined extracts were dried (Na₂SÛ4) and concentrated to afford 2-mcthyl-2-(4'(methylsulfonyl)-[l,T-biphenyl]-4-yl)propanoic acid as an off-white solid (0.954 g, 100%). This compound and quinuclidin-3-ol were reacted according to General Procedure H to generate the title compound as an off-white solid. *H NMR (400 MHz, DMSO-rfâ) δ 8.02-7.96 (m, 2H), 7.96-7.87 (m, 2H), 7.73-7.42 (m, 5H), 4.56-4.46 (m, IH), 3.30-3.10 (m, IH), 3.25 (s, 3H), 3.00-2.52 (m, 5H), 2,03-1.80 (m, 2H), 1.76-1.33 (m, 9H) ppm. ^I3C NMR (100 MHz, DMSO-î/₆) δ 154.3, 148.7, 144.9, 139.4, 136.0, 127.6,

127.3, 126.8, 125.6, 68.8, 54.6, 54.3, 46.5, 45.5, 43.6, 29.3, 24.8, 22.8, 18.4 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.74 min; (M+H⁴) 443.

Example 236 l-(3-Ethylquinuclidin-3-yl)-3-(2-(4'-(methylsulfonyl)-[l,l’-biphenyl]-4-yI)propan-2yl)urea

Using General Procedure H and the reaction inputs 2-methyl-2-(4'-(mcthylsulfonyI)-[l,l'biphenyl]-4-yl)propanoic acid (prepared as described in Example 235) and Intermediate 2, the title compound was prepared as an off-white solid. ’H NMR (400 MHz, DMSO-t/e) δ 8.01-7.96 (m, 2H), 7.96-7.90 (m, 2H), 7.70-7.63 (m, 2H), 7.52-7.45 (m, 2H), 6.30 (br s, IH), 5.86 (br s, IH), 3.25 (s, 3H), 2.80-2.52 (m, 6H), 1.93-1.74 (m, 3H), 1.71-1.44 (m, 8H), 1.43-1.25 (m, 2H), 0.76 (t, J= 7.3 Hz, 3H) ppm. ¹³C NMR (100 MHz, DMSO-î/₆) 6

156.8, 150.0, 145.0, 139.3,135.7, 127.6, 127.3, 126.6, 125.6, 62.5, 53.8, 53.2,46.3,46.1,

43.6, 30.4, 29.8, 27.7, 27.7, 22.3, 22.0, 8.0 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention lime: 0.76 min; (M+H⁴) 470.

Example 237 l-(2-(4'-(Methylsulfonyl)-[l,r-biphenyl]-4-yl)propan-2-yl)-3-(3-propylquinuclidin-3yl)urea

Using General Procedure H and the réaction inputs 2-methyl-2-(4'-(mcthylsulfonyl)-[l,l'biphenyl]-4-yl)propanoic acid (prepared as described in Example 235) and Intermediate

17, the title compound was prepared as an off-white solid. *H NMR (400 MHz, DMSOdà 8 8.02-7.96 (m, 2H), 7.95-7.88 (m, 2H), 7.68-7.61 (m, 2H), 7.51-7.44 (m, 2H), 6.24 (brs, IH), 5.76 (brs, IH), 3.25 (s, 3H), 2.73-2.45 (m, 6H), 1.89-1.83 (m, IH), 1.83-1.68 (m, 2H), 1.68-1.45 (m, 2H), 1.41-1,14 (m, 4H), 0.86 (t, J= 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, DMSO-J) δ 156.8, 150.0, 145.0, 139.3, 135.7, 127.6, 127.3, 126.6, 125.6,

262

63.1, 53.8, 53.2, 46.5, 46.3, 43.6, 37.8, 30.6, 29.6, 28.2, 22.7, 22.3, 16.7, 14.6 ppm.

Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.81 min; (M+H⁴) 484.

Example 238

Quinuclidin-3-yl (2-(4*-((cycIopropylmethyl)sulfonyl)-[l,r-biphenyl]-4-yl)propan-2yl)carbamate

Using General Procedure F and the reaction inputs ethyl 2-mcthyl-2-(4-(4,4,5,5tctramethyl-1,3,2-dîoxaboroIan-2-yl)phenyl)propanoate and 1 -bromo-4((cyclopropylmethyl)sulfonyl)bcnzene, ethyl 2-(4’-((cyclopropylmcthyl)sulfonyl)-[l, 1 biphenyl]-4-yl)-2-methylpropanoate was prepared as an amber gum. To a stirred solution of this compound (1.93 g, 4.99 mmol) in 1:1:1 (v/v/v) tetrahydrofuran/ethanol/water (36 mL) was added lithium hydroxidc monohydratc (1.05 g, 25.0 mmol). After stirring at room température ovemight, the reaction was heated at reflux for 2 hours, cooled and concentrated. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was treated with 1.0 N hydrochloric acid (27 mL) and extracted with ethyl acetate. The combined extracts were dried (Na₂SÛ4) and concentrated to afford 2-(4'((cyclopropylmcthyl)sulfonyl)-[l,l'-biphcnyl]-4-yl)-2-mcthylpropanoic acid as an offwhite solid (1.81 g, 100%). This compound and quinuclidin-3-ol were reacted according to General Procedure H to generate the title compound as an off-white solid. *H NMR (400 MHz, DMSO-<7₆) δ 8.01-7.85 (m, 4H), 7.71 (d, 8.1 Hz, 2H), 7.65-7.33 (m, 3H),

4.49-4.36 (m, IH), 3.29 (d, 7=7.1 Hz, 2H), 3.11-2.24 (m, 6H), 2.10-1.15 (m, 11H), 0.970.78 (m, IH), 0.53-0.41 (m, 2H), 0.20-0.08 (m, 2H) ppm. ^,3C NMR (100 MHz, DMSO</₆) δ 154.5, 148.9, 144.9, 137.9, 135.9, 128.6, 127.1, 126.8, 125.5, 70.1, 59.4, 55.4, 54.2,

46.9, 45.9, 29.3, 25.2, 24.1, 19.2, 4.6, 3.8 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.85 min; (M+H⁴) 483.

Example 239 l-(2-(4'-((Cyclopropylmethyl)sulfonyl)-[l,r-biphenyl|-4-yl)propan-2-yl)-3-(3ethylquinudidin-3-yl)urea

Using General Procedure H and the reaction inputs 2-(4'-((cyclopropylmethyl)sulfonyl)[l,r-biphcnyl]-4-yl)-2-mcthylpropanoic acid (prepared as described in Exemple 238) and Intermediate 2, the title compound was prepared as a white solid. ’H NMR (400 MHz, DMSO-</₆) δ 7.99-7.89 (m, 4H), 7.68 (d, J = 8.6 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 6.26 (s, IH), 5.79 (s, IH), 3.29 (d, J= 7.1 Hz, 2H), 2.74-2.48 (m, 6H), 1.92-1.73 (m, 3H), 1.71-1.47 (m, 8H), 1.41-1.21 (m, 2H), 0.93-0.81 (m, IH), 0.76 (t, J= 7.3 Hz, 3H), 0.510.42 (m, 2H), 0.18-0.10 (m, 2H) ppm. ¹³C NMR (100 MHz, DMSO-O δ 156.7, 150.1,

144.9, 137.8, 135.6, 128.6, 127.1, 126.6, 125.6, 62.7, 59.4, 53.8, 53.2, 46.4, 46.2, 30.4,

27.8, 27.7, 22.5, 22.2, 8.0,4.6, 3.8 ppm. Purity: 100%, 98.8% (210 & 254 nm) UPLCMS; rétention time: 0.87 min; (M+H⁴) 510.

Exampie 240

1-(2-(4’-((Cyclopropylmethyl)sulfonyl)-[l,l*-biphenyI]-4-yl)propan-2-yl)-3-(3methyIquinucIidin-3-yl)urea

Using General Procedure H and the reaction inputs 2-(4'-((cyclopropylmethyl)sulfonyl)[l,r-biphcnyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 238) and

Intermediate 1, the title compound was prepared as a white solid. ^fH NMR (400 MHz,

DMSO-t/e) δ 7.98-7.90 (m, 4H), 7.69 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H), 6.24

263 (s, IH), 5.82 (s, IH), 3.29 (d,./ = 7.1 Hz, 2H), 2.74-2.51 (m, 6H), 1.92-1.74 (m, 2H), 1.67-1.47 (m, 7H), 1.44-1.20 (m, 5H), 0.93-0.82 (m, IH), 0.51-0.42 (m, 2H), 0.18-0.10 (m, 2H) ppm. ¹³CNMR (100 MHz, DMSO-J₆) δ 156.9, 150.0, 144.9, 137.8,135.6, 128.6,

127.1, 126.6, 125.6, 63.4, 59.4, 53.9, 50.7, 46.1, 46.0, 30.4, 30.3, 29.9, 25.1, 22.9, 22.2,

4.6, 3.8 ppm. Purity: 100%, 98.7% (210 & 254 nm) UPLCMS; rétention time: 0.84 min; (M+H⁴ ) 496.

Example 241 l-Azabicyclo[3.2.2]nonan-4-yl (2-(4’-((cyclopropylmethyl)sulfonyl)-[l,r-biplienyl]-4yl)propan-2-yl)carbamate

Using General Procedure H and the reaction inputs 2-(4'-((cyclopropylmethyl)sulfonyl)[l,l'-biphcnyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 238) and Intermediate 3, the title compound was prepared as a beige solid. ‘H NMR (400 MHz, DMSO-</₆) δ 8.00-7.87 (m, 4H), 7.70 (d, J = 8.1 Hz, 2H), 7.53 (br s, IH), 7.46 (d,./= 7.9 Hz, 2H), 4.65-4.56 (m, IH), 3.29 (d, J = 7.1 Hz, 2H), 3.01-2.41 (m, 6H), 1.99-1.31 (m, 13H), 0.94-0.80 (m, IH), 0.51-0.41 (m, 2H), 0.17-0.10 (m, 2H) ppm. ^I3C NMR (100 MHz, DMSO-i/e) Ô 154.2, 149.0, 144.9, 137.8, 135.9, 128.6, 127.1, 126.7, 125.6, 77.1,

59.3, 54.2, 47.7, 44.6, 40.1, 33.5, 30.6, 29.5, 24.7, 22.1, 4.6, 3.8 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.86 min; (M+H⁺) 497.

Example 242

Quinuclîdin-3-yl (2-(4'-((3-methoxypropyl)suIfonyl)-ll,r-biphenyl]-4-yl)propan-2yl)carbamate

Using General Procedure F and the reaction inputs ethyl 2-mcthyl-2-(4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)phcnyl)propanoatc and 1 -bromo-4-((3methoxypropy l)su 1 fony l)benzene, et hy I 2-(4'-((3-methoxypropy l)sulfonyl)-[ 1, Γbiphenyl]-4-yl)-2-methylpropanoate was prepared as a yellow oil. To a stirred solution of this compound (1.43 g, 3.54 mmol) in 1:1:1 (v/v/v) tetrahydrofuran/ethanol/watcr (20 mL) was added lithium hydroxide (0.302 g, 12.6 mmol). After stirring at 50 °C ovemight, the reaction was cooled and concentrated. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was treated with 1.0 N hydrochloric acid (20 mL) and extracted with ethyl acetate. The combined extracts were dried (N 328(+4) and concentrated to afford 2-(4'-((3-methoxypropyl)sulfonyl)-[l,r-biphenyl]-4-yl)-2methylpropanoic acid as a white solid (1.12g, 84%). This compound and quinudidin-3-ol were reacted according to General Procedure H to generate the title compound as a white solid. ‘H NMR (400 MHz, DMSO-î/ù) δ 8.01-7.85 (m, 4H), 7.77 (m, 5H), 4.50-4.36 (m, IH), 3.42-3.25 (m, 4H), 3.17 (s, 3H), 3.11-2.25 (m, 6H), 2.11-1.70 (m, 4H), 1.70-1.16 (m, 9H) ppm. ^I3C NMR (100 MHz, DMSO-J₆) δ 154.5, 148.9, 145.1, 137.4, 135.9, 128.3,

127.4, 126.8, 125.6, 69.9, 69.4, 57.8, 55.3, 54.2, 52.0, 46.9, 45.9, 29.3, 25.2, 24.1, 22.8, 19.1 ppm. Purity: LCMS 99.9%, 99.9% (210 & 254 nm) UPLCMS; rétention time: 0.81 min; (M+H⁴) 501.5.

Example 243 l-(3-Ethylquinuclidin-3-yi)-3-(2-(4'-((3-methoxypropyl)sulfonyl)-ll,l'-biphenyl]-4yl)propan-2-yi)urea

Using General Procedure H and the reaction inputs 2-methyl-2-(4^,-(melhylsulfonyl)-[l,rbiphcnyl]-4-yl)propanoic acid (prepared as described in Example 242) and Intermediate

264

2, the title compound was prepared as a white solid. ^lH NMR (400 MHz, DMSO-ifo) δ 8.07-7.81 (m, 4H), 7.68 (d, J= 8.5 Hz, 2H), 7.49 (d, J= 8.5 Hz, 2H), 6.27 (s, IH), 5.81 (s, IH), 3.43-3.24 (m, 4H), 3.17 (s, 3H), 2.83-2.54 (m, 6H), 1.92-1.74 (m, 5H), 1.71-1.47 (m, 8H), 1.42-1.24 (m, 2H), 0.76 (t, J= 7.3 Hz, 3H) ppm. ¹³C NMR (100 MHz, DMSOrf₆) Ô 156.7, 150.1, 145.1, 137.3, 135.6, 128.3, 127.3, 126.6, 125.6, 69,4, 62.6, 57.8, 53.8,

53.2, 52.1, 46.4, 46.2, 30.4, 29.8, 27.7, 27.7, 22.8, 22.4, 22.1, 8.0 ppm. Purity: 99.9%, 99.9% (210 & 254 nm) UPLCMS; rétention time: 0.83 min; (M+H⁴) 528.6.

Exampie 244

1-(2-(4'-((3-Methoxypropyl)sulfonyl)-[l,l’-biphenyl]-4-yl)propan-2-yl)-3-(3propylquinuclidin-3-yl)urea

Using General Procedure H and the réaction inputs 2-methyl-2-(4'-(methylsulfonyl)-[l,l'biphenyI]-4-yl)propanoic acid (prepared as described in Example 242) and Intermediate 17, the title compound was prepared as a white solid. ^lH NMR (400 MHz, DMSO-i/g) δ 8.12-7.86 (m, 4H), 7.66 (d, J= 8.1 Hz, 2H), 7,48 (d, J= 8.3 Hz, 2H), 6.53 (brs, IH), 6.33 (br s, IH), 3.40-3.27 (m, 4H), 3.17 (s, 3H), 3.10-2.66 (m, 6H), 2.03-1.90 (m, 2H), 1.901.36 (m, 13H), 1.32-1.13 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, DMSO-i/e) δ 156.9, 150.0, 145.2, 137.3, 135.6, 128.4, 127.3, 126.6, 125.6, 69.4, 60.6,

57.8, 53.9, 52.8, 52.0, 45.7, 45.4, 37.5, 30.8, 29.3, 27.4, 22.8, 20.6, 20.3, 16.5, 14.4 ppm. Purity: 99.9%, 99.9% (210 & 254 nm) UPLCMS; rétention time: 0.87 min; (M+H⁴)

542.6.

Exampie 245

Quiniiclidin-3-yl (2-(4'-((3,3-dimethylbutyl)sulfonyl)-[l,r-biphenyl]-4-yI)propan-2yl)carbamate

To a stirred solution of 4-bromothiophenol (6.36 g, 33.6 mmol) in N,Ndimethylformamide (70 mL) was added sodium hydride (60% dispersion in minerai oil; 1.48 g, 37.0 mmol). After 40 minutes, l-chloro-3,3-dimcthylbutanc (5.6 mL, 40.3 mmol) was added and the mixture was left stirring ovemight. The reaction was then concentrated and the residue was taken up in ethyl acetate. The solution was washed with water, dried (Na₂SO4) and concentrated. The crude product was purified by flash chromatography over silica using a hexane/ethyl acetate gradient to afford (4-bromophenyl)(3,3dimethylbutyl)sulfane as a colorless oil (8.71 g, 95%). To a stirred solution of this compound (8.69 g, 31.8 mmol) in méthylène chloride (130 mL), was added, portion wise over 20 minutes, 3-chloroperbcnzoic acid (77%; 14.97 g, 66.80 mmol). The resulting suspension was stirred at room température ovemight and then washed with aqueous 0.5 N sodium hydroxide solution. The organic layer was dried (Na₂SO4) and concentrated to afford l-bromo-4-((3,3-dimethylbutyl)sulfonyl)benzene, which was used without purification, as a white solid (9.82 g, 100%). This compound and ethyl 2-mcthyl-2-(4(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propanoate were reacted according to General Procedure F to generate ethyl 2-(4’-((3,3-dimethylbutyl)sulfonyl)-[l,l'biphenyl]-4-yl)-2-methylpropanoatc. To a stirred solution of this intermediate (2.17 g, 5.21 mmol) in 1:1:1 (v/v/v) tetrahydrofuran/ethanol/water (36 mL) was added lithium hydroxide monohydratc (1.09 g, 26.0 mmol). After stirring at room température ovemight, the reaction was heated at reflux for 2.5 hours, cooled and concentrated. The residue was dîssolved in water and washed with diethyi ether. The aqueous layer was treated with 1.0 N hydrochloric acid (30 mL) and extracted with ethyl acetate. The combined extracts were dried (Na₂SÛ4) and concentrated to afford 2-(4-((3,3

265 dimethylbutyl)sulfonyl)-[l,r-biphcnyl]-4-yl)-2-methylpropanoic acid as a white solid (1.94 g, 96%). This compound and quinuclidin-3-ol were reacted according to General Procedure H to generate the title compound as a white solid. *H NMR (400 MHz, DMSOde) δ 8.00 (m, 4H), 7.71 (d,./= 8.3 Hz, 2H), 7.63-7.39 (m, 3H), 4.46-4.39 (m, IH), 3.333.24 (m, 2H), 3.10-2.31 (m, 6H), 2.05-1.72 (m, 2H), 1.67-1.24 (m, 11H), 0.84 (s, 9H) ppm. ¹³C NMR (100 MHz, DMSO-de) δ 154.5, 149.0, 144.9, 137.6, 135.9, 128.3, 127.3,

126.8, 125.6, 70.0, 55.4, 54.2, 51.5, 46.9, 45.9, 35.3, 29.8, 29.3, 28.7, 25.3, 24.2, 19.2 ppm, Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 1.02 min; (M+H⁴) 513.

Example 246 l-(2-(4*-((3,3-DimethylbutyI)sulfonyl)-[l,r-biphcnyl]-4-yl)propan-2-yl)-3-(3methylquinuclidin-3-yl)urea

Using General Procedure H and the réaction inputs 2-(4’-((3,3-dimethylbutyl)sulfonyl)[l,r-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 245) and Intermediate 1, the title compound was prepared as a white solid. *H NMR (400 MHz, DMSO-de) 6 8.00-7.91 (m, 4H), 7.69 (d, J = 8.4 Hz, 2H), 7.48 (d, J= 8.4 Hz, 2H), 6.23 (s, IH), 5.81 (s, IH), 3.32-3.24 (m, 2H), 2.72-2.52 (m, 6H), 1.91-1.74 (m, 211), 1.43-1.44 (m, 9H), 1.43-1.22 (m, 5H), 0.84 (s, 9H) ppm. ¹³C NMR (100 MHz, DMSO-de) δ 156.9,

150.1, 145.0, 137.5, 135.6, 128.3, 127.2, 126.6, 125.6, 63.5, 53.9, 51.5, 50.7, 46.2, 46.0,

35.3, 30.4, 30.3, 29.9, 29.8, 28.7, 25.1, 22.9, 22.3 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 1.00 min; (M+H⁴) 526.

Example 247 l-(2-(4^,-((3,3-Dimethylbutyl)sulfonyl)-[l,l’-biphenyl]-4-yl)propan-2-yl)-3-(3ethylquinuclidin-3-yl)urea

Using General Procedure H and the réaction inputs 2-(4'-((3,3-dimcthylbutyl)sulfbnyl)[l,l'-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 245) and Intermediate 2, the title compound was prepared as a white solid. *H NMR (400 MHz, DMSO-de) δ 8.00-7.90 (m, 4H), 7.68 (d, J= 8.5 Hz, 2H), 7.48 (d, J= 8.5 Hz, 2H), 6.25 (s, IH), 5.78 (s, IH), 3.33-3.24 (m, 2H), 2.75-2.50 (m, 6H), 1.92-1.73 (m, 3H), 1.71-1.42 (m, 10H), 1.42-1.20 (m, 2H), 0.84 (s, 9H), 0.76 (t, J= 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, DMSO-de) δ 156.7, 150.1, 145.0, 137.5, 135.6, 128.3, 127.2, 126.6, 125.6, 62.8,

53.8, 53.2, 51.5, 46.4, 46.2, 35.3, 30.4, 29.8, 29.8, 28.7, 27.8, 27.7, 22.5, 22.2, 8.0 ppm. Purity: 100%, 98.6% (210 & 254 nm) UPLCMS; rétention time: 1.03 min; (M+H⁴) 540.

Example 248 l-(2-(4'-((3,3-Dimethylbutyl)suIfonyl)-[l,l '-biphenyl]-4-yl)propan-2-yl)-3-(4-metliyll-azabïcyclo[3.2.2]nonan-4-y))urea

Using General Procedure H and the réaction inputs 2-(4-((3,3-dimcthylbutyl)sulfonyl)[l,r-biphenyl]~4-yI)-2-methylpropanoic acid (prepared as described in Example 245) and Intermediate 5, the title compound was prepared as a white solid. ’H NMR (400 MHz, DMSO-de) δ 7.99-7.90 (m, 4H), 7.68 (d, J= 8.4 Hz, 2H), 7.49 (d, J= 8.4 Hz, 2H), 6.31 (s, IH), 5.79 (s, IH), 3.33-3.23 (m, 2H), 2.93-2.65 (m, 6H), 2.12-2.05 (m, IH), 1.85-1.35 (m, 13H), 1.34-1.19 (m, 4H), 0.85 (s, 9H) ppm. ^I3C NMR (100 MHz, DMSO-de) δ 156.8,

150.1, 145.0, 137.5, 135.6, 128.3, 127.4, 126.6, 125.7, 57.2, 53.8, 52.7, 51.5, 48.0, 45.0,

266

39.1, 36.2, 35.3, 30.4, 29.8, 29.7, 28.7, 26.2, 24.3, 23.8 ppm. Purity: 100%, 100% (210 &

254 nm) UPLCMS; rétention time: 1.01 min; (M+H¹) 540.

Example 249

Quinuclidin-3-yl (2-(4^,-(((l-(mcthoxymethyl)cyclopropyl)methyl)su!fonyl)-(l,l’biphenyl]-4-yl)propan-2-yl)carbamate

To a stirred and cooled (0 °C) solution of (1 -(methoxymethyl)cyclopropyl)methanol (3.65 g, 31.4 mmol) and triethylamine (5.5 mL, 39.5 mmol) in methylene chloride (100 mL) was added, dropwise, methanesulfonyl chloride (2.7 mL, 34.7 mmol). After 2 hours, the reaction solution was washed with an aqueous sodium bicarbonate solution. The organic layer was combined with methylene chloride back extracts of the aqueous layer, dried (NaiSCh) and concentrated. The crude (l-(mcthoxymethyl)cyclopropyl)mcthyl methanesulfonate, which was used without purification, was afforded as a pale amber oil (6.15 g, 100%). To a stirred solution of 4-bromothiophenol (4.98 g, 26.3 mmol) in N,Ndimethylformamide (60 mL) was added sodium hydride (60% dispersion in minerai oil; 1.21 g, 31.6 mmol). After 1 hour, a solution of the mesylate intermediate in N,Ndimcthylformamide (20 mL) was added and the mixture was stirred for 3 days at room température. The réaction was then concentrated and the residue was taken up in ethyl acetate, washed with water, dried (Na₂SO4) and concentrated. The resulting faint amber oil was purified by flash chromatography over silica using a hexane/ethyl acetate gradient to afford (4-bromophcnyl)((l-(methoxymethyl)cyclopropyl)methyl)sulfane as a colorless oil (6.98 g, 92%). To a stirred solution of this material (6.97 g, 24.3 mmol) in methylene chloride (100 mL) was added, portion wise, 3-chloropcrbenzoic acid (77%; 11.42 g, 50.96 mmol). The resulting suspension was stirred at room température ovemight and then washed with aqueous 0.5 N sodium hydroxide solution. The organic layer was dried (Na₂SOi) and concentrated to afford l-bromo-4-(((l(methoxymcthyl)cyclopropyl)mcthyl)sulfonyl)benzcne, which was used without purification, as a white solid (9.82 g, 100%). This compound and ethyl 2-methyl-2-(4(4,4,5,5-tetramethyl-I,3,2-dioxaborolan-2-yl)phenyl)propanoate were reacted according to General Procedure F to generate ethyl 2-(4’-(((l(methoxymethyl)cyclopropyl)methyl)sulfonyl)-[l,r-biphenyl]-4-yl)-2-methylpropanoate. To a stirred solution of this intermediate (3.54 g, 9.11 mmol) in 1:1:1 (v/v/v) tetrahydrofuran/ethanol/water (60 mL) was added lithium hydroxide monohydrate (1.34 g, 31.9 mmol). After heating at reflux ovemight, the reaction was cooled and concentrated. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was treated with 1.0 N hydrochloric acid (40 mL) and extracted with ethyl acetate. The combined extracts were dried (Na^SO.i) and concentrated to afford 2-(4-(((1(mcthoxymcthyl)cyclopropyl)mcthyl)sulfonyl)-[ 1,1 ’-biphcnyl]-4-yl)-2-methylpropanoic acid as a white solid (3.21 g, 88%). This compound and quinuclidin-3-ol were reacted according to General Procedure H to generate the title compound as an off-white solid. ’H NMR (400 MHz, DMSO-î/₆) δ 8.02-7.85 (m, 4H), 7.71 (d, J= 8.0 Hz, 2H), 7.65-7.38 (m, 3H), 4.50-4.36 (m, IH), 3.40 (s, 2H), 3.18 (s, 2H), 3.13 (s, 3H), 3.13-2.24 (m, 6H), 2.091.20 (m, 11H), 0.53-0.37 (m, 4H) ppm. ¹³C NMR (100 MHz, DMSO-</₆) δ 154.5, 149.0, 145.0, 138.7, 135.8, 128.4, 127.2, 126.8, 125.6, 75.3, 69.9, 58.8, 57.8, 55.3, 54.2, 46.9,

45.9, 29.3, 25.2, 24.1, 19.1, 15.8, 9.5 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.85 min; (M+H¹) 527.

Example 250

267 l-(3-Ethylquinuc)idin-3-yl)-3-(2-(4'-(((l(methoxymethyl)cyclopropyl)methyl)sulfonyl)-[l,r-biphcnyl|-4-yl)propan-2-yl)urea

Using General Procedure H and the réaction inputs 2-(4'-(((l(methoxymethyi)cyclopropyl)methyl)sulfonyl)-[ l, r-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 249) and Intermediate 2, the title compound was prepared as a white solid. ^!H NMR (400 MHz, DMSO-t/e) 8 7.98-7.90 (m, 4H), 7.68 (d, J = 8.4 Hz, 2H), 7.48 (d, ./ = 8.4 Hz, 2H), 6.25 (s, IH), 5.77 (s, IH), 3.39 (s, 2H), 3.18 (s, 2H), 3.13 (s, 3H), 2.73-2.47 (m, 6H), 1.92-1.72 (m, 3H), 1.71-1.46 (m, 8H), 1.41-1.20 (m, 2H), 0.76 (t, J = 7.2 Hz, 3H), 0.51-0.39 (m, 4H) ppm. ¹³C NMR (100 MHz, DMSO-^) δ

156.7, 150.1, 145.0, 138.7, 135.5, 128.4, 127.2, 126,6, 125.6, 75.3, 62.8, 58.9, 57.8, 53.8,

53.3, 46.5, 46.3, 30.4, 29.8, 27.8, 27.7, 22.6, 22.3, 15.8, 9.5, 8.0 ppm. Purity: 97.6%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.86 min; (M+H⁴) 554,

Exampie 251 l-(2-(4'-(((l-(Methoxymethyl)cyclopropyl)methyl)suIfonyl)-[l,l'-biplienyl]-4yl)propan-2-yl)-3-(3-propylquinuclïdin-3-yl)urea

Using General Procedure H and the reaction inputs 2-(4'-(((l(methoxymcthyl)cyclopropyl)methyl)sulfonyl)-[ 1, r-biphenyl]-4-yl)-2-methy!propanoic acid (prepared as described in Example 249) and Intermediate 17, the title compound was prepared as a white solid. ‘H NMR (400 MHz, DMSO-</₆) δ 7.98-7.89 (m, 4H), 7.66 (d, J = 8.4 Hz, 2H), 7.48 (d, J= 8.4 Hz, 2H), 6.24 (s, IH), 5.76 (s, IH), 3.39 (s, 2H), 3.17 (s, 2H), 3.13 (s, 3H), 2.74-2.46 (m, 6H), 1.90-1.83 (m, IH), 1.83-1.68 (m, 2H), 1.68-1.43 (m, 8H), 1.40-1.13 (m, 4H), 0.85 (t, J = 7.1 Hz, 3H), 0.52-0.38 (m, 4H) ppm. ^I3C NMR (100 MHz, DMSO-4) δ 156.8, 150.1, 145,1, 138.7, 135.6, 128.4, 127.2, 126.6, 125.6, 75.3,

63.1, 58.9,57.8, 53.8, 53.2,46.4,46.3, 37.8, 30.6,29.6,28.2,22.7, 22.3, 16.7, 15.8, 14.5,

9.5 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.90 min; (M+H⁺) 568.

Example 252

Quinuclidin-3-yl (2-(4'-(mcthylcarbamoy!)-il,l^,-biphenyl]-4-yl)propan-2yl)carbamate

To stirred solution of 4-bromobenzoic acid (6.00 g, 29.8 mmol) in methylene chloride (80 mL) was added 7V-(3-dimethylaminopropyl)-N^,-cthylcarbodiimide hydrochloride (6.30 g, 32.9 mmol), 4-(dimethylamino)pyridine (7.70 g, 63.0 mmol) and methylamine hydrochloride (2.23 g, 33.0 mmol). The mixture was stirred ovemight and then washed with 1.0 N hydrochloric acid, dried (Na₂SC>4) and concentrated. The crude material was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford 4-bromo-jV-mcthylbcnzamidc as a white solid (5.80 g, 90%). To a stirred solution of this compound (4.00 g, 18.9 mmol) in 1,4-dioxane (10 mL) was added bis(pinacolato)diboron (11.9 g, 46.8 mmol), potassium acetate (5.50 g, 56.1 mmol) and [1,1bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (0.410 g, 0.560 mmol). The mixture was heated at 90 °C ovemight, filtered and concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford 2V-methyI-4-(4,4,5,5-tetramcthyl-l,3,2-dioxaborolan-2~yl)benzamide as a white solid (4.50 g, 91%). This compound and ethyl 2-(4-bromopheny1)-2-methylpropanoate were reacted according to General Procedure F to generate ethyl 2-methyl-2-(4'(methylcarbamoyl)-[l,r-biphenyl]-4-yl)propanoatc as an off-white solid. To a stirred

268 solution of this intermediate (l.OO g, 3.07 mmol) in a mixture of tetrahydrofuran (4 mL), methanol (8 mL) and water (3 mL) was added solid sodium hydroxide (0.640 g, 16.0 mmol). After stirring at room température ovemight, the reaction was concentrated and taken up in water. The solution was made acidic (pH -6) with l N hydrochloric acid and extracted with ethyl acetate. The combined cxtracts were washed with brine, dried (Na₂SÜ4) and concentrated to afford 2-mcthyl-2-(4'-(mcthylcarbamoyl)-[l,r-biphcnyl]-4yl)propanoic acid as a white solid (0.950 g, 100%). This compound was used without purification and reacted with quinuclidin-3-ol according to General Procedure I to generate the title compound as an off-white solid. *H NMR (500 MHz, DMSO-<t),) δ 8.47 (q, J = 4.5 Hz, IH), 7.91 (d, J = 8.5 Hz, 2H), 7.74 (d, J= 6.5 Hz, 2H), 7.67-7.65 (d, J =

8.5 Hz, 2H), 7.60 (s, IH), 7.44 (d,./= 6.5 Hz, 2H), 4.43 (m, IH), 3.76 (m, IH), 2.81-2.63 (m, 7H), 2.47-2.36 (m, IH), 1.85 (m, 2H), 1.56-1.34 (m, 9H) ppm. ^I3C NMR (125 MHz, CD₃OD)ô 170.4, 156.9, 149.1, 145.3, 139.2, 134.1, 128.8, 127.9, 126.7,71.4, 56.1, 55.9, 48.0, 47.0, 30.0, 29.9, 27.0, 26.5, 24.6, 20.0 ppm. Purity: 100% (214 & 254 nm) LCMS; rétention time: 1.72 min; (M+H¹) 422.3.

Example 253 JV-Methyl-4*-(2-(3-(3-methylquinuclidin-3-yl)ureido)propan-2-yl)-[l,r-bipIieny]]-4carboxamide

Using General Procedure I and the reaction inputs 2-methyl-2-(4'-(methylcarbamoyl)[l,r-biphenyl]-4-yl)propanoic acid (prepared as described in Example 252) and Intermediate 1, the title compound was prepared. ’H NMR (500 MHz, DMSO-i/e) δ 8.47 (q,./= 4.5 Hz, IH), 7.90 (d, J= 9.0 Hz, 2H), 7.74 (d, J= 9.0 Hz, 2H), 7.64 (d, J= 8.0 Hz, 2H), 7.44 (d, J= 9.0 Hz, 2H), 6.20 (s, IH), 5.79 (s, IH), 2.80 (d, J= 4.5 Hz, 3H), 2.672.52 (m, 6H), 1.88-1.78 (m, 2H), 1.61-1.25 (m, 12H) ppm. ⁿC NMR (125 MHz, DMSOJfi) δ 166.3, 156.9, 149.2, 142.4, 136.5, 133.0, 127.7, 126.3, 126.2, 125.4, 63.5, 53.8,

50.7, 46.2, 46.1, 30.4, 29.9, 26.3, 25.1, 223.0, 22.3 ppm. Purity: >95% (214 & 254 nm) LCMS; rétention time: 1.32min; (M+H¹) 435.3.

Example 254 l-Azabicyclo[3.2.2]nonan-4-yl (2-(4'-(methyIcarbamoyl)-ll,r-biphenyI|-4-yl)propan2-yl)carbamate

Using General Procedure I and the reaction inputs 2-methyl-2-(4'-(methylcarbamoyl)[l,l'-biphenyl]-4-yl)propanoic acid (prepared as described in Example 252) and Intermediate 3, the title compound was prepared. *H NMR (500 MHz, CDCl₃) δ 7.837.81 (d, J= 8.5 Hz, 2H), 7.64-7.62 (d, 8.5 Hz, 2H), 7.58-7.56 (d, J ~ 8.0 Hz, 2H),

750-7.48 (d, J= 8.0 Hz, 2H), 6.22 (s, IH), 5.15 (s, IH), 4.78-4.77 (m, IH), 3.16-2.62 (m, 9H), 2.07-1.55 (m, 13H) ppm. ^I3CNMR(125 MHz, CDClj) Ô 168.0, 154.2, 147.0, 143.7,

138.2, 133.2, 127.4, 127.1, 127.0, 125.4, 78.1, 55.0, 51.6, 48.0, 46.3, 33.6, 30.4, 29.6,

26.9, 26.4, 24.6, 22.0 ppm. Purity: >97% (214 & 254 nm) LCMS; rétention time: 1.70 min; (M+H¹) 436.3.

Example 255 7V-Methyl-4’-(2-(3-(4-methyI-l-aza-bicyclo[3.2.2]nonan-4-yl)ureido)propan-2yl)biphenyI-4-carboxamide

Using General Procedure I and the réaction inputs 2-methyl-2-(4^,-(mcthylcarbamoyl)[l,l'-biphenyl]-4-yl)propanoic acid (prepared as described in Example 252) and

269

Intermediate 5, the title compound was prepared. *H NMR (500 MHz, DMSO <4,) δ 8.488.47 (q, J= 4.5 Hz, IH), 7.91-7.90 (d, J= 8.5 Hz, 2H), 7.75- 7.73 (d, J= 8.5 Hz, 2H), 7.64-7.62 (d, ./=8.5 Hz, 2H), 7.46-7.44 (d, J= 9.0 Hz, 2H), 6.26 (s, IH), 5.75 (s, IH), 2.87-2.69 (m, 9H), 2.07 (m, IH), 1.79-1.25 (m, 15H) ppm. ^I3C NMR (125 MHz, CDCh) Ô 168.0, 156.8, 146.3, 143.2, 139.2, 133.5, 127.7, 127.3, 127.1, 126.2, 58.7, 54.6, 52.6,

48.3, 45.2, 39.5, 36.5, 31.2, 29.6, 26.9, 26.1,24.3, 23.8 ppm. Purity: 96.8%, 95.1% (214 nm & 254 nm) UPLCMS; rétention time: 1.17 min; (M+H⁺) 449.3.

Example 256 N-(2-(4'-(Metliylcarbamoyl)bÎphenyl-4-yl)propan-2-yl)-l,4diazabicyclo[3.2.2]nonanc-4-carboxamide

Using General Procedure I and the réaction inputs 2-mcthyl-2-(4'-(mcthylcarbamoyl)[l,l'-biphenyl]-4-yl)propanoic acid (prepared as described in Example 252) and Intermediate 6, the title compound was prepared. ’H NMR (500 MHz, CDCIj) δ 7.817.80 (d, J = 8.5 Hz, 2H),7.63-7.62 (d, J = 8.0 Hz, 2H), 7.58-7.55 (d, J = 8.0 Hz, 2H), 7.48-7.46 (d, ./=8.5 Hz, 2H), 6.28-6.27 (q, J= 5.0 Hz, IH), 4.78 (s, IH), 4.02 (m, IH), 3.63 (t, J= 5.5 Hz, 2H), 3.14-3.08 (m, 2H), 3.03-2.98 (m, 7H), 2.07-2.01 (m, 2H), 1.801.70 (m, 8H) ppm. ^,3C NMR (125 MHz, CDCI3) δ 168.1, 155.6, 148.1, 143.9, 137.9,

133.1, 127.3, 127.1, 127.0, 125.3, 57.6, 55.3, 48.1, 46.2, 41.3, 30.2, 27.4, 26.9 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.13 min; (M+H⁺) 421.1.

