EA046304B1 - Glucosylceramide synthase inhibitors - Google Patents

Description

Field of technology to which the invention relates

The invention relates to the field of therapeutic agents against polycystic diseases, cancer and metabolic diseases. More specifically, the invention relates to glucosylceramide synthase (GCS) inhibitors useful for the treatment of diseases such as metabolic diseases, including lysosomal storage diseases, either alone or in combination with enzyme replacement therapy, for the treatment of a neuropathic disease, a cystic disease or for the treatment of cancer.

Review of the State of the Art

Glucosylceramide synthase (GCS) is the primary enzyme that catalyzes the initial glycosylation step in glucosylceramide (GSL)-based glycosphingolipid biosynthesis, namely by the major transfer of glucose from UDP-glucose (UDP-Gle) to ceramide to form glucosylceramide (see Table 1). Fig. 1). GCS is a type III transmembrane integral protein localized in the cis/medial Golgi cisternae. Glycosphingolipids (GSLs) are believed to be integral to the dynamics of many events in the cell membrane, including cellular interactions, signal transduction and transport. It has been shown (see Yamashita et al., Proc. Natl. Acad. Sci. USA, 1999, 96(16), 9142-9147) that the synthesis of GSL structures is essential for embryonic development and for the differentiation of certain tissues. Ceramide plays a central role in sphingolipid metabolism, and downregulation of GCS activity has been shown to have a marked effect on sphingolipid structure, with reduced glycosphingolipid expression. Sphingolipids (SL) play a role as biomodulators in physiological as well as pathological conditions. In particular, sphingolipids and their regulatory enzymes appear to play a role in the adaptive responses to chronic hypoxia in the neonatal rat heart (see EI Alwanit et al., Prostaglandins & Other Lipid Mediators, 2005, 78(1-4), 249- 263).

GCS inhibitors have been proposed for the treatment of a number of diseases (see, for example, WO 2005068426). Such treatments include treatment of glycolipid storage diseases (eg, Tay-Sachs disease, Sandhoff disease, GM2 activator deficiency, GM1 gangliosidosis, and Fabry disease), glycolipid storage diseases (eg, Gaucher disease; the GCS inhibitor miglustat (Zaveska) is approved for the treatment of patients with Gaucher disease type 1, see Treiber et al., Xenobiotica, 2007, 37(3), 298-314), diseases that cause hypertrophy or hyperplasia of the kidney, such as diabetic nephropathy; diseases that cause hyperglycemia or hyperinsulinemia; oncological diseases in which the synthesis of glycolipids is abnormal, infectious diseases caused by organisms that use surface glycolipids as receptors, infectious diseases in which the synthesis of glucosylceramide is necessary or important, diseases in which excessive synthesis of glycolipids occurs (for example, atherosclerosis, polycystic kidney disease and renal hypertrophy), neuronal diseases, neuronal damage, inflammatory diseases or disorders associated with macrophage recruitment and activation (eg, rheumatoid arthritis, Crohn's disease, asthma and sepsis) and diabetes and obesity (see WO 2006053043).

In particular, GCS overexpression has been shown to be involved in multidrug resistance and disrupt ceramide-induced apoptosis. For example, Turzanski et al. (Experimental Hematology, 2005, 33(1), 62-72) showed that ceramide induces apoptosis in acute myeloid leukemia (ALM) cells and that P-glycoprotein (p-gp) confers resistance to ceramide-induced apoptosis, with modulation The ceramide-glucosylceramide pathway makes a significant contribution to such resistance in TF-1 cells. Thus, GCS inhibitors can be used to treat proliferative disorders by inducing apoptosis in disease-prone cells.

The essence of the invention

The present invention relates to a method of treating a lysosomal storage disease in a subject, wherein the lysosomal storage disease is selected from the group consisting of Gaucher disease, Fabry disease, G _M1 gangliosidosis, G _M2 activator deficiency, Tay-Sachs disease or Sandhoff disease, where the method includes administering to the subject an effective amount of a compound represented by the following structural formula

or a pharmaceutically acceptable salt thereof, where n is 1, 2;

m is 0 or 1;

p equals 1;

t is 0 or 1;

y is 1;

- 1 046304 z is equal to 0 or 1;

E represents O;

X ¹ represents CR ¹ when m is 1, or N when m is 0;

X ² represents O or -NH;

X ³ represents a direct bond or -NH;

X ⁴ represents direct link or CR4R ⁵ ;

X ⁵ represents a direct connection or O;

R ¹ represents H or (C ₁ -C ₆ )alkyl;

R ⁴ and R ⁵ are selected independently from (C 1 -C ₆ )alkyl or, taken together with the carbon atom to which they are attached, form a spuro(C ₃ -C ₁₀ )cycloalkyl ring;