Example 257

Quinuclidîn-3-yl 2-(4'-(dimethylcarbamoyl)biphenyl-4-yl)propan-2-ylcarbamate

Exchanging methylamine hydrochloride for dimcthylamine hydrochloride, the reaction sequence outlined in Example 252 was used to préparé 2-(4'-(dimethylcarbamoyl)-[l,rbiphenyl]-4-yl)-2-mcthylpropanoic acid. This intermediate and quinuclidin-3-ol were reacted according to General Procedure I to generate the title compound. *H NMR (500 MHz, DMSO-ί/ΰ) δ 7.70 (d, J = 7.0 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.59 (s, IH), 7.48 (d, J= 8.0 Hz, 2H), 7.44 (d, J= 7.0 Hz, 2H), 4.42 (m, IH), 3.00-2.96 (m, 7H), 2.72-2.55 (m, 3H), 2.46-1.98 (m, 2H), 1.84-1.75 (m, 2H), 1.56-1.24 (m, 9H) ppm. ^I3C NMR (125 MHz, CDCI3) δ 171.5,154.5, 146.6, 142.0, 138.6, 135.0, 127.7, 127.1, 126.9, 125.4, 71.0,

55.5, 55.1, 47.3, 46.4, 39.7, 35.4, 29.3, 25.3, 24.5, 19.4 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.79 min; (M+H⁴) 436.3.

Example 258 7V,/V-Dimethyl-4’-(2-(3-(3-metliylquiniiclÎdin-3-yl)ureido)propan-2-y])biplienyl-4carboxamide

Using General Procedure I and the reaction inputs 2-(4'-(dimethylcarbamoyl)-[l,rbiphenyI]-4-yl)-2-methylpropanoic acid (prepared as described in Example 257) and Intermediate 1, the title compound was prepared. ’H NMR (500 MHz, CDCI3) Ô 7.60-

7.59 (m, 6H), 7.50-7.49 (d, J= 8.5 Hz, 2H), 4.88 (br s, IH), 4.33 (br s, IH), 3.14 (s, 3H), 3.04 (s, 3H), 2.73-2.66 (m, 5H), 2.17 (m, IH), 1.92-1.64 (m, 8H), 1.45-1.22 (m, 6H) ppm. ^,3C NMR (125 MHz, CDC1₃) δ 171.6, 157.1, 146.7, 141.9, 138.9, 135.0, 127.6, 127.4, 127.0, 125.9, 63.5, 54.5, 52.0, 46.5, 46.2, 39.7, 35.5, 30.6, 30.3, 25.0, 23.0, 22.2 ppm. Purity: >98% (214 & 254 nm) LCMS; rétention time: 1.38 min; (M+H¹) 449.3.

Example 259

270 l-Azabicyclo[3.2.2]nonan-4-yl 2-(4'-(dimethylcarbamoyl)biphenyl-4-yl)propan-2ylcarbamate

Using General Procedure 1 and the reaction inputs 2-(4'-(dimethylcarbamoyl)-[l,rbiphenyl]-4-yl)-2-methyIpropanoic acid (prepared as described in Example 257) and Intermediate 3, the title compound was prepared. 'H NMR (500 MHz, CDCI3) δ 7.61-

7.59 (d, J= 8.0 Hz, 2H), 7.56-7.54 (d, J= 8.0 Hz, 2H), 7.49-7.47 (m, 4H), 5.20 (s, IH), 4.78-4.77 (m, IH), 3.13-2.72 (m, I2H), 2.28 (m, IH), 2.05-1.18 (m, 12H) ppm. ¹³C NMR (125 MHz, CDClj) δ 171.5, 154.3, 146.8, 142.1, 138.5, 135.0, 127.7, 127.1, 126.8, 125.4,

78.1, 55.0, 51.7, 48.3, 45.0, 39.6, 35.4, 33.7, 31.0, 30.7, 29.7, 24.9, 22.3 ppm. Purity: 100% (214 & 254 nm) UPLC; rétention time: 1.39 min; (M+H⁴) 450.3.

Example 260 7V-(2-(4'-(DiniethyIcarbamoyl)biphenyl-4-yI)propan-2-yl)-l,4diazabicyclo|3.2.2]nonane-4-carboxainide

Using General Procedure I and the reaction inputs 2-(4’-(dimcthylcarbamoyl)-[l,rbiphenyl]-4-yl)-2-mcthylpropanoic acid (prepared as described in Example 257) and Intermediate 6, the title compound was prepared. *H NMR (500 MHz, CDCI3) δ 7.61-

7.60 (d, J= 8.5 Hz, 2H), 7.56-7.55 (d, J= 8.5 Hz, 2H), 7.48-7.46 (m, 4H), 4.78 (s, IH), 4.04 (m, IH), 3.64 (t, J= 6.0 Hz, 2H), 3.15-2.99 (m, 12H), 2.08-2.03 (m, 2H), 1.81-1.73 (m, 8H) ppm. ^,3C NMR (125 MHz, CDCI3) Ô 171.6, 155.6, 147.9, 142.2, 138.1, 134.8,

127.6.127.1, 126.9, 125.3, 57.6,55.3, 48.0, 46.2,41.3, 39.7, 35.4, 30.2, 27.4 ppm. Purity: 100% (214 & 254 nm) UPLC; rétention time; 1.35 min; (M+H⁴) 435.4.

Example 261 7V,/V-Dimethyl-4'-(2-(3-(4-methyi-l-azabicyclo(3.2.2]nonan-4-yl)ureido)propan-2yl)biphenyl-4-carboxamide

Using General Procedure 1 and the reaction inputs 2-(4'-(dimethylcarbamoyl)-[l,Tbiphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 257) and Intermediate 5, the title compound was prepared. *H NMR (400 MHz, CDCI3) δ 7.627.58 (m, 6H), 7.51-7.49 (d, J= 8.4 Hz , 2H), 4.74 (s, IH), 4.07 (s, IH), 3.14 (s, 3H), 3.05 (s, 3H), 2.91-2.70 (m, 4H), 2.51-2.28 (m, 2H), 2.17-2.17 (m, IH), 1.84-1.50 (m, 10H), 1.47-1.15 (m, 5H)ppm. ¹³CNMR(100 MHz,CDCl₃)Ô 171.5, 157.0, 146.4, 141.8, 139.2,

135.2, 127.7, 127.5, 127.0, 126.1, 58.6, 54.5, 52.7, 48.2, 45.2, 39.7, 39.5, 36.5, 35.4, 31.1,

29.8, 26.1, 24.3, 23.8 ppm. Purity: >95% (214 & 254 nm) LCMS; rétention time: 1.35 min; (M+H⁴) 463.3.

Example 262

Quinuclidin-3-yl 2-(4'-(piperidine-l-carbonyl)biphenyl-4-yl)propan-2-ylcarbamate

Exchanging methylamine hydrochloride for piperidine, the reaction sequence outlined in Example 252 was used to préparé 2-methyl-2-(4'-(piperidine- l-carbonyl)-[l,Γ-biphcnyl]4-yl)propanoic acid. This intermediate and quinuclidin-3-ol were reacted according to General Procedure I to generate the title compound. ^]H NMR (500 MHz, CDCI3) δ 7.527.51 (d, J= 7.5 Hz, 2H), 7.48-7.47 (d, J= 8.0 Hz, 2H), 7.42-7.37 (m, 4H), 5.26 (s, IH), 4.55 (m, IH), 3.65 (m, 2H), 3.33 (m, 2H), 3.09-2.33 (m, 6H), 2.19-1.77 (m, 2H), 1.631.32 (m, 15H) ppm. ^l3C NMR (125 MHz, CDCI3) δ 170.2, 154.6, 146.6, 141.9, 138.6,

135.1, 127.4,127.1, 126.9, 125.4, 71.0, 55.6, 55.0, 48.9, 47.4, 46.4, 43.2, 29.7, 26.6,25.6,

271

25.4, 24.6, 19.5 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: l.l I min; (M+H⁴) 476.3.

Exampie 263 l-Azabicyclo[3.2.2]nonan-4-yl 2-(4'-(piperidine-l-carbonyI)biphenyl-4-yI)propan-2ylcarbamate

Using General Procedure 1 and the reaction inputs 2-methyl-2-(4'-(piperidine-l-carbonyl)[l,l'-biphenyl]-4-yl)propanoic acid (prepared as described in Example 262) and Intermediate 3, the title compound was prepared. ^JH NMR (500 MHz, CDC13) δ 7.607.58 (d, J= 8.0 Hz, 2H), 7.56-7.54 (d, J= 8.0 Hz, 2H), 7.49-7.45 (m, 4H), 5.20 (s, IH), 4.78 (m, IH), 3.73 (m, 2H), 3.41 (m, 2H), 3.10-2.49 (m, 7H), 2.05-1.36 (m, 18H) ppm. ¹³C NMR (125 MHz, CDC13) δ 170.2, 154.2, 146.7, 141.9, 138.6, 135.1, 127.4, 127.1, 127.0, 125.4, 78.2, 55.0, 51.6, 48.9, 48.2, 44.9, 43.2, 33.6, 30.6, 29.6, 26.6, 25.7, 24.6, 22.1 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.34 min; (M+H⁴) 490.2.

Exampie 264 l-(3-Ethylquinuclidin-3-yl)-3-(2-(4'-(piperidine-l-carbonyl)biplienyl-4-yl)propan-2yl)urea

Using General Procedure I and the reaction inputs 2-methyl-2-(4'-(pîperidine-l-carbonyl)[l,r-biphcnyl]-4-yl)propanoic acid (prepared as described in Exampie 262) and Intermediate 2, the title compound was prepared. *H NMR (500 MHz, CDCI3) Ô 7.507.45 (m, 6H), 7.38-7.37 (d, J = 7.5 Hz, 2H), 5.12 (s, IH), 4.26 (s, IH), 3.66-4.34 (m, 4H), 2.61-2.37 (m, 6H), 1.88-1.10 (m, 19H), 0.59 (t, J = 7.5 Hz, 3H) ppm. ^l3C NMR (125 MHz, CDCI3) δ 167.2, 155.7, 145.4, 140.7, 138.1,134.2, 126.5, 126.4,126.0, 125.0, 62.1,

53.8, 53.4, 45.6, 29.7, 29.2, 27.1, 27.0, 23.6, 21.8, 21.4, 7.0 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.13 min; (M+H⁴) 503.4.

Example 265

Quinuclîdin-3-yl 2-(4^,-(morpholine-4-carbonyl)biphenyl-4-yl)propan-2-ylcarbamate

Exchangïng methylamine hydrochloride for morpholine, the réaction sequence outlined in Example 252 was used to préparé 2-methyl-2-(4’-(morpholine-4-carbonyl)-[l,rbiphenyl]-4-yl)propanoic acid. This intermediate and quinuclidin-3-ol were reacted according to General Procedure I to generate the title compound. *H NMR (500 MHz, CDCI3) δ 7.62-7.60 (d, ./= 7.5 Hz, 2H), 7.56-7.54 (d, 8.5 Hz, 2H), 7.50-7.46 (m, 4H),

5.29 (s, IH), 4.63 (m, IH), 3.73-3.54 (m, 8H), 3.17-2.53 (m, 6H), 2.28-2.17 (m, 2H), 1.98-1.40 (m, 9H) ppm. ^I3CNMR(125 MHz, CDCl₃)ô 170.3, 154.5,146.7,142.4, 138.4,

133.9, 127.7, 127.1, 125.4, 71.0, 66.9, 55.5, 55.0, 48.4, 47.3, 46.2, 42.7, 29.4, 25.3, 24.5,

19.5 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.21 min; (M+H⁴) 478.3.

Example 266 l-Azabicyclo[3.2.2]nonan-4-yl 2-(4'-(tnorpholinc^l-carbonyl)biplienyI-4-yl)propan2-ylcarbamate

Using General Procedure I and the réaction inputs 2-mcthyl-2-(4'-(morpholine-4carbonyl)-[l,l'-biphenyl]-4-yl)propanoic acid (prepared as described in Exampie 265) and Intermediate 3, the title compound was prepared. *H NMR (500 MHz, CDCI3) δ 7.627.61 (d, J= 8.0 Hz, 2H), 7.55-7.54 (d, 8.0 Hz, 2H), 7.49-7.47 (m, 4H), 5.20 (s, IH),

272

4.78-4.77 (m, IH), 3.76-3.54 (m, 8H), 3.09-2.72 (m, 6H), 2.27-1.53 (m, 13H) ppm. ^l3C NMR (125 MHz, CDCh) δ 170.3, 154.3, 146.9, 142.5, 138.4, 133.9, 127.7, 127.1, 126.9,

125.4, 78.3, 66.9, 55.0, 51.7, 48.2, 44.9, 42.5, 33.7, 30.6, 29.5, 28.7, 24.8, 22.2 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.22 min; (M+H⁺) 492.3.

Exampie 267 l-(3-Metliylquinuclidin-3-yl)-3-(2-(4’-(niorpholine-4-carbonyl)biphenyl-4-yl)propan2-yl)urea

Using General Procedure I and the reaction inputs 2-methyl-2-(4'-(morpholine-4carbonyl)-[l,r-biphcnyl]-4-yl)propanoic acid (prepared as described in Example 265) and Intermediate 1, the title compound was prepared. *H NMR (500 MHz, CDCh) δ 7.617.53 (m, 6H), 7.48-7.47 (d, J = 7.5 Hz, 2H), 5.14 (s, 1 H), 4.42 (s, 1 H), 3.77-3.53 (m, 8H), 2.73-2.43 (m, 6H), 1.86 (m, IH), 1.64-1.63 (m, 7H), 1.38-1.18 (m, 6H) ppm. ¹³C NMR (125 MHz, CDCh) δ 171.5, 157.0, 146.4, 141.8, 139.2, 135.2, 127.7, 127.0, 126.1, 125.1,

58.6, 54.5, 52.7, 48.2, 45.2, 39.7, 39.5, 36.5, 35.4, 31.1, 29.8, 26.1, 24.3, 23.8 ppm. Purity: 100% (214 & 254 nm) LCMS; rétention time: 1.32 min; (M+H*) 491.3.

Example 268 l-(4-Methyl-l-azabicyclo[3.2.2]nonan-4-yl)-3-(2-(4'-(morpholme-4carbonyl)biphenyl-4-yI)propan-2-yI)urea

Using General Procedure I and the reaction inputs 2-methyl-2-(4'-(morpholine-4carbonyl)-[l,l'-biphenyl]-4-yl)propanoic acid (prepared as described in Example 265) and Intermediate 5, the title compound was prepared. *11 NMR (500 MHz, CDCh) δ 7.64-

7.60 (m, 6H), 7.49-7.48 (d, J= 8.5 Hz, 2H), 4.76 (s, IH), 4.07 (s, IH), 3.75-3.54 (m, 8H), 2.89-2.70 (m, 4H), 2.47-2.18 (m, 3H), 1.70-1.63 (m, 8H), 1.54-1.15 (m, 7H) ppm. ^I3C NMR (125 MHz, CDCh) δ 170.2, 156.9, 146.2, 142.0, 139.3, 134.2, 127.8, 127.6, 127.2,

126.2, 66.9, 58.7, 54.6, 52.5, 48.3, 45.0, 39.3, 36.4, 31.4, 29.5, 26.1, 24.0, 23.7 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.34 min; (M+H⁺) 505.2.

Example 269 A^f-(2-(4'-(Morpholine-4-carbonyl)biphenyl-4-y))propan-2-yl)-l,4diazabicycio[3.2.21nonane-4-carboxamide

Using General Procedure I and the reaction inputs 2-methyl-2-(4'-(morpholinc-4carbonyl)-[l,l'-biphenyl]-4-yl)propanoic acid (prepared as described in Example 265) and Intermediate 5, the title compound was prepared. *H NMR (500 MHz, CDCh) ô 7.62-

7.61 (d, 8.0 Hz, 2H), 7.55-7.54 (d, J = 8.5 Hz, 2H), 7.48-7.46 (m, 4H), 4.77 (s, IH),

4.04 (m, IH), 3.74-3.48 (m, 10H), 3.15-3.09 (m, 2H), 3.04-2.99 (m, 4H), 2.17-3.03 (m, 2H), 1.78-1.63 (m, 8H) ppm. ¹³C NMR (125 MHz, CDCh) δ 170.4, 155.5, 148.0, 142.7,

137.9, 133.7, 127,7, 127.1, 127.1, 125.3, 66.9, 57.6, 55.3, 48.0, 46.2, 41.3, 30.2, 27.4 ppm. Purity: >96% (214 & 254 nm) LCMS; rétention time: 1.34 min; (M+H⁴) 477.3.

Exampie 270

Quinuclidin-3-yl 2-(4’-(4,4-difluoropiperidine-l-carbonyl)biphenyl-4-yl)propan-2ylcarbamatc

Exchanging methylamine hydrochloride for 4,4-difluoropiperidine, the reaction sequence outlined in Example 252 was used to préparé 2-(4^,-(4,4-difluoropiperidine-l-carbonyl)17263

273 [l,r-biphenyl]-4-yl)-2-mcthylpropanoic acid. This intermediate and quinuclidin-3-ol were reacted according to General Procedure I to generate the title compound. *H NMR (500 MHz, CDCh) δ 7.63-7.61 (d,./ = 8.5 Hz, 2H), 7.57-7.55 (d, J = 8.5 Hz, 2H), 7.517.47 (m, 4H), 5.21 (s, IH), 4.63 (m, IH), 3.86-3.65 (m, 4H), 3.17-2.67 (m, 5H), 2.17-2.00 (m, 6H), 1.84-1.36 (m, 10H) ppm. ¹³C NMR (125 MHz, CDCh) δ 170.5, 154.5, 146.8,

142.7, 138.4, 133.8, 127.5, 127.2, 127.1, 125.4, 121.6 (t, J = 241 Hz), 71.0, 55.6, 55.1,

47.4, 46.3, 34.4, 29.5, 25.4, 24.5, 19.5 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.47 min; (M+H¹) 512.2.

Example 271 l-Azabicyclo[3.2.2]nonan-4-yl 2-(4'-(4,4-diÎluoropiperidinc-l-carbonyl)biphenyl-4yl)propan-2-ylcarbamate

Using General Procedure I and the reaction inputs 2-(4'-(4,4-difluoropiperidine-lcarbonyl)-[l,T-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 270) and Intermediate 3, the title compound was prepared. *H NMR (500 MHz, CDCh) ô 7.63-7.61 (d, J = 8.0 Hz, 2H), 7.56-7.54 (d, J = 8.5 Hz, 2H), 7.50-7.47 (m, 4H), 5.19 (s, IH), 4.79-4.77 (m, IH), 3.84-3.66 (m, 4H), 3.09-2.72 (m, 6H), 2.41-2.32 (m, IH), 2.17-1.54 (m, 16H) ppm. ¹³C NMR (125 MHz, CDCh) δ 170., 154.2, 146.9, 142.7, 138.3,

133.8, 127.5, 127.2, 127.1, 125.4,121.5 (1,./=241 Hz), 78.2,55.0,51.7, 48.2, 45.0,39.4,

34.2, 33.7, 30.6, 29.6, 24.8, 22.2 ppm. Purity: >97% (214 & 254 nm) LCMS; rétention time: 1.14 min; (M+H¹) 526.3.

Examnle 272 l-(2-(4'-(4,4-Dinuoropiperidinc-l-carbonyl)biphenyI-4-yl)propan-2-yl)-3-(3“ ethylquinuclidin-3-yl)urea

Using General Procedure 1 and the reaction inputs 2-(4'-(4,4-difluoropiperidine-lcarbonyl)-[l,r-biphcnyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 270) and Intermediate 2, the title compound was prepared. *H NMR (500 MHz, CDCh) δ 7.62-7.57 (m, 6H), 7.49 (d, J= 8.0 Hz, 2H), 5.06 (s, IH), 4.15 (s,lH), 3.88-3.42 (m, 4H), 2.71-2.39 (m, 6H), 2.04-1.57 (m, 14H), 1.37-1.15 (m, 3H), 0.66 (t, J= 7.0 Hz, 3H) ppm. ¹³C NMR (125 MHz, CDC1₃) δ 170.5, 156.6, 146.3, 142.4, 139.1, 134.1, 127.6,

127.5, 127.2, 126.1, 121.5 (t, 7 = 241 Hz), 63,1, 54.9, 54.5, 46.6, 30.8, 30.1, 28.0, 28.0,

22.7, 22.3, 7.9 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.13 min; (M+H*) 539.3.

Example 273

Quinuclidin-3-yl 2-(4^,-(3,3-difIuoroazetidine-l-carbonyl)biphenyl-4-yl)propan-2ylcarbamate

Exchanging methylamine hydrochloride for 3,3-difluoroazetidinc hydrochloride, the reaction sequence outlined in Example 252 was used to prépare 2-(4'-(3,3difluoroazetidine-l-carbonyl)-[l,r-biphenyl]-4-yl)-2-methylpropanoic acid. This intermediate and quînuclidin-3-ol were reacted according to General Procedure 1 to generate the title compound. 'H NMR (500 MHz, CDCh) δ 7.72-7.71 (d, 7 = 8.0 Hz, 2H), 7.66-7.64 (d, J= 8.0 Hz, 2H), 7.59-7.51 (m, 4H), 5.21 (s, IH), 4.64-4.56 (m, 5H), 3.19-

2.27 (m, 6H), 2.12-1.99 (m, 3H), 1.86-1.41 (m, 8H) ppm. ^l3C NMR (125 MHz, CDC1₃) ô 170.6 (t, 7=3.0 Hz), 154.5, 147.9, 147.2, 144.2, 138.1, 130.6, 128.5, 127.2, 125.5, 115.4

274 (t, J= 272 Hz), 71.0, 55.6, 55.0, 47.3, 46.4, 29.6, 29.5, 25.4, 24.5, 19.5 ppm. Purity: >98% (214 & 254 nm) LCMS; rétention time: 1.29 min; (M+H*) 484.2.

Exampie 274 l-Aza-bicyclo[3.2.2]nonan-4-yl 2-(4'-(3,3-difluoroazcticIine-l-carboiiyl)biphenyl-4yl)propan-2-ylcarbamate

Using General Procedure 1 and the reaction inputs 2-(4-(3,3-difiuoroazetidîne-lcarbonyl)-[l,r-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 273) and Intermediate 3, the title compound was prepared. 'H NMR (500 MHz, CDCh) δ 7.73-7.71 (d, J = 8.5 Hz, 2H), 7.66-7.65 (d, 8.0 Hz, 2H), 7.59-7.57 (d, J =

8.0 Hz, 2H), 7.52-7.50 (d, J= 8.0 Hz, 2H), 5.14 (s, IH), 4.82-4.78 (m, IH), 4.59 (t, J = 12.0 Hz, 4H), 3.13-2.76 (m, 6H), 2.08-1.55 (m, 13H) ppm. ^I3C NMR (125 MHz, CDClj) Ô 170.6, 154.2, 147.2, 144.3, 138.0, 130.6, 128.5, 127.1, 125.5, 115.4 (t, J = 340 Hz),

78.1, 55.0, 51.6, 48.1, 44.9, 33.6, 30.4, 29.6, 24.6, 22.0 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.46 min; (M+H*) 498.3.

Example 275 l-(2-(4’-(3,3-Dînuoroazeti(line-l-carbonyl)biphenyl-4-yl)propan-2-yl)-3-(3ethylquinuclidin-3-yi)urea

Using General Procedure I and the reaction inputs 2-(4^,-(3,3-difluoroazctidine-lcarbonyi)-[l,r-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 273) and Intermediate 2, the title compound was prepared. *H NMR (500 MHz, CDC1₃) δ 7.73-7.61 (m, 8H), 4.89 (s, IH), 4.58 (t, J= 12.0 Hz, 4H), 4.04 (s, IH), 2.712.18 (m, 6H), 1.97-1.20 (m, 13H), 0.66 (t, J = 7.5 Hz, 3H) ppm. ^l3C NMR (125 MHz, CDClj) δ 170.6 (t, J= 3.0 Hz), 156.4, 146.4, 143.9, 138.9, 130.9, 128.6, 127.7, 127.2,

126.2, 115.3 (t, J= 272 Hz), 62.9, 55.0, 54.5, 50.6, 46.5, 30.7, 28.0, 28.0, 22.6, 22.6, 7.9 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.46 min; (M+H*) 511.3.

Example 276 l-(4-Methyl-l-azabicycio[3.2.2]nonan-4-yl)-3-(2-(3-(3-(morpholme-4carbonyî)phenoxy)phenyl)propan-2-yl)urea

To stirred solution of 3-hydroxybenzoic acid (8.28 g, 59.9 mmol) in N,Ndimethylfonnamide (150 mL) was added 7V-(3-dimcthylammopropyl)-JVethylcarbodiimide hydrochloride (6.30 g, 32.9 mmol), N,N-diisopropylethylamine (17.0 g, 132 mmol), 1-hydroxybenzotriazole hydrate (8.80 g, 66.0 mmol) and morpholine (5.75 g, 66,0 mmol). The mixture was stirred ovemight and thon diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried (NaîSO^) and concentrated. The crude material was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford (3hydroxyphenyl)(morpholino)mcthanonc as a white solid (5.80 g, 47%). To a stirred solution of this compound (5.00 g, 24.1 mmol) in 7V,A/-dimethylformamide (100 mL) was added ethyl 2-(3-bromophcnyl)-2-mcthylpropanoate (8.00 g, 31.1 mmol), césium carbonate (15.7 g, 48.2 mmol), copper(l) iodide (1.40 g, 7.35 mmol) and 2(dimethylamino)acetic acid hydrochloride (2.10 g, 14.5 mmol). The mixture was heated at 120 °C ovemight. After cooling, the réaction was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na₂SO₄) and concentrated. The crude material was purified by flash chromatography over silica using

275 a hexane/ethyl acetate cluant to afford ethyl 2-mcthyl*2-(3-(3-(niorpholine-4carbonyl)phcnoxy)phenyl)propanoatc as a viscous, colorless oil (4.40 g, 46%). To a stirred solution of this intermediate (4.40 g, 11.5 mmol) in l:l (v/v) mcthanol/water (40 mL) was added solid sodium hydroxide (2.30 g, 57.5 mmol). After stirring for 6 hours, the reaction was concentrated and taken up in water. The solution was made acidic (pH ~6) with l N hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with brine, dried (NaiSOj and concentrated to afford 2-methyl-2-(3-(3(morpholine-4-carbonyl)phcnoxy)phenyi)propanoic acid as a white solid (3.60 g, 85%). This compound was used without purification and reacted with Intermediate 5 according to General Procedure I to generate the title compound as an off-white solid. ’H NMR (500 MHz, CDCl₃) δ 7.39-7.34 (m, 2H), 7.29-7.23 (m, 2H), 7.13-7.12 (d, J = 7.5 Hz, IH), 7.06-7.022 (m, 2H), 6.92-6.90 (m, IH), 4.78 (s, IH), 4.17 (s, IH), 3.76-3.47 (m, 8H), 2.94-2.44 (m, 6H), 2.18 (m, IH), 1.71-1.48 (m, 10H), 1.36-1.21 (m, 5H) ppm. ¹³C NMR (125 MHz, CDCh) Ô 169.5, 157.3, 157.0, 156.7, 149.4, 137.0, 130.3, 130.1, 121.7, 120.7,

119.8, 117.6, 117.3, 116.7, 66.8, 58.7, 54.7, 52.8, 48.2, 45.3, 42.6, 39.5, 36.5, 31.0, 29.7, 26.0, 24.4, 23.9 ppm. Purity: >97% (214 & 254 nm) LCMS; rétention time: 1.78 min; (M+H⁺) 521.3,

Example 277 l-(3-Methylquinuclidin-3-yl)-3-(2-(3-(3-(morpholine-4carbonyl)phenoxy)phenyl)propan-2-yl)urea

Using General Procedure 1 and the reaction inputs 2-mcthyl-2-(3-(3-(morpholine-4carbonyl)phenoxy)phenyl)propanoic acid (prepared as described in Example 276) and Intermediate 1, the title compound was prepared. *H NMR (500 MHz, CDCh) δ 7.397.34 (m, 2H), 7.28-7.27 (m, 2H), 7.13-7.12 (d, J= 7.5 Hz, IH), 7.06-7.02 (m, 2H), 6.926.91 (m, IH), 4.73 (s, IH), 4.14 (s, IH), 3.77-3.46 (m, 8H), 2.75-2.49 (m, 6H), 1.95-1.60 (m, 8H), 1.42-1.26 (m, 6H) ppm. ¹³C NMR (125 MHz, CDCI3) δ 169.6, 157.4, 156.9,

156.7, 149.4, 137.0, 130.2, 130.2, 121.6, 120.7, 119.7, 117.7, 117.2, 116.7, 66.8, 63.6,

54.7, 52.2, 46.5, 46.3, 30.7, 30.5, 30.1, 24.9, 23.1, 22.4 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.76 min; (M+H¹) 507.3.

Example 278 l-Aza-bicyclo[3.2.2]nonan-4-yl 2-(3-(3-(morpholine-4carbonyI)phenoxy)phenyI)propan-2-ylcarbamate

Using General Procedure I and the reaction inputs 2-methyl-2-(3-(3-(morpholine-4carbonyl)phenoxy)phenyl)propanoic acid (prepared as described in Exemple 276) and Intermediate 3, the title compound was prepared. ^lH NMR (500 MHz, CDCI3) δ 7.35-

7.28 (m, 2H), 7.19-7.04 (m, 5H), 6.87-6.87 (m, IH), 5.10 (s, JH), 4.77 (m, IH), 3.76-3.45 (m, 8H), 3.09-2.46 (m, 6H), 2.18-1.31 (m, 13H) ppm. ¹³C NMR (125 MHz, CDCI3) Ô

169.6, 157.7, 156.3, 154.1, 149.7, 137.0, 130.0, 129.7, 121.4, 120.4, 119.5, 117.3, 117.0,

116.4, 78.0, 66.8, 55.0, 51.5, 48.0, 44.9, 42.5, 33.4, 30.3, 30.2, 29.3, 29.4,24.6, 21.9 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.40 min; (M+H⁺) 508.3.

Example 279

Quinuclidin-3-yl 2-(3-(3-(morpholine-4-carbonyl)phenoxy)plienyl)propan-2ylcarbamate

276

Using General Procedure I and the réaction inputs 2-methyl-2-(3-(3-(morpholine-4carbonyl)phenoxy)phcnyl)propanoic acid (prepared as described in Example 276) and quinuclidin-3-ol, the title compound was prepared. ‘H NMR (500 MHz, CDCI3) Ô 7.37-

7.28 (m, 2H), 7.20-7.03 (m, 5H), 6.86-6.85 (d, .7 = 8.0 Hz, IH), 5.19 (s, IH), 4.61 (m, IH), 3.75-3.16 (m, 8H), 2.83-2.37 (m, 6H), 1.95-1.12 (m, I1H) ppm. ^,3C NMR (125 MHz, CDCI3) δ 169.6, 157.6, 156.3, 154.4, 149.7, 137.0, 130.1, 129.7, 121.431, 120.4,

119.5, 117.2, 117.0, 116.3, 70.9, 66.8, 55.5, 55.0,48.1, 47.2, 46.4, 42.5, 30.5, 29.5, 29.3,

25.3, 24.5, 19.5 ppm. Purity: >97% (214 & 254 nm) LCMS; rétention time: 1.39 min; (M+H*) 494.2.

Example 280 l-(3-MetliyIquinuclidin-3-yl)-3-(2-(4-(4-(morpholine-4ca r bo ny l)p henoxy)p heny l)p ro p a n -2-y l)u rea

Exchanging ethyl 2-(3-bromophenyl)-2-methylpropanoate for ethyl 2-(4-bromophenyl)-2methylpropanoate and 3-hydroxybenzoic acid for 4-hydroxybcnzoic acid, the reaction sequence outlined in Example 276 was used to préparé 2-mcthyl-2-(4-(4-(morpholine-4carbonyl)phenoxy)phenyl)propanoic acid. This intermediate and quinuclidin-3-ol were reacted according to General Procedure 1 to generate the title compound. ^!H NMR (500 MHz, CDCI3) δ 7.51-7.49 (d, .7= 9.0 Hz, 2H), 7.42-7.40 (d, .7= 9.0 Hz, 2H), 7.05-7.00 (m, 4H), 4.82 (s, IH), 4.21 (s, IH), 3.72-3.48 (m, 8H), 2.78-2.51 (m, 6H), 1.86-1.89 (m, IH), 1.72-1.65 (m, IH), 1.64-1.62 (d, J= 8.0 Hz, 6H), 1.49-1.40 (m, 2H), 1.37 (s, 3H), 1.31-1.25 (m, lH)ppm. ¹³CNMR(125 MHz, CDCI3) δ 170.0, 158.7, 156.9, 155.2, 142.4,

129.8, 129.2,127.0, 119.5, 118.2, 66.8,63.4, 54.4, 52.1, 46.5, 46.2, 30.7, 30.4, 24.9,22.9, 22.2 ppm. Purity: >100% LCMS (214 & 254 nm) LCMS; rétention time: 1.73 min; (M+H*) 507.3.

Example 281 l-(4-Methyl-l-azabicycIo(3.2.2]nonan-4-yl)-3-(2-(4-(4-(morpholine-4carbonyl)phenoxy)phenyl)propan-2-yl)urea

Using General Procedure I and the reaction inputs 2-methyl-2-(4-(4-(morpholine-4carbonyl)phenoxy)phenyl)propanoic acid (prepared as described in Example 280) and Intermediate 5, the title compound was prepared. ’H NMR (500 MHz, CDCI3) δ 7.527.51 (d, J= 8.0 Hz, 2H), 7.42-7.41 (d, J= 7.5 Hz, 2H), 7.04-7.01 (m, 4H), 4.90 (s, IH),

4.29 (s, IH), 3.72-3.57 (m, 8H), 2.97-2.56 (m, 6H), 2.23 (m, IH), 1.75-1.55 (m, 10H), 1.42-1.24 (m, 5H) ppm. ^I3C NMR (125 MHz, CDC1₃) δ 170.0, 158.7, 156.951, 155.2,

142.7, 129.8, 129.2, 127.0, 119.4, 118.3, 66.8, 58.4, 54.4, 52.8, 48.4, 45.2, 39.0, 36.3, 31.0, 30.0, 26.1, 24.0, 23.5 ppm. Purity: >98% (214 & 254 nm) LCMS; rétention time: 1.72 min; (M+H*) 521.3.

Example 282 l-Azabicyclo[3.2.2]nonan-4-yl 2-(4-(4-(morpholine-4carbonyl)phenoxy)phenyl)propan-2-ylcarbamate

Using General Procedure I and the reaction inputs 2-methyl-2-(4-(4-(morpholine-4carbonyl)phcnoxy)phenyl)propanoic acid (prepared as described in Example 280) and

Intermediate 3, the title compound was prepared. *H NMR (500 MHz, CDCI3) δ 7.427.38 (m, 4H), 7.03-6.98 (m, 4H), 5.15 (s, IH), 4.83 (m, IH), 3.72-3.49 (m, 8H), 3.12-2.97 (m, 6H), 2.24-1.68 (m, 13H) ppm. ¹³C NMR (125 MHz, CDCI3) δ 170.3, 158.8, 154.9,

277

153.7, 142.5, 129.7, 129.2, 126.4, 119.1, 118.2, 66.9, 55.0, 51.0, 47.3, 45.3, 32.5, 30.6,

29.4, 28.7, 22.9, 20.0 ppm. Purity: >98% (214 & 254 nm) LCMS; rétention time: 1.72 min; (M+H) 508.3.

Exampie 283

Quinuclidin-3-yl 2-(4-(4-(dimethylcarbamoyl)phenoxy)phenyl)propan-2yicarbamate

Exchanging ethyl 2-(3-bromophenyl)-2-methylpropanoate for ethyl 2-(4-bromophenyl)-2mcthylpropanoate, 3-hydroxybenzoic acid for 4-hydroxybenzoic acid, and morpholine for dimcthylaminc hydrochloride, the reaction sequence outlined in Exampie 276 was used to préparé 2-(4-(4-(dimcthylcarbamoyl)phenoxy)phcnyl)-2-methyipropanoic acid. This intermediate and quinuclidin-3-ol were reacted according to General Procedure I to generate the title compound. 'H NMR (500 MHz, CDCh) δ 7.42-7.37 (m, 4H), 6.99-6.96 (m, 4H), 5.24 (s, IH), 4.65-4.62 (m, IH), 3.17-3.02 (m, 7H), 2.88-2.61 (m, 5H), 1.99-1.39 (m, llH)ppm. ^I3C NMR (125 MHz, CDCh) δ 171.2, 158.5, 154.9, 154.5, 142.6, 130.8,

129.1, 126.3, 119.1, 117.9, 70.8, 55.5, 54.9, 47.3, 46.3, 39.7, 35.5, 29.6, 25.3, 24.4, 19.4 ppm. Purity: >97% (214 & 254 nm) LCMS; rétention time: 1.89 min; (M+H) 452.3.

Exampie 284 /V,A-Dimethyl-4-(4-(2-(3-(3-methylquinuclidin-3-yI)ureido)propan-2yl)phenoxy)benzamide

Using General Procedure 1 and the réaction inputs 2-(4-(4(dimethylcarbamoyl)phenoxy)phcnyl)-2-methylpropanoic acid (prepared as described in Exampie 283) and Intermediate 1, the title compound was prepared. *H NMR (500 MHz, CDCh) δ 7.48 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 8.5 Hz, 2H), 7.02-6.99 (m, 4H), 5.00 (s, IH), 4.48 (s, IH), 3.11-3.04 (m, 6H), 2.78-2.62 (m, 6H), 1.72 (m, IH), 1.72-1.68 (m, IH), 1.62-1.60 (m, 6H), 1.49-1.46 (m, 2H), 1.38 (s, 3H), 1.32-1.25 (m, IH) ppm. ^I3C NMR (125 MHz, CDCh) δ 171.2, 158.4, 157.0, 155.3, 142.4, 130.9, 129.1, 127.0, 119.4, 118.1,

63.1, 54.4, 52.0, 46.5, 46.2, 39.8, 35.5, 30.6, 30.6, 30.4, 24.9, 22.8, 22.1 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.22 min; (M+H) 465.2.

Example 285 AyV-Dimethyl-4-(4-(2-(3-(4-methyl-l-azabicyclo[3.2.2|nonan-4-yl)ureido)propan-2yl)phenoxy)benzamide

Using General Procedure I and the reaction inputs 2-(4-(4(dimcthylcarbamoyl)phcnoxy)phcnyl)-2-mcthylpropanoic acid (prepared as described in Example 283) and Intermediate 5, the title compound was prepared. *H NMR (500 MHz, CDCh) δ 7.43-7.41 (d, J = 8.5 Hz, 2H), 7.38-7.36 (d, J = 8.5 Hz, 2H), 6.97-6.94 (m, 4H), 5.35 (s, IH), 4.79 (s, IH), 3.07-2.68 (m, 12H), 2.21 (m, IH), 1.68-1.28 (m, 15H)ppm. ¹³C NMR (125 MHz, CDCI3) δ 171.2, 158.5, 157.1, 155.1, 143.0, 130.7, 129.03 126.9, 119.243, 118.078, 58.253, 54.305, 52.771, 48.292, 45.203, 39.738, 38.770, 36.243, 35.5,

30.8, 30.2, 26.1, 23.9, 23.3 ppm. Purity: >96% LCMS (214 & 254 nm) LCMS; rétention time: 1.23 min; (M+H) 479.3.

Example 286 l-Azabicyclo[3.2.2]nonan-4-yl 2-(4-(4-(dimethylcarbamoyl)phenoxy)phenyl)propan2-ylcarbamate

278

Using General Procedure I and the reaction inputs 2-(4-(4(dimethyIcarbamoyl)phenoxy)phenyl)-2-methylpropanoic acid (prepared as described in Example 283) and Intermediate 3, the title compound was prepared. *H NMR (500 MHz, CDCl₃) δ 7.43-7.38 (m, 4H), 7.02-6.98 (m, 4H), 5.08 (s, IH), 4.82-4.78 (m, IH), 3.112.75 (m, 12H), 2.09-1.55 (m, 13H) ppm. ⁿC NMR (125 MHz, CDCh) δ 171.2, 158.5, 154.9, 154.1, 142.7, 130.8, 129.1, 126.4, 119.0, 118.1, 77.9, 54.8, 51.6, 48.1, 45.0, 39.7,

35.5, 33.5, 30.3, 29.6, 24.5, 21.9 ppm. Purity: >98% (214 & 254 nm) LCMS; rétention time: 1.73 min; (M+H⁴) 466.3.

Example 287 Quinucll(iin-3-yl 2-(4-(4-(dimethylcarbamoyl)plienoxy)phenyl)propan-2ylcarbamate

Exchanging morpholine for dimcthylamine hydrochloride, the réaction sequence outlincd in Example 276 was used to préparé 2-(3-(3-(dimethylcarbamoyl)phcnoxy)phenyl)-2mcthylpropanoic acid. This intermediate and quinuclidin-3-ol were reacted according to General Procedure 1 to generate the title compound. ^lH NMR (500 MHz, CDCh) δ 7.34 (t, J= 8.0 Hz, IH), 7.21 (t, J= 8.0 Hz, IH), 7.18-7.17 (d, J= 8.5 Hz, IH), 7.13-7.10 (m, 2H), 7.04-7.00 (m, 2H), 6.86 (m, IH), 5.20 (s, IH), 4.62 (m, IH), 3.16-2.33 (m, 12H), 1.96-1.36 (m, 11H) ppm. ¹³C NMR (125 MHz, CDCh) Ô 170.8, 157.4, 156.6, 154.4,

149.6, 138.0, 129.9, 130.0, 121.5, 120.2, 119.4, 117.2, 117.1, 116.2, 71.0, 55.5, 55.1, 47.3, 46.4, 39.5, 35.3, 29.5, 25.3, 24.5, 19.5 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.82 min; (M+H⁴) 452.3.

Example 288

1-Aza-bicyclo[3.2.2] nonan-4-yl 2-(3-(3(dimethylcarbamoyl)phenoxy)phenyl)propan-2-ylcarbamate

Using General Procedure 1 and the réaction inputs 2-(3-(3(dimethylcarbamoyl)phenoxy)phenyl)-2-methylpropanoic acid (prepared as described in Example 287) and Intermediate 3, the title compound was prepared. *H NMR (500 MHz, CDCh) δ 7.34-7.28 (m, 2H), 7.18-7.10 (m, 3H), 7.04-7.02 (m, 2H), 6.87-6.85 (m, IH), 5.11 (s, IH), 4.78-4.75 (m, IH), 3.09-2.63 (m, 12H), 2.03-1.18 (m, 13H) ppm. ^I3C NMR (125 MHz, CDCh) δ 170.8, 157.4, 156.5, 154.106, 149.7, 138.0, 129.8, 129.7, 124.8,

121.5, 120.2, 119.3, 117.2, 116.2, 78.1, 55.0, 51.6, 48.1, 45.0, 39.5, 35.3, 33.5, 30.4, 30.2,

29.5, 29.4, 24.6, 21.9 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time; 1.39 min; (M+H⁴) 466.3.

Example 289 /V,7V-Dimethyl-3-(3-(2-(3-(3-methylqiiinuclidïn-3-yl)ureïdo)piOpaii-2yl)phenoxy)benzamide

Using General Procedure 1 and the reaction inputs 2-(3-(3(dimethylcarbamoyl)phenoxy)phenyl)-2-methylpropanoic acid (prepared as described in

Example 287) and Intermediate 1, the title compound was prepared. *H NMR (500 MHz,

CDCh) δ 7.38-7.33 (m, 2H), 7.28-7.21 (m, 2H), 7.15-7.13 (d, J= 7.5 Hz, IH), 7.04-7.03 (m, 2H), 6.93-6.91 (m, IH), 4.82 (br s, IH), 4.30 (br s, IH), 3.10 (s, 3H), 2.99 (s, 3II),

2.72-2.47 (m, 6H), 1.83-1.60 (m, 8H), 1.46-1.23 (m, 6H) ppm. ^I3C NMR (125 MHz,

CDCh) Ô 170.8, 157.2, 157.0, 156.8, 149.5, 138.0, 130.2, 130.0, 121.6, 120.6, 119.6,

279

H7.6, 117.1, 116.5, 63.4, 54.7, 52.1, 46.5, 46.3, 39.5, 35.3, 30.7, 30.5, 30.0, 24.9, 23.0,

22.2 ppm. Purity: >97% (214 & 254 nm) LCMS; rétention time: 1.83 min; (M+H⁴) 465.4.

Example 290 JV^V-Dimethyl-4-(4-(2-(3-(4-methy)-l-aza-bicyclo[3.2.2]nonan-4-yl)ureido)propan-2yl)phenoxy)benzamide

Using General Procedure I and the réaction inputs 2-(3-(3(dimethylcarbamoyl)phcnoxy)phenyl)-2-mcthylpropanoîc acid (prepared as described in Example 287) and Intermediate 5, the title compound was prepared. *H NMR (500 MHz, CDCb) δ 7.37-7.31 (m, 2H), 7.28-7.25 (m, IH), 7.21 (t,./= 2.0 Hz, IH), 7.14-7.12 (d, J = 7.5 Hz, IH), 7.04-7.01 (m, 2H), 6.91-6.89 (m, IH), 4.91 (s, IH), 4.32 (s, IH), 3.08 (s, 3H), 2.98 (s, 3H), 2.90-2.74 (m, 4H), 2.59-2.44 (m, 2H), 2.18-2.17 (m, IH), 1.69-1.21 (m, 15H) ppm. ^I3C NMR (125 MHz, CDCb) Ô 170.8, 157.1, 157.1, 156.8, 149.5, 138.0,

130.2, 130.0, 121.7, 120.6, 119.6, 117.5, 117.2, 116.5, 58.6, 54.7, 52.8, 48.1,45.3, 39.5,

39.4, 36.4, 35.3, 30.8, 29.8, 26.0,24.3, 23.8 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.77 min; (M+H⁺) 479.4.

Example 291

Quinuclidin-3-yl 2-(4-(4-(mcthylcarbamoyl)phenoxy)phenyl)propan-2-ylcarbamate

Exchanging ethyl 2-(3-bromophcnyl)-2-methylpropanoatc for ethyl 2-(4-bromophenyl)-2methylpropanoate, 3-hydroxybenzoic acid for 4-hydroxybenzoic acid, and morpholine for methylamine hydrochloride, the réaction sequence outlined in Example 276 was used to préparé 2-methyl-2-(4-(4-(methylcarbamoyl)phcnoxy)phenyl)propanoic acid. This intermediate and quinuclidin-3-ol were reacted according to General Procedure I to generate the title compound. *H NMR (500 MHz, CDCb) δ 7.74 (d, J = 9.0 Hz, 2H), 7.42 (d, J = 9.0 Hz, 2H), 7.02-6.99 (m, 4H), 6.15 (s, 1 H), 5.13 (s, IH), 4.67-4.64 (m, IH), 3.19-2.70 (m, 9H), 1.97-1.38 (m, HH) ppm. ¹³C NMR (125 MHz, CDCb) δ 167.6, 160.2,

154.6, 154.4, 142.8, 129.1, 128.8, 126.4, 119.3, 117.8, 71.0, 55.5, 54.9, 47.2, 46.3, 30.9,

29.6, 26.8, 25.3, 24.4, 19.5 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.75 min; (M+H⁴) 438.3.

Example 292 l-Aza-bicyclo[3.2.2]nonan-4-yl 2-(4-(4-(methylcarbamoyl)phcnoxy)pheny])propan2-ylcarbamate

Using General Procedure 1 and the reaction inputs 2-methyl-2-(4-(4(mcthylcarbamoyl)phenoxy)phcnyl)propanoic acid (prepared as described in Example 291) and Intermediate 3, the title compound was prepared. ’H NMR (500 MHz, CDCb) δ 7.75-7.73 (d, J= 8.5 Hz, 2H), 7.41-7.40 (d, J= 8.5 Hz, 2H), 7.00-6.98 (m, 4H), 6.17 (brs, IH), 5.09 (s, IH), 4.81-4.77 (m, IH), 3.11-2.73 (m, 9H), 2.10-1.521(m, 13H) ppm. ^l3C NMR (125 MHz, CDCb) δ 167.6, 160.2, 154.5, 143.0, 129.1, 128.7, 126.4, 119.3, 117,8,

78.2, 54.8, 51.7, 48.2, 45.0, 33.6, 30.6, 29.7, 26.8, 24.8, 22.2 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.19 min; (M+l) 452.2.

Example 293 /V-Methyl-4-(4-(2-(3-(3-methyIquinuclidin-3-yl)ureido)propan-2yl)phenoxy)benzamide

280

Using General Procedure I and the reaction inputs 2-methyl-2-(4-(4(mcthylcarbamoyl)phenoxy)phcnyl)propanoic acid (prepared as described in Example 291) and Intermediate 1, the title compound was prepared. *H NMR (500 MHz, CDCI₃) δ 7.77-7.75 (d, J= 8.5 Hz, 2H), 7.53-7.51 (d, ./= 8.5 Hz, 2H), 7.06-7.00 (m, 4H), 6.15 (br s, IH), 4.73 (br s, IH), 4.12 (br s, IH), 3.03-3.02 (d, J = 5.0 Hz, 3H), 2.79-2.52 (m, 6H), 1.86-1.64 (m, 8H), 1.49-1.22 (m, 6H) ppm. ^l3C NMR (125 MHz, CDC1₃) δ 167.5, 159.9,

156.8, 155.3, 142.1, 129.4, 128.8, 127.2, 119.7, 118.0, 63.6, 54.5, 52.2, 46.5, 46.3, 30.8,

30.7, 30.3, 26.9, 24.9, 23.0, 22.3 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.18 min; (M+l ) 451.2.

Example 294 7V-Methyl-4-(4-(2-(3-(4-methyl-l-aza-bicyclo[3.2.2]nonan-4-yl)ureido)propan-2yl)phenoxy)benzamide

Using General Procedure I and the reaction inputs 2-methyl-2-(4-(4(mcthylcarbamoyl)phcnoxy)phenyl)propanoic acid (prepared as described in Example 291) and Intermediate 5, the title compound was prepared. *H NMR (500 MHz, CDCl₃) δ 7.77-7.75 (d, J = 8.0 Hz, 2H), 7.55-7.53 (d, J = 9.0 Hz, 2H), 7.07-7.05 (d, J = 8.5 Hz, 2H), 7.03-7.01 (d, J= 9.0 Hz, 2H), 6.17 (m, IH), 4.67 (s, IH), 4,03 (s, IH), 3.03-3.02 (d, J=4.5 Hz, 3H), 2.95-2.83 (m, 4H), 2.58-2.38 (m, 2H), 2.19 (m, IH), 1.75-1.51 (m, 10H), 1.42-1.19 (m, 5H) ppm. ¹³CNMR(125 MHz, CDC1₃) Ô 167.5, 159.8,156.8, 155.5, 142.0,

129.5, 128.8, 127.2, 119.7,118.1,58.7, 54.4, 52.8, 48.2, 45.4, 39.5, 36.5,31.3,29.8, 26.9, 26.0, 24.3, 23.8 ppm. Purity: >96% (214 & 254 nm) LCMS; rétention time: 1.19 min; (M+l) 465.2.

Example 295 2-(3-(3-(Methylcarbamoyl)phenoxy)phenyI)propan-2-yicarbamate

Exchanging morpholinc for methylamine hydrochloride, the reaction sequence outlined in Example 276 was used to préparé 2-methyl-2-(3-(3(methylcarbamoyl)phenoxy)phenyl)propanoic acid. This intermediate and quinuclidin-3ol were reacted according to General Procedure I to generate the title compound. *H NMR (500 MHz, DMSCU) δ 8.47 (s, IH), 7.60-7.59 (d, J = 7.5 Hz, IH), 7.52 (s, IH), 7.47.7.44 (m, 2H), 7.33 (t, J = 7.5 Hz, IH), 7.15-7.09 (m, 2H), 6.98-6.83 (m, 2H), 440 (m, IH), 2.98-2.37 (m, 9H), 1.76-1.24 (m, 11H) ppm. ^,3C NMR (125 MHz, CDC1₃) δ

167.9, 157.8, 156.2, 154.6, 149.1, 136.6, 129.9, 121.8, 121.2, 120.6, 117.7, 116.4, 115.7,

115.5, 71.0, 55.3, 47.2, 46.4, 29.7, 26.8, 25.3, 24.4, 19.4 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.20 min; (M+H⁺) 438.2.

Example 296 A'-Methyl-3-(3-(2-(3-(3-methyiquinucIidin-3-yl)ureido)propan-2yl)phenoxy)benzamide

Using General Procedure I and the reaction inputs 2-methyl-2-(3-(3(methylcarbamoyl)phenoxy)phenyl)propanoic acid (prepared as described in Example

295) and Intermediate l, the title compound was prepared. *H NMR (500 MHz, CDC1₃) ô

7.60-7.59 (d, J= 8.0 Hz, IH), 7.42 (t,./= 8.0 Hz, IH), 7.36 (t, J= 8.0 Hz, JH), 7.26-7.13 (m, 5H), 6.90-6.88 (d, ./= 7.5 Hz, IH), 4.78 (br s, IH), 4.23 (br s, IH), 2.95-2.94 (d, J =

4.5 Hz, 3H), 2.69-2.32 (m, 6H), 1.95 (m, 2H), 1.64 (s, 3H), 1.60 (s, 3H), 1.45-1.41 (m,

2H), 1.33 (s, 3H), 1.24-1.18 (m, IH) ppm. ^l3C NMR (125 MHz, CDCI₃) δ 167.8, 157.2,

281

156.9, 156.9, 149.4, 136.7, 130.2, 130.0, 122.4, 121.8, 120.9, 117.4, 116.6, 116.2, 63.7,

54.8, 52.0, 46.7, 46.1, 30.8, 30.3, 29.8, 26.9, 24.7, 22.9, 22.2 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.79 min; (M+H*) 451.3.

Example 297 JV-Methyl-3-(3-(2-(3-(4-methyl-l-aza-bicyclo[3.2.2]nonan-4-yl)ureido)propan-2yl)phenoxy)benzamide

Using General Procedure I and the reaction inputs 2-methyl-2-(3-(3(mcthylcarbamoyl)phcnoxy)phenyl)propanoic acid (prepared as described in Example 295) and Intermediate 5, the title compound was prepared. *H NMR (500 MHz, CDCI3) δ 7.69-7.67 (m, 2H), 7.44 (t, J= 8.0 Hz, IH), 7.37-7.33 (m, 2H), 7.24-7.21 (m, 3H), 6.906.88 (dd, 8.0 & 2.0 Hz, IH), 4.82 (s, IH), 4.31 (s, IH), 2.91-2.81 (m, 7H), 2.48-2.18 (m, 2H), 1.76-1.49 (m, 9H), 1.37-1.22 (m, 7H) ppm. ¹³C NMR (125 MHz, CDCia) δ

167.7, 157.2, 156.9, 156.6, 149.3, 136.5, 130.3, 130.2, 122.9, 122.0, 120.5, 117.0, 117.0,

115.7, 58.4, 54.8, 52.8, 49.0, 44.7, 39.3, 36.4, 32.1, 28.7, 27.0, 26.4, 24.5, 23.8 ppm. Purity: >98% (214 & 254 nm) LCMS; rétention time: 1.74 min; (M+H⁺) 465.4.

Example 298 l-Aza-bicyclol3.2.2]nonan-4-yl 2-(3-(3-(methylcarbamoyl)phenoxy)phenyl)propan2-ylcarbamate

Using General Procedure I and the reaction inputs 2-methyl-2-(3-(3(methylcarbamoyl)phcnoxy)phenyl)propanoic acid (prepared as described in Ex ample 295) and Intermediate 3, the title compound was prepared. *H NMR (500 MHz, CDCI3) δ 7.55-7.54 (m, IH), 7.41-7.35 (m, 2H), 7.19-6.78 (m, 6H), 5.10 (s, IH), 4.65 (m, IH), 3.04-2.70 (m, 9H), 1.96-1.43 (m, 13H) ppm. ¹³C NMR (125 MHz, CDC1₃) Ô 167.7, 158.0, 156.0, 154.3, 149.1, 136.4, 129.9, 121.7, 121.1, 120.7, 117.8, 116.8, 115.2, 78.2, 55.2,

51.5, 47.9, 44.9, 33.4, 30.4, 29.8, 29.7, 26.8, 24.6, 21.9 ppm. Purity: >97% (214 & 254 nm) LCMS; rétention time: 1.77 min; (M+H⁴) 452.3.

Example 299 l-Aza-bicyclo|3.2.2|nonan-4-yl 2-(4-(4-(piperidine-l-carbonyl)phenoxy)phenyl) propan-2-ylcarbamate

Exchanging ethyl 2-(3-bromophenyl)-2-methylpropanoate for ethyl 2-(4-bromophcnyl)-2methylpropanoate, 3-hydroxybenzoic acid for 4-hydroxybcnzoic acid, and morpholine for piperidine, the reaction sequence outlined in Example 276 was used to préparé 2-methyl2-(4-(4-(pipcridinc-l-carbonyl)phcnoxy)phcnyl)propanoic acid. This compound and Intermediate 3 were reacted according to General Procedure I to generate the title compound. ‘il NMR (500 MHz, CDCI3) δ 7.39-7.37 (m, 4H), 7.00-6.97 (m, 4H), 5.11 (s, IH), 4.80-4.76 (m, IH), 3.70-3.41 (m, 4H), 3.09-2.72 (m, 6H), 2.16 (m, IH), 2.04-1.55 (m, 18H) ppm. ^Î3C NMR (125 MHz, CDCI3) δ 169.9, 158.4, 154.9, 154.2, 142.7, 131.0,

128.8, 126.4, 119.0, 118.1, 78.4, 54.8, 51.7, 49.0, 48.1, 45.0, 43.3, 33.6, 30.6, 29.6, 26.3,

25.9, 24.8, 24.6, 22.1 ppm. Purity: >96% (214 & 254 nm) LCMS; rétention time: 1.49 min; (M+H') 506.3.

Example 300 l-(4-Methyl-l-aza-bicyclo[3.2.2]nonan-4-yl)-3-(2-(4-(4-(pjperidine-lcarbonyl)phenoxy)phenyl)propan-2-yl)urea

282

Using General Procedure I and the reaction inputs 2-methyl-2-(4-(4-(piperidine-lcarbonyl)phenoxy)phcnyl)propanoic acid (prepared as described in Example 299) and Intermediate 5, the title compound was prepared. *H NMR (500 MHz, CDCI3) δ 7.487.47 (d, J- 8.5 Hz, 2H), 7.39-7.37 (d, V = 8.0 Hz, 2H) 7.02-6.99 (m, 4H), 4.94 (s, IH),

4.29 (s, IH), 3.69-3.39 (m, 4H), 2.93-2.43 (m, 6H), 2.17 (m, IH), 1.70-1.35 (m, 21H) ppm. ^,3C NMR (125 MHz, CDCI3) δ 169.9, 158.2, 156.9, 155.6, 142.2, 131.2, 128.8, 127.0, 119.3, 118.3, 58.6, 54.4, 52.8, 48.9, 48.2, 45.4, 43.0, 39.4, 36.5, 31.0, 30.0, 26.2, 26.0, 24.5, 24.3, 23.8 ppm. Purity: >97% (214 & 254 nm) LCMS; rétention time: 1.34 min; (M+H⁴) 519.3.

Example 301 l-Azabicyclo[3.2.2]nonan-4-yl 2-(4-(4-(4,4-difluoropiperidine-lca rbo nyl)p henoxy)phenyl)pr op a n-2-ylca rba m a te

Exchanging ethyl 2-(3-bromophenyl)-2-methylpropanoate for ethyl 2-(4-bromophcnyl)-2methylpropanoate, 3-hydroxybenzoic acid for 4-hydroxybenzoic acid, and morpholine for 4,4-difluoropiperidinc, the reaction sequence outlined in Example 276 was used to préparé 2-(4-(4-(4,4-difluoropiperidine-1 -carbonyl)phenoxy)phenyl)-2-methylpropanoic acid. This compound and Intermediate 3 were reacted according to General Procedure I to generate the title compound. 'H NMR (500 MHz, CDC1₃) δ 7.40-7.38 (m, 4H), 7.02-6.91 (m, 4H), 5.19 (s, IH), 4.80-4.78 (m, IH), 3.84-3.73 (m, 4H), 3.22-2.75 (m, 6H), 2.17-1.47 (m, 17H) ppm. ’³C NMR (125 MHz, CDCI3) δ 170.2, 159.1, 154.6, 153.9, 142.8, 129.5, 129.0, 126.4, 121.5 (t, J= 241 Hz), 119.2, 118.1, 78.0, 54.9, 51.2, 47.7, 45.1, 34.4, 33.0,

29.5, 23.7, 20.9 ppm. Purity: >98% (214 & 254 nm) LCMS; rétention time: 1.92 min; (M+H⁴) 542.4.

Example 302

1-(2-(4-(4-(4,4-Dîfluoropiperidine-l-carbony])phenoxy)phenyl)propan-2-yl)-3-(4methvl-I-azabicyclo[3.2.2|nonan-4-yl)urea

Using General Procedure I and the reaction inputs 2-(4-(4-(4,4-difluoropiperidine-lcarbonyl)phenoxy)phenyl)-2-methylpropanoic acid (prepared as described in Example 301) and Intermediate 5, the title compound was prepared. *H NMR (500 MHz, CDCh) δ 7.49-7.47 (d, J= 8.5 Hz, 2H), 7.40-7.38 (d, J= 8.5 Hz, 2H), 7.01-6.99 (m, 4H), 5.09 (s, IH), 4.44 (s, IH), 3.82-3.71 (m, 4H), 2.95-2.52 (m, 6H), 2.20-1.97 (m, 5H), 1.74-1.23 (m, 15H) ppm. ^I3C NMR (125 MHz, CDCI3) δ 170.2, 158.9, 156.9, 155.2, 142.6, 129.7, 129.0, 127.1, 121.4 (t, J= 241 Hz), 119.5, 118.3,58.5, 54.4, 52.8, 48.3,45.2, 39.1,36.4,

34.2, 31.0, 30.0, 26.1, 24.1, 23.6 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.84 min; (M+H⁴) 555.4.

Example 303 l-(2-(4-(4-(33-Difluoroazetidine-l-carbonyl)phenoxy)phenyl)propan-2-yl)-3-(4methyl-I-aza-bicyclo[3.2.2]nonan-4-yl)urea

Exchanging ethyl 2-(3-bromophenyl)-2-mcthylpropanoate for ethyl 2-(4-bromophcnyl)-2methylpropanoatc, 3-hydroxybenzoic acid for 4-hydroxybenzoic acid, and morpholinc for

3,3-difluoroazetidinc hydrochloride, the réaction sequence outlined in Example 276 was used to préparé 2-(4-(4-(3,3-difluoroazetidine-1 -carbonyl)phenoxy)phenyl)-2methylpropanoic acid. This compound and Intermediate 5 were reacted according to

283

General Procedure I to generate the title compound. *H NMR (500 MHz, CDCI3) δ 7.667.63 (m, 2H), 7.55-7.53 (d, ./=9.0 Hz, 2H), 7.06-7.01 (m, 4H), 4.56 (t, J = 12.0 Hz, 4H), 3.08-2.76 (m, 5H), 2.31 (m, IH), 1.79-1.61 (m, 11 Fl), 1.44-1.27 (m, 6H) ppm. ^I3C NMR (125 MHz, CDClj) Ô 187.9, 170.2, 160.4, 156.7, 154.9, 130.1, 127.2, 126.6, 119.9, 117.9,

115.3, 71.6, 58.4, 54.4, 52.9, 48.6, 45.0, 36.2, 31.1, 30.0, 26.1, 23.0 ppm. Purity; >98% (214 & 254 nm) LCMS; rétention time: 1.30 min; (M+H⁴) 527.3.

Examnle 304

Quinuclidin-3-yl 2-(4-(4-phenylpiperazine-l-carbonyl)phenyl)propan-2-ylcarbamate

To a stirred solution of 2-(4-bromophenyl)propan-2-aminc (1.00 g, 4.67 mmol) in methylene chloride (10 mL) was added di-tert-butyl dicarbonate (6.10 g, 27.9 mmol) and triethylamine (1.3 mL, 9.3 mmol), The mixture was stirred ovemight and then concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate gradient to afford tert-butyl (2-(4-bromophenyl)propan-2yl)carbamate as a light yellow solid (1.25 g, 85%). To a stirred and cooled (-78 °C) solution of this compound (1.80 g, 5.75 mmol) in tetrahydrofuran (320 mL) was added a 1.6 M solution of M-butyllithium in hexane (5.4 mL, 8.6 mmol). After stirring at -78 °C for 1 hour, carbon dioxide gas was slowly bubbled tlirough the reaction for 1.5 hours. The mixture was then allowed to warm to -10 °C, quenched with the addition of water and partitioned between ethyl acetate and water. The aqueous phase was acidified with the addition of 1 N hydrochloric acid and extracted with ethyl acetate. The combined extracts were dried (Na₂SO₄) and concentrated to afford 4-(2-((tertbutoxycarbonyl)amino)propan-2-yl)benzoic acid as a white solid (1.20 g, 75%). To a stirred solution of this intermediate (1.20 g, 4.30 mmol) in tetrahydrofuran (20 mL) was added carbonyl diimidazole (1.05 g, 6.44 mmol) and, 1 hour later, 1-phenylpiperazinc (1.05 g, 6.44 mmol). The reaction was stirred for an additional 2 hours before diluting with ethyl acetate and washing with, in order, aqueous citric acid solution, water and aqueous sodium carbonate solution. The organic layer was dried (Na₂SO₄) and concentrated. The crude material was purified by flash chromatography over silica using a hexane/ethyl acetate gradient to afford tert-butyl (2-(4-(4-phenylpiperazine-lcarbonyl)phenyl)propan-2-yl)carbamate as a white solid (1.23 g, 68%). To a stirred solution of this compound (1.20 g, 2.84 mmol) in methylene chloride (8 mL) was added trifluoroacctic acid (5 mL). After 2 hours the reaction was concentrated and partitioned between aqueous 4 N sodium hydroxide solution and ethyl acetate. The organic layer was combined with additional ethyl acetate extracts, washed with brine, dried (Na₂SO4) and concentrated to afford (4-(2-aminopropan-2-yl)phcnyl)(4-phenylpîperazin-lyl)methanone as a white solid (0.850 g, 93%). To a stirred suspension of this intermediate (0.200 g, 0.618 mmol) in water (3 mL) and concentrated hydrochloric acid (0.3 mL) was added toluene (3 mL). The mixture was cooled (0 °C) and treated with, simultaneously over I hour, solutions of triphosgene (0.275 g, 0.928 mmol) in toluene (3 mL) and saturated, aqueous sodium bicarbonate (5 mL). Following the additions, the reaction was stirred for an additional 30 minutes before the upper toluene layer was removed and dried (Na₂SO4). At the same time, a stirred solution of quinuclidtn-3-ol (0.200 g, 0.573 mmol) in tetrahydrofuran (2 mL) was treated with sodium hydride (60% dispersion in minerai oil; 0.046 g, 1.15 mmol). This mixture was stirred for 1 hour and then added to the solution of crude isocyanate in toluene. The reaction was stirred ovemight, quenched with the addition of an aqueous ammonium chloride solution (10 mL) and extracted with 4:1 (v/v) chloroform/isopropanol. The combined extracts were dried (Na₂SÛ4) and concentrated. The residue was purified by flash chromatography over reversed phase

284 silica to afford the title compound as a white solid (0.110 g, 37%). *H NMR (500 MHz, CDCl₃) δ 7.48-7.42 (m, 4H), 7.32-7.28 (m, 2H), 6.96-6.91 (m, 3H), 5.18 (s, IH), 4.654.63 (m, IH), 3.94-3.64 (m, 4H), 3.20-2.71 (m, 9H), 2.32-1.86 (m, 3H), 1.68-1.42 (m, 9H) ppm. ¹³CNMR(125 MHz, CDC1₃) δ 170.3, 154.5, 150.9, 148.9, 133.8, 129.2, 127.3, 125.0, 120.6, 116.7, 71.1, 55.6, 55.2, 49.7, 47.3, 46.4, 42.2, 29.6, 25.4, 24.5, 19.5 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.25 min; (M-H) 477.2.

Example 305

JV-(2-(4-(4-(Methy lcar bamoy l)p h en oxy)pheny l)p r op an-2-yl)-1,4-di azabicyclo[3.2.2]nonane-4-carboxamide

Exchanging quinuclidin-3-ol for Intermediate 3, the reaction sequence outlined in Exemple 304 was used to prépare the title compound. *H NMR (500 MHz, CDC1₃) δ 7.47-7.46 (d, J= 8.0 Hz, 2H), 7.43-7.41 (d, J= 8.0 Hz, 2H), 7.32-7.29 (m, 2H), 6,96-6.91 (m, 3H), 5.11 (s, IH), 4.80-4.77 (m, IH), 3.94-3.65 (m, 4H), 3.25-2.76 (m, 10H), 2.071.55 (m, 13H) ppm. ¹³C NMR (125 MHz, CDC1₃) δ 170.4, 154.1, 150.9, 149.0, 133.7,

129.3, 127.3, 125.0, 120.6, 116.7, 78.4, 55.1, 51.7, 50.0,48.2,45.0, 42.2, 33.6, 30.6, 29.7,

29.5, 24.8, 22,1 ppm. Purity: >98% (214 & 254 nm) LCMS; rétention time: 1.25 mîn; (M+H⁴) 491.2.

Example 306 l-(3-Ethylquinuclidin-3-yI)-3-(2-(4-(4-plienylpiperazine-l-carbonyl)phenyl)propan-

2-yl)urea

Exchanging quinuclidin-3-ol for Intermediate 2, the reaction sequence outlined in Example 304 was used to prépare the title compound. ^lH NMR (500 MHz, CDC13) δ 7.52-7.50 (d, ./= 8.0 Hz, 2H), 7.43-7.42 (d, J= 8.5 Hz, 2H), 7.32-7.29 (m, 2H), 6.96-6.92 (m, 3H), 5.11 (s, IH), 4.54 (br s, IH), 3.94-3.63 (m, 4H), 3.27-3.13 (m, 4H), 2.77-2.69 (m, 6H), 2.03-1.80 (m, 3H), 1.69-1.30 (m, 10H), 0.73 (t, J= 7.0 Hz, 3H) ppm. ¹³C NMR (125 MHz, CDC13) δ 170.2, 156.6, 150.8, 149.4, 133.9, 129.3, 127.4, 125,6, 120.7, 116.8,

62.9, 54.7, 49.7, 47.7,46.7, 46.6, 42.2, 30.5, 28.1,22.6,22.3, 8.0 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.16 min; (M+H⁴) 504.3.

Exampie 307

QuinucIidin-3-yI 2-(4-(6-(2-methoxyethoxy)pyridin-3-yl)phenyI)propan“2ylcarbamate

To a stirred solution of 5-bromopyridin-2-ol (3.00 g, 17.2 mmol) in N,Ndimcthylformamidc (30 mL) was added l-chloro-2-mcthoxyethane (2.45 g, 26.0 mmol) and potassium carbonate (4.80 g, 34.7 mmol. The reaction was heated ovemight at 90 °C for 8 hours, cooled to room température and diluted with water. The mixture was extracted with ethyl acetate and the combined cxtracts were washed with brine, dried (NajSCU) and concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate gradient to afford 5-bromo-2-(2-methoxyethoxy)pyridine as a light yellow solid (1.70 g, 43%). This compound and ethyl 2-methyl-2-(4-(4,4,5,5tetramcthyl-l,3,2-dioxaborolan-2-yl)phenyl)propanoate were reacted according to General Procedure F to generate to afford ethyl 2-(4-(6-(2-methoxyethoxy)pyrîdin-3yl)phenyl)-2-methylpropanoate. To a stirred solution of this intermediate (0.800 g, 2.43 mmol) in 1:1 (v/v) water/methanol (10 mL) was added solid sodium hydroxide (0.300 g,

7.50 mmol). After heating at 88 °C for 2 hours, the reaction was concentrated and taken

285 up in water. The solution was made acidic (pH ~6) with l N hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na₂SO<i) and concentrated to afford 2-(4-(6-(2-mcthoxyethoxy)pyridin-3-yl)phenyl)-2methylpropanoic acid as a yellow solid (0.600 g, 78%). This compound was used without purification and reacted with quinucltdin-3-ol according to General Procedure 1 to generate the title compound as a yellow solid. ^lH NMR (500 MHz, CDCI3) ô 7.63-7.61 (dd, J= 9.0 Hz & 2.0 Hz, IH), 7.57-7.57 (d, J= 2.5 Hz, IH), 7.47-7.45 (d, J = 8.5 Hz, 2H), 7.39-7.37 (d, J= 8.0 Hz, 2H), 6.66-6.64 (d, J= 9.0 Hz, IH), 5.20 (s, IH), 4.64-4.63 (m, IH), 4.19 (t, .7= 5.0 Hz, IH), 3.71 (t, J= 5.0 Hz, IH), 3.34 (s, IH), 3.17-2.62 (m, 6H), 2.18-1.40 (m, 1 IH) ppm. ^I3C NMR (125 MHz, CDCI3) δ 161.9, 154.4, 146.0, 139.4,

136.3, 134.9, 125.8, 125.5, 120.5, 119.2, 71.0, 70.4, 59.0, 55.6, 55.0, 50.0, 47.4, 46.4,

30.9, 29.6, 25.4, 24.6, 19.5 ppm. Purity: >96% (214 & 254 nm) LCMS; rétention time: 1.66 min; (M+H⁴) 440.3.

Example 308

QuinucIidin-3-yl 2-(4-(5-(2-methoxyethoxy)pyridin-2-yl)phenyl)propan-2ylcarbamate

To a stirred solution of 6-chloropyridin-3-ol (3.00 g, 23.0 mmol) in N,Ndimethylformamidc (30 mL) was added l-chloro-2-methoxyethane (3,30 g, 34.5 mmol), potassium carbonate (6.40 g, 46.0 mmol) and potassium iodide (0.200 g, 1.20 mmol). The reaction was heated ovemight at 100 °C, cooled to room température and diluted with water. The mixture was extracted with ethyl acetate and the combined extracts were washed with brine, dried (NaîSO^) and concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate gradient to afford 2-chloro-5-(2mcthoxyethoxy)pyridinc as a yellow oil (3.80 g, 88%). This compound (0.570 g, 3.00 mmol, ethyl 2-methy 1-2-(4-(4,4,5,5-tetramethy 1-1,3,2-dioxaborolan-2yl)phenyl)propanoatc (1.10 g, 3.60 mmol), potassium carbonate (1.20 g, 8.68 mmol), [l,r-bis(diphcnylphosphino)ferrocenc]dichloropalladium(]I) (0.110 g, 0.150 mmol) and 5:1 (v/v) 1,4-dioxane/watcr (3 mL) were loaded into a mïcrowavc reaction vessel. The reaction was stirred and heated (130 °C) under microwave irradiation for 2 hours. After cooling, the reaction was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried (NaiSO.)) and concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford ethyl 2-(4-(5-(2-methoxycthoxy)pyridin-2-yl)phcnyl)-2-mcthylpropanoate as a yellow solid (0.520 g, 52%). To a stirred solution of this intermediate (0.520 g, 1.58 mmol) in a mixture of water (3 mL), methanol (4 mL) and tetrahydrofuran (4 mL) was added solid sodium hydroxide (0.253 g, 6.32 mmol). After stirring ovemight, the reaction was concentrated and taken up in water. The solution was made acidic (pH -6) with 1 N hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na₂SO4) and concentrated to afford 2-(4-(5-(2-methoxyethoxy)pyridin-

2-yl)phenyl)-2-methylpropanoic acid as a white solid (0.500 g, 100%). This compound was used without purification and reacted with quinuclidin-3-ol according to General Procedure I to generate the title compound as a yellow solid. ^!H NMR (500 MHz, CDCh) δ 8.33-8.32 (d, J = 2.5 Hz, IH), 7.82-7.80 (d, J = 8.5 Hz, 2H), 7.57-7.55 (d, J = 9.0 Hz, IH), 7.41-7.40 (d,.7= 8.0 Hz, 2H), 7.22-7.20 (m, IH), 5.24 (s, IH), 4.55 (m, IH), 4.13 (t, J = 4.5 Hz, 2H), 3.71 (t, J = 4.5 Hz, 2H), 3.39 (s, 3H), 3.09-1.97 (m, 7H), 1.90-0.99 (m, 10H) ppm. ^t3C NMR (125 MHz, CDCh) δ 154.5, 154.0, 150.0, 147.1, 137.5, 137.4,

126.4, 125.1, 122.1, 120.6, 70.9, 67.8, 59.3, 55.6, 55.1, 47.4, 46.4, 29.7, 29.5, 29.2, 25.4,

286

24.5, 19.5 ppm. Purity: >96% (214 & 254 nm) LCMS; rétention time: 1.09 min; (M+H⁴)

440.2.

Exampie 309 Quinuclidin-3-yl 2-(3-(5-(2-methoxyethoxy)pyridin-2-yl)phenyl)propan-2ylcarbamate

Exchangïng ethyl 2-mcthyl-2 -(4-(4,4,5,5-tctramethyl-l, 3,2-dioxaborolan-2yl)phenyl)propanoate for ethyl 2-mcthyl-2-(3-(4,4,5,5-tetramcthyl-l,3,2-dioxaborolan-2yl)phenyl)propanoatc, the reaction sequence outlincd in Example 304 was used to prépare 2-(3-(5-(2-methoxycthoxy)pyridin-2-yl)phenyl)-2-methylpropanoic acid. This compound was reacted with quinuclidin-3-ol according to General Procedure I to generate the title compound. ’H NMR (500 MHz, CDCl₃) δ 8.41-8.41 (d, J= 3.0 Hz, IH), 8.01 (s, IH), 7.75-7.74 (d, J= 11.5 Hz, IH), 7.65-7.63 (d, J- 9.0 Hz, IH), 7.43-7.39 (m, 2H), 7.31-

7.29 (dd, J = 9.0 Hz & 3.0 Hz, IH), 5.20 (s, IH), 4.62 (s, 1 H), 4.21 (t, ./=4,5 Hz, 2H),

3.79 (t, ./=4.5 Hz, 2H), 3.48 (s, 3H), 3.17-2.45 (m, 6H), 2.03-0.99 (m, 11 H) ppm. ¹³C NMR (125 MHz, CDCIj) Ô 154.1, 150.4, 148.3, 147.5, 139.2, 137.5, 128.7, 124.8, 123.0,

122.2, 121.0, 70.9, 67.8, 59.3, 55.6, 55.4, 47.4, 46.4, 46.3, 29.5, 29.3, 25.4, 24.6, 19.5 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.89 min; (M+H⁴) 440.3.

Example 310 l-Azabicyclo[3.2.2]nonan-4~yl 2-(4-(5-(2-methoxyethoxy)pyridin-2yl)phenyl)propan-2-ylcarbamate

Using General Procedure I and the réaction inputs 2-(4-(5-(2-mcthoxyethoxy)pyridin-2yl)phenyl)-2-methylpropanoic acid (prepared as described in Example 308) and Intermediate 3, the title compound was prepared. ’H NMR (500 MHz, CDCI3) δ 8.40-

8.40 (d, J = 2.8 Hz, IH), 7.89-7.87 (d, J = 8.4 Hz, 2H), 7.64-7.62 (d, J = 8.8 Hz, IH), 7.48-7.46 (d, J= 8.0 Hz, 2H), 7.30-7.27 (m, IH), 5.20 (s, IH), 4.79-4.76 (m, IH), 4.20 (t, J= 4.4 Hz, 2H), 3.78 (t, J= 4.4 Hz, 2H), 3.46 (s, 3H), 3.07-2.71 (m, 6H), 2.37 (m, IH), 2.03-1.52 (m, 12H) ppm. ¹³C NMR (125 MHz, CDCI3) δ 154.3, 154.0, 150.1, 147.2,

137.5, 137.4, 126.3, 125.2, 122.2, 120.6, 78.2, 70.9, 67.8, 59.3, 55.0, 51.7, 48.2, 45.1,

33.6, 30.6, 29.4, 24.8, 22.2 ppm. Purity: >99% LCMS (214 & 254 nm) LCMS; rétention time: 1.10 min; (M+H⁴) 454.2.

Example 311 l-Azabicyclo[3.2.2]nonan-4-yl 2-(3-(5-(2-methoxyethoxy)pyridin-2yl)phenyl)propan-2-ylcarbamate

Using General Procedure I and the reaction inputs 2-(3-(5-(2-mcthoxyethoxy)pyridin-2yI)phenyl)-2-methylpropanoic acid (prepared as described in Example 309) and Intermediate 3, the title compound was prepared. ’H NMR (500 MHz, CDCI3) δ 8.41-

8.41 (d, J= 3.0 Hz, IH), 8.00 (s, IH), 7.75-7.74 (m, IH), 7.65-7.63 (d, J= 8.5 Hz, IH), 7.41-7.40 (m,2H), 7.31-7.29 (m, IH), 5.16 (s, IH), 4.77 (m, IH), 4.22 (t, J=4.5 Hz, 2H),

3.80 (t, J= 4.5 Hz, 2H), 3.48 (s, 3H), 3.10-2.62 (m, 6H), 2.16-1.53 (m, 13H) ppm. ¹³C NMR (125 MHz, CDC1₃) ô 154.3, 154.1, 150.4, 147.6, 146.5, 139.1, 137.5, 128.7, 124.774, 123.056, 122.156, 120.914, 77.938, 70.896, 67.819, 59.309, 55.355, 51.605,

50.7, 48.1, 45.1, 33.5, 30.4, 29.4, 24.6, 22.0 ppm. Purity: >96% (214 & 254 nm) LCMS; rétention time: 0.94 min; (M+H⁴) 454.3.

287

Example 312

QuinucIidin-3-yl (2-(3-(6-(3-methoxypropoxy)pyridazin-3-yl)phenyl)propan-2yl)carbamate

To a stirred solution of 3-mcthoxy-l-propanol (5.0 mL, 52 mmol) in W,Ndimethylformamidc (300 mL) was added sodium hydride (60% dispersion in minerai oil; 3.14 g, 78.4 mmol). After 2 hours, 3,6-dichloropyridazine (7.79 g, 52.3 mmol) was added. The reaction was stirred at room température ovemight, concentrated and partitioned between chloroform and water. The organic layer was washed with aqueous sodium bicarbonate solution and brine, dried (NaîSOj and concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate gradient to afford 3-chloro-6-(3-methoxypropoxy)pyridazine as a pale yellow oil (8.05 g, 76%). A stirred suspension of this compound (1.77 g, 5.58 mmol), ethyl 2-methyl-2-(3-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propanoate (1.77 g, 5.58 mmol) and potassium carbonate (4.90 g, 35.5 mmol) in 4:1 (v/v) Α,Λ'-dimcthylformamidc/watcr (75 mL) was deoxygenated by bubbling nitrogen through the mixture for scvcral minutes. Bis(triphenylphosphine)palladium(ll) dichloride (0.089 g, 0.127 mmol) was added and the reaction was heated at 100 °C for 6 hours. At this time, the reaction was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with aqueous sodium bicarbonate solution and brine, dried (Na2SOj and concentrated. The crude material was purified by flash chromatography over silica using a hexane/ethyl acetate gradient to afford ethyl 2-(3-(6-(3-methoxypropoxy)pyridazin-3-yl)phenyl)-2methylpropanoate as a colorless oil (1.58 g, 87%). To a stirred solution of this compound (1.58 g, 4.41 mmol) in 1:1:1 (v/v/v) tctrahydrofuran/ethanol/water (30 mL) was added lithium hydroxide monohydrate (0.925 g, 22.0 mmol). After heating at reflux ovemight, the reaction was cooled and concentrated. The residue was dissolved in water and washed with diethyl cther. The aqueous layer was treated with 1.0 N hydrochloric acid (22 mL) and extracted with ethyl acetate. The combined extracts were dried (NaîSOj and concentrated to afford 2-(3-(6-(3-methoxypropoxy)pyridazin-3-yl)phenyl)-2methylpropanoic acid as a colorless solid (1.41 g, 97%). This compound and quinuclidin-

3-ol were reacted according to General Procedure H to generate the title compound as a pale tan solid. *H NMR (400 MHz, DMSO-O δ 8.20-7.99 (m, 2H), 7.91-7.76 (m, IH), 7.67-7.34 (m, 3H), 7.30 (d, J = 9.2 Hz, IH), 4.53 (t, J= 6.4 Hz, 2H), 4.47-4.34 (m, IH),

3.51 (t, 6.2 Hz, 2H), 3.27 (s, 3H), 3.11-2.15 (m, 6H), 2.13-1.10 (m, 13H) ppm. ¹³C

NMR (100 MHz, DMSO-e/_fi) δ 163.9, 154.8, 154.6, 149.0, 135.6, 128.6, 127.8, 125.8, 124.0, 122.8, 117.6, 70.0, 68.5, 64.1, 57.9, 55.3, 54.5, 46.9, 45.9, 29.4, 28.6, 25.2, 24.2, 19.2 ppm. Purity: 97.8%, 98.7% (210 & 254 nm) UPLCMS; rétention time: 0.76 min; (M+H⁺) 455.3.

Example 313 l-Azabicyclo[3.2.2]nonan-4-yl (2-(3-(6-(3-methoxypropoxy)pyndazin-3yl)phenyl)propan-2-yl)carbamate

Using General Procedure H and the reaction inputs 2-(3-(6-(3methoxypropoxy)pyridazin-3-yl)phenyl)-2-methylpropanoic acid (prepared as described in Example 312) and Intermediate 3, the title compound was prepared. ^lH NMR (400

MHz, DMSO-Je) δ 8.10 (d, J= 9.3 Hz, IH), 8.06 (br s, IH), 7.98-7.74 (m, IH), 7.53 (br s, IH), 7.46-7.35 (m, 2H), 7.30 (d, J= 9.3 Hz, IH), 4.64-4.48 (m, 3H), 3.51 (t, J = 6.3 Hz,

2H), 3.27 (s, 3H), 3.01-2.36 (m, 6H), 2.04 (quin, J= 6.4 Hz, 2H), 1.97-1.28 (m, 13H) ppm. ^I3C NMR (100 MHz, DMSO-î/₆) δ 163.9, 154.8, 154.3, 149.0, 135.6, 128.5, 127.7,

288

125.8, 124.0, 122.8, 117.6, 77.1, 68.5, 64.1, 57.9, 54.4, 51.4, 47.7, 44.6, 33.4, 30.6, 29.6, 28.6, 24.7, 22.2 ppm. Purity: >99.9%, 99.5% (210 & 254 nm) UPLCMS; rétention time: 0.76 min; (M+H ') 469.4.

Example 314 /V-(2-(3-(6-(3-MethoxypiOpoxy)pyridazin-3-yI)phenyl)propan-2-yl)-l,4diazabicyclo[3.2.2|nonane-4-carboxamide

Using General Procedure H and the reaction inputs 2-(3-(6-(3methoxypropoxy)pyridazin-3-yl)phenyl)-2-methylpropanoic acid (prepared as described in Example 312) and Intermediate 6, the title compound was prepared. *H NMR (400 MHz, DMSO-de) Ô 8.09 (d, J= 9.3 Hz, IH), 8.07-8.03 (m, IH), 7.82-7.71 (m, IH), 7.487.34 (m, 2H), 7.29 (d, J = 9.3 Hz, IH), 6.21 (br s, IH), 4.53 (t, 6.5 Hz, 2H), 4.22-4.14 (m, IH), 3.61-3.44 (m, 4H), 3.27 (s, 3H), 2.96-2.67 (m, 6H), 2.04 (quin, J= 6.4 Hz, 2H), 1.95-1.81 (m, 2H), 1.66-1.49 (m, 8H) ppm. ¹³C NMR (100 MHz, DMSO-de) δ 163.9,

155.4, 155.0, 150.4, 135.3, 128.3, 127.7, 125.9, 123.5, 122.8, 117.6, 68.5, 64.1, 57.9,

57.5, 54.8, 46.6, 45.9, 41.5, 30.2, 28.6, 27.0 ppm. Purity: >99.9%, 99.1% (210 & 254 nm) UPLCMS; rétention time: 0.70 min; (M+H⁺) 454.4,

Example 315

Quinuclidin-3-yl (2-(3-(5-(3-methoxypropoxy)pyrazin-2-yl)phenyl)propan-2yl)carbamate

To a stirred solution of 3-methoxy-l-propanol (3.2 mL, 34 mmol) in N,Ndimethylformamide (200 mL) was added sodium hydride (60% dispersion in minerai oil; 2.02 g, 50.6 mmol). After 30 minutes, 2,5-dichloropyrazme (5.03 g, 33.7 mmol) was added. The réaction was stirred at room température overnight, concentrated and partitioned between ethyl acetate and water. The organic layer was washed with aqueous sodium bicarbonate solution and brine, dried (Na₂SO4) and concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate gradient to afford 2-chloro-5-(3-methoxypropoxy)pyrazine as a colorless oil (4.47 g, 65%). A stirred suspension of this compound (1.00 g, 4.94 mmol), ethyl 2-methy 1-2-(3-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propanoate (1.73 g, 5.43 mmol) and potassium carbonate (4.78 g, 34.6 mmol) in 4:1 (v/v) 7V,7V-dimethylformamide/water (75 mL) was deoxygenated by bubbling nitrogen through the mixture for several minutes. Bis(triphenylphosphine)palladium(n) dichloride (0.087 g, 0.124 mmol) was added and the réaction was heated at 100 °C for 6 hours. At this time, the reaction was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with aqueous sodium bicarbonate solution and brine, dried (Na₂SC>4) and concentrated. The crude material was purified by flash chromatography over silica using a hexane/ethyl acetate gradient to afford ethyl 2-(3-(5-(3-methoxypropoxy)pyrazin-2-yl)phenyl)-2methylpropanoate as a colorless oil (1.37 g, 77%). To a stirred solution of this compound (1.37 g, 3.81 mmol) in 1:1:1 (v/v/v) tetrahydrofuran/ethanol/water (25 mL) was added lithium hydroxide monohydrate (0.800 g, 19.1 mmol). After heating at reflux overnight, the reaction was cooied and concentrated. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was treated with 1.0 N hydrochloric acid (19 mL) and extracted with ethyl acetate. The combined extracts were dried (Na₂SO<i) and concentrated to afford 2-(3-(5-(3-methoxypropoxy)pyrazin-2-yl)phenyl)-2methylpropanoic acid as a colorless solid (1.20 g, 95%). This compound and quinuclidin-

3-ol were reacted according to General Procedure H to generate the title compound as a

289 pale amber solid. *H NMR (400 MHz, DMSO-de) δ 8.74 (d, ./=1.3 Hz, IH), 8.36 (br s, IH), 8.03 (br s, IH), 7.86-7.77 (m, IH), 7.57 (br s, IH), 7.49-7.32 (m, 2H), 4.44-4.35 (m, 3H), 3.49 (t, J= 6.3 Hz, 2H), 3.26 (s, 3H), 3.06-2.23 (m, 6H), 2.00 (quin, ./=6.4 Hz, 2H), 1.95-1.19 (m, 10H) ppm, ^l3C NMR (100 MHz, DMSO-de) Ô 158.9, 154.6, 149.1, 144.4,

137.5, 135.5, 134.2, 128.5, 125.2, 123.3, 122.3, 70.1, 68.5, 63.5, 57.9, 55.4, 54.5, 46.9,

45,9, 29.5, 28.6, 25.2, 24.2, 19.2 ppm. Purity; >99.9%, 98.7% (210 & 254 nm) UPLCMS; rétention time: 0.84 min; (M+H⁺) 455.4.

Exampie 316 l-Azabîcyclo[3.2.2|nonan-4-yl (2-(3-(5-(3-methoxypropoxy)pyrazin-2yl)phenyl)propan-2-yl)carbamate

Using General Procedure H and the réaction inputs 2-(3-(5-(3-mcthoxypropoxy)pyrazin2-yl)phcnyl)-2-mcthylpropanoic acid (prepared as described in Exampie 315) and Intermediate 3, the title compound was prepared. *H NMR (400 MHz, DMSO-de) δ 8.73 (d, J= 1.3 Hz, IH), 8.40-8.33 (m, IH), 8.00 (brs, IH), 7.85-7.76 (m, IH), 7.52 (br s, IH), 7.46-7.33 (m, 2H), 4,64-4.53 (s, IH), 4.40 (t, J = 6.5 Hz, 2H), 3.49 (t, J = 6.3 Hz, 2H), 3.26 (s, 3H), 3.00-2.33 (m, 6H), 2.00 (quin, J= 6.5 Hz, 2H), 1.95-1.26 (m, 13H) ppm. ^I3C NMR (100 MHz, DMSO-d_fi) 0158,8, 154.2, 149.0, 144.5, 137.5, 135.5, 134.2, 128.5,

125.2, 123.3, 122.4, 77.1, 68.5, 63.5, 57.9, 54.4, 51.4, 47.9, 44.7, 33.5, 30.6, 29.7, 29.5, 28.6, 24.7, 22.2 ppm. Purity: >99.9%, >99.9% (210 & 254 nm) UPLCMS; rétention time: 0.85 min; (M+H' ) 469.4.

Exampie 317 ./V-(2-(3-(5-(3-Methoxypropoxy)pyrazin-2-yl)phenyl)propan-2-yl)-l,4diazabicyclo(3.2.2]nonanc-4-carboxamide

Using General Procedure H and the reaction inputs 2-(3-(5-(3-methoxypropoxy)pyrazin2-yl)phenyl)-2-methylpropanoic acid (prepared as described in Example 315) and Intermediate 6, the title compound was prepared. ‘H NMR (400 MHz, DMSO-de) Ô 8.72 (d, J= 1.4 Hz, IH), 8.35 (d, J= 1.4 Hz, IH), 7.98 (s, IH), 7.80-7.74 (m, IH), 7.37 (d, J = 4.8 Hz, 2H), 6.19 (br s, IH), 4.39 (t, J = 6.5 Hz, 2H), 4.18 (s, IH), 3.49 (t, J = 6.2 Hz, 4H), 3.26 (s, 3H), 3.04-2.66 (m, 6H), 2.00 (quin, J = 6.4 Hz, 2H), 1.95-1.82 (m, 2H), 1.66-1.49 (m, 8H) ppm. ^I3C NMR (100 MHz, DMSO-de) δ 158.8, 155.4, 150.4, 144.7,

137.4, 135.3, 134.1, 128.3, 125.2, 122.9, 122.4, 68.5, 63.5, 57.9, 57.6, 54.8, 46.7, 45.9,

41.5, 30.2, 28.6, 27.0 ppm. Purity: 95.4%, 97.7% (210 & 254 nm) UPLCMS; rétention time: 0.78 min; (M+H⁴} 454.4.

Exampie 318

Quinuclidin-3-yl (2-(3-(6-ethoxypyrldazin-3-yl)phenyl)propan-2-yl)carbamate

Exchanging 3-methoxy-l-propanol for éthanol, the reaction sequence outlined in Example 312 was used to prépare the title compound. ^JH NMR (400 MHz, DMSO-de) δ 8.17-8.02 (m, 2H), 7.87-7.80 (m, IH), 7.65-7.34 (m, 3H), 7.28 (d, J= 9.3 Hz, IH), 4.54 (q, J= 7.0 Hz, 2H), 4.45-4.33 (m, IH), 3.12-2.18 (m, 6H), 2.05-1.10 (m, 14H) ppm. ¹³C NMR (100 MHz, DMSO-de) δ 163.9, 154.7, 154.6, 149.0, 135.6, 128.6, 127.7, 125.8, 124.0, 122.7, 117.6, 70.1, 62.7, 55.3, 54.5, 46.9, 45.9, 29.4, 25.2, 24.2, 19.2, 14.4 ppm. Purity: >99.9%, 99.5% (210 & 254 nm) UPLCMS; rétention time: 0.78 min; (M+H⁴)

411.3.

290

Exampie 319 l-Azabicyclo[3.2.2]nonan-4-yl (2-(3-(6-ethoxypyridazin-3-yI)phenyl)propan-2yl)carbamate

Exchanging 3-methoxy-l-propanol for éthanol and quinuclidin-3-ol for Intermediate 3, the reaction sequence outlined in Example 312 was used to prépare the title compound. *H NMR (400 MHz, DMSO-O δ 8.10 (d, J = 9.3 Hz, IH), 8.07 (brs, IH), 7.86-7.79 (m, III), 7.60-7.37 (m, 3H), 7.28 (d, J = 9.3 Hz, IH), 4.64-4.55 (m, IH), 4.54 (q, J= 7.0 Hz, 2H), 3.01-2.34 (m, 6H), 1.98-1.21 (m, 3H) ppm. ^I3C NMR (100 MHz, DMSO-d_fi) δ

163.9, 154.7, 154.2, 149.1, 135.6, 128.5, 127.7, 125.8, 123.9, 122.8, 117.5, 77.1, 62.7,

54.4, 51.4, 47.6, 44.7, 33.4, 30.6, 29.6, 24.7, 22.1, 14.4 ppm. Purity: >99.9%, 99.4% (210 & 254 nm) UPLCMS; rétention time: 0.79 min; (M+H⁴) 425.3.

Example 320 Quinuclidin-3-yl (2-(4-(5-(3-methoxypropoxy)pyrazin-2-yl)phenyl)propan-2yl)carbamate

Exchanging ethyl 2-mcthyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)propanoatc for ethyl 2-mcthyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phcnyl)propanoatc, the reaction sequence outlined in Example 315 was used to prépare the title compound. *H NMR (400 MHz, DMSO-<4) δ 8.74 (d, J= 1.2 Hz, IH), 8.35 (d, J = 1.3 Hz, IH), 7.93 (d, J = 7.9 Hz, 2H), 7.56 (br s, IH), 7.45 (d, J = 7.5 Hz, 2H), 4.55-

4.30 (m, 3H), 3.49 (t, J =6.3 Hz, 2H), 3.26 (s, 3H), 3.08-2.24 (m, 6H), 2.00 (quin, J = 6.4 Hz, 2H), 1.92-1.19 (m, 11 H) ppm. ^l3C NMR (100 MHz, DMSO-<7₆) δ 158.8, 154.5,

148.9, 144.2, 137.3, 134.2, 133.7, 125.5, 125.2, 70.0, 68.5, 63.4, 57.9, 55.4, 54.3, 46.9,

45.9, 29.3, 28.6, 25.2, 24.2, 19.2 ppm. Purity: >99.9%, >99.9% (210 & 254 nm) UPLCMS; rétention time: 0.86 min; (M+H⁴) 455.4.

Example 321 l-Azabicyclo[3.2.2]nonan-4-yl (2-(4-(5-(3-methoxypropoxy)pyrazin-2yl)phenyl)propan-2-yl)carbamate

Exchanging ethyl 2-mcthyl-2-(3-(4,4,5,5-tctramethyl-l ,3,2-dioxaborolan-2yl)phcnyl)propanoatc for ethyl 2-mcthyl-2-(4-(4,4,5,5-tctramethyl-l,3,2-dioxaborolan-2yl)phcnyl)propanoatc and quinuclidin-3-ol for Intermediate 3, the réaction sequence outlined in Exampie 315 was used to prépare the title compound. ^]H NMR (400 MHz, DMSO-i/c) δ 8.74 (d, J =1.2 Hz, IH), 8.35 (d, J= 1.3 Hz, IH), 7.92 (d, J= 8.4 Hz, 2H),

7.51 (brs, IH), 7.43 (d, J= 8.2 Hz, 2H), 4.65-4.55 (m, IH), 4.39 (t, J= 6.5 Hz, 2H), 3.49 (t, J= 6.3 Hz, 2H), 3.26 (s, 3H), 3.01-2.41 (m, 6H), 2.00 (quin, J= 6.4 Hz, 2H), 1.95-1.30 (m, 13H) ppm. ^l3C NMR (100 MHz, DMSO-J₆) δ 158.8, 154.2, 148.9, 144.2, 137.3, 134.2, 133.6, 125.4, 125.3, 77.1, 68.5, 63.4, 57.9, 54.2, 51.4, 47.7, 44.6, 33.4, 30.6, 29.5,

28,6, 24.7, 22.2 ppm. Purity: 98.8%, >99.9% (210 & 254 nm) UPLCMS; rétention time: 0.87 min; (M+H⁴) 469.4.

Example 322 A^r-(2-(4-(5-(3-methoxypropoxy)pyrazin-2-yl)phenyl)propan-2-yl)-l,4diazabicyclo[3.2.2|nonane-4-carboxaimde

Exchanging ethyl 2-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phcnyl)propanoate for ethyl 2-mcthyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2291 yl)phcnyl)propanoatc and quinuclidin-3-ol for Intermediate 6, the reaction sequence outlined in Example 315 was used to préparé the title compound. *H NMR (400 MHz, DMSO-A) δ 8.73 (d, J= 1.4 Hz, IH), 8.35 (d, J= 1.4 Hz, IH), 7.89 (d, J= 8.5 Hz, 2H), 7.42 (d, J= 8.5 Hz, 2H), 6.17 (s, IH), 4.39 (t, J =6.5 Hz, 2H), 4.22-4.16 (m, IH), 3.49 (t, J =6.2 Hz, 4H), 3.26 (s, 3H), 3.09-2.70 (m, 6H), 2.00 (quin, J= 6.4 Hz, 2H), 1.94-1.82 (m, 2H), 1.65-1.49 (m, 8H) ppm. ^I3C NMR (100 MHz, DMSO-rfe) Ô 158.7, 155.4, 150.3,

144.4, 137.2, 134.2, 133.1, 125.3, 125.2, 68.5, 63.4, 57.9, 57.5, 54.6, 46.6, 46.0, 41.5, 30.1, 28.6, 27.0 ppm. Purity: >99.9%, >99.9% (210 & 254 nm) UPLCMS; rétention time: 0.80 min; (M+H') 454.4.

Example 323

Quinuclidin-3-yl (2-(3-(5-(3-methoxypropoxy)pyrimidm-2-yl)phenyl)propan-2yljcarbamate

To a stirred solution 2-chloropyrimidin-5-ol (5.04 g, 38.6 mmol) in N,Ndimethylformamide (25 mL) was added l-bromo-3-mcthoxypropane (10.8 mL, 96.5 mmol) and potassium carbonate (12.26 g, 88.74 mmol). The mixture was heated at 60 °C ovemight, concentrated and partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was washed with brine, dried (Na₂SO«) and concentrated. The residue was purified by flash chromatography over silica using a hexanc/ethyl acetate gradient to afford 2-chloro-5-(3-methoxypropoxy)pyrimidine as a white solid (4.90 g, 63%). This compound and ethyl 2-methyl-2-(3-(4,4,5,5-tetramethyll,3,2-dioxaborolan-2-yl)phenyl)propanoate were reacted according to General Procedure F to afford ethyl 2-(3-(5-(3-methoxypropoxy)pyrimidin-2-yl)phenyl)-2methylpropanoate. To a stirred solution of this intermediate (1.93 g, 5.38 mmol) in 1:1:1 (v/v/v) tetrahydrofuran/ethanol/watcr (36 mL) was added lithium hydroxide monohydrate (1.13 g, 26.9 mmol). After heating at reflux ovemight, the reaction was cooled and concentrated. The residue was dîssolved in water and washed with diethyl ether. The aqueous layer was treated with 1.0 N hydrochloric acid (27 mL) and extracted with ethyl acetate. The combined extracts were dried (Na₂SÛ4) and concentrated to afford 2-(3-(5(3-mcthoxypropoxy)pyrimidin-2-yI)phenyl)-2-methylpropanoic acid as a colorless solid (1.49 g, 84%). This compound and quinuclidin-3-ol were reacted according to General Procedure H to generate the title compound as an off-white solid. *H NMR (400 MHz, DMSO-Jô) δ 8.63 (br s, 2H), 8.36 (brs, IH), 8.15-8.09 (m, IH), 7.61 (brs, IH), 7.50-7.37 (m, 2H), 4.44-4.35 (m, IH), 4.24 (t, J = 6.4 Hz, 2H), 3.50 (t, J= 6.3 Hz, 2H), 3.26 (s, 3H), 3.07-2.23 (m, 6H), 2.00 (quin, J = 6.4 Hz, 2H), 1.93-1.21 (m, 11H) ppm. ¹³C NMR (100 MHz, DMSO-î/ô) δ 156.4, 154.6, 151.4, 148.7, 144.0, 136.7, 128.3, 126.3, 124.7,

123.5, 70.0, 68.2, 65.8, 58.0, 55.4, 54.4, 47.0, 45.9, 29.5, 28.8, 25.2, 24.2, 19.2 ppm. Purity: 96.8%, 97.9% (210 & 254 nm) UPLCMS; rétention time: 0.79 min; (M+H⁺)

455.4.

Exampie 324 l-Azabicyc)o[3.2.2]nonan-4-yl (2-(3-(5-(3-methoxypropoxy)pyrimidin-2yl)phenyl)propan-2-yl)carbamate

Using General Procedure H and the reaction inputs 2-(3-(5-(3mcthoxypropoxy)pyrimidin-2-yi)phcnyl)-2-methylpropanoic acid (prepared as described in Example 323) and Intermediate 3, the title compound was prepared. ’H NMR (400

MHz, DMSO-J₆) Ô 8.63 (s, 2H), 8.34 (br s, IH), 8.15-8.09 (m, IH), 7.50 (br s, IH), 7.467.36 (m, 2H), 4.63-4.53 (m, IH), 4.24 (t, J= 6.4 Hz, 2H), 3.50 (t, J= 6.3 Hz, 2H), 3.26 (s,

292

3H), 2.99-2.32 (m, 6H), 2.01 (quin, J= 6.6 Hz, 2H), 1.96-1.29 (m, 11H) ppm. ¹³C NMR (100 MHz, DMSO-Jfi) δ 156.5, 154.2, 151.4, 148.7, 144.0, 136.7, 128.2, 126.3, 124.6,

123.6, 77.1, 68,2, 65.8, 58.0, 54.3, 51.5,47.7, 44.6, 33.4, 30.6, 29.7, 29.4, 28.8, 24.7, 22.2 ppm. Purity: 96.8%, 98.2% (210 & 254 nm) UPLCMS; rétention time: 0.80 min; (M+H¹) 5 469.4.

Example 325 l-(3-Ethylquinuclidm-3-yl)-3-(4-(4-(2-methoxyethyI)phenyl)-2-methylbut-3-yn-2yl)urea

To a stirred solution of l-bromo-4-(2-methoxyethyl)benzene (2.09 g, 9.73 mmol) in diisopropylamine (10 mL) was added copper(I) iodide (0.185 g, 0.973 mmol) and tertbutyl (2-mcthylbut-3-yn-2-yl)carbamatc (2.14 g, 11.7 mmol). Nitrogen was bubblcd through the mixture for several minutes and then bis(triphenylphosphine)palladium(n) 15 dichloride (0.342 g, 0.487 mmol) was added. The reaction was heated at reflux ovemight, diluted with ethyl acetate and water and filtered through a plug of Celite. The organic layer of the filtrate was washed with aqueous sodium bicarbonate solution and brine, dried (Na₂SÛ4) and concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate gradient to afford tert-butyl (4-(4-(220 methoxycthyl)phenyl)-2-mcthylbut-3-yn-2-yl)carbamate as an orange oil (2.22 g, 72%).

To a stirred solution of this compound (2.22 g, 6.99 mmol) in 1,4-dioxane (20 mL) was added a 4 M solution of hydrogen chloride in 1,4-dioxane (20 mL). After ovemight stirring, the reaction was concentrated and partitioned between 1 N hydrochioric acid and diethyl ether. The aqueous layer was made basic (pH -10) with the addition of 25 concentrated ammonium hydroxide and extracted with ethyl acetate. The combined extracts were dried (Na₂SO4) and concentrated to afford 4-(4-(2-mcthoxyethyl)phenyl)-2methylbut-3-yn-2-amine as a yellow oil (1.07 g, 70%). This compound and Intermediate 2 were reacted according to General Procedure J to generate the title compound as a white solid. ’H NMR (400 MHz, DMSO-î/₆) δ 7.28-7.16 (m, 4H), 5.99 (br s, IH), 5.75 (br s, 30 IH), 3.52 (t, J= 6.7 Hz, 2H), 3.23 (s, 3H), 2.80 (t, J = 6.7 Hz, 2H), 2.77-2.50 (m, 6H), 2.00-1.86 (m, 2H), 1.86-1.66 (m, 2H), 1.66-1.47 (m, 7H), 1.44-1.20 (m, 2H), 0.73 (t, J = 7.3 Hz, 3H) ppm. ¹³C NMR (100 MHz, DMSO-J₆) δ 156.8, 139.3, 131.0, 129.0, 120.5,

94.8, 79.3, 72.4, 62.7, 57.8, 53.4, 46.6, 46.4, 46.3, 35.1, 29.8, 29.8, 27.8, 27.7, 22.5, 22.2, 8.0 ppm. Purity: >99.9%, >99.9% (210 & 254 nm) UPLCMS; rétention time: 0.86 min; 35 (M+H⁴) 398.5.

Example 326 l-(4-(4-(2-Methoxyethyl)phenyl)-2-methylbut-3-yn-2-yl)-3-(3-propylqumuclidin-3yl)urea

Using General Procedure J and the réaction inputs 4-(4-(2-methoxyethyl)phenyl)-2methylbut-3-yn-2-amine (prepared as described in Example 325) and Intermediate 17, the title compound was prepared. *H NMR (400 MHz, DMSO-rf₆) δ 7.27-7.16 (m, 4H), 5.95 (br s, IH), 5.73 (br s, IH), 3.51 (t, J= 6.8 Hz, 2H), 3.22 (s, 3H), 2.79 (t, J= 6.8 Hz, 2H), 45 2.76-2.50 (m, 6H), 1.96-1.91 (m, IH), 1.91-1.66 (m, 2H), 1.66-1.46 (m, 7H), 1.43-1.09 (m, 2H), 0.83 (t, J= 73 Hz, 3H) ppm. ⁱ³C NMR (100 MHz, DMSO-î/₆) δ 156.8, 139.3,

131.0, 128.9, 120.5, 94.8, 79.3, 72.4, 63.1, 57.8, 53.3, 46.6, 46.4, 46.3, 37.9, 35.1, 29.8,

29.7, 28.2, 22.6, 22.3, 16.7, 14.6 ppm. Purity; >99.9%, >99.9% (210 & 254 nm)

UPLCMS; rétention time: 0.91 min; (M+H⁴) 412.6.

293

Exampie 327 l-(3-Ethylquinuclidin-3-yl)-3-(4-(4-(methoxymethyl)phenyl)-2-methylbut-3-yn-2yl)urea

Exchanging l-bromo-4-(2-methoxyelhyl)benzene for l-bromo-4(mcthoxymcthyl)bcnzcnc, the reaction sequence outlined in Exampie 325 was used to préparé the title compound. *H NMR (400 MHz, DMSO-î/û) δ 7.49-7.15 (m, 4H), 5.99 (br s, IH), 5.74 (br s, IH), 4.40 (s, 2H), 3.28 (s, 3H), 2.84-2.55 (m, 6H), 2.02-1.85 (m, 2H), 1.85-1.63 (m, 2H), 1.63-1.46 (m, 7H), 1.45-1.19 (m, 2H), 0.73 (t, J= 7.3 Hz, 3H) ppm. ¹³C NMR (100 MHz, DMSO-</₆) δ 156.8, 138.3, 131.0, 127.5, 121.9, 95.2, 79.2, 73.1,

62.8, 57.6, 53.4, 46.6, 46.4, 46.3, 29.8, 29.7, 27.8, 27.7, 22.6, 22.2, 8.0 ppm. Purity; 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.82 min; (M+H⁴) 384.5.

Example 328 l-(4-(4-(Methoxymethyl)phenyl)-2-methylbut-3-yn-2-yl)-3-(3-propylquinucIidm-3yl)urea

Exchanging l-bromo-4-(2-methoxyethyl)benzene for l-bromo-4(methoxymethyl)benzene and Intermediate 2 for Intermediate 17, the reaction sequence outlined in Example 325 was used to prépare the title compound. *H NMR (400 MHz, DMSO-O δ 7.40-7.19 (m, 4H), 5.96 (br s, IH), 5.72 (br s, IH), 4.40 (s, 2H), 3.28 (s, 3H), 2.80-2.52 (m, 6H), 1.97-1.92 (m, IH), 1.92-1.79 (m, IH), 1.79-1.64 (m, 2H), 1.641.44 (m, 7H), 1.42-1.31 (m, IH), 1.31-1.09 (m, 3H), 0.82 (t, J= 7.3 Hz, 3H) ppm. ¹³C NMR (100 MHz, DMSO-Jf,) δ 156.8, 138.3, 131.0, 127.5, 121.9, 95.2, 79.2, 73.1, 63.1,

57.5, 53.3, 46.6, 46.4, 46.3, 37.9, 29.8, 29.7, 28.2, 22.6, 22.3, 16.7, 14.6 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.88 min; (M+H⁴) 398.5.

Exampie 329

Quinuclidin-3-yl (4-(4-(2-methoxyethoxy)plienyl)-2-methylbut-3-yn-2-yl)carbamate

Exchanging l-bromo-4-(2-methoxyethyl)benzene for l-bromo-4-(2mcthoxycthoxy)benzene and Intermediate 2 for quinuclidin-3-ol, the reaction sequence outlined in Example 325 was used to préparé the title compound. ^lH NMR (400 MHz, DMSO-i/fi) δ 7.35 (br s, IH), 7.26 (d, J= 8.8 Hz, 2H), 6.91 (d, ./= 8.8 Hz, 2H), 4.63-4.51 (s, IH), 4.13-4.05 (m, 2H), 3.68-3.60 (m, 2H), 3.30 (s, 3H), 3.13-3.03 (m, IH), 2.77-2.41 (m, 5H), 1.92-1.71 (m, 2H), 1.64-1.40 (m, 8H), 1.36-1.24 (m, IH) ppm. ¹³C NMR (100 MHz, DMS0-î/₆) δ 158.2, 148.8, 132.7, 129.9, 114.7, 114.6, 92.7, 79.4, 70.2, 67.0, 58.1,

55.5, 46.9, 46.8, 46.0, 29.4, 25.3, 24.2, 19.3 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.76 min; (M+H⁴) 387.5.

Exampie 330 l-(4-(4-(2-Methoxyethoxy)phenyl)-2-methylbut-3-yn-2-yl)-3-(3-propylquinucIïdin-3yl)urea

Exchanging l-bromo-4-(2-methoxyethyl)benzene for l-bromo-4-(2methoxyethoxy)benzene and Intermediate 2 for Intermediate 17, the reaction sequence outlined in Example 325 was used to prépare the title compound. 'H NMR (400 MHz,

DMSO-rfû) δ 7.24 (d, J= 8.6 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H), 5.93 (br s, IH), 5.71 (br s,

IH), 4.19-3.97 (m, 2H), 3.80-3.58 (m, 2H), 3.30 (s, 3H), 2.83-2.50 (m, 6H), 1.99-1.45 (m,

IH), 1.45-1.07 (m, 4H), 0,83 (t, J= 7.2 Hz, 3H) ppm. ¹³C NMR (100 MHz, DMSO-J₆) Ô

294

158.2, 156.8, 132.6, 114.9, 114.6, 93.7, 79.2, 70.3, 67.0, 63.0, 58,1,53.3, 46.6,46.4,46.3,

37.8, 29.9, 29.8, 28.2, 22.6, 22.2, 16.7, 14.6 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.79 min; (M+H⁴) 478.6.

Example 331 Quinuclidin-3-yl (4-(4-(3-methoxypropoxy)phenyl)-2-niethylbut-3-yn-2yl)carbamatc

Exchanging l-bromo-4-(2-methoxycthyl)benzene for l-bromo-4-(3methoxypropoxy)benzene and Intermediate 2 for quinuclidin-3-ol, the réaction sequence outlined in Example 325 was used to préparé the title compound. *H NMR (400 MHz, DMSO-ί/ΰ) δ 7.35 (s, IH), 7.29-7.18 (m, 2H), 6.95-6.76 (m, 2H), 4.57 (s, IH), 4.01 (t, J = 6.4 Hz, 2H), 3.45 (t, J= 6.3 Hz, 2H), 3.24 (s, 3H), 3,1-2.99 (m, IH), 2.76-2.43 (m, 5H), 1.97-1.72 (m, 4H), 1.63-1.40 (m, 8H), 1.35-1.25 (m, IH) ppm. ^I3C NMR (100 MHz, DMSO-Je) 5 158.3, 158.3, 132.7, 132.6, 114.6, 114.6, 92.7, 79.4, 68.4, 64.7, 57.9, 55.5,

46.9, 46.8, 45.9, 29.5, 28.8, 25.3, 24.2, 19.3 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.85 min; (M+H⁴) 401.5.

Example 332 l-(3-Etliylquinuclidin-3-yl)-3-(2-methyl-4-(4-((pyridin-3yimethoxy)methyl)phenyl)but-3-yn-2-yl)urea

Exchanging l-bromo-4-(2-methoxyethyl)bcnzcne for 3-(((4bromobcnzyl)oxy)methyl)pyridinc (prepared as described in Example 215), the reaction sequence outlined in Example 325 was used to préparé the title compound. *H NMR (400 MHz, DMSO-i/c) δ 8.72-8.36 (m, 2H), 7.89-7.65 (m, IH), 7.59-7.07 (m, 5H), 6.08 (br s, IH), 5.89 (br s, IH), 4.56 (br s, 4H), 2.94-2.37 (m, 6H), 2.15-1.12 (m, 13H), 0.74 (br s, 3H) ppm. ¹³C NMR (100 MHz, DMSO-rf₆) δ 156.8, 148.9, 148.8, 138.1, 135.4, 133.7, 131.1, 127.6, 123.5, 122.0, 95.3, 79.2, 71.2, 69.1, 62.1, 53.4, 46.6, 46.2, 46.0, 29.8, 29.7,

27.7, 27.5, 22.0, 21.7, 7.9 ppm. Purity: 99.9%, 99.6% (210 & 254 nm) UPLCMS; rétention time: 0.61 min; ((M+2H⁴)/2) 231.4,

Example 333 l-(2~Methy]-4-(4-((pyridin-3-ylmethoxy)methyl)phenyl)but-3-yn-2-yl)-3-(3propylquinuclidin-3-yl)urea

Exchanging l-bromo-4-(2-mcthoxycthyl)bcnzcne for 3-(((4bromobcnzyl)oxy)methyl)pyridine (prepared as described in Example 215) and Intermediate 2 for Intermediate 17, the reaction sequence outlined in Example 325 was used to prépare the title compound. *H NMR (400 MHz, DMSO-î/g) δ 8.79-8.38 (m, 2H), 7.77 (d, .7= 7.6 Hz, IH), 7.53-7.10 (m, 5H), 6.04 (br s, IH), 5.84 (br s, IH), 4,56 (br s, 4H), 2.94-2.47 (m, 6H), 2.06-1.00 (m, 15H), 0.83 (t, J= 7.1 Hz, 3H) ppm. ^I3C NMR (100 MHz, DMSO-Jg) δ 156.9, 148.9, 148.8, 138.1, 135.4, 133.6, 131.1, 127.5, 123.5, 122.0,

95.3, 79.2, 71.2, 69.1, 62.7, 53.2, 46.6, 46.3, 46.2, 37.8, 29.8, 29.7, 28.1, 22.3, 22.0, 16.6, 14.5 ppm. Purity: 99.9%, 99.9% (210 & 254 nm) UPLCMS; rétention time: 0.67 min; (M+H⁴) 475.5.

Example 334

Quinuclidin-3-yl (4-(4-((3,3-dïn)ethylbutyI)sulfonyl)phenyl)2-methylbut-3-yn-2-yl)carbamate

295

Exchanging l-bromo-4-(2-methoxycthyl)benzenc for l-bromo-4-((3,3dimethylbutyl)sulfonyl)benzene (prepared as described in Example 245) and Intermediate 2 for quinuclidin-3-ol, the reaction sequence outlined in Example 325 was used to préparé the title compound. *H NMR (400 MHz, DMS0-î4) δ 7.88 (d, J= 8.5 Hz, 2H), 7.60 (d,,/ = 8.5 Hz, 2H), 7.51 (brs, IH), 4.64-4.57 (m, IH), 3.30-3.21 (m, 2H), 2.80-2.50 (m, 5H), 1.95-1.87 (m, IH), 1.86-1.74 (m, IH), 1.65-1.43 (m, 8H), 1.43-1.27 (m, 3H), 0.81 (s, 9H) ppm. ¹³C NMR (100 MHz, DMSO-î/₆) δ 154.5, 138.0, 132.0, 128.0, 128.0, 98.1, 78.4,

70.3, 55.3, 51.3, 46.8, 46.8, 45.9, 35.4, 29.8, 29.1, 28.6, 25.2, 24.0, 19.1 ppm. Purity: 90.0%, 99.6% (210 & 254 nm) UPLCMS; rétention time: 0.95 min; (M+l) 461,

Example 335 l-Azabicyclo[3.2.2|nonan-4-yl (4-(4-((3,3-dimethylbutyl)sulfonyl)phenyl)-2methylbut-3-yn-2-yl)carbamate

Exchanging l-bromo-4-(2-methoxyethyl)benzene for l-bromo-4-((3,3dimethylbutyl)sulfonyl)benzene (prepared as described in Example 245) and Intermediate 2 for Intermediate 3, the reaction sequence outlined in Example 325 was used to préparé the title compound. *H NMR (400 MHz, DMSO-7₆) δ 7.88 (d, J= 8.5 Hz, 2H), 7.60 (d, J = 8.5 Hz, 2H), 7.44 (br s, IH), 4.80-4.72 (m, IH), 3.30-3.22 (m, 2H), 2.98-2.62 (m, 6H), 2.01-1.50 (m, 12H), 1.47-1.33 (m, 3H), 0.81 (s, 9H) ppm. ¹³C NMR (100 MHz, DMSOd₆) δ 154.2, 138.0, 132.0, 128.0, 128.0, 98.2, 78.4, 77.6,51.4,51.3,47.7, 46.7,44.6,35.5,

33.4, 30.6, 29.8, 29.2, 28.6, 24.6, 22.1 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.96 min; (M+l) 475.

Example 336

1-(4-(4-((3,3-Dimethylbutyl)sulfonyl)phenyl)-2-methy]but-3-yn-2-yl)-3-(4-methy)~lazabicyclo|3.2.2]nonan-4-yl)urea

Exchanging l-bromo-4-(2-methoxyethyl)benzene for l-bromo-4-((3,3dimcthylbutyl)sulfonyi)benzcne (prepared as described in Example 245) and Intermediate 2 for Intermediate 5, the réaction sequence outlined in Example 325 was used to préparé the title compound. ‘H NMR (400 MHz, DMSO-7_f>) δ 7.88 (d, J= 8.5 Hz, 2H), 7.57 (d, J = 8.5 Hz, 2H), 6.15 (s, 1H), 5.79 (s, IH), 3.30-3.20 (m, 2H), 2.90-2.70 (m, 6H), 2.23-2.17 (m, IH), 1.88-1.64 (m, 3H), 1.62-1.42 (m, 8H), 1.42-1.25 (m, 6H), 0.81 (s, 9H) ppm. ^l3C NMR (100 MHz, DMSO-</₆) S 156.7, 137.8, 131.9, 128.3, 128.0, 99.5, 78.1, 57.3, 52.7,

51.3, 48.0, 46.4, 44.9, 38.9, 36.2, 35.4, 29.8, 29.7, 29.5, 28.6, 26.1, 24.1, 23.7 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.94 min; (M+l) 488.

Example 337 l-(4-(4-((33-DimethylbutyI)sulfonyl)phenyl)-2-methylbut-3-yn-2-yl)-3-(3methylquinuclidin-3-yl)urea

Exchanging l-bromo-4-(2-mcthoxycthyl)benzenc for l-bromo-4-((3,3dimethylbutyl)sulfonyl)benzene (prepared as described in Example 245) and Intermediate for Intermediate 1, the reaction sequence outlined in Example 325 was used to prépare the title compound. *H NMR (400 MHz, DMSO-</₆) δ 7.88 (d, J= 8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 6.04 (s, IH), 5.77 (s, IH), 3.29-3.21 (m, 2H), 2.75-2.56 (m, 6H), 1.96-1.91 (m, IH), 1.81-1.51 (m, 8H), 1.45-1.33 (m, 7H), 0.81 (s, 9H) ppm. ¹³C NMR (100 MHz,

DMSO-rfe) δ 156.7, 137.9, 131.9, 128.3, 128.0, 99.4, 78.1, 63.4, 51.3, 50.9, 46.5, 46.2,

296

46.0, 35.4, 30.4, 29.6, 29.5, 28.6, 25.0, 22.9, 22.2 ppm. Purity: 97.8%, 99.2% (210 & 254 nm) UPLCMS; rétention time: 0.93 min; (M+l) 474.

Example 338 l-(4-(4-((3,3-Diniethylbutyl)sulfonyl)phenyI)-2-methylbut-3-yn-2-y!)-3-(3elhylquinucJidin-3-yl)urea

Exchanging l-bromo-4-(2-methoxyethyI)benzene for l -bromo-4-((3,3dimcthylbutyl)sulfonyl)bcnzenc (prepared as described in Example 245), the reaction sequence outlined in Example 325 was used to prépare the title compound. *H NMR (400 MHz, DMSO-ùV,) δ 7.88 (d, J= 8.5 Hz, 2H), 7.57 (d, ./= 8.5 Hz, 2H), 6.04 (s, IH), 5.74 (s, IH), 3.29-3.21 (m, 2H), 2.76-2.53 (m, 6H), l.98-1.87 (m, 2H), 1.80-1.67 (m, 2H), 1.65-1.49 (m, 7H), 1.42-1.20 (m, 4H), 0.81 (s, 9H), 0.73 (t, J = 7.3 Hz, 3H) ppm. ¹³C NMR (100 MHz, DMSO-î/₆) δ 156.7, 137.9, 131.9, 128.2, 128.0, 99.4, 78.1, 62.8, 53.5,

51.3,46.5, 46.4, 46.3, 35.4, 29.8, 29.6, 29.5, 28.6, 27.8, 27.7, 22.6, 22.3, 8.0 ppm. Purity: 97.5%, 98.3% (210 & 254 nm) UPLCMS; rétention time: 0.96 min; (M+l) 488.

Exampie 339 l-(4-(4-(l-Methoxy-2-methylpropan-2-yl)phenyl)-2-methylbut-3-yn-2-yl)-3-(3methvlquinuclidin-3-yl)urea

To a stirred and cooled (0 °C) suspension of lithium aluminum hydride (1.81 g, 47.7 mmol) in tetrahydrofuran (100 mL) was added a solution of ethyl 2-(4-bromophenyl)-2methylpropanoate (11.25 g, 41.47 mmol) in tetrahydrofuran (40 mL), dropwise over 15 minutes. The reaction was stirred cold for 1 hour before quenching with the slow addition of ethyl acetate (-15 mL). After another 30 minutes, the reaction was diluted with 1 N hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with 1 N hydrochloric acid and brine, dried (NaîSOi) and concentrated to afford 2-(4bromophenyl)-2-methylpropan-l-ol as a white solid (9.50 g, 100%). To a stirred solution of the crude alcohol (1.92 g, 8.38 mmol) in Af,A^f-dimethylformamide (17 mL) was added sodium hydride (60% dispersion in minerai oil; 0.402 g, 10.1 mmol). After 20 minutes, iodomethane (0.70 mL, 10.9 mmol) was added, dropwise, via syringe. The reaction was stirred ovemight, concentrated and partitioncd between ethyl acétate and water. The organic layer was washed with aqueous sodium bicarbonate solution and brine, dried (Na2SÜ4) and concentrated. The crude product was purified by flash chromatography over silica using a hexane/ethyl acetate gradient to afford l-bromo-4-(l-methoxy-2mcthylpropan-2-yl)benzene as a colorless oil (1.26 g, 62%), Exchanging l-bromo-4-(2methoxyethyl)bcnzene for the this intermediate and Intermediate 2 for Intermediate 1, the reaction sequence outlined in Example 325 was used to préparé the title compound. ^lH NMR (400 MHz, DMSO-</₆) δ 7.34 (d, J= 8.5 Hz, 2H), 7.25 (d, /= 8.5 Hz, 2H), 5.99 (s, IH), 5.80 (s, IH), 3.34 (s, 2H), 3.19 (s, 3H), 2.82-2.57 (m, 6H), 1.96-1.90 (m, IH), 1.831.73 (m, IH), 1.71-1.60 (m, IH), 1.55 (d, J =5.0 Hz, IH), 1.47-1.18 (m, 11H) ppm. ¹³C NMR (100 MHz, DMSO-O δ 156.7, 147.6, 130.7, 126.2, 120.2, 94.7, 81.6, 79.3, 63.2,

58.6, 50.8, 46.6, 46.1, 45.9, 38.8, 30.4, 29.8, 29.8, 25.8, 25.0, 22.7, 22.1 ppm. Purity: 100%, 99.5% (210 & 254 nm) UPLCMS; rétention time: 0.94 min; (M+H⁴) 412.5.

Example 340

QuinucIidin-3-yl (2-(2-(4-(3-methoxypropoxy)phenyl)thiazol-4-yl)propan-2-yl)carbamate

297

To a stirred suspension of 4-mcthoxythiobcnzamide (9.99 g, 59.7 mmol) in éthanol (75 mL) was added ethyl 4-chloroacctoacetate (8.1 mL, 60 mmol). The mixture was heated at reflux for 4 hours before cooling, adding additional ethyl 4-chloroacetoacetate (0.81 mL, 6.0 mmol) and rctuming to reflux. After 4 more hours of heating the reaction was concentrated and partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was combined with additional ethyl acetate extracts, dried (Na₂SO4) and concentrated. The crude product was purified by flash chromatography over silica using a hexane/ethyl acetate gradient to afford ethyl 2-(2-(4mcthoxyphenyl)thiazoI-4-yl)acctate as a pale amber oil (14.51 g, 87%). To a stirred solution of this compound (14.48 g, 52.2 mmol) in A/,M dimethyl forma mi de (125 mL) was added sodium hydride (60% dispersion in minerai oil; 6.27 g, 157 mmol), portion wise over 15 minutes. The resulting red suspension was cooled (0 °C) and treated, dropwise over 10 minutes, with iodomcthanc (9.80 mL, 157 mmol). The cooling bath was removed and the réaction was allowed to stir 4 hours before concentratïng and partitioning the residue between ethyl acetate and water. The organic layer was washed twice more with water, dried (Na₂SC>4) and concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate gradient to afford ethyl 2(2-(4-methoxyphenyl)thiazol-4-yl)-2-methylpropanoate as a pale amber oil (14.12 g, 89%). To a stirred solution of this intermediate (14.12 g, 46.24 mmol) în methylene chloride (250 mL) was added boron tribromide (11.0 mL, 116 mmol), dropwise over 5 minutes, After stirring ovemight, the réaction was quenched by the slow addition of methanol (-20 mL) and then concentrated. The residue was taken up in methanol (250 mL) and concentrated sulfuric acid (7.0 mL). The stirred solution was heated at reflux for 2 hours, concentrated and partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was combined with a second ethyl acetate extract of the aqueous layer, dried (Na₂SO₄) and concentrated to afford methyl 2-(2-(4hydroxyphenyl)thiazol-4-yl)-2-methylpropanoate as a white solid (12.56 g, 98%). To a stirred solution of l-bromo-3-methoxypropane (1.66 g, 10.8 mmol) in acetone (30 mL) was added the phénol intermediate (2.00 g, 7.21 mmol) and potassium carbonate (1.25 g, 9.04 mmol). The mixture was heated ovemight at reflux, filtered and concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate gradient to afford methyl 2-(2-(4-(3-methoxypropoxy)phenyl)thiazol-4-yl)-2methylpropanoate as a faint amber gum (2.47 g, 98%). To a stirred solution of this compound (2.45 g, 7.01 mmol) in 1:1:1 (v/v/v) tetrahydrofuran/ethanol/watcr (45 mL) was added lithium hydroxide monohydrate (1.47 g, 35.0 mmol). After ovemight stirring, the reaction was concentrated and partitioned between water and diethyl ether. The aqueous layer was treated with 1.0 N hydrochloric acid (40 mL) and extracted with ethyl acetate. The combined extracts were dried (Na₂SÜ4) and concentrated to afford 2-(2-(4(3-mcthoxypropoxy)phenyl)thiazol-4-yl)-2-methylpropanoic acid as a white solid (2.19 g, 93%). This compound and quinuclidin-3-ol were reacted according to General Procedure H to generate the title compound as a soft, faint amber solid. *H NMR (400 MHz, DMSO-rie) Ô 7.82 (d, J= 8.9 Hz, 2H), 7.36 (br s, IH), 7.24 (br s, IH), 7.03 (d, J= 8.9 Hz, 2H), 4.49-4.41 (m, IH), 4.07 (t, J = 6.4 Hz, 2H), 3.48 (t, J= 6.4 Hz, 2H), 3.26 (s, 3H), 3.09-2.26 (m, 6H), 2.02-1.91 (m, 2H), 1.91-1.03 (m, 11H) ppm. ¹³C NMR (100 MHz, DMSO-Je) δ 165.8, 162.4, 160.0, 154.6, 127.5, 126.1, 114.9, 112.1, 70.1, 68.4, 64.8,

57.9, 55.4, 53.5, 46.9, 45.9, 28.9, 28.3, 25.2, 24.2, 19.2 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.87 min; (M+H⁴) 460.

Example 341

298 l-Azabicyclo[3.2.2]nonan-4-yl (2-(2-(4-(3-methoxypropoxy)phenyl)thiazol-4y l)p ro p a n -2-y l)ca r b a mate

Using General Procedure H and the reaction inputs 2-(2-(4-(3mcthoxypropoxy)phcnyl)thiazol-4-yl)-2-mcthylpropanoic acid (prepared as described in Example 340) and Intermediate 3, the title compound was prepared. *H NMR (400 MHz, DMSO-i/_f,) δ 7.81 (d, J = 8.8 Hz, 2H), 7.29 (br s, IH), 7.21 (s, IH), 7.03 (d, J= 8.8 Hz, 2H), 4.68-4.60 (m, IH), 4.07 (t, J= 6.4 Hz, 2H), 3.48 (t, J= 6.3 Hz, 2H), 3.26 (s, 3H), 3.00-2.51 (m, 6H), 2.03-1.30 (m, 15H) ppm. ^t3C NMR (100 MHz, DMSO-)₆) δ 165.7, 163.0, 160.0, 154.3, 127.5, 126.2, 114.9, 112.1, 77.1, 68.4, 64.8, 57.9, 53.4, 51.4, 47.7,

44.7, 33.4, 30.6, 28.9, 28.3, 24.7, 22.1 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.88 min; (M+H⁴) 474.

Example 342 jV-(2-(2-(4-(3-Methoxypropoxy)phenyl)thiazol-4-yl)propan-2-yl)-l,4diazabicyclo[3.2.2|nonane-4-cai*boxamide

Using General Procedure H and the reaction inputs 2-(2-(4-(3mcthoxypropoxy)phcnyl)thiazol-4-yl)-2-mcthyIpropanoic acid (prepared as described in Example 340) and Intermediate 6, the title compound was prepared. ^lH NMR (400 MHz, DMSO-î/ê) δ 7.81 (d, J= 8.8 Hz, 2H), 7.19 (s, IH), 7.03 (d, J= 8.8 Hz, 2H), 6.08 (s, IH), 4.16-4.11 (m, IH), 4.08 (t, J= 6.5 Hz, 2H), 3.54-3.44 (m, 4H), 3.26 (s, 3H), 2.95-2.74 (m, 6H), 2.01-1.88 (m, 4H), 1.69-1.53 (m, 8H) ppm. ¹³C NMR (100 MHz, DMSO-40 δ

165.4, 164.2, 160.0, 155.6, 127.4, 126.2, 114.9, 111.6, 68.4, 64.8, 57.9, 57.5, 54.0, 46.9,

45.9, 41.3, 28.9, 28.8, 26.9 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.82 min; (M+H⁴ ) 459.

Example 343

Quinuclidin-3-yl (2-(2-(4-(2-methoxyethoxy)phenyl)thiazoI-4-yl)propan-2yl)carbamate

To a stirred solution of 2-bromoethyl methyl ether (1.88 g, 13.5 mmol) in acetone was added methyl 2-(2-(4-hydroxyphenyl)thiazol-4-yl)-2-methylpropanoate (prepared as described in Example 185; 2.00 g, 7.21 mmol) and potassium carbonate (1.56 g, 11.3 mmol). After heating at reflux ovemight, the mixture was treated with additional 2bromocthyl methyl ether (1.88 g, 13.5 mmol) and potassium carbonate (1.56 g, 11.3 mmol). The réaction was heated at reflux for a second night, filtered and concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate gradient to afford methyl 2-(2-(4-(2-methoxyethoxy)phenyl)thiazol-4-yl)-2methylpropanoate as a white solid (2.71 g, 90%). To a stirred solution of this compound (2.71 g, 8.08 mmol) in 1:1:1 (v/v/v) tctrahydrofuran/cthanol/water (50 mL) was added lithium hydroxide monohydrate (1.70 g, 40.5 mmol). After ovemight stirrîng, the reaction was concentrated and partîtioned between water and dicthyl ether. The aqueous layer was treated with 1.0 N hydrochloric acid (41 mL) and extracted with ethyl acetate. The combined extracts were dried (Na₂SÛ4) and concentrated to afford 2-(2-(4-(2methoxyethoxy)phenyl)thiazol-4-yl)-2-mcthylpropanoic acid as a white solid (2.57 g, 99%). This compound and quinuclidin-3-ol were reacted according to General Procedure H to generale the title compound as a pale amber solid. *H NMR (400 MHz, DMSO-)) δ 7.82 (d, J = 8.8 Hz, 2H), 7.36 (br s, IH), 7.24 (br s, IH), 7.04 (d, J = 8.8 Hz, 2H), 4.494.41 (m, IH), 4.19-4.12 (m, 2H), 3.71-3.65 (m, 2H), 3.32 (s, 3H), 3.11-2.87 (m, IH),

299

2.86-2.19 (m, 5H), 1.92-1.16 (m, 11H) ppm. ^I3C NMR (100 MHz, DMSO-t/₆) δ 165.7,

162.9, 159.9, 154.6, 127.5, 126.2, 114.9, 112.2, 70.3, 70.1, 67.1, 58.2, 55.4, 53.5, 46.9,

45.9, 28.3, 25.2, 24.3, 19.2 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.85 min; (M+H⁴) 446.

Example 344 l-Azabicyclo[3.2.2|nonan-4-yl (2-(2-(4-(2-methoxyethoxy)phenyl)thiazol-4yl)propan-2-yl)carbamate

Using General Procedure H and the reaction inputs 2-(2-(4-(2methoxyethoxy)phenyl)thiazol-4-yl)-2-mcthylpropanoic acid (prepared as described in Example 343) and Intermediate 3, the title compound was prepared. ’H NMR (400 MHz, DMSO-î/ô) 6 7.81 (d, J= 8.8 Hz, 2H), 7.29 (br s, IH), 7.21 (br s, IH), 7.04 (d, J= 8.8 Hz, 2H), 4.67-4.60 (m, IH), 4.18-4.12 (m, 2H), 3.71-3.65 (m, 2H), 3.32 (s, 3H), 3.00-2.50 (m, 6H), 1.99-1.25 (m, 13H) ppm. ¹³C NMR (100 MHz, DMSCWe) δ 165.7, 163.0, 159.9,

154.3, 127.5,126.2, 114.9, 112.1, 77.1, 70.3, 67.1, 58.2, 53.4, 51.4,47.6, 44.7, 33.4, 30.6,

28.3, 24.7, 22.1 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.86 min; (M+H⁴) 460.

Example 345 A^r-(2-(2-(4-(2-Metlioxyethoxy)phenyl)thiazol-4-yl)propan-2-yl)-l,4diazabicyclo[3.2.2]nonane-4-carboxaniide

Using General Procedure H and the reaction inputs 2-(2-(4-(2methoxyethoxy)phenyl)thiazol-4-yl)-2-mcthylpropanoic acid (prepared as described in Example 343) and Intermediate 6, the title compound was prepared. ^lH NMR (400 MHz, DMSO-e/c) δ 7.82 (d, J= 8.8 Hz, 2H), 7.20 (s, IH), 7.05 (d, J = 8.8 Hz, 2H), 6.09 (s, IH), 4.20-4.10 (m, 3H), 3.71-3.65 (m, 2H), 3.54-3.47 (m, 2H), 3.32 (s, 3H), 2.96-2.73 (m, 6H), 2.00-1.88 (m, 2H), 1.70-1.53 (m, 8H) ppm. ¹³C NMR (100 MHz, DMSO-</₆) δ 165.4,

164.2, 159.9, 155.6, 127.4, 126.3, 114.9, 111.7, 70.3, 67,1, 58.2, 57.5, 54.0, 46.9, 45.9,

41.2, 28.8, 26.8 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.79 min; (M+H⁴) 445.

Example 346

Quinuclidin-3-yl 2-(5-(4-(2-methoxyetlioxy)phenyl)pyridin-2-yl)propan-2ylcarbamate

Using General Procedure F and the reaction inputs 5-bromopicolinonitrile and 2-(4-(2methoxyethoxy)phenyl)-4,4,5,5-tetramcthyl-l,3,2-dioxaborolane, 5-(4-(2methoxyethoxy)phenyl)picolinonitrilc was prepared. Cercium trichloride (8.05, 21.6 mmol) was loaded into a flask and dried by heating (170 °C) under vacuum for 3 hours. The solid was taken up in tetrahydrofuran (20 mL) and stirred vigorously for 30 minutes. The suspension was cooled to -78 °C and treated, dropwise, with a 3.0 M solution of mcthyllithium in dicthyl ether (7.2 mL, 21.6 mmol). Following addition, the réaction was stirred at -78 °C for 1 hour before adding a solution of the above arylborate (1.83 g, 7.20 mmol) in tetrahydrofuran (20 mL). The mixture was maintained at -78 °C for 2 hours and then allowed to warm to room température. At this time, the reaction was quenched b y the addition of aqueous ammonium hydroxide (10 mL) and filtered through a plug of Celite. The filtrate was extracted with ethyl acetate and the combined extracts were washed with brine, dried (Na₂SÜ4) and concentrated. The residue was purified by flash

300 chromatography over silica using ethyl acetate eluant to afford 2-(5-(4-(2methoxycthoxy)phenyl)pyridin-2-yl)propan-2-amine as a yellow solid (0.800 g, 39%). To a stirred suspension of this intermediate (0.500 g, 1.75 mmol) in water (10 mL) and concentrated hydrochloric acid (0.44 mL) was added toluene (10 mL). The mixture was cooled (0 °C) and treated with, simultaneously over 1 hour, solutions of triphosgcnc (0.776 g, 2.62 mmol) in toluene (10 mL) and sodium bicarbonate (2.2 g, 26 mmol) in water (20 mL). Following the additions, the reaction was stirred for an additional 30 minutes before the upper toluene layer was removed and dried (Na₂SO4). At the same time, a stirred solution of quinuclÎdin-3-ol (0.445 g, 3.64 mmol) in tetrahydrofuran (10 mL) was treated with sodium hydride (60% dispersion in minerai oil; 0.154 g, 3.85 mmol). This mixture was stirred for 5 minutes and then added to the solution of crude isocyanate in toluene. The reaction was stirred for 10 minutes, quenched with the addition of brine (5 mL) and extracted with ethyl acetate. The combined extracts were dried (NuîSOi) and concentrated. The residue was purified by flash chromatography over reversed phase silica to afford the title compound as a light yellow solid (0.100 g, 13%). ‘H NMR (500 MHz, CDC1₃) δ 8.70-8.70 (d, J= 2.0 Hz, IH), 7.83-7.81 (m, IH), 7.497.47 (d, J= 9.0 Hz, 2H), 7.45-7.43 (d,.7 = 8.0 Hz, IH), 7.03-7.01 (d, J= 8.5 Hz, 2H), 6.63 (br s, IH), 4.68-4.66 (m, IH), 4.16 (t, J= 5.0 Hz, 2H), 3.77 (t, .7 = 5.0 Hz, 2H), 3.45 (s, 3H), 3.19-2.70 (m, 6H), 2.15-1.89 (m, 2H), 1.76 (s, 6H), 1.73-1.36 (m, 3H) ppm. ^|3C NMR (125 MHz, CDCI3) δ 162.7, 158.9, 154.9, 145.9, 134.8, 134.3, 130.1, 128.1, 119.2,

115.2, 71.0, 70.8, 67.4, 59.2, 55.9, 55.7, 47.4, 46.5, 46.4, 27.9, 25.4, 24.6, 19.5 ppm. Purity: >99% (214 & 254 nm) LCMS; rétention time: 1.32 min; (M+H⁴) 440.2.

Example 347 l-Azabicyclo|3.2.2]nonan-4-yl 2-(5-(4-(2-methoxyethoxy)phenyl)pyridin-2yl)propan-2-ylcarbamate

Exchanging quinuclidin-3-ol for Intermediate 3, the reaction sequence outlined in Example 346 was used to préparé the title compound. *H NMR (500 MHz, CDCI3) δ 8.71 (s, IH), 7.85-7.83 (m, IH), 7.50 (d, J= 8.5 Hz, 2H), 7.45 (d, J= 8.5 Hz, IH), 7.04 (d, J = 8.5 Hz, 2H), 6.54 (s, IH), 4.85-4.82 (m, IH), 4.18 (t, .7 = 4,5 Hz, 2H), 3.79 (t, .7=4.5 Hz, 2H), 3.46 (s, 3H), 3.12-2.76 (m, 6H), 2.35-1.43 (m, 13H) ppm. ^liC NMR (125 MHz, CDCI3) δ 162.7, 158.9, 154.6, 145.9, 134.9, 134.3, 130.1, 128.1, 119.2,115.2, 77.9, 71.0,

67.4, 59.2, 56.0, 51.6, 48.1, 45.0, 33.5, 30.4, 29.7, 28.0, 24.7, 22.0 ppm. Purity: >97% (214 & 254 nm) LCMS; rétention time: 1.02 min; (M+H⁴) 454.2.

Example 348 l-Azabicyclo[3.2.2]nonan-4-yl 2-(5-(4-(2-methoxyethoxy)phenyl)pyridin-2yl)propan-2-ylcarbamate (single enantiomer A)

Using General Procedure F and the reaction inputs methyl 2-(5-bromopyridin-2-yI)-2methylpropanoate (Org. Leu. 2005, 7(21), 4585-4588) and 4-(2methoxyethoxy)phenylboronic acid, methyl 2-(5-(4-(2-methoxyethoxy)phenyl)pyridin-2yl)-2-methylpropanoate was prepared. To a stirred solution of this compound (7.00 g, 21.3 mmol) in 1:1:1 (v/v/v) tctrahydrofuran/ethanol/water (135 mL) was added lithium hydroxide monohydrate (2.68 g, 63.9 mmol). After ovemight stirring, the réaction was concentrated and partitioned between water and diethyl ether. The aqueous layer was treated with 1.04 N hydrochloric acid (61.4 mL) and extracted with ethyl acetate. The combined ex tracts were dried (Na₂SC>4) and concentrated to afford 2-(5-(4-(2methoxyethoxy)phenyl)pyridin-2-yl)-2-methylpropanoic acid as an off-white solid (5.90

301 g, 88%). This compound and Intermediate 15 were reacted according to General Procedure H to generate the title compound as an off-white solid. ’H NMR (400 MHz, DMSO-î/₆) δ 8.74 (d, J= 2.1 Hz, IH), 7.96 (dd, J = 8.3, 2.4 Hz, IH), 7.63 (d, J = 8.3 Hz, 2H), 7.51 (br s, IH), 7.44 (d, J= 8.3 Hz, IH), 7.06 (d, J= 8.8 Hz, 2H), 4.69-4.57 (m, IH), 4.17-4.11 (m, 2H), 3.71-3.65 (m, 2H), 3.32 (s, 3H), 3.00-242 (m, 6H), 1.98-1.33 (m, 13H) ppm. ⁿCNMR (100 MHz, DMSO-î/₆) δ 163.9, 158.5, 154.2, 145.4, 134.0, 132.8, 129.4, 127.8, 119.0, 115.1, 77.2, 70.4, 67.0, 58.2, 56.1, 51.4, 47.8, 44.6, 33.5, 30.6, 28.2, 24.7, 22.2 ppm. Purity: 100%, 100% (210 & 254 nm) UPLCMS; rétention time: 0.65 min; (M+H⁴) 454.4.

Example 349 l-Azabicyclo[3.2.2]nonan-4-yl 2-(5-(4-(2-methoxyethoxy)plienyl)pyridin-2yl)propan-2-ylcarbamate (single enantiomer B)

Exchanging Intermediate 15 for Intermediate 16, the reaction sequence outlined in Example 348 was used to préparé the title compound. NMR data matched that of Example 348. Purity: 100%, 99.4% (210 & 254 nm) UPLCMS; rétention time: 0.65 min; (M+H⁴) 454.4.

Example 350

Inhibition of glucosylceramide synthase activity for certain compounds of the invention were measured with 1) a microsomal assay that directly mcasurcs the conversion of ceramide to glucosylceramide by HPLC and 2) second, cell based, phenotypic assay that monitors cell surface expression of the downstream lipid GM3 by antibody mediated immunofluorescence. The cell based assay was performed in two different cell types, B16 and C32. Cell viability was also assessed in the second, cellbascd assay.

Results of these assays are set forth in Table 1 below. The “Compound Number” in the table corresponds to the compound disclosed in the Example of the same number. The results of the microsomal assay arc expressed as “GCS IC50”, which represents the concentration ofthe compound causing 50% inhibition of glucosylceramide synthase activity. The results of the cell based assays (performed in two different cell Systems, i.e. B16 mousc melanoma or C32 human melanoma cells) are expressed as “GM3 B16 IC50” or “GM3 C32 IC50” for the B16 assay and the C32 assay, respectively. These values represent the concentration ofthe compound causing 50% inhibition ofGM3 expression on the cell surface. The results of the viability assays are expressed as “Viability, B16 IC50” or “Viability, C32 IC50”, respectively. These values represent the concentration of the compound causing 50% cell dcath. Values greater than 10 represent a lack of cell death.

302

		ftxanaH t	0.719	1.26	0.109
l	4-(( 1 ,r-Biphenyl]-4-yl)-N-(3n»ethylquinuciiditi-3-yl)pipeiazine· 1caibownide	7.16	10.
2	4-([ 1 ,l'-Bipheny!]-4-yl)-A'-(qujnuclidin-3yl)piperazmel -caibOTsmide	2	6.93	1.6	0.667	5.28	7.58
3	4-((1,1 ’-Biphcnyl]-4-yl)-?/-{laznbicyclo[3.2.2jQ<.'nan-4'yI)pîpcrazine· 1 ctirboxamidû	3	t0.9	6.84	1.0	4.18	231
4	4-((1,1 '-BiphenyI]-4-yl)-A‘-{4-uietliyl-1 - aziibicyc]o[3.2.2]nonan-4-yl)pÎperazine-1 carboxaniide	4	1.0	1.38	0.0625	6.16	6.31
5	(4 -<[ 1 ,l'-Biphenyl]-4-yl)pipera7j n-1 -y IX1,4diazabicyclo[3.2.2]nonan-4-yl)mcthanone	5	30.	2.0	2.0	2.0	2.0
6	Quinuclidni-3-yl 4-([ 1,1 ’-biphenyl]-4yl)piperazinc-l -carboxylate	6	5.6	3.52	1.0	5.21	4.12
7	»UPhcnyiW-<qiiwiuç\|jdin-3*yl)piiKra7AiU5-l· carbüxamide	7	12.2	>10	7.08	10.	10.
8	N-{ J -Azabicyclo[3 22]nonan‘4yn*4plienylpipcrfiiiinû-l-carbaxiijjyde	8	331	>10	0.518	10.	10.
9	M(3-MeshyiquinuclidÎn-3-yJ}-4· phcnylpipieiwàne-1-carboxaiiiÎds	9	12.2	>10	7.59	10.	10.
ΙΟ	M(d-Meiliyi-l.uzabÎcyclo[3.2.2Jnomui-4yl>-4*ph(siyipiperazine-1 -catboxnmide	10	14.7	>10	4.24	10.	10.
11	1,4-Diazabicycto[3.2.2]nonan-4-y 1(4phenylpipenian-l-yl)mcthiinone	11	20.8	>10	>10	10.	10.
12	Quinuclidin-3-yl 4-phenylpiperazine-lcuboxylate	12	12.2	>10	>10	10.	10.
13	4-([l,r-Biphcnyl]-3-yl)-.\'(4uiûiicïidüi-3y!)piperazine-l-crulxrxarnide	13	2.47	6.8	0.697	8.59	10.

303

14	4-([ I ,l'-Biphcnyl]-3-yl)-.V· (1 nzabtcyda[3.2.2]iiûnan-4-yl)pi\|>crazÎae-l«irbaxnnüdc	14	0.705	3.39	0.108	6.79	10.
15	4-([ 1 ,l*-Biplienyl]-3-yl}-?/.(3 · mediylqn iau did in-3-yt)piperazine-1 carbctxamidc	15	0.839	0.368	0.172	10.	10.
16	4-((1,1 ’-Biphcnyl]-3-yl)-A^,-(4-ntethyl-l azabicydo[3.2.2]nonaa-4-yl)piperazin<: 1 · ciu'bwaniide	16	0.0495	0.181	0.0124	6.76	1.0
17	(4-((1,r-Biphcnyl]-3-yl)pipcrazin-l-ylXl,4dinzabicydo(3.2.2]nonan-4-yl}mcthanone	17	12.2	6.31	6.36	10.	10.
18	Quinudidîn-3-yl 4-([l,l’-biplicnyl]-3yi}pipcrazine-l -carboxylate	18	0.551	2.04	0.563	8.36	10.
19	l-Azabicyclo[3.2.2]nonan-4-yl 4-((1,1biphenyl]-3-yl)piperazine-1 -carboxylate	19	2.67	1.48	0.456	7.09	9.09
20	l-A'znbjcyc\|o[3.2.2]nomm-3-yi 4-{[l_tVbtphenyl]-3 -yl)pipcrazine~1 -carboxylate	20	16.6	4.47	10.7	7.71	15.1
21	4-([ 1 ,l'-Biphetiyl]-3-yl)-.V-(3ethylquinud(din-3-yl)pipetuzme- ! carboxainide	21	0.288	0.168	0.0252	7.23	3.16
22	4-(4'-Fluoro-[ 1,1 ’-biphcnyi]-3-yl)-A-(4· uietliyl-l-a?abicycJo[3.2.2]iionan-4yi)piperazine-l -carboxamide	22	0.613	0.629	0.0411	7.06	1.0
23	7/-(3-I?JiylquÎnudidin-3-yl)-4-6i'-Îluûro· [1,1 '-biphenylJ-3-yl)piperaziiic- icarbcxamide	23	1.58	0.351	0.0909	7.07	3.16
24	l-A2abicydo[3.2.2]nonan-4-yl 4-(4'-f]uoro[1,1 '-biphenyl]-3-yl)pÎperazine-1 carboxylate	24	9.52	1.68	1.08	3.61	3.98
25	l -Azabicyclo[3.2.2]noiuui-3-yl 4-(4'-fluoro[1,1 '-biphcnyl]-3-yl)pipcrazinc- i carboxylate	25	3.48	4.86	9.38	5.39	5.41
26	jV-(4-Mi:thyl-1 -azabicydo[3.2.2 \|/ioiuib-4yl)-4-(3(pyrimidin-2-yi)phenyl)piperazine1-c.nrboxaniidc	26	6.9	>10	0.36	10.	10.
27	JV-(4-Mcthyl-l ·»ζ«1ήίν«1ο(3.2.2 ]nonan-4yl)-4-(3-(pyiirnidin-5-y!}phciiyl)pipeniziiw1-carboxantide	27	16.5	>10	0.798	10.	10.
28	4-(3-Iscpropylphcnyl}-A^r-(4-nicthyl-lazabicydo[3.2.2Ja'?nan-4-yl;pipi:razüic-lcarboxantide	28	1.59	1.44	0.0866	10.	3.16

304

29	4-(3-Cyclohexylphcnyi)-AI-(4-melhyl-liizabicyclo[3,2.2]nc>nan-4-yt)piiœra7.inc · i carboxatnide	29	0.309	2.66	0.0382	7.81	1.0
30	4-([ 1 ,r-Biphcnyl]-3-yl}-2-mctliykV (4 mû1hyU-nzabicyelo[3.2.2]mJiiaii-4yljpipciazinc-1 -cniboxamidc	30	0.376	0.864	0.0639	7.64	1.0
31	4-([ 1 ,r-Biphenyl]-3-yl)-3-methyl-iV-(4methyl-1 -nzabicyclo[3.2.2]nonan-4 yljpiperazino-1 -ouboxaniidc	31	0.00406	0.0707	0.001 SI	7.62	1.0
32	4-([ 1 ,r-Biphenyl]-3-yl)-3-metliyl-Ai-(4· methyl-l-nznbicyelù[3.2.2]noivni-4yl/piperazine· l-cerboxamidc	32	0.544	0.462	0.0465	7.29	3.16
33	1-(4'-F1uok>.[ I, Γ-h i pbc i>y 1 ]-3-yl)-A'-(3 melhylqttÎnuelidiii-3-yi)pipcridmc-4crubnxainido	33	0.0221	0.237	Û.00S02	6.91	1.0
34	l-(4'-Fluoro-[ 1 ,r-biphcnyl]-3-yl)-.Vyk methyl- J -07Abicyclo(3,2.2]nonan-4yl)pip<.'ridinc-4-eaiboxnrrude	34	0.00478	0.079	0.000872	4.72	0316
35	1 -ί 11 ,l’-Biphenyl]-3-yl)-.V-(3nr>o!hylquinuclidiji-3-yi)pipcriditie-4L'atboxamidc	35	0.0496	0.149	0.00711	7.31	1.0
36	l-([l,r-Bipheiiyl]-3-yl)-A'-(4-me1iiyHazabicycio[3.2.2]nonaii-4--yl!piperidùie-4cnfboxamide	36	0.0103	0.136	0.0025	7.57	1.0
37	l-([l,l’-BÎphenyl]-4-yl>-W3- mcthylquùuichdin-3-yl)piperidÎne-4carboxamidc	37	155	1.8	0.131	7.05	6.9
38	l-t[l,l'-Biphenyl]-4-yl)-Æ-(4-inclliyl-la2abicyclo[3.2.2]aon;in-4-yl)pipt;ridttu>4carboxamide	38	1.05	2.6	0.0894	6.62	6.74
39	Af-(4-MeÜiyl-1 -azMbicyclo[3.2.2]uonan-4yl)-l-(3-{pyrtmtdin-2-yljpl>enyl)pîperidine4-eaibûxaniide	39	1.8	7.24	0.126	10.	3.16
40	M(4-Methyl-1 azabicyelo[3^.2]nonan-d·· ylÿl-(3-{pyrimidm-5-yi)phonyi)pipûridwte4-caibt7xamidc	40	0.291	5.5	0.0152	0.0713	1.0
41	l-(4-(4-Fluorophenyl)pyrimidin-2-yl)-iV-(4methyl· l-azabicyclo[3.2.2]nonan-4·· ylJpÎperidme-4-cartxrainide	41	0.00114	0.0097	0.000124	6.44	0.020
42	1-( 4-(4-Fluorophenyl Jpyri rnidin-2-yl)-jV(4· niethyl-l-tcMbicyc[o[3.2.2]noMn*4yi)pipcndinc-4-caihoxamidc (single enantiomer A)	42	0.0941	0.918	0.00982	7.66	4.64
43	l-(4-(4-Fluoropheny[)pyrimidin-2-yl)-iV4'4m ethyl-1 -az;ibicyclo[3.2.2]nc-nan-'lyljpiperidine-d-cartwxamide (single enantiomer B)	43	0.00125	0.00654	0.000065 5	7.14	8.92

305

<14	l (4-(4-Fluotophenyl)pyriniiditi-2-yl)-jV (3 nKihylquiimclidin-3-^)pipcridine-4carbuxumîdc	44	0.00124	0.0499	0.000205	9.27	0316
45	1-(4-( 4-Flu orophenyl)pyrimidin-2-yl)-.V(quuinclid 1/1-3^1))11 peridÎiic-4-eiirboxatnnle	45	0.00267	0.125	0.000457	10.	1.0
46	1-(6-(4- Flüorophenyl)pyrazin-2-yl}-)V-(4- methyl-1 -azabicyclo[3.2.2Jnonan-4yljpipcri<Jinc-4-cirtx>xsiiiide	46	0.00279	0.0766	0.000425	731	0316
47	l-(6-(4-Fluorophcnyl)pyrazin-2-yl)-A'-(4· inclhyl-l-KzabicycJo[3.2.2\|nûn«n-4yl)pipcridine-4-caiboxnmide (single emuitiouier A)	47	0.258	2.19	0.050	7.83	3.16
48	l-(6-(4-Fluorophcnyl)pyiazin-2-yl)-A'-(4methyl-l-azabicyclo[3.2.2]nc.'nan-4y!)piporidûie-4-ca/boxiinùde (single enantiomer B)	48	0.00161	0.0477	0.000096	7.76	0.00517
49	l-(6-(4-Fluorophcnyl)pyraziii-2-yl)-iV-(3· nwüiylquinjic1idin-3-jd)pipcridine-4cnrboxiiiiiide	49	0.0041	0.145	0.000822	8.16	1.0
50	l-(4-(4-FluoiOphcnyl)-l,3,5-triazin-2-yl)-iV· (4-methyl-1 -a'zabicycloi3.2.2]nonan-4y! )pipcridine-4-catboxiimtde	50	0.0325	0.162	0.000708	10.	3.16
51	l-(2-(4-Fluorophcnyl)pyrimidin-4-y!)-_IV-(4methyl ·1 ·αζαΝ«γίΙο13.2.2]ηοηηη-4· yl)pj\|)cridine-4-<.'uboxnmide	51	0.0466	0.335	0.00388	8.26	3.16
52	4-([ 1, l '-Biplienyt]-3-yl)-jV-(4-inetliy 1-1 - HZjibicyeto[3.2.2]noniui-i-yl)pipwidine-lcaiboxanâde	52	0.503	1.06	0337	7.36	8.64
53	4-([l, r-Biphcnyi]-4-yl)-,Y-i4-indliy!-l - :t'zabkyilo[3.2.2]nonan-4-yl)piperidÈne-lcatboxnmide	53	221	1.24	0.175	6.74	6.29
54	l-(5-Fluoro-4-(4-iluorophciiyl)pyrimidin-2yl)-V-(3-mcthylquiiiuc!idiii-3-yi)pi\|>eridinûd-eaiboxaoiide	54	0.00073 4	0.106	0.000090 2	5.13	8.04
55	l-(5-Fluoro-4-(4-Iluorophenyl)pyrimidin-2- yl)-.V-(4-metliyl-l-nzabicycki[+2.2]nonnn- 4-yl )piperidine-4-carboxanùdc	55	0.00073 6	0.0475	0.000047 9	3.74	0.10
56	l-(5-Fluoro-4-(4-(2- methoxyethoxy)phenyl)pyriiiiidin-2-yl)-A- (4-uKtliyl-l-aaibicyck'[3.2.2jnünîui-4- yI)piperidinc-4-caitwoimidc	56	0.00463	0.0209	0.000173	6.76	7.42
57	l-(5-Fluoro-4-(4-(2- melhoxyclliuxy)phenyl)pyrimidiii-2-yl)-iV(3-mcdiylquiniiclidin-3-yl)pipcridine-4caiboxainide	57	0.00241	0.0693	0.000169	10.	1.0
58	l-i5-FIuoro4-(4-((2- melhoxyetlioxy)mcthyl)phenyl)pyrimidin-2- yl)-A^r-{4-mcthyl-i-/izabicyclc)[3.?..2^,](ionan- 4-yl)pipcridine-4-carbùx<imide	58	0.00339	0.0405	0.00017	10.	1.0

306

59	l-(5-Fluoro-4-(4-((2- methoxycthoxy)mclhy1)\|ihcnyl)pyriniidin-2yi)-.¥-(3-methylquinuclidin-3yl)piperidine· 4-carboxïiiudc	59	0.00918	0.152	0.000339	10.	0.464
60	l-(5-Flnom-4-(4- (methoxymetliyl)phenyl)pyrimidÎn-2-yl)-;V- (4-inethyl-l-azabÎcyclo[3.2.2\|n<niaii-4- yi)piperidine-4-cart>oxaniide	60	0.00168	0.0155	0.0001	3.5	0.0464
61	l-(5-FIuon>-4-(4- (methoxymethyl)phcnyl)pyrimidin-2-yl)-iV(3-uiclhyIquûiuclidin-3-yl)pi^><;iidÎiic-4uiflioxumida	6!	0.00141	0.0524	0.00013	8.54	0.0464
62	l-(5-Fluoro-4-(4-(3- methoxypropoxy)phenyl)pyriniidin-2-yl)-,V- (4-nicthybl-xzabicyclo[3.2J]iinniui-4yl)pïperidine-4-Ciirtx>x*iiùde	62	0.00093 1	0.0105	0.000109	2.39	0.10
63	l-(5-Fluort>4-(4-(3mcllioxypropoxy)pheayl)pyri midin-2-yl)-¥(3-methylqu inuclidin-3-y l)piporidine-4 · caiboxrirnide	63	0.00058 6	0.0408	0.000098 8	3.52	0.10
64	1-(4-(3,4-Di iluorophenyl)pyriniÎdin-2-yl)- Af-(4-nirthyl-l-anibicydo[3.2.2]nonan-4- yl)pipcridine-4-carboxamide	64	0.0017	0.0329	0.000062	3.42	5-53
65	1-(4-(3,5-Di fluorophenyOpyri nudtn-2-yt)- A44-metbyi-I-MMbicyc!0i3.2.2]n<Miwi-4- yl)piperidinc-4-carboxawidc	65	0.00131	0.0561	0.000093 4	4.14	0.215
66	1-(4-(4-(2- Mcthoxycthoxy)phenyl)pyn midin-2-yl)-A'(4-tnelhyl-l-n2iibieyelu[3,2.2]nonati-4yî)pijx:ridïue-4-cartxixoulidL·	66	0.00317	0.0693	0.000329	8.2	0.215
67	1-(4-(4-(3- Mclhoxypropoxy)phenyl)pyrimÎdin-2-yl>- AA(4-mcîhyi-f-<iaibicyd<i[3.2.2]iioii«ii-4yl)pipK'riilinc-4-caiboxAtnidc	67	0.00188	0.00724	0.000114	4.95	1.0
68	l-(4'-(2-Methoxycthaxy)-[ 1,1 '-biphcay 1] -3- yl)-/V-(4-üielhyi-l-azabicycki[3.2.2]ni>mui- 4-yl )pipcriduic-4-cnrtx>X(inÎitc	68	0.0213	0.132	0.00353	7.12	3.16
69	l-(4'-((2-Melhoxyelhoxy)mcthyl)-[ 1, Γbiphcayl]-3-yl)-¥-(4-rnctliyl-1 azabicyclo(3.2.2Jnonaii-4-yl)piperidine-4carbfixnrnidc	69	0.0362	0.303	0.00464	4.64	1.0
70	1 -(4-(4-(Methoxynicthyl)phcnyl)pyrimidin- 2-yi>W-(d-inethyl-laznbieyck>[3.2.2]nonan-4-yl)pÎpcridHœ-4catbüxamide	70	0.00396	0.0156	0.000090 5	1.0	1.0
71	1- (4-(4-(2-Fluoroethoxy)pheayl)pyrimidui- 2- yl)-,¥-(4-mediyl-1 uzabicyclo[3.2.2jn<?run-l-yl;pipcridinc-4cnrboxamiile	71	0.00248	0.00429	0.000126	2.15	0.010
72	1-(4-(4-(3- Melhoxypropoxy)phenyl)pyrimidin-2-yl)/V-(quinuclidÎn-3-yt)pipcridinc-4corboxatnide	72	0.00116	0.0795	0.00026	8.63	0.464
73	1- (4-(4-(Meüioxyincthyl)phenyl)pynniidin- 2- yl)-.¥-(3-mcthy[quinuclïdm-3- yE)pipcridine-4-cutx>XAnudc	73	0.00346	0.0474	0.00025	4.64	0.631

307

74	1- (4-(4-((2- Mcthoxycthoxy)mclhyl)phcnyl)pyriniidÎn- 2- yl)-,V-(4-uiclhyl-l· ii7jibicyclo[3.2.2]nùnnri-4-yl)piperidùie-4Îarbuxamide	74	0.0128	0.0325	0.00071	10.	0.215
75	4-Fluoro-1-(4-( 4- (mcthoxymclhyl)phenyl)pyrimidin-2-yl)-A'(4-ΐϋϋύινΙ-Ι-»ζΐιΙ)ί<:)Έΐο[3.2.2]ΐΗΉΐιιιι-4yi)pipcridÎne Ί- carboxamide	75	0.00283	0.0489	0.000383	5.27	0316
76	4-Fhioro-1-(4-(4-(3- methoxypropoxy)phenyl)pyrimidin-2-yl)-.V(3-methytquimielidin-3-yi)pipcridinc-4· enibrjxninide	76	0.00134	0.0587	0.000141	3.87	1.0
77	4-Fluoro-1 -(5-fliioro-4-(4-((2meÜioxycthoxy}mcthyl)plicnyI)pyrimidin-2yl)-A^,-(4-me1hyl-l-oziibîçyilo[3.2.2]uoiiaiid-ylJt’ipcridine-d-cnrfxixamidc	77	0.00167	0.0863	0.000316	3.76	0316
78	4-Fluoro-l-(5-fluoro-4-(4-((2methoxyethoxy)methyl)phenyt)pyrimidin-2yl)-A'-(4-nictliy!· 1 -a7abicyclo[3.2.2]nûnan4-yDpiperidmo-4-carbaxstnidc (single enunttoinei A)	78	0.0647	3.12	0.00487	3.54	1.0
79	4-Fluoro-l-(5-fluoro-4-(4-((2metlioxyethoxy)methyl)phenyl)pyrimidin-2yl)-A'-(4 -melhÿi-1 -azabicyclo\|3.2.2 Jnoaan4-y\|)pipei^,idrac-4-cariwxaiuiilc (single entmliomer B;	79	0.0018	0.109	0.000191	4.28	0215
80	4-Fiuoro-l-(4-{4- (niethoxymcthyl)phenyl)pyrimidin-2-yl)-A'· (3-icelhylquiuuclidin-3-yI)i>ipûridine-4caiboxumide	80	0.0040	0.0685	0.000525	10.	0.215
81	(£)-4-1111010-1-(4-(4- (methoxymethyi)phenyl)pyrimidin-2-yl)-A'(3-methylquinuclidm-3-yl)pip<:ndine-4cartmxamitfe	81	0.0023	0.0481	0.000222	10.	0316
82	4-Fluoro-l-(4-(4-(3methoxypropoxy)phenyl)pyrimÎdiii-2-yl)-jV(4-nictliyl-1 -azabîcyclo[3.22]nminn-4yl)piperidine-4-caiboxamide	82	0.00126	0.0421	0.000128	2.79	1.0
83	4-Fluoro-l-(4-(4-((2- methoxyethoxy)methyl)phenyi)pyrimidiii-2yl)W-(3-mcÛiylquiniiclidiii-3-yi)pipcridino4-cnrboxainidû-	83	0.0134	0.119	0.00113	10.	1.0
84	(.S'M-Fluoro-i -(4-(4-((2nicllioxycllioxyÎmcdiyhpJiciiyl}pyfiinidÎn-2yl}W-(3-methyiquintK:lidia-3.yl)pipcridine· d-carboxsnùde	84	0.00535	0.0903	0.000621	10.	1.0
85	4-Fluoro-l-(4-(4-(2mctlioxyelhoxy)phcnyl)pyrimidin-2-yl)-jV. (3-ineüiylquiniicitdüi-.3-yl)piticiid«ie-4carboxamide	85	0.0105	0.0799	0.000389	10.	0316
86	(£)-4-Fluoro-l-(4-(4-(2uœûioxyclhoxy)phciiyt)pyrimidin-2-yl)-A'(3 •melhylquùiuciidin-3-yl)pÎperidine-4 cattocrinüde	86	0.00346	0.048	0.000241	10.	1.0
87	4-Fiuoro-1-(4-(4-(2- ÎIuoroeÜtoxy)pIicnyl)pyrimidin-2-yl)-.V- (quinuctidin-3yl)piperidinc-4-carbcx timide	87	0.00191	0.0643	0.000177	8.91	0.215
88	(SJ-4-Fluoro-1-(4-(4-(2fluorocthoxy)phcnyl)pyriinidiii-2-yl)-.¥· (qoituicli<lm-3-yl)piperidiitc-4-ewboxamidc	88	0.00168	0.0568	0.000252	10.	1.0

308

89	4-Fiuoro-l-(4-(4-((2mcthoxyethoxy)methyl)phenyl}pyrimÎdin-2yl)-.¥-(4-methyl-l-az.abicyclo[3.2.2]noniLn· 4-yl }pÎpeiidine-4-wiiboxtirnide	89	0.00823	0.109	0.00117	9.47	0.316
90	4-Fluoro-1 -(4-(4-(2fluorocthoxy)phenyl)pyrimidin-2-yl}-iV-(4· mclJiyl-l-nznbicyclù[3.2.2\|iiojfflM-4y))piperidiiio-4-cajboxarnide	90	0.00226	0.0134	0.000095 3	3.06	0315
91	4-Fluoro-t-(5-fluoro-4-(4-(2melhoxyclhoxy)phcnyl)pyritnîdiii-2-yl)-¥(4-mdhyU -ajwbiçyctoj3.2.2 inünan-4yl)pif>eridinis-4-cail'x'>xnniidc	91	0.00204	0.0714	0.000117	2.66	0.10
92	4-Fluoro-l-(4-(4-(2- iluorodhoxy)phcnyl}pyrimidin-2-yl)-.V-(3methyl<iuinueîidm-3-yt)pÎperidincUciirboxauddo	92	0.00146	0.029	0.000106	6.83	0.10
93	4-Fluoro-I-(4-(4-(2mellioxyeihoxy)phenyl)pyrimidia-2-yl)-A'(4-mclhyl-J-iizabicyciûf3.2.2\|nanJUi-4yl )pi péri dii>c-4-carboxaaüde	93	0.00396	0.0439	0.000261	3.96	0316
94	4- Fluoro-1 -(4-(4- fluoropheayljpyri midin-2yl)-M(4-inethyl-1 -a7jbicyclo[3-2.2]nonan4-yl)pifK:ridino-4-oaiboximide	94	0.00073 6	0.0144	0.000096 4	2.1	0.0464
95	4-Fluoro-l-(4-(4-fluorophenyl)pyrimidin-2yl)-(V-(3-mclbyl<iuinuclidiu-3-yl)pipcrtdino4-cftrboxamidû	95	0.00058 5	0.020	0.000083 6	4.69	0.0316
96	1- (4-(4-(Metlioxyniethyl)phenyl)pyrimidin- 2- yl)-4-mcthyl-À'-(4-methyl-litaibieycl<j[3.2.2]nonan-4-yt)pipcridÛM:-4carboxnmîde	96	0.0070	0.145	0.000804	3.39	1.0
97	1- (4-(4-((2- Melhoxyethoxy)mcthyl)phenyl)pyrimidui- 2- yl)-4-mcthyl-A^r(4-rncthyll azabieycl<j[3.?..2]nouaa-4-yl)piperidinc-4caiboxamide	97	0.0134	0.285	0.00136	10.	1.0
98	1-(4-(4-((2- Mcthoxyclhoxy)meüiyl)phenyl)pyrimidin- 2-yl)-4-mcthyl-A'-(3-inethyl<]UÎiuichditi-3- yl)piporidiue-4-çtirtx>xauiidc	98	0.0769	1.91	0.00813	8.19	1.0
99	1 -{4-(4-Fluorophenyl)pyrimidm-2-yl)-4hydroxy-,¥-(4-mctliyl-1azsbicyclo[3.2.2]nonan-4-yi;piperidine-4· oiuboxnmidc	99	0.00223	0.012	0.000055 2	3.78	0.0464
ιοο	l-(4-(4-Fluorophenyl)pyri mîdin-2-yt}-4mclhoxy-JV-(4 -melhyl- I a»ibicyelfif3.2.?.]noium-4-yl)pipeiÎdine-4çarboxamide	100	0.00368	0.0265	0.000109	1.9	1.0
101	4-Mclhoxy-1-(4-(4-(3mcthoxypropoxy)phcnyl)pyrimidiii-2-yl)-/V(4-tr.ethyl-l-azabicyclo[3.2.2]n'jntiu-4ylJpilwidînM-cnrfxixanûde	101	0.00338	0.0785	0.000436	2.03	1.0
102	l-(5-Fluoro-4-(4-(2fluorocthoxy)phenyl)pyri tnidm-2-yl)-4methoxy-N-{4-methyl-1 azabicycto[3.2.2]noiuin-4-yl)piperidine-4carboxamide	102	0.00103	0.0929	0.000258	2.85	0.10
103	1 -(4-(4-(2-Fluoroethoxy)phaiyl)pyriinidin· 2-yl)-4-mcthoxy-¥-( 4-methyl-1azabicydo[3.2.2]nonan-4-yl)pjperidiae-4cnrboxnmide	103	0.00365 \|	0.0738	0.00029	3.11	0.316

309

I04	1-(4-( 4-FluorophenyI)-5-(2meüioxyethoxyjpyri midin^-ylJ-jV-idmethyl· l azab:cyclo[3.2.2]tionan· 4yIXûpendiui.'-4-âufxtx«nûdc	104	0.0251	0.0513	0.0030	10.	1.0
105	t-(4-(4-Fluorophenyl)-6-(2mdhoxycthoxy)pyrimidin-2-yl)-A'-{4niclJiyl-J-nzabicycl(>f3.2.2]noiwji-4ybpipt'tÎdine-d-carboxaniide	105	0.0105	0.272	0.0020	3.66	1.0
106	l-(4-(4-Fluorophenyl)pyridin-2-yl)-A-(4methyl-1 - azabicyclo[3.2.2]nc-niin- 4y))pll«ÎridItie-4-cnrlxixm»Îdc	106	0.00085 8	0.0153	0.000095	6.97	9.02
107	l-(5-(4-Fluorophenyl)pyridin-3-yl)-A'-(4îTieÜiyl- J -.v.abicy<.'lû[3.2.2\|nnnai:-4y!)piperidine-4caiboxainide	107	0.00476	0.299	0.000935	10.	0.0785
t08	i -(2-{4-FIuorophcnyl)pyridùi-4-yl)-A'-(4methyl-1 -itzabicyclo(3.2.2 ]nonan-4yl)pipendinfr-4-ewbùxnniide	108	0.0808	1.08	0.0541	5.65	3.16
109	l-(4-(4-Fluorophenyl)pynnudÎn-2-yl)-A'metliyl-A7-(quinuclïditi-3-yl)pipcridine4cafboxtimide	109	0.0401	2.23	0.00899	9.53	3.16
l ΙΟ	l-A™bîcyclo[3.2.2[nooan-4-yl 1-(4-(4iluorophenyl)pyrimidin-2-yl)pipcridinc-4carboxylate	110	0.00122	0.528	0.00239	3.81	1.0
111	l-(5-FIuoro-4-(4-(3- methoxypropoxy)phenyl)pynmidi»-2-yl)-A'(4-tnûthyl-l-î<Zi(bicyelo[3.2.2]nonan-4ylJüzetidiitB-î-vîuboxaniide	111	0.0020	0.119	0.00019	3.65	1.0
112	l-(5-Fluoro-4-(4-fluorophenyl)pyrimidîn-2- yl)-,V-(4-iiiethyl-l-a‘/;ibicycio[3.2.2]nonnn- 4--yl)azirtidine-3-ciiAoxamide	112	0.00737	0.122	0.000238	7.24	0316
113	[-(4-(4-FluoraphcnyI)pyrimidin-2-yl)-A^r-(4mclhyl-1 -azabicyelû[3.2.2]nwuiti-'lyllazctidine-3-caiboxamide	113	0.00831	0.546	0.000884	10.	0.316
114	t-(4'-Fluoro-[l,r-biphenyl]-3-yl)-A'-(4methyi-1 -nzabicyelo[3.2.2]noiiaii-4yl)azelidinc-3-<:tuboxanilde	114	0.051	0.272	0.0111	3.46	1.0
115	l-(4-(4-Fluorophenoxy)pyrimidin-2-yl)-.M(4-melhyl-1 -azabicyclo[3,2.2]nomm-4yl)piperidinc-4-carboxuniidc	115	0.00245	0.00894	0.00014	9.3	0.0464
116	4-Fluoro-1 -(4-(4-fluoropheaoxy)pyrimidin2-yl)-,V-(4 -methyl-1 uKibicyc!r43.2.2]n'>rvm-4-yrjpiiX.Tidtnc:-4· carboxnmide	116	0.00143	0.0159	0.000155	5.72	0.10
117	4-FIuoro-l -(4-(4-iluorophenoxy)-1,3,5lriaan-2-yl)-iV-(4-methyl- i azabicyc !o[3.2.2]non»n4-yl)piperiilitie-4curbcMcarnidc	117	0.168	0.0884	0.00905	10.	1.0
118	4-Ftuoro-I -(4-(4-Îluorophcnaxy)-13.5triazia-2-yl)-A^r(<lmethyl· 1 üïxbicycl<i[3.2.2]nonan-4-yi)pi\|'>ei^,irliiu!-4earboxanade	118	0.00254	0.0634	0.00116	4.64	1.0

310

119	l-(4-(4-Cyanophenoxy)pyrimidin-2-yl)-4iluorcHV-ï3-metliylquinuclktin-3ylïpijK'ridinüJl-caibûxamide	119	0.00671	0.0544	0.000476	10.	0316
120	t-(4-(4-Cyanophcnoxy)pyriniÎdin-2-yl)-4- fluoro-iV-(4-inelhyl-1 - azubicyclol3.2.2\|itonan-4-yl)pipeiidiu<:-4carboxamidc	120	0.00412	0.0188	0.000332	10.	0.316
121	l-(4-(4-Fliiorophcnoxy)pyrimidin-2-yl)-.V- (3-œethylquinuclidiiv3yl)piperidine-4· ciuhoxnnûdc	121	0.00)33	0.0263	0.000093	7.65	0.10
122	i -(5-Cyant>-4-(4-iluorophcnoxy)pyriinidin- 2-yl)-4-iluoro-,V-(3-nietiiylquiiruclidiii-3- y Dpipcridine-4-carbox3mÎde	122	0.00441	0.112	0.000639	10.	0316
123	4-Fluoro-.V-(4-mctliyl-1 azabicyclo[3.2.2]noruin-4-yi)· 1 -(4 ((tetmhydio2H-pymn-4-yl)ôxy)pyiin)idûi2-yl)pipcridÎnc-4-cartx>xamidc	123	0.0423	0.226	0.00226	10.	1.0
124	4-Fluoro-1 -(4-((4fluorobcnzyl)oxy)pyritnidin-2-yl)-Ai-(4ntethyl··1 -azabicyclo[3.2.2]nonaji-4· yl)pi[Xiiitinc-4-eiulwxamide	124	0.00055 3	0.0178	0.000084 9	3.42	0.10
125	4-Fluoro-1 -(4-((4- lluorobenzyl)oxy)pyritnidin-2-yl)-.'V<3meüiylqiiÎiiiicfidÎn-3-yi)pipentJine-4carboxamide	125	0.00064 3	0.0177	0.000050 9	4.29	0.158
126	4-Fluoro-1 -(6-(4-fluorophenoxy)pyraztn-2- yl)-M(4-iTiclhyl-l-aaibicyclo[3.2.2]nonaii- 4-yl)pipcridine-4-earboxamide	126	0,00157	0.036	0.000726	6.26	1.0
127	4-Fluoro-1 -(5-(4-fluorophenoxy)pyridin-3yl}-JV-(4-meÜiyl-l-a2abicyclo[3.2.2]nonan4-yl)piperidine-4-cart>oxamidc	127	0.00227	0.106	0.000569	6.98	0.316
128	4-FIuoro-1 -(4-((4- fluorobcnzy I)oxy ) 1,3,5triaziii-2-yi)-,V(4methyi· 1azabicyûkj[3.2.2]noJum-4-yI)pÎpciidÎne-4cnjboxamido	128	0.0198	0.654	0.0034	10.	1.0
129	4-l^;luoro-l-(5-(4-nuorophenoxy)pytimidin- 2-yl)-Af(3-mcdiylquinuc!Îdin-3- yl)pipcridi nc-4-carboxamidû	129	0.00427	0.0978	0.00038	8.26	0316
130	1-(5-( 4-Fluorophenoxy )p yrimidin-2-yl)-jV- (4-methyl-l-uzabreydo[3.2.2jiionnii-4yd)pjpcridinc-4-raiboxaniide	130	0.00088 9	0.0169	0.000156	5.67	0316
131	4-Fluoro-l-(5-(4-(2methoxyethoxy)phenoxy)pyrimidin-2-yl)A(3-mcthylquini;cbdùi-3-yl)piperidiiie-4enrboxanûda	131	0.00681	0.0527	0.000858	10.	1.0
132	4-Fluoro-1-(5-((4fluürobenzyl)oxy)pyriinidin-2-yl)-.V-(4ui&hyt-l-ft7.abicyck}[3.2.2]nona[i-4yl)pîpûridino4-carboxamidc	132	0.0107	0.115	0.00265	4.59	1.0
133	4-Fluoro-1 -(5-( 4-fluorophenoxy)pymzin-2ylJ-jV-(3-methylquÎnucLidin-3-yl)piperidine4-caiboxamide	133	0.0459	0.467	0.00483	10.	1.0

311

134	4-Fluoro-l-(6-(4-fliiurophcnoxy)pyridnzin- 3-/)-/^-(4-1110111 yl-1- az^^bicyclo[3.2.2]nonan-‘1-yl)pipcridilιe-4carboxnmidc	134	0.0145	0.343	0.00283	10.	1.0
135	4-Fluoro-1 -(4-((4- iluoroplicnuxy)rncthyl)pyrimîdin-2-yl)-/v'· (3-mcthylrjuinuelidiii-3-yl)pif>cridiue-4carbexamide	135	0.00138	0.0317	0.000132	8.25	0.0464
136	4-f^;luoro-1 -(5-(4-nuorobenzyl)pyrimidin-2- yl)-,V (3-methylquinuclidin-3-yl)piperidino 4-c.irlKixamide	136	0.0079	0.0249	0.000716	10.	1.0
137	(3fl)-3-Mclhyl-V-(4-incthyl-lnzabicyclo[3.2.2]nonan-4-yl)-4-(4phenylpyrimidin-2-yl)piperaziiie-l carboxamide (single enantiomer B)	137	0.0032	0.0501	0.000198	5.72	1.0
138	(3A)-3-Meihyl-W-(4-mclhyl-la7abicycto[3.2.2]nonati-4-yl)-4-(4phenylpyrimidin-2-yl)piperazinc-l* carboxnmidc(sîngic enantiomer A)	138	0.902	>10	0.0636	9.31	3.16
139	(3.V)-3-Methyl-A-(4-mcthyl-1 azabicyclo[3.2.2]nonnn-4-yl)-4-(4phenyl pyrimtdin-2-yl)piperazînc-lcarboxamide (single enantiomer B)	139	0.0173	0.067	0.00137	5.25	3.16
140	(ÎS^-Methyl-J^d-methyl-l azabicyclo[3.2.2]non>n-4-yl}-4-(4phenylpyrimidin-2-yl)pipcrazine-lcafboxnnûdo ( single enantiomer A)	140	0.0469	9.08	0.574	6.49	3.16
14]	3-MclhyW(4-tneiliyl-l azabicyclo[3.2.2]nonan-4-yl)-4-(4phcnylpyrimidin-2-yl)pijK‘iaziiie-lcarboxamide	141	0.00596	0.209	0.000888	4.67	0.316
142	3-Elhyl-A'-(4mcthyl-1azabÎcycki[3.2.2]nonan-4-yiy4-(<K phenyl pyrimidiu-2-yl)pipcraziiie-l carboxamide	142	0.00769	0.10	0.000861	5.34	9.21
143	3-Ethyl-iV-(4-methyl-lazabicyelo[3.2.2Jnonaii.4-yl)-4>(4pheuylpyriinidin-?.-yl )piperazine-l corboxamida	143	0.00179	0.0523	0.000304	3.11	3.16
144	3-(Mothoxymcthyl)-jV-(4-mdhyl-1 azabicyisk>[3. ?..2jnoaari-l-yl )-4-(4phenylpyrimidin-2-yI)piperazine-1earboxnitiide	144	0.0673	0.529	0.00633	10.	1.0
145	4-(4-(4-Fluorophenyl)pyritnidin-2-yl)-3meLhyl-A'-ïd-methyl· 1 azabicyclo[3.2.2}nor>an-4-yl)piperazinc-lcarboxamide	145	0.00801	0.0763	0.000507	6.98	0.316
146	4-(4-(4-Fluorophenyl)pyrimidin-2-yl)-3methyl-jV-(4-methyl-1 azabicycIo[3.2.2\|nonan-4-yl)piperazine-lcarboxninide	146	0.0166	0.11	0.000559	6.37	1.0
147	c£s-3,5-DÎmethyl#(4-mcthyJ-l· azabicyelti[3.2.2]nonan-l-yi)-4-(4phenylpyrimidin-2-yl jpipernzine-1 earboxnmide	147	0.00545	0.096	0.0010	3.51	1.0
148	4-{5-FluaK>-4-(4- (methoxymethy l)pheny l)pyri midin-2-y i)-3 isopmpyl-.V-(4-methyl-1 - azabicyclo[3.2.2Jaonan-4-yl Jpipcrazine-1 cnrboxninide	148	0.0174	0.39	0.00859	3.46	1.0

312

MP	4-(4-(4-(Mctiioxyntctltyl)phcnyl)pyrimidiu- 2-yl)-^-(4-melliyl-J - azabicyclo[3.2.2]nonan4.yl). 3(tiifJuomnielhyl)pi\|x:razj.tte-i-cnrboxiu.iùda	149	0.0109	0.279	0.0015	4.31	1.0
I50	3-(Difluoroniethyl)-4-(4-(4(tnclhoxyn>cthyl)phcayl}pyrimidin-2-yl)-jV(‘l-aiet!iyl-!-a?jibicydo[3.2.2\|iiciiini-4yllpiperazine- 1-carboxamide	150	0.023	0.195	0.00106	5.44	1.0
I5l	3-Isopropyl-4-(4-(4(mcthoxymethyl)phcnyi)-1,3,5-triazin-2-yl)?/-(4-inelhyl·· ! -aa>bicydo[3.2.2]nonan4· yljpîpcraained-cntboxamiilü	151	0324	1.82	0.0956	9.84	1.0
152	(3Λ)··4·(5 -('l-Fiiior&phenoxy)pyrimidin-2 yiÿ-3-mc!hy'l-A'-(4-methyi-1 azjil>icyc!o[3.2.2Jnoaan-4-yl)pipcr»zinc-l · carboxaiEiide	152	0.00288	0.0763	0.000439	6.77	0.316
153	3-Ethynyl-4-(4-(4- (melhoxymethyl)phenyl)pyrimidin-2-yl)-2V(4-incthyl- 1 -azabicyelof 3-2.2]nonmi-4yljpipcrazine-1 -csrtxïxaniidc	153	0.0534	2.64	0.0117	10.	1.0
154	l-Azabicycto[3.2,2]nonan-4-yl 3-mcthyl-4(4-pheny!pyrimidin-2-yl)piperazine-lcarboxylate	154	0.057	1.93	0.0165	2.84	1.0
155	QüLnuclidin’3-yl (2-(4L(2’tïieihoxyeUioKy)[l,P-biphcnyl]-4-yI)propan*2-yi)caîbanuitc	155	0.00348	0.0386	0.000657	1.0	0315
156	(S)-Qiijiiudidin-3-yl (2-(4’-(2niethoxyethoxy)-[ l,l’-biphinyl]-4yl)f>rot>aa-2-ylX:aibank’iic	156	0.00414	0.0437	0.00131	4.74	0.763
157	(Aj-l -(2-(4'-(2-.MetliûxytÜwxy)-[ 1,1'. biphenyi]-4-yi)propaa-2-yI}-3-(3. melhylqui nudidin-3-yl)ttren	157	0.228	0.538	0.042	3.16	3.16
158	(S> 1 X2^4'-(2-MctboxyeÜi<»xyj-[ 1.1 biplienylj-4-yi)propan-2-yl)-3-(3methyJqtiititiclidin-3-yl}urea	158	0.00285	0.00762	0.000529	0.631	0.631
159	1 -(3-Ethylquinuclidia-3 -yl)-3-(2-(4’-(2methoxycthoxy)-[ 1,1 '-biphcnyl]-4yl)propan-2-yl)urca	159	0.0056	0.00446	0.000636	1.0	1.0
160	1 -(2-(4^l-(2-Methoxyethoxy)-[ l ,Γ-biphenylJ- 4-yl)propan-2-yl)-3-(4-mcthyl-l- azabicydo[3.2.2]nonaii-4-yl)iirea	160	0.00391	0.0019	0.000544	1.0	1.0
161	M(2q4X2-Medtoxy«!thûxyH 1,1 bipheaylJ-4-yt}prupaii'2-yl)-l_f'l· diazebicydofS .2.2Îiionarie-4-e«rhoxanji<.le	161	0.25	0.311	0.0327	3.16	3.16
162	l-(l-(4^l-(2-MeÎhoxyeLhoxy)-[ 1, l'-biphenyl]- 4-yl)cydopropyl)-3-(quimididin-3-yl)urea	162	0.0281	0.0727	0.00221	3.54	1.0
163	1~( 1 -(4'-(2-Mcthoxyethoxy}-[ 1,1 '-biphcnyl]- 4.yi)cydopropyl)-3-(3-inethy!quinudidÎti- 3-yl}urea	163	0.00849	0.00657	0.000539	1.0	0.173

313

I64	l-(3-ElhylquÎnudidin-3-yl)-3-(I-(4'-{2mclhoxyethoxy)-[ 1,1 '-bip1ienyl]-4ylXyclopropylJurea	164	0.00616	0.00251	0.000205	1.0	0.173
165	1 -t I -(4’-(2-Mcthoxyethoxy}-[ 1,1 ’-biphenyl]- 4-yl)cyclopropyl)-3-(4-mcthyl-l- azabÎcyclo[3.2.2Jnonnn-4-yt)urea	165	0.00415	0.00051 6	0.00024	0.316	0.0316
166	Quinuclidin-3-yl (l-(442-nictlioxycthoxy)[1,1 ’-biphcnyl] -4-yl)cyclopropyl)c#rbamalc	166	0.00569	0.0219	0.00181	0316	0.215
167	Quinuclldin-3-yl (24342-niethoxycthoxy)[ 1,1 '-biphenyl]-4-yl)propan-2-yl)caibamatc	167	0.0104	0.109	0.00531	10.	1.0
168	1-Azabicych(3.2.2] notion -4-yl (2-(342mclhoxycthoxyH i ,1 '-biplicnyl]-4yl)propan-2-yl)caibanuitc	168	0.00556	0.0793	0.00334	10.	1.0
169	//•(2>(3’-(2-Mçthoxyet}iùxy)-i 1,1'biphenyl]-4-yl)propaB-2-yl)-1,4dinÎabîcyclo[3.2.Î)nonane-4-ciutioxaniide	169	0.257	0.283	0.018	10.	1.0
170	Qu inuclidin-3-yl (2-(4'-(2-mcthoxycthoxy}[ 1, l'-biphcnyl]-3-yl)propan-2-yi)caibainatc	170	0.0267	0.0295	0.00494	10.	10.
171	l-Azabicyclo[3.2.2]nonan-4-yl (2-(442methoxyelhoxy)-[ 1 ,r-biphenyl]-3yl)propnn-2-yl)caibaniatc	171	0.0325	0.0119	0.00145	0.0746	3.98
172	Quinuclidin-3-yl (2-{4'-(3mcthoxypropoxy)-[ 1,1 -biphenyl]-4yl)propan-2-yl)carbainalc	172	0.00241	0.0666	0.00156	8.29	10.
173	l-(2-(4^,-(3-Mclhoxypropoxy)-[ 1,1'- bipheiiyl]-4-yl)propan-2-ylj-3-(3mclhylquitiuclidin-3-yl)urc>	173	0.00198	0.0203	0.000766	10.	10.
174	Λ42-(4'-{3-Μ c1hoxypj«fK»xy)-[ 1 ,Γbiphcnyl]-4-yl)propan-2-yl}-l ,4d iazabicyck,>(3.2.2 Jnenane-4-carboxiimidi	174	0.134	0.386	0.0225	10.	1.0
175	Quinuclidin-3-yl (2-(4’-(2-nicthoxycthoxy)[1,1 '-biphenyl]-3-yl)propan-2-yl)carbamatc	175	0.0025	0.0713	0.00187	10.	9.0
176	1 -(1 -(4’-(3-Mcthoxypropoxy)-[ 1, i 'biplienyl]-4-yl)cyctopropyl)-3-(3tncüiylquinuclidûi-Î-yl^irca	176	0.0041	0.022	0.00147	10.	10.
177	14 14443-Mctlioxypropoxy)-[1,1'biphetiyl]-4-yt)cyclopropyl)-344-niethyl-1 azabicyclo[3.2.2]nonan-4-yi}urca	177	0.00159	0.00175	0.000497	10.	10.
178	l-Azabicyclo[3.2.2]nonan~4-yi (1-(443melhoxypropoxy)-[ 1,1 '-biphenyl]-4yljcyclopropyljcarbamatc	178	0.00354	0.0679	0.00261	10.	7.1

314

179	Quinuclidin-3-yl (2-(4'-(2-(l/Jpyraz<ji-l- yi)cllioxy)-[i, ! '.bip!ieuyl]-4.yl)prcp3n-2vi)caibanuilc	179	0.00673	0.0952	0.00499	8.73	3.16
180	1-(2-(442-(1//- Pyrazol-1 -yl)ethoxy>-[ 1, Γbiphcuyl] -4-yl)propan-2-yl>3-(3 tnetliylquinucIidin-3-yl)urea	180	0.0053	0.0463	0.00181	3.16	3.16
181	1 -(2-(442-( 1 //-Pytaral- i-ylklhr>xy)-[ 1.1‘biphenyl]-4-yl)propan 2-yl)-3.(4· methyl-1 n?abicycii.>[3.2.2]iwrian-4-y!)urca	181	0.00233	0.00515	0.000587	1.0	1.0
182	Quinuclidin-3-yl (2-(442-( 1 iï-ï ,23-triazoll-yl)cthoxy}-[ 1,1 '-bipiienyJ]-4-yl)fV0p<ut-2y])c Hibernale	182	0.0431	0.388	0.0131	3.16	1.0
183	1-(2-(442-( 1/7-1,23-Ttiozx)!-l -yijethmcy)(l,r-bïpk*ayl]-4-yl)pK>pan-2-yl)-3-(3metliylquiiiuci:din-3-yl Jures	183	0.0316	0.969	0.0102	5.62	2.51
184	l-(2-(4'-(2-( 1/7-1,23-Triiuwl-l -yl)slhc>xy)- [l,i’-biphenyl]-4-yl)propan-2-yi)-3-(3ethyiquiiwlidüv3-yl)urea	184	0.0211	0.188	0.00346	3.16	1.0
185	1-(2-(442-(1//-1,23-Trinzol· Lyljethoxy)· flJ'-biphcnyl]“4-yl)pfopaii-2-yl)-3-(4meîiiyf-J-azabkyelo[3.2.2]nonan-4-yl)urett	185	0.0129	0.0999	0.00387	3.16	LO
186	QuinuclidÎn-3-yl (2-(442-mcthoxycÜioxy)[ 1 ,l*-biphcnyl]-3-yl)propan-2-yl)caibamate	186	0.045	0.157	0.0107	10.	1.0
187	l-Azabicyclo[3.2.2]nonan-4-yl(2-(443- (1/7- l,2,'J-tnazol-l-yl)ptopoxy)-[ 1.1'biphenyl] -4-yl)prcpan-2-yt)caibaniatc	187	0.0202	0.106	0.00774	10.	1.0
188	/9-(2-(443-(1//-1,23-Triazol-lyl)proi>oxy)-[l,P-biphenylj-4-yl)prepan-2yl)“ 1,4-diazAbicydo[3.7..?.]iionnac^Icarboxamide	188	0.597	0.365	0.0774	10.	1.0
189	Quimiclidin-3-yi (2-(4'-(3-cynnopropoxy)[ l. 1 '-biphenyl]-4-y i)propan-2-y Ocartmmate	189	0.00957	0.0865	0.00322	10.	8.47
190	Qu inuclidin-3-yl (2-i44cyaaomeUioxy)[1,1 ’-biphenyl]-4-yl)propan-2-yl)caibamate	190	0.00259	0.0477	0.000775	10.	1.0
191	Qu inuclidin-3-yl (2-(44(3-tnetliyioxetan-3yl)mcthoxy)-[ t, 1 '-biplicnyl]-4-yI)propan-2yljcarbamatc	191	0.0072	0.0718	0.00324	5.25	1.0
192	1-Azabicyclo[3.2.2] ποηηη-4-yl (2-(44(3methyloxetan-3-yl)mellioxy)-[ 1, Γbiphetiyl]-4-yl)propan-2-yl)carbnmate	192	0.00569	0.0816	0.00186	5.84	1.0
193	1 -Azabicyclo[3.2.2]nonan-4-yl (2-(44(3methyloxetan-3-yl)methoxy)-[ 1,1'biphenyl]-4-yl)prop.-ui-2-yl)cart)timatc	193	0.297	0,318	0.0447	10.	10.

315

I94	Quinuclidin-3-yl (2-(4'-(2-(oxetan-3· yl)clhoxy)-[ l, I '-biphcnyl]-4-yl)propnn-2yl)carbamele	194	0.0105	0.115	0.00406	9.93	1.0
195	l-Azabicyclo[3.2.2]nonan-4-yl (2-(442(oxetan-3-yl)cthoxy)-[l ,l'-biplicnyl]-4yl)propon-2-yl)caibamatc	195	0.00567	0.0948	0.00101	8.03	0.10
I96	.7-(2-(442 -(Oxetiiii-3-yJ Jel1ii>xy>[ 1,1'- biphcnyl]-4.yl)propiui.2-yl)-l,4·· diazabieyclo[3.2.?.jnonMie-4-cuiboxriii>ide	196	0.538	0.274	0.0283	10.	1.0
197	Quinuclidin-3-yl (2-(44(2tnethoxycthoxy)methyl)-[ 1,1’-biplicnyl]-4yl)propan-2-yi)caibaiiiatc	197	0.0322	0.309	0.00967	10.	10.
198	1 -(2-(44(2- Mcthoxycthoxy)mcÜiyl)-[ 1, Γbiphetiyl]-4-yl)propan-2-yl}-3-(3metliylqu i nuclid in-3-yl)urca	198	0.0252	0.118	0.00324	10.	10.
199	l-(3-Elhylqu inuclid in-3-yl)-342-(4'-((2mcthoxyeÜioxy)nicÎhyl)-[ 1,1 ’-biphenyl]-4yl)propan-2-yl)urca	199	0.0147	0.0317	0.0018	1.0	1.0
200	l-AzabicycIo[3.2.2]nonan-4-yl (2-(44(2mcihoxycthoxy)methyl)-[l,l'-biphenyl]-4yl)propan-2-yl)cartninwte	200	0.024	0.22	0.00616	10.	1.0
201	l-(2-(44(2-Methoxyclhoxy)methyl)-[l,rbiphtmyl]-4-yl)propan-2-yl)-3-(4-mclhy'l-lazabicycIo[3.2.2]noiuin-4-yl)urea	201	0.0139	0.023	0.00076	10.	0316
202	/V-(2-(44(2-MeUioxyothoxylnistliyr>-f 1,1biplu'nyl]-4-yJ )propf«i-2-yl)-l ,4dÎ3zabicyBlo[3.2.2]nonano-4-ciiibcxamide	202	235	0.933	0.154	10.	10.
203	Quinuclidin-3-yl (2-04(2methoxycthoxy)mcthyl)-[l ,1 '-biphcnylJ-3yi)propnn-2-yI)caibainate	203	0.0296	0.0963	0.00653	10.	1.78
204	l-Azabicyclo[3.2.2]nonan-4-yt (1444(2mcthoxyclhoxy)mcthyl)-[ 1 ,r-biphcnyl]-4yl)cyclopropyl)cart>ainatc	204	0.0433	0.0993	0.00826	10.	1.47
205	141 -(44(2-Methoxycthoxy)methyl)-[ 1,1'biphenyi]-4-yl)cyclopropyl)-3-(3tnelhylquinuclid in-3-yl)urea	205	0.0515	0.156	0.00531	10.	1.78
206	143-E*hylquinuclidin-3-yl)-341-(44(2mcthoxyethoxy)mcthyl)-( 1 ,l'-biphcnyl]-4yl)cyclopropyl)urca	206	0.0278	0.0596	0.00266	10.	1.78
207	141 -(44(2-McÜioxycÜioxy}melhyl}-[l ,1 biphenyl]-4-yl)cyclopropyl)-344-nieIhyl-laznbicyc!o[3.2.2]nonan-4-yl)urea	207	0.0123	0.0313	0.00139	10.	1.78
208	l43-Ethyiquinuclîdin-3-yl)-3-(l-(44(2melhoxyethoxy)methyl)-[ 1,1 '-biphenyl]-4ylJcydopropylXirca (single cnantiomer Λ)	208	2.71	0.988	0.0739	10.	10.

316

209	l-(3-EÜiyIquinucl<din-3-yI)-3<l(4'-((2mBÜioxyeihoxy)ineiliyl)-[l,l’-biphenyl]-4yl)cyclopropyi)urca (single cnanliotner B)	209	0.0174	0.0392	0.00105	10.	1.78
2)0	(£)-l-<l-(4'-((2-Methoxyelhoxy)melhyl)· ! 1, r-bipheiiyl;-4-y lXyck>propyl)-3 -(3 mctliy!quinuclidin-3-yi)ujïa	210	0.0502	0.087	0.00334	10.	10.
2!l	(ft)-l -(l-(4'-((2-Mcth<jxyelht>xy)mefhyl)[1,1' biphenylj-'l -yl)cycloprûpyl)-3~(î· mdhylquitwidi<lin-3-yi)iirea	211	0.938	0.683	0.072	10.	3.16
2I2	l-Azabicyclo[3.2.2]nonan-4-yl (1-(4^(3methoxypropyl)-[l ,r-biphenyl)-4yl)cyclopropyl)cari>amdc	212	0.00385	0.0479	0.00253	6.36	10.
213	l-( l-(4'-(3-McLlioxypropyl)-[ 1,1 '-biphcnylj4-yi)cyclcipropy l)-3-(4-mcthyl-1 azabicyck>[3.2.2]nonan-4-yl )u rea	213	0.00112	0.0059	0.00035	9.22	10.
214	1-(1-( 4'-(3-Methoxypropyl)-[l,l’-biphciiyl)- 4-yl)cydopropyl)-3-(3-metliylqumuclidui- 3-yl)urea	214	0.00329	0.0329	0.00126	10.	10.
215	l-(3-ElhylquinucIidin-3-yl>3^1-(4q3mcthoxypropyl)-[ 1,1 '-biphenyl]-4yl)cyctopropyl)urea	215	0.00248	0.0162	0.000542	7.55	10.
216	Quinudidin-3-yi (l-(4’-((pyridin-3ylmcthoxy)methyl)-[1,1 ’-biplictiy l]-4yljcydopropyljcnibnmnte	216	0.00933	0.201	0.0111	7.94	10.
217	l -(3 -EthyIqu inu did i n-3 -y 1)-3-( 1 -(4'((pyridin-3-ylmethoxy)methyl)-[ 1,1biplicnyl]-4-yl)cyclopiOpyl)urea	217	0.0133	0.168	0.00402	10.	10.
218	l-(3-Propyiquiiiüclidiii-3-yl)-3-(l-(4'((pyridîn-3-yimetkoxy)mcthyl)-[ 1,1’biphenyl]-4-yl)cyclopropyl)urea	218	0.011	0.0809	0.00297	7.95	10.
219	Quinuclîdin-3-yl ( l-(4'-((pyrimidin-5yl mctlioxy)rticÜiyl)-[ 1,1 '-biphenyl]-4yl)cydopropyl)carbnmate	219	0.0466	0.118	0.0209	10.	10.
220	l-(3-EthyiquÎnuclidin-3-yl)-3-(l-(4’((pyri midùi-5 -ylinotlioxy)mclliyl)[ 1,1'bipheayl]-4-yl)cydopropyl)urea	220	0.0516	0.114	0.00606	10.	3.16
221	l-Azabicyclo[3.2.2]nontin-4-yl (l-(4‘((pyrimidin-5-ylnrethoxy)niethyl)-[ 1 ,Γbiphcnyl]-4-yl)cycloprupyl)cRrbamatc	221	0.0521	0.0992	0.0211	10.	10.
222	l-(2-(4’-(3-McÜioxypropyl)-[l,l'-biphenyl]- 4-yl)propan-2-yl)-3-(3-mclhylquinuclÎdin-3yljurca	222	0.0017	0.0307	0.000758	10.	10.
223	Quinuclidin-3-yl (2-i4'-(JiydioxymeÜiyl)[ 1, r-biph<*nyl]-4-yl)propan-2-yl)caibamate	223	0.454	0.881	0.0216	10.	10.

317

224	l-(2-(4'-(2-Hydroxyclhyl)-[ l,l '-biphcnylJ-4yt)propan-2-yl)-3-(3-propylquinucIidin-3yljurea	224	0.0202	0.0643	0.0016	10.	10.
225	1- (3-Ethylquinuclidin-3-yl)-3-(2-(4’-(2hydroxyethy l)-[ l, l '-biphcnyI]-4-yl)propan- 2- yl)utca	225	0.0294	0.229	0.00192	10.	10.
226	QuinuclidÎn-3-yl (2-(4'-(2-hydroxycÜiyl)[ l, r-biphcnyl]-4-yl)propan-2-yl)ctijbamatc	226	0.148	0.656	0.0223	10.	10.
227	Quinuclidin-3-yl(2-(442-()/i-l,23-tïiazoÎ- 4-yI)ethyl)-[l,l'-l«plicjiyl]-4-yl)propan-2ybcarbatnate	227	0.027	0.122	0.0104	10.	1.0
228	l-Aznbicyclo[3.2.2]noaan-4-yl (2-(4’-(2(I H~\,2 3-triaw.>i-4-yI )cthy l )-[ 1,1’bip1tenyl]-4-yl)\|Htq»in-2-yJ)c>ubatnalc	228	0.0182	0.0808	0.00608	7.65	3.16
229	Quinuclidin-3-yl (2-(4‘(morpliolinomethyl)-[ 1,1 ’-biphenyi] -4 yl}propan-2-yl)caibainate	229	0.158	0.524	0.0532	10.	10.
230	MV2-(4' •(Merpli<.4inocnetiiyL)j 1, Γhiphanyl]-4-yl)propan-2-yl)-J,4dinzabÎcyfli^fJ^^Jnon.i/ic-d-tnrbOxamide	230	2.28	1.79	0.417	10.	10.
231	Quinuclîdin-3-yl (2-(4^,-moipholino-[l,l'biphcnyl]-4-yl)propnn-2-yl)carbamQtc	231	0.071	0.23	0.015	2.0	2.0
232	l-(3-Mctliylquinuclidia-3-yl)-3-(2-(4'morpholino-[ 1,1 '-biphcnyl]-4-yl)propnn-2yl)urea	232	0.0309	0.0642	0.00717	1.0	1.0
233	l-{4-Mcthyl-l-azabicyclo[3.2.2]nonan-4yl)-3-(2-(4'-mnrp!iotÎno-[ 1,1 '-biphenyl] -4yl)propaa-2-yi)arca	233	0.00568	0.00551	0,000726	1.0	1.0
234	l-(3-Ethylquinuclidiii-3-yl)-3-(2-(4·morpholi ao-[l, 1 ’-biplicnyl] -4-yl)propan-2yl)urea	234	0.0146	0.0326	0.00181	1.0	1.0
235	QuinuclÎdÎn-3-y! (2-{4'-(melhylsulibnyl)[1,1 '-bip!ienyl]-4-yl)propan-2-yl)cartMitnâte	235	0.111	0.118	0.0199	10.	10.
236	l-^-Ethylquinuclidinô-ylJ-J-^-^'- (methylsu lfonyl)-[ 1, l’-biphcny l]-4yl)propan-2-yl)urea	236	0.0538	0.0744	0.00946	10.	10.
237	1 -(2-(4'-(McthylsuIfonyl)-[ 1, ) *-bi pb cny] J -4yI}piopan-2-yl}-3-(3-piOpylqiiinuclidüi-3yl)urca	237	0.0354	0.0329	0.00671	10.	10.
238	Quinuclidin-3-yi (2-(4((cyclopropyinicthyl)sulfanyl)-[ l, Γbiphenyl]-4-yl)propaa-2-yl)cafbamate	238	0.0154	0.0501	0.00445	10.	1.0

318

239	l-(2-(4'-((Cyclopropylmelhyl)s<itfonyl)[ 1, l'-biphcnyl]-4-yl)propan-2-yl)-3-(3ethytquinuclidin-3-yl)urca	239	0.00987	0.0285	0.00321	10.	1.0
240	l-(2-(4'-((Cyclopropylmclhyl)sulfonyl)[l,l’-biphenyl]-4-yl)propan-2-yl)-3-(3mcthylquinuctidin-3-yl)urea	240	0.0133	0.0865	0.00597	10.	1.0
24]	l-Azabicyck>[3.2.2]nonan-4-yl (2-(4¹((cycloρropylπl<:thyl)sulfonyl}-[l,l‘bipbcnyl]-4-yl)pfopaa-2-yl)cartianiatc	241	0.00423	0.0122	0.00144	10.	3.16
242	Quinuclidin-3-yl (2-(4'-((3mcthoxypropyl)sülfonyl)-[ 1 ,l'-biphenyl]-4yl)propan-2-yl)carbamatc	242	0.0325	0.0825	0.0102	10.	3.16
243	l-(3-EihylquÎnucLidin-3-yl)-3-(2-(4'-((3methoxypropyl)aulfonyl)-[ 1,1 ’-biphenyl]-4yl)propan-2-yl)urea	243	0.0328	0.0573	0.00749	10.	3.16
244	1-(2-( 4'-((3-Melhoxypropyl)sulfonyl)-[ 1,1‘biphcnyl]-4-yi)propan-2-yl)-3-(3propylquinuclidin-3-yl)urea	244	0.0371	0.0341	0.00699	10.	3.16
245	Quinuclidin-3-yl (2-(4'-((3,3dimelhylbutyl)sutfoayl)-[l,l‘-bÎpheiiyl]-4yl)prapan-2-yl)catbamate	245	0.00185	0.0663	0.000716	6.74	0316
246	1 -(2-( 4’-((33-L)>nicthylbutyl)sullbnyI)-[ J, 1 'biphenyl]-4-yl)propan-2-yl)-3-(3 mclhylquinuclidui-3-yl)urea	246	0.0017	0.0114	0.000624	10.	J.O
247	l-(2-(4'-((3_r3-Dimcthytbutyl)sulr<jiiyl)-[ 1, Γbiphenyl]-4-yl)propaa-2-yl)-3-(3cthyIquinuclidm-3-yl)urca	247	0.00166	0.00428	0.000396	6.64	1.0
248	l-(2-(4’-((3,3-Diniethylbutyl)suIfonyl)-[l,l‘biphenyi]-4-yl)propan-2-yl)-3 -(4-mctliyl-1 azabicyclo[3.2.2]aotuin-4-yl)urea	248	0.00080 4	0.00684	0.000315	7.73	1.0
249	Quinuclidin-3-yl (2-(4*-((( 1(tnclhoxytndhyl)cyclopropyL)incthyl)suUbn yl)-[1.1 '-biphcnyi] -4-yl)proptui-2yi)cart>amate	249	0.0535	0.247	0.00582	10.	2.15
250	l-(3-Elhylquinuctidin-3-yl)-3-(2-(4*-((( 1 (melhoxytnetliyl)cyc!opropyl)mctliyl)sulf<m yl)-[l,l'-bipheiiyl]-4-yl)prôpan-2-yi)urea	250	0.0201	0.0845	0.00441	10.	1.0
251	l<2-(4'-(((l- (MeUioxymethyl)cyclopropyl)melhyl)siilfon yl)-\|l,l'-biphenyl]-4-yl)propan-2-yl)-3-(3piupylqüinuclidin-3-yl)urca	251	0.021	0.0475	0.00501	10.	1.0
252	Qu inuclidîn-3-y 1 (2-(4'-(mcthylciirbainuyl)[ 1, Γ-biphcnyl] -4-yl)propan-2-y IJcarbnmaic	252	1.84	1.5	0.22	10.	10.
253	A'-Metliyl-4'-(2-(3“(3-i>æÜiylqiiinm:lidin-3- yl)u«.^JM(.i)pMpan-2-yl)-( Ι,Γ-bipheiiyl] carboxamide	253	0.751	2.0	0.201 \|	2.0	2.0

319

254	l-Azabicyclo[3.2.2]nonan-4-yl (2-(4’- (metliylcarbamoyl)-[l,r-biplienyl]-4yl)propan-2-yl)carbainatc	254	0.60	0.65	0.0638	10.	10.
255	jV-Mclhyl-4'-(2O-(4-incthy I-1 -azabicyclo[3.2.2]tionati“4-yl)ureido)propan-2yl)biphenyl-4-cart>oxamide	255	0.0469	3.42	0.0201	6.79	1.0
256	N-(2-(4'-(Methylctirbamoyl)biphenyl-4- yl)propan-2-yl)-1,4- dinzabÎcyclo[3.2.2]nonanc-4-carboxamide	256	12.3	4.44	0.729	10.	10.
257	Quituiclidin-3-yl 2-(4'(dimclhylcarbamoyl)biphcnyl-4-yl)propan2-jdcartwimalc	257	0365	0.786	0.0772	10.	10.
258	AW-Dimcthyl-4'-(2-(3-(3methyIqüinucIidin-3-yi)urcido)propan-2yl)biphenyl-4-cartx>xamide	258	0.281	234	0.049	10.	10.
259	1- Azabicyclo[3.2.2]noaan4-yi 2-(4'(dimethylcarbamoyl)bipticnyl-4-yl)propan- 2- yicarbamnte	259	0.134	0.179	0.0205	10.	10.
260	W-(2-(4^,-(Dimc!liy!carbanioyl)biphenyl-4yl)propan-2-yi)-1,4dmzabicydo[3.2.2]non&nc-4-caibox timide	260	8.55	1.64	0302	10.	10.
261	A',A'-Dimcthyl-4'-(2-(3<4-niclhyl-1nzabicyclo[3.2.2]nonan-4-yl)ureido)propan2-yt)biphcnyl-4-caiboxamide	261	0.0608	0.354	0.0141	10.	3.16
262	Quinuclidin-3-yl 2-f4'-(piperidinc-lcarbonyl)biphenyl-4-yl)propan-2ylcaibamnte	262	0.0196	0.112	0.0035	10.	1.0
263	l-Azabicyclo[3.2.2]noniui-4-yl 2-(4(piperidiiie-l-caibonyl)biphenyl-4yl)propan-2-ylcarbamatc	263	0.0145	0.075	0.00301	10.	1.0
264	1^3-Ethylquinuclidin-3-yl)-3-(2-(4'(pipcridinc-l-carbonyl)biphenyt-4yl)propan-2-yl)urca	264	0.0137	0.0674	0.00213	10.	1.0
265	Quinuclidin-3-yl 2-(4'-(moipholinc-4caibony l)bi phenyl-4-ylJpropan-2ylcarbamate	265	0.48	0.454	0.0399	10.	2.15
266	l-Azabicyclo[3.2.2]nonan-4-yl 2-(4'(maqiholine-4-ciirbonyl)biphenyl-4yl)propan-2-ylcaibamatc	266	0399	0.284	0.0227	10.	1.0
267	l-(3-MeÜiylquinuclidia-3-yl)-3-(2-(4’(moipliolinc-4-carbonyl)bipheny!-4yI)propan-2-yl)urcn	267	0363	2.77	0.119	0.565	10.
268	l-(4-Methyl-1 -azabicyclo[3.2.2]nonan-4yl)-3-{2-(4'-(moipholîne-4caibonyl)biphenyl-4-yl)propan-2-yi)utea	268	0.166	0.648	0.0315	10.	1.0

320

269	A^,-(2-(4'-(Morpholine-4-ciirbonyl)biphcnyl- 4-yi)propon-2-yl)-1,4- diazabicyclo[3.2.2]nonane-4-carboxninidc	269	23.	2.16	0.518	10.	10.
270	Quinuclidin-3-yl 2-(4'-(4,4difluoropipcridinc-l -caibonyl)biphenyl-4yl)propan-2-ylcart>amatc	270	0.025	0.067	0.00356	10.	1.0
271	l-Azabicyclo[3.2.2]nonan-4-yl 2-{4'-(4,4dilluoropipcridinc-l-carbonyl)biphcayl-4yl)propnn-2-ylcarbamatc	271	0.00942	0.0607	0,00264	10.	0316
272	l-(2-(4'-(4_r4-DifluoiOpiperidme-lcarbonyl)biphcnyl-4- yljpropan-2-yl )-3-(3cthytquinuclîdin-3-yl)urca	272	0.0164	0.0249	0.00215	10.	1.0
273	Quinuclidin-3-yl 2-(4'-(3.3diiluoroazclidi lie-1 -carbonyl)biphenyl-4 yl)propan-2-ylcnrbamatc	273	0.108	0.074	0.0106	10.	3.16
274	l-Aza-bicyclo[3.2.2]nonan-4-yl 2-(4'-(3,3diiluaroïzetÎdine-l-carbonyljbiphcnyMyl)propan-2-ylcarbamate	274	0.0304	0.0673	0.00478	10.	1.0
275	1-(2-(4¹-(3,3-Difluoroazetidine-1 carbonyl)biphenyI-4-yl)propan-2-yl)-3-(3clhylquinuclidin-3-yl)urea	275	0.0756	0.0554	0.00292	10.	1.0
276	l-{4-Methyl-l-azabicyclo[3.2.2]nonan-4- yi)-3-(2-(3-(3-(motpholine-4caibonyl)phenoxy)phenyI)propan-2-yl)urea	276	0.020	1.53	0.0296	10.	3,16
277	l-(3-Mclhylquinuclidin-3-yl)-3-(2-(3-(3- (motpholinc-4carbonyl)phcnoxy)phcnyl)propan-2-yl)urea	277	0.0917	2.03	0.0801	10.	10.
278	l-Aza-bicyclo[3.2.2]nonan-4-yl 2-(3-(3(morpholine-4caibonyl)phenoxy)phcnyl)propan-2ylcarbamatc	278	0.593	1.44	0.053	10.	10.
279	Quinudidin-3-yl 2-{3-(3-(inotpholiiie-4carbonyl)phenoxy)phenyl)propan-2ylcarbamatc	279	4.33	3.92	0.217	10.	3.16
280	l-(3-Methylquinuclidin-3-yl)-3-{2-(4-(4- (moipholine-4caibonyl)phcnoxy)phenyt)piOpan-2-yl)urca	280	0.164	1.94	0.0491	10.	1.0
281	1 -(4-Methyl-1 -azabicyclo[3.2.2]aonan-4- yl)-3-(2-(4-(4-(moipholme-4carbonyI)phcnoxy)phenyl)propan-2-yl)urca	281	0.0316	0.44	0.00779	10.	1.0
282	l-Azabicycto[3.2.2]nonan-4-yl 2-(4-(4(morpholine-4caibonyl)phcnoxy)phenyl)propan-2ylcarbamatc	282	0.479	0.66	0.0404	10.	3.16
283	Quinuclidin-3-yl 2-(4-(4(dîmcthylcarbamoyl)phenoxy)phenyl)propa ίΐ-2-ytcnibrtmute	283	0.606	1.03	0.114	10,	10.

321

284	JVJV-Dimcthyl-4-(4-(2-(3-(3mclhylquÎtiuclidin-3-yl)urcido)propan-2yl)phenoxy)benzamide	284	0.201	3.78	0.0607	10.	10.
285	ALV-Diinelhyl-d-(4-(2-(3-(4-inctliyl-lazabicyclo[3.2.2]aonan-4-yl)urcido)propan2-yl)plicnoxy)benaimidc	285	0.0163	0.725	0.00648	10.	1.0
286	l-Azabicyclo[3.2.2]nonan-4-yl 2-(4-(4(dimcüiylcarbamoyl)phcnoxy)phcnyl)propa n-2-yIcarbamatc	286	0.437	0.793	0.0316	10.	10.
287	Quinucliditi-3-yl 2-(4-(4- (dimethyicarbamoyl)phenoxy}phenyl)propa n-2-ylcnrbamatc	287	133	2.2	0229	10.	3.16
288	l-Aza-bicyclo[3.2.2]aonnn-4-yl 2-(3-(3(diinelhylcaibamoyl)phcnoxy)phcnyl)propa n-2-ylcarbamatc	288	0.203	1.18	0.0502	10.	10.
289	AW-Dimcthyi-3-(3-(2-(3-(3mcthylquinuclidin-3-yl)ureido)propan-2yl)phenoxy)beazamide	289	0.104	1.41	0.0917	926	10.
290	MM-Dimclliyl-4-{4-(2-(3 -(4-melliyl-1 -azabicyclo[32.2]nonan-4-yl)ureido)propan-2yi)plieaoxy)benzamide	290	0.0191	2.58	0.0268	10.	3.16
291	QuinucLidin-3-yl 2-(4-(4(mc11iylcatbamoyl)phenoxy)pkenyl)propan2-ytcaibamatc	291	1.91	2.31	0.0902	10.	3.16
292	1- Aza-bicyclo[3.2.2]nonan-4-yI 2-(4-(4(mcthylcatbamoyl}phenaxy)phenyl)piDpnn- 2- ykarbamatc	292	0207	1.22	0.0412	10.	10.
293	A(-Mcthyl-4-(4-(2-(3-(3-meÜiylquinuclidin- 3-yl}ureido)propan-2yl)plienoxy)bcnzamide	293	0.186	537	0.046	10.	1.0
294	jV-Metliyl-4-(4-(2-(3-(4-melhyl-1 -aznbicyclo[32.2]nonan-4-yl)ureido)propan-2yl)phenoxy)benznmidc	294	0.0124	0.843	0.00706	10.	1.0
295	2-(3-(3- (Me(hylcarbatnoyÎ)phenoxy)phenyl)propan2-ylcaibamatc	295	1.02	1.75	0.147	10.	10.
296	JV-Methyl-3-(3-{2-(3-(3-mclhylquinuclidin- 3-yl)ureido)pK>pan-2yi)phcnoxyjbenzamide	296	0.20	5.47	0.155	10.	10.
297	MMethyl-3-(3-(2-(3-(4-mcthyH-azabicyclo[3.2.2]nonan-4-yl)urcido)propan-2yl)phenoxy)bcnzumide	297	0.0102	1.37	0.0132	10.	1.0
298	1- Aza-bicyclo{3.22]nonan-4-yl 2-(3-(3- (methylcarbamoyi)pbenaxy)phenyl)piopan- 2- ylcarbamatc	298	0.138 1	l.l	0.0308	10.	3.16 1

322

299	l-Aza-bicyclo[3.2.2]nonun-4-yl 2-(4-(4(pîperidùie-l-carbonyl)phcnoxy)phenyl) propaa-2-ylcaibamatc	299	0.0154	0.192	0.00367	10.	1.0
300	l-(4-MeÜiyl-l-aza-bicyclo[3.2.2]nonan-4yl)-3-(2-(4-(4-{pÎperid ίηο-1 cûrbonyl}p)ieiioxy)phcnyl)pmptin-2-yi)urca	300	0.00685	0.0876	0.00154	10.	0316
301	l-Azabicyclo[3.2.2]nonan-4-yl 2-(4-(4-(4,4difluoropipcridinc-lcarbonyl)plictioxy)phcnyl)propan-2ylcaibamatc	301	0.0172	0.0494	0.00339	10.	1.0
302	1-(2-(4-(4-(4,4-Difluorop ipcridinc-1 carbonyl)phenoxy)phcnyl)propan-2-yl)-3(4-methyl-l-azabicyclo[3.2.2]nonan-4yljurea	302	0.00422	0.0317	0.00147	10.	1.0
303	1-(2-(4-(4-(3,3-Ditluoroazctidine-1 caibonyl)phenoxy)pheiiyl}propan-2-yl)-3(4-mcthyl-l-a2a-bicyclo[3.2.2]nonnn-L yl)urca	303	0.00763	0.0389	0.00124	10.	0.316
304	Qumuclidin-3-yl 2-{4-(4-phcnylpipcinzÎnc- l-corix>nyl)plicny!)propan-2-ylcart>ainate	304	1.73	0.355	0.0959	10.	10.
305	^/-(2-(4-(4(Methylcarbamoyl)phenoxy)phcnyl)propan2-yl)-1 ,4-diaza-l>icyclo[3.2.2] nonane-4carboxamide	305	0399	0.299	0,0195	10.	1.0
306	l-(3-Ethylquinuclidiii-3-yl)-3-(2-(4-(4phonylpipcrazinc-1catbonyl)phenyl)propan-2-yl)urea	306	0.0951	0.257	0.032	10.	3.16
307	Quinucüdin-3-yl 2-(4-(6-(2mclhoxyethoxy)pyridin-3yl)phcnyl)propan-2-ylcarbamatc	307	0.735	4.34	0.0972	10.	10.
309	Quinuclidin-3-yl 2-(4-(6-(2methoxycthoxy)pyridin-3yl)phenyl)propan-2-ylcatbamate	309	0.106	0.188	0.014	10.	3.16
308	Quinuclidin-3-yl 2-(4-(5-(2methoxyethoxy)pyndin-2yl)phenyl}piÎipui-2-ylcaibaniate	308	0.254	0.314	0.0358	7.77	1.0
312	QuÎnuclidin-3-yl (2-(3-(6-(3mothoxypropoxy)pyrÎdazin-3yl)phenyl)propan-2-yl)cart>amate	312	1.66	134	0.103	10.	1.0
3I3	l-Azabicyclo[3.2.2]nonan-4-yl (2-(3-(6-(3mcthoxypropoxy)pyridazin-3yl)phenyl)propan-2-yl)cartianintc	313	0.0889	0.47	0.0107	10.	10.
314	jV-(2-(3-(6-(3-Mctlioxypropoxy)pyridazin- 3-yl)phenyl)propan-2-yl)-1,4- dïazabicyclo[3.2.2]nonano-4-cartx>xamide	314	2.63	4.91	0.118	10.	10.
3I5	QuinuclidÎn-3-yI (2-(3-(5-(3melhoxypfopoxy)pynian-2yl)phenyl)propan-2-yt)caibaniate	315	0.197	0.435	0.0259	10.	1.0

323

3J6	1 -Azabicyclo[3.2.2]nonan-4-yl (2-(3-(5-(3mctlioxypropoxy)pyrazin-2yl)phenyl)propan-2-yl)carbamn1e	316	0.028	0.152	0.00439	10.	10.
317	N-(2-{3-(5-(3-Methoxypropoxy)pyrazin-2y IJphcny l)propan-2-yl)-l ,4diazabicyc!o[3.2.2]nonane-4-carbox amide	317	0.295	0.656	0.0291	10.	1.0
318	QumucUdin-3-yl (2-(3-( 6-cihoxypyridazin- 3-yl)phcnyl)propan-2-yl)carbamatc	318	1.46	0.635	0.0699	#NUM!	1.0
319	l-Azabicyclo[3.2.2]nonan-4-yl (2-(3-(6ethoxypyridazin-3-yl)phenyl)propan-2yljcarbamalc	319	0.075	0.121	0.00804	10.	10.
3 ΙΟ	1 -Azabicyclo[3.2.2]nonan-4-y l2-(4-(5-(2melhoxyciboxy)pyridin-2yl)phcnyl)propan-2-ylcarbamatc	310	0.123	0.145	0.0121	10.	3.16
320	Qumuclidin-3-yl (2-(4-(5-(3mcthoxypropoxy)pyrazin-2yl)phenyl)propan-2-yl)cartiamale	320	0.131	0.201	0.0112	10.	1,0
321	l-Azabicyclo[3.2.2]nonaii-4-yl (2-(4-(5-(3methoxypropoxy)pyraziii-2yi)phenyl)propan-2-yi)carbania1c	321	0.0461	0.108	0.00639	10.	1.0
322	7V-(2-(4-(5-(3-methoxypropoxy)pynizin-2- yt)phenyl)propan-2-ylf 1,4- diazabicyclo[3.2.2]nonane-4-carboxamidc	322	1.07	1.44	0.0999	10.	1.0
311	l-Azabicyclo[3.2.2]nonan-4-yl 2-(3-(5-(2mcthoxyclhoxy)pyridin-2yi)phenyl)propan-2-ylcart>amate	311	0.076	0.103	0.0085	10.	3.16
323	Quinuclidin-3-yl (2-(3-(5-(3mcthoxypropoxy)pyrimidin-2yl)phenyl)propan-2-yi)carbamate	323	1.16	0.508	0.0488	10.	1.0
324	l-Azabicyclo[3.2.2]nomui-4-yl (2-(3-(5-(3- mctlioxypropoxy)pyrimidin-2- yl)phcnyl)propxxi-2-yl)cûrbamate	324	0.0969	0.157	0.00849	10.	1.0
325	l-(3-Ethylquinuclidin-3-yl)-3-(4-(4-(2n»lhoxycthyl)phcnyl)-2-mclhyibut-3-yn-2yljurea	325	0.092	0.399	0.00794	10.	10.
326	1-(4-( 4-(2-Mcthoxycthyl)phenyl)-2methylbut-3-yn-2-yl)-3-(3prc>pyiquinuclidin-3-yl)urca	326	0.0266	0.123	0.00429	3.16	3.16
327	1- (3-Ethylquinuclidin-3-yl)-3-(4-(4- (methoxymcthyl)plienyl)-2-methylbut-3-yii- 2- yl)urca	327	0.0962	0.343	0.0147	10.	10.
328	1 -(4-(4-(MothoxymcÜiyl)phcnyl)-2mediylbut-3-yn-2-yl}-3-(3propylquinuclidin-3-yl)urea	328	0.0251	0.115	0.00332 \|	3.16	3.16

324

329	QuÎnuclidin-3-yl (4-(4-(2methoxyethoxy)plieiiyl)-2-inethylbut-3-yn2-yl)carbamate	329	3.14	2.7	0.284	10.	10.
330	l-(4-(4-(2-McUioxyethoxy)phenyl)*2methylbut-3-yn-2-yl)-3-(3propylquinuclidin-3-yl Jures	330	0.104	0.203	0.00641	10.	3.16
331	Quinuclidin-3-yl (4-(4-(3mcthoxypropoxy)phcnyl)-2-methylbut-3yn-2-yI)carbatnalc	331	133	1.76	0.118	10.	10.
332	l-(3-Ethylquiiiuclidin-3-yl)-3-(2-mcthyl-4(4-((pyridin-3ytmcthoxy)mcthyl)phcnyl)but-3-yii-2yljurea	332	0.0494	0.945	O.OI55	10.	10.
333	l-(2-Mcthyl-4-(4-((pyridiit-3ylmethoxy)mcthyl)plienyl)but-3-yii-2-yl)-3(3-propylquinuclidin-3-yl)urea	333	0.0161	0.413	0.00618	10.	3.16
334	QuinuclÎdin-3-yl (4-(4-((3,3dimelhylbutyl)sutfonyl)phenyl)-2methylbul-3-yn-2-yl)carbamatc	334	0.0802	0317	0.0118	3.28	10.
335	l-Azabicyclo[3.2.2]nonan-4-yl (4-(4-((3,3dimcthylbu tyl)sulfonyl)phenyl)-2methylbut-3-yn-2-yl)caibamatc	335	0.0146	0.193	0.00432	2.15	1.0
336	1-(4-(4-((3,3- Dimcthylbutyljsu lfonyl)phenyi)-2methylbut-3-yn-2-yl)-3-(4-methyl-1 aaibicyclu[3.2.2]nonan-4-ylJurea	336	0.0012	0.0388	0.000902	10.	10.
337	1-(4-(4-((33- Di melhylbutyl)siilfonyl)plietiyl)-2methylbut-3-yn-2-yl)-3-(3nethylquinuclidin-3-yl)urea	337	0.0)45	0.0941	0.00254	2.15	1.0
338	1-(4-(4-((33- Dimethylbutyl)sulfonyl)phcnyl)-2methylbut-3-yn-2-yl)-3-(3-ethylquinuclidÎn3-y1)urea	338	0.00445	0.0721	0.000984	2.15	1.0
339	l-{4-(4-(l-Mcthoxy-2-methylpropan-2ylJphcnyl)-2-mclhylbut-3-yu-2-yl)-3-(3melhylquinuc)idui-3-yl)uiea	339	0.136	0.72	0.0257	10.	10.
340	Quinuclidin-3-yl (2-(2-(4-(3inethoxypropoxyjphcnyljlhiazol-'l-yl)propan-2-yl)caibainate	340	0.17	0.197	0.0426	10.	10.
341	l-Azabicyclo[3.2.2]nonan-4-yl (2-(2-(4-(3methoxypropoxy)plienyl)thÎazol-4yl)propan-2-yl)caiiminatc	341	0.0193	0.0904	0.00719	10.	10.
342	V-(2-(2-(4-(3- McUioxypropoxy)plienyl)Üiiazol-4yÎ)propsis-2-yI)-1,4. dûizabicyclo{3.2.2]mmauo-4-carboxanùde	342	0.666	0393	0.0851	10.	10.
343	Quiauclidin-3-yl (2-(2-(4-(2methoxyclhoxy)phenyl)thiazol-4-yl)prcpan2-yi)carbamate	343	036	0.106	0.0198	10.	1.0

325

344	1- Aznbicyclo[3.2,2]nontin4-yi (2-(2-(4-(2mclhoxyeÜioxy)phenyl)lhituol-4-yt)propan- 2- yl)carb(irruitc	344	0.0658	0.0564	0.00876	10.	1.0
345	Melhoxyelhoxy)plieiiyl)tliiaz‘.>l-4>yl)propan- 2-yl)-l ,4-din7Jibicyclo[3.2.2]no;janc-4carboxamide	345	2.54	0.369	0.091	10.	3.16
346	Quinuclidin-3-yl 2-(5-(4-(2melhoxycihoxy)phenyi)pyridin-2yl)propnn-2-yknrbamatc	346	0.0507	0.266	0.0111	10.	3.16
347	l-Azabicyclo[3.2.2]noniui-4-yl 2-(5-(4-(2- mcthoxycthoxy)plicnyl)pyridia-2yl)propan-2-ylcatbamatc	347	0.0368	0.15	0.00582	10.	1.41
348	l-Azabicyclo[3.2.2]nonan-4-yl 2-(5-(4-(2- mcthoxycthoxy)phcnyl)pyridin-2yl)propan-2-y)cart>amatc (single enantiomer A)	348	0.0278	0.0872	0.00352	10.	1.0
349	l-Aznbicyclo[3.2.2]nonan-4-yl 2-(5-(4-(2nKlhoxycthoxy)phenyl)pyridin-2yl)propan-2-ylcaibamntc (single enantiomer B)	349	0.25	0.233	0.0144	10.	1.0

Example 351 Glucosylceramide synthase inhibition in a model of polycystic kidney disease.

Mice homozygous for the Nek8jck mutation develop polycystic kidney disease (“jck mice”). Histology revcals that the kidneys of some 3 day old pups from heterozygous parents had small isolated cysts lined by cuboidal épithélial cells, and 15 day old pups had cysts lined by flattened epithelia. Disease is progressive but not évident by kidney palpation until at least 4 to 5 weeks of âge. Homozygotes generally remain active until shortly before death and usually die between 20 and 25 weeks of âge. Homozygous fcmales are fertile but do not consistent!y care for their littcrs; homozygous males arc fertile but dccrcascd fertility is reported after 15 weeks of âge. No histologie abnormalities are found in the liver, spleen, or pancréas. (Atala et al., 1993).

To evaluate the effects of a GCS inhibitor on polycystic kidney disease, Compound 156, (S)-quinuclidin-3-yl (2-(4'-(2-mcthoxycthoxy)-[l,r-biphcnyl]-4yl)propan-2-yl)carbamate was administered in the feed ofJck mice at doses of 15, 30 and 50 mg/kg. A second compound, quinuclidin-3-yl (2-(4'-fluoro-[l,r-biphenyl]-3yl)propan-2-yl)carbamatc (hereinafter “GZ 161”) was administered in the feed of Jck mice at a dose of 60 mg/kg.

326

Administration of the compound was started between 3 and 4 weeks of âge, and continued until the mice were sacrificed at 9 weeks of âge. The effect of the compounds on the disease phenotype was evaluated by measurement of body weight, blood urea nitrogen (“BUN”), and sérum GLl. Additional effects on kidney/body weight (K/BW), cyst volume, BUN, kidney GLl, and sérum GLl were also measured at the end of life time point of the study.

As demonstrated in Figure 3, Compound 156 caused a dosc-depcndent inhibition of GLl that is associated with reduced cyst growth and préservation of kidney function. The dose dépendent réductions are provided graphically as well as numerically wherein the percentages expressed are the percent réductions in the GLl levels as compared to the vehicle control groups. Figure 3 demonstrates the body weight measurements between the vehicle control group, the thrcc doses of Compound 156 groups tested, and the GZ 161 group, wherein the 30 mg/kg and 50 mg/kg doses Compound 156 are statistically different from the vehicle control group. Figure 3 also demonstrates the kidney to body weight measurements between the vehicle control group, the three doses of Compound 156 groups tested, and the GZ 161 group, wherein ail of the Compound 156 groups and the GZ 161 groups are statistically different from the vehicle control group. Figure 3 also demonstrates the cyst volume and the BUN measurements between the vehicle control group, the three doses of Compound 156 tested, and the GZ 161 group, wherein ail of the GZ 406 groups and the Compound 156 groups arc statistically different from the vehicle control group.

Claims

Claims

1, A compound represented by the following structural formula, or a pharmaceutically acceptable sait thereof, wherein:

10 n is 1, 2 or 3;

m is 0 or 1;

p is 0 or 1;

t is 0, 1 or 2;

y is 1 or 2;

15 zisO, 1 or 2;

E is S, O, NH, NOH, NNO₂, NCN, NR, NOR or NSO₂R;

X’is CR¹ when m is 1 or N when m is 0;

X² is O, -NH, -CH2-, SO₂, NH-SO₂;CH(Ci-C₆) alkyl or-NR² ;

X³ is a direct bond, O, -NH, -CH₂-, CO, - CH(Ci-C₆) alkyl, SO₂NH, -CO-NH- or 20 NR³;

X⁴ is a direct bond, CR⁴R⁵, CH2 CR⁴R⁵or CH2 -(Ci-C₆) alkyl-CR⁴R⁵;

X⁵ is a direct bond, O, S, SO2, CR⁴R⁵, (Ci-Câ)alkyl, (Ci-C6)alkyloxy, -O- (CiCô)alkyl, (Ci-Cô)alkenyl, (Ci-Côjalkenyloxy, - R⁷-(C3-Cio)cycloalkyl, (C3-Cio)cycloalkyl R⁷-,- R⁷- (C6-Ci2)aryl, (Cô-Ci₂)aryl - R⁷-, - R⁷- (C2-C9)heteroaryl, (C2-C9)heteroaryl- R⁷-, 25 R⁷- (C2-C9)heterocycloalkyl, and (C₂-C9)heterocycloalkyl - R⁷-, wherein R⁷ is a direct bond, O, S, SO₂, CR⁴R⁵, (Ci-C6)alkyl, (Ci-C6)alkyloxy, -O- (Ci-C6)alkyl, (Ci-C6)alkenyl, (Ci-Céjalkenyloxy ; and further wherein when X⁵ is defined as - R⁷-(C3-Cio)cycloalkyl, (C3Cio)cycloalkyl - R⁷-,- R⁷- (C6-C|2)aryl, (Cô-Ci2)aryl - R⁷-, - R⁷- (C₂-C9)heteroaryl, (C₂17263

328

Cy)hcteroaryl- R⁷-, - R⁷- (C2-C9)heterocycloalkyl, and (C2-C9)heterocycloalkyl-R7-, wherein the (C3-Cio)cycloaikyl, (Câ-Ci2)aryl, (C2-C9)heteroaryl, (C2-C9)heterocycloalkyl groups are optionally substîtuted by one or more substituents selected from the group consisting of halo, (Ci-C6)alkyl, (Ci-Cejalkylenyl, amino, (Ci-Ci) alkylamino, (CiCôjdialkylamino, (C[-C6)alkoxy, O(C3-Cô cycloalkyi), (C3-Cô) cycloalkoxy, nitro, CN, OH, (Ci-Côjalkyloxy, (C3-Cô) cycloalkyi, (Ci-Ce) alkoxycarbonyl, (Ci-C&) alkylcarbonyl, (CiCe) haloalkyl, (C2-C9)heterocycloalkyl, R⁸R⁹N-CO- wherein R⁸ and R⁹ are each independently selected from the group consisting of hydrogen and (Ci-C6)alkyl or R⁸ and R⁹ can be taken together with the nitrogen to which they are attached to form a (C2C9)heterocycloalkyl or (C2-C9)heterocycloalkyl group optionally substîtuted by one to three halo groups, (Ci-C6)alkylsulfonyl optionally substîtuted by one or two groups selected from (Ci-Cô)alkoxy and (C3-Cio)cycloalkyi;

(Ci-Ce)alkyl substîtuted by one to four substituents selected from the group consisting of halo, hydroxy, cyano, (Ci-C6)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkoxy, (C2C9)heterocycloalkyl, (C2-C9)heteroaryl optionally substîtuted by (Ci-Ce)alkoxy; or (C₃C[o)cycloalkoxy optionally substîtuted by (Ci-Cô)alkoxy; and (Ci-Cô)alkyloxy substîtuted by one to four substituents selected from the group consisting of halo, hydroxy, cyano, (Ci-Cô)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkoxy, (C2Cgjheterocycloalkyl, (C2-C9)heteroaryl optionally substîtuted by (Ci-C6)alkoxy; or (C₃Cio)cycloalkoxy optionally substîtuted by (Ci-C6)alkoxy;

R is (Cô-Ci2)aryl, (C2-C9)heteroaryl, (Ci-Cô)alkyl, (C2-C9)heteroaryl(Ci-C&)alkyl; R¹ is H,CN, (Ci-C6)alkylcarbonyl, or (Ci-Cûjalkyl;

R² and R³ are each independently -H, (Ci-Ce)alkyl optionally substîtuted by one or more substituents selected from the group consisting of halogen, (Ci-Cô)alkyl, (C6-Ci2)aryl, (C2-C9)heteroaryl, (Ci-Cô)alkyl(C6~Ci2)aryl, halo(C6-Ci2)aryl, and halo(C2-C9)heteroaryl, or optionally when X² is -NR² and X³ is -NR³, R² and R³ may be taken together with the nitrogen atoms to which they are attached form a non-aromatic heterocyclic ring optionally substîtuted by with one or more substituents selected from halogen, (Ci-C6)alkyl, (CôCi2)aryl, (C2-C9)heteroaryl, (Cj-C6)alkyl(C6-Ci2)aryl, halo(C6-Ci2)aryl, and halo(C2C9)heteroaryl;

R⁴ and R⁵ are independently selected from H, (Ci-Cô)alkyl, or taken together with the carbon to which they are attached to form a spiro (C₃-Cio)cycloalkyl ring or spiro (C₃Cio)cycloalkoxy ring;

329

R⁶ is -H, halogen, -CN, (C6-Ci2)aryl, (Cô-Ci2)aryloxy, (Ci-C6)alkyloxy;

(Ci-Cô)alkyl optionally substituted by one to four halo or (Ci-Côjalkyl;

A¹ is (C2-Cô)alkynyl; (C3-Cio)cycloalkyl, (Cf,-Ci2)aryl, (C2-C9)heteroaryl, (C2C<))heterocycloalkyl or benzo(C2-C9)heterocycloalkyl wherein A¹ is optionally substituted with one or more substituents selected from the group consisting of halo, (Ci-Cô)alkyl optionally substituted by one to three halo; (Ci-Cô)alkenyl, amino, (Ci-C6)alkylamino, (CiC6)dialkylamino, (C]-C6)alkoxy, nitro, CN, -OH, (Ci-Câ)alkyioxy optionally substituted by one to three halo; (Ci-Cô)alkoxycarbonyl, and (Ci-Cô) alkylcarbonyl;

A² is H, (C3-Cio)cycloalkyl, (Cô-Cnjaryl, (Cî-Cgjheteroaryl, (C2Cgjheterocycloalkyl or benzo(C2-C9)heterocycioalkyl wherein A² is optionally substituted with one or more substituents selected from the group consisting of halo, (Ci-C6)alkyl, (CiC&)alkylenyl, amino, (Ci-C&) alkylamino, (Ci-Côjdialkylamino, (Ci-C6)alkoxy, O(C3-Cô cycloalkyl), (C3-C6) cycloalkoxy, nitro, CN, OH, (Ci-Cô)alkyloxy, (C3-C6) cycloalkyl, (CjCô) alkoxycarbonyl, (C|-C&) alkylcarbonyl, (Ci-Cô) haloalkyl, (C2-C9)heterocycloalkyl, R⁸R⁹N-CO- wherein R⁸ and R⁹ are each independently selected from the group consisting of hydrogen and (C]-Cô)alkyl or R⁸ and R⁹ can be taken together with the nitrogen to which they are attached to form a (C2-C9)heterocycloalkyl or (C2-C9)heterocycloalkyl group optionally substituted by one to three halo groups, (C]-Cô)alkyisulfonyl optionally substituted by one or two groups selected from (Ci-Ce)alkoxy and (C3-Cio)cycloalkyl;

(Ci-Cfi)alkyl substituted by one to four substituents selected from the group consisting of halo, hydroxy, cyano, (Ci-Cô)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkoxy, (C2Cgjheterocycloalkyl, (C2-C9)heteroaryl optionally substituted by (Ci-Ce)alkoxy; or (C3Cfo)cycloalkoxy optionally substituted by (Cj-CôJalkoxy; and (Ci-Cejalkyloxy substituted by one to four substituents selected from the group consisting of halo, hydroxy, cyano, (Ci-C6)alkoxy, (Ci-C6)aIkoxy(Ci-C6)alkoxy, (C2Cgjheterocycloaikyl, (C2-C9)heteroaryl optionally substituted by (Ci-Ce)alkoxy; or (C₃Cio)cycloalkoxy optionally substituted by (Ci-C6)alkoxy;

with the proviso that the sum of n + t + y + z is not greater than 6;

with the proviso that when p is 0; X² is NH-SO2 and X³ is NH;

with the proviso that when n is 1 ; t is 0; y is 1 ; z is 1 ; X² is NH; E is Ο; X³ is NH; A² is H and X⁵ is a direct bond; A¹ is not unsubstituted phenyl, halophenyi or isopropenyl phenyl;

330 with the proviso that when n is 1; t is 0; y is 1; z is 1; X² is O; E is Ο; X³ is NH; A¹is (Cô-Cnjaryl and X⁵ is a direct bond; A² is H and R⁴ is H then R⁵ is not cyclohexyl;

with the proviso that when n is 1 ; t is 0; y is 1 ; z is 1 ; X² is NH; E is Ο; X³ is CH₂;

R⁴ and R⁵ are both hydrogen; A² is H and X⁵ is a direct bond; then A¹ is not unsubstituted

5 phenyl; and with the proviso that when X³ is O, -NH, -CH2-, CO, - CH(Ci-Cô) alkyl, SO2NH, CO-NH- or-NR³;and X⁴ is CR⁴R⁵, CH2 CR⁴R⁵or CH2 -<Ci-C6) alkyl-CR⁴R⁵; then A²must be (C3-Cio)cycloalkyl, (C6-Ci2)aryl, (C2-C9)heteroaryl, (C2-C9)heterocycloalkyl or benzo(C₂-C9)heterocycloalkyl substituted with one or more substituents selected from the 10 group consisting of, (C₂-C9)heterocycloalkyl, R⁸R⁹N-CO- wherein R⁸ and R⁹ are each independently selected from the group consisting of hydrogen and (Ci-C6)alkyl or R⁸ and R⁹ can be taken together with the nitrogen to which they are attached to form a (C₂C<))heterocycloalkyl or (C2-C9)heterocycloalkyl group optionally substituted by one to three halo groups, (C]-C6)alkylsulfonyl optionally substituted by one or two groups

15 selected from (Ci-Cejalkoxy and (Cj-Cio)cycloalkyl;

(Ci-C6)alkyl substituted by one to four substituents selected from the group consisting ofhydroxy, cyano, (Ci-Cô)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkoxy, (C2C9)heterocycloalkyl, (C2-C9)heteroaryl optionally substituted by (Ci-Ce)alkoxy; or (C3Cio)cycloalkoxy optionally substituted by (Ci-Cô)alkoxy;

20 or (Ci-Côjalkyloxy substituted by one to four substituents selected from the group consisting ofhydroxy, cyano, (Ci-Cô)alkoxy, (Ci-C6)alkoxy(Ci-Cô)alkoxy, (C2Cçjheterocycloalkyl, (C2-C9)heteroaryl optionally substituted by (Cj-Cûjalkoxy; or (C3Cio)cycloalkoxy optionally substituted by (C]-C6)alkoxy.
2. A compound according to claim 1, or a pharmaceutically acceptable sait, selected 25 from the group consisting of:

l-azabicyclo[2.2.2]oct-3-yl [2-(2,4'-difluorobiphenyl-4-yl)propan-2-yl]carbamate;

1 -azabicyclo[2.2.2]oct-3-yl (2-[4-(l ,3-benzothiazol-6-yl)phenyl]propan-2-yl)carbamate; l-azabicyclo[3.2.2]non-4-yl {l-[5-(4-fluorophenyl)pyridin-2-yl]cyclopropyl}carbamate; l-azabicyclo[2.2.2]oct-3-yl (l-[3-(4-fluorophenoxy)phenyl]cyclopropyl}carbamate;

30 l-azabicyclo[2.2.2]oct-3-yl {l-[4-(l,3-benzothiazol-5-yl)phenyl]cyciopropyl}carbamate;

1 -azabicyclo[2.2.2]oct-3-yl [ 1 -(4'-fluoro-3'-methoxybiphenyl-4yl)cyclopropyl]carbamate; l-azabicyclo[2.2.2]oct-3-yl [3-(4'-fluorobiphenyl-4-yl)oxetan-3-yl]carbamate;

1 -azabicyclo [2.2.2]oct-3 -y 1 {1 - [6-(4-fl uorophenoxy )py ridin-2-y 1] cyclopropyl} carbamate ;

331 l-azabîcyclo[2.2.2]oct-3-yl [3-(4’-fluorobiphenyl-4-yl)pentan-3-yl]carbamate;

l-azabicyclo[2.2.2]oct-3-yl {2-[2-(4-fluorophenyl)-2H-indazol-6-yl]propan-2 yljcarbamate;

l-azabicyclo[2.2.2]oct-3-yl {2-[2-(lH-pyrrol-l-yl)pyridin-4-yl]propan-2-yl}carbamate;

l -(3-ethyl-1 -azabicyclo[2.2.2]oct-3-yl)-3-[ l -(4'-fluorobiphenyl-4-yl)cyclopropyl]urea;

N-(l-azabicyclo[2.2.2]oct-3-yl)-N'-[l-(4'-fluorobiphenyl-4yl)cyclopropyl]ethanediamide;

l -azabicyclo[2.2.2]oct-3-yl ( l -{4[(4,4difluorocyclohexyl)oxy]phenyl}cyclopropyl) carbamate;

1- (4-methyl-l-azabicyclo[3.2.2]non-4-yl)-3-[l-(5-phenylpyridin-2-yl)cyclopropyl]urea;

l -[ l -(4'-fluorobiphenyl-4-yl)cyclopropyl]-1 -methyl-3-(3-methyl-l-azabicyclo[2.2.2]oct3-yl)urea;

l -[ l -(4'-fluorobiphenyl-4-y l)cyclopropyl]-1 -methyl-3-(3-methyi-1 -azabicyclo[2.2.2]oct3-y l) urea;

1 - {2- [4'- (2-methoxy ethoxy )bi phenyl -4-y I] propan-2-y I} -3 -(3 -methy 1-1 azabicyclo[2,2.2]oct-3-yl)urea;

2- (l-azabicyclo[3.2.2]non-4-yl)-N-[l-(5-phenylpyridin-2-yl)cyclopropyl]acetamide;
3- (4'-fluorobiphenyl-4-yl)-3-methyl-N-(4-methyl-l-azabicyclo[3.2.2]non-4yl)butanamide;

N-[2-(biphenyl-4-yl)propan-2-yl]-N'-(3-methyl-l-azabicyclo[2.2.2]oct-3-yl)sulfuric diamide;

N-[2-(4'-fl uorobipheny 1-4-y l)propan-2-y 1]-N'-(3-methy I -1-azabicyclo [2.2.2] oct-3 yljsulfuric diamide;

1 -(3-butyl-1 -azabicyclo[2.2.2]oct-3-yl)-3-{ 2-[ 1 -(4-fluorophenyl)-lH-pyrazol-4yl] propan-2-y 1} urea;

l-azabicyclo[2.2.2]oct-3-yl [4-(4-fluorophenyl)-2-methylbut-3-yn-2-yl]carbamate;

l-(3-butyl-l-azabicyclo[2.2.2]oct-3-yl)-3-[4-(4-fluorophenyl)-2-methylbut-3-yn-2y I] urea;

N-[l-(4^,-fluorobiphenyl-4-yl)cyclopropyl]-l,4-diazabicyclo[3.2.2]nonane-4-carboxamide; l-(2-(4'-fluoro-[l,r-biphenyl]-4-yl)propan-2-yl)-3-(3-methyl-l-azabicyclo[3.2.2]nonan3-yl)urea;

l-(2-(4'-fluoro-[l_ir-biphenyl]-4-yl)propan-2-yl)-3-(4-methyl-l-azabicyclo[4.2.2]decan-4yl)urea;

332 l-(2-(4'-fluoro-[l, r-biphenyl]-4-yl)propan-2-yl)-3-(3-methyl-l-azabicyclo[4.2.2]decan-3yl)urea; and l-(2-(4'-fluoro-[l,r-biphenyl]-4-yl)propan-2-yl)-3-(5-methyl-l-azabicyclo[4.2.2]decan-5yl)urea.

3. A method for treating a disease or disorder mediated by glucosylceramide synthase (GCS) or a disease or disorder in which GCS is implicated in a subject in need of such treatment comprising administering to the subject an effective amount of a compound according to claim 1, wherein the disease or disorder is cancer, a metabolic disorder or a neuropathie disease.
4. A method of treating a subject diagnosed as having a lysosomal storage disease, comprising administering to the subject an effective amount of the compound according to claim 1.
5. The method of claim 4, wherein the lysosomal storage disease is selected from the group consisting of Gaucher, Fabry, GMi-ganglîosidosis, Gm2 Actîvator deficiency, TaySachs and Sandhoff.
6. The method of claim 4, further comprising the step of administering to the subject a therapeutically effective amount of a lysosomal enzyme.
7. The method of claim 3 or 4, wherein the compound is represented by the following structural formula, or a pharmaceutically acceptable sait thereof.
8. A compound according to claim 1, wherein m is 1 ; E is Ο; X² is O and X³ is direct bond.
9. A compound according to claim 1, wherein m is 1 ; E is Ο; X² is NH and X³ is direct bond.
10. A compound according to claim 1, wherein m is 1 ; E is Ο; X² is CH₂ and X³ is direct bond.

333
11. A compound according to claim 1, wherein m is 1 ; E is S; X² is NH and X³ is direct bond.
12. A compound according to claim 1, wherein m is 0; E is Ο; X¹ is NH and X³ is direct bond.
13. A compound according to claim 1, wherein m is 1 ; p is 0; X² is NH-SO2 and X³ is direct bond.
14. A compound according to claim 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1; E is Ο; X² is O and X³ is direct bond.
15. A compound according to claim 1, wherein n is 1 ; 2 or 3; t is 0,1 or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is Ο; X² is NH and X³ is direct bond.
16. A compound according to claim 1, wherein n is 1; 2 or 3; t is 0,1 or 2; y is 0 or 1 ; z is 0,1 or 2; X¹ is CR¹; m is I; E is Ο; X² is CH₂ and X³ is direct bond.
17. A compound according to claim 1, wherein n is 1 ; 2 or 3; t is 0, I or 2; y is 0 or 1 ; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; E is S; X² is NH and X³ is direct bond.
18. A compound according to claim 1, wherein n is 1; 2 or 3; t is 0,1 or 2; y is 0 or 1; z îs 0, 1 or 2; X¹ is CR¹; m is 0; E is Ο; X¹ is NH and X³ is direct bond.
19. A compound according to claim 1, wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or I; z is 0, 1 or 2; X¹ is CR¹; m is 1 ; p is 0; X² is NH-SO₂ and X³ is direct bond.
20. A compound according to claim 1, wherein X⁵ is a direct bond, O, S, SO₂, CR⁴R⁵; (Ci-Cô)alkyl, (Ci-Cbjalkyloxy, (Ci-C6)alkenyl or (Cj-Cô)alkenyloxy.
21. A compound according to claim 1, wherein X⁵ is -O- (Ci-Cô)alkyl, - R⁷-(C3Cio)cycloalkyl, (C3-Cio)cycloalkyl - R⁷-,- R⁷- (C6-Ci2)aryl, (C6-Ci2)aryl - R⁷-, - R⁷- (C2Cgjheteroaryl, (C2-C9)heteroaryl- R⁷- , - R⁷- (C2-Cg)heterocycloalkyl, and (C₂C9)heterocycloalkyl - R⁷-, wherein R⁷ is a direct bond, O, S, SO2, CR⁴R⁵; (Ci-Cûjalkyl, (Cj-CsJalkyloxy, -O- (Ci-C6)alkyl, (Ci-C6)alkenyl or (Cj-Côjalkenyloxy.
22. A compound according to claim 1, wherein A² is H, (C3-Cio)cycloalkyl, (Cf>Ci2)aryl, (C₂-C9)heteroaryl, (C₂-C9)heterocycloalkyl or benzo(C₂-C9)heterocycloalkyl optionally substituted with one or more substituents selected from the group consisting of halo, (Ci-Ce)alkyl optionally substituted by one to three halo; (Cj-Cô)alkylenyi, amino, (CiCâ) alkylamino, (Ci-Côjdialkylamino, (Ci-Ce)alkoxy, O(C3-Ce cycloalkyl), (Cj-Cô) cycloalkoxy, nitro, CN, OH, (Ci-Cô)alkyloxy optionally substituted by one to three halo; (C3-C6) cycloalkyl, (Ci-Cô) alkoxycarbonyl, (Ci-Cô) alkylcarbonyl or (Ci-Cô) haloalkyl.

334
23. A compound according to claim l, wherein A² is (C3-Cio)cycloalkyl, (C6-Ci2)aryl, (C2-C9)heteroaryl, (C2-C9)heterocycloalkyl or benzo(C2-C9)heterocycioalkyl wherein A²is substituted with one or more substituents selected from the group consisting of (C2Cgjheterocycloalkyl, R⁸R⁹N-CO- wherein R⁸ and R⁹ are each independently selected from the group consisting of hydrogen and (Ci-C6)alkyl or R⁸ and R⁹ can be taken together with the nitrogen to which they are attached to form a (C₂-C9)heterocycloalkyl or (C₂-C9)heterocycloalkyl group optionally substituted by one to three halo groups, (C iCejalkylsulfonyl optionally substituted by one or two groups selected from (C]-C6)alkoxy and (C3-Cio)cycloalkyl;

(C]-Cô)alkyl substituted by one to four substituents selected from the group consisting of hydroxy, cyano, (Ci-Cejalkoxy, (Ci-C6)alkoxy(Ci-C6)alkoxy, (C₂C9)heterocycloalkyl, (C₂-C9)heteroaryl optionally substituted by (C)-Cô)alkoxy; or (C3Cio)cycloalkoxy optionally substituted by (Ci-C6)alkoxy; and (Ci-Cô)alkyloxy substituted by one to four substituents selected from the group consisting ofhydroxy, cyano, (Ci-Côjalkoxy, (CrC6)alkoxy(Ci-C6)alkoxy, (C₂Cgjheterocycloalkyl, (C₂-C9)heteroaryl optionally substituted by (Cj-CeJalkoxy; or (C3Cio)cycloalkoxy optionally substituted by (Ci-Cû)alkoxy.
24. A compound according to claim l, wherein X³ is O, -NH, -CH2-, CO, - CH(C)-Cô) alkyl, SO2NH, -CO-NH- or -NR³; X⁴ is CR⁴R⁵, CH2 CR⁴R⁵ or CH2 -(Ci-Cô) alkylCR⁴R⁵;and A² is (C3-Cio)cycloalkyl, (Cô-Ci2)aryl, (C2-C9)heteroaryl, (C₂Cçjheterocyclo alkyl or benzo(C₂-C9)heterocycloalkyl wherein A² is substituted with one or more substituents selected from the group consisting of, (C2-C9)heterocycloalkyl, R⁸R⁹NCO- wherein R⁸ and R⁹ are each independently selected from the group consisting of hydrogen and (C]-C6)alkyl or R⁸ and R⁹ can be taken together with the nitrogen to which they are attached to form a (C2-C9)heterocycloalkyl or (C₂-C9)heterocycloalkyl group optionally substituted by one to three halo groups, (Ci-Côjalkylsulfonyl optionally substituted by one or two groups selected from (Ci-C6)alkoxy and (C3-Cjo)cycloalkyl;

(Ci-Cô)alkyl substituted by one to four substituents selected from the group consisting of hydroxy, cyano, (Ci-C6)alkoxy, (Cj-C6)alkoxy(Ci-C6)alkoxy, (C₂C9)heterocycioalkyl, (C₂-C9)heteroaryl optionally substituted by (Ci-Ce)alkoxy; or (C₃C]o)cycloalkoxy optionally substituted by (Ci-Cô)alkoxy;

335 or (Ci-Cô)alkyloxy substituted by one to four substituents selected from the group consisting of hydroxy, cyano, (Ci-Cô)alkoxy, (Cj-C6)alkoxy(Ci-Cô)alkoxy, (C2Cg)heterocycloalkyl, (C2-C9)heteroaryl optionally substituted by (Ci-C&)alkoxy; or (C3Cio)cycloalkoxy optionally substituted by (Ci-Ce)alkoxy.
25. A compound according to claim l, wherein A¹ is phenyl.
26. A compound according to claim 1, wherein X⁵ is a direct bond.
27. A compound according to claim 1, wherein A² is phenyl substituted by (Ci-Câ) alkoxy(Ci-Ce) alkoxy.
28. A compound according to claim 1, wherein n is 1; t is 0; y is 1; z is 1; X¹ is CR¹; m is 1; p is 1 ; E is 0; X² is Ο; X³ is NH; R¹ is H; X⁴ is CR⁴R⁵ wherein R4 and R5 are each independently methyl; R⁶ is a hydrogen; A¹ is phenyl; X⁵ is a direct bond, O or CR⁴R⁵and A2 is phenyl substituted by (Ci-Ce) alkoxy(Ci-Cô) alkoxy.
29. A compound of the formula or a pharmaceutically acceptable sait thereof.
30. A compound according to claim 1, wherein A¹ is piperdine optionally substituted by halo.
31. A compound according to claim 1, wherein X⁵ is pyrimidine optionally substituted by halo.