R ⁶ represents -H or (C1-C ₆ )alkyl, optionally substituted with one to four halogen atoms;

A ¹ is (C6-C12)aryl, (C2-C9)heteroaryl or (C2-C9)heterocycloalkyl, wherein A ¹ is optionally substituted with one or more substituents selected from the group consisting of halogen, (C1-C6)alkyl, optionally substituted with one to three halogen atoms; (C1- _C6 )alkoxy, -OH;

A ² is (C6-C12)aryl or (C2-C9)heteroaryl, wherein A ² is substituted with one or more substituents selected from the group consisting of halogen, (C2- _C9 )heterocycloalkyl;

R ⁸ R ⁹ N-CO-, wherein each of R ⁸ and R ⁹ is selected independently from the group consisting of hydrogen and (C1-C6)alkyl, or R ⁸ and R ⁹ can be taken together with the nitrogen atom to which they attached to form a (C2- _C9 )heterocycloalkyl group, optionally substituted with one to three halogen groups;

(C1- _C6 )alkylsulfonyl, optionally substituted with one or two groups selected from (C1- _C6 )alkoxy and ( _C3 - _C10 )cycloalkyl;

(C ₁ -C ₆ )alkyl substituted with one to four substituents selected from the group consisting of halogen, hydroxy, cyano, (C1-C ₆ )alkoxy, (C1-C ₆ )alkoxy, (C1-C ₆ )alkoxy, (C ₂ -C ₉ )heterocycloalkyl, (C ₂ -C ₉ )heteroaryl, optionally substituted (C1 -C ₆ )alkoxy; or (C ₃ -C ₁₀ )cycloalkoxy, optionally substituted (C1 -C ₆ )alkoxy; and (C1- _C6 )alkyloxy substituted with one to four substituents selected from the group consisting of halogen, hydroxy, cyano, (C1-C6)alkoxy, (C1- _C6 )alkoxy(C1- _C6 )alkoxy, ( C ₂ -C ₉ )heterocycloalkyl, (C ₂ -C ₉ )heteroaryl, optionally substituted (C1 -C ₆ )alkoxy; or (C ₃ -C ₁₀ )cycloalkoxy, optionally substituted (C1 -C ₆ )alkoxy;

with the proviso that when X ³ is -NH and X ⁴ is CR4R ⁵ then A ² must be substituted with one or more substituents selected from the group consisting of (C2-C9)heterocycloalkyl, R ⁸ R ⁹ N- CO-, wherein R ⁸ and R ⁹ are each independently selected from the group consisting of hydrogen and (C1-C6)alkyl, or R ⁸ and R ⁹ may be taken together with the nitrogen atom to which they are attached to form (C2 -C9)heterocycloalkyl or (C2-C9)heterocycloalkyl group, optionally substituted with one to three halogen groups;

(C1- _C6 )alkylsulfonyl, optionally substituted with one or two groups selected from (C1- _C6 )alkoxy and ( _C3 - _C10 )cycloalkyl;

(C1- _C6 )alkyl substituted with one to four substituents selected from the group consisting of hydroxy, cyano, (C1- _C6 )alkoxy, (C1- _C6 )alkoxy, (C1- _C6 )alkoxy, ( _C2 -C ₉ )heterocycloalkyl, (C ₂ -C ₉ )heteroaryl, optionally substituted (C1-C ₆ )alkoxy; or (C ₃ -C ₁₀ )cycloalkoxy, optionally substituted (C1 -C ₆ )alkoxy;

or (C1- _C6 )alkyloxy substituted with one to four substituents selected from the group consisting of hydroxy, cyano, (C1- _C6 )alkoxy, (C1- _C6 )alkoxy(C1- _C6 )alkoxy, (C ₂ -C ₉ )heterocycloalkyl, (C ₂ -C ₉ )heteroaryl, optionally substituted (C1 -C ₆ )alkoxy; or (C ₃ -C ₁₀ )cycloalkoxy, optionally substituted (C 1 -C ₆ )alkoxy, provided that the compound is not 1-{2-[4'-(2-methoxyethoxy)biphenyl-4yl]propan-2- yl} -3 -(3 -methyl-1 -azabicyclo[2.2.2] oct-3 -yl)urea, where in each case, (C ₂ -C ₉ )heterocycloalkyl contains from 3 to 10 ring atoms, where from 2 up to 9 ring atoms are carbon atoms and the remaining ring atoms are selected from the group consisting of nitrogen, sulfur and oxygen; and wherein in each case (C ₂ -C ₉ )heteroaryl contains 5-10 ring atoms, where 2-9 ring atoms are carbon atoms and the remaining ring atoms are selected from the group consisting of nitrogen, sulfur and oxygen.

In a preferred embodiment of the proposed method, in the above compound, n is 1; t is 0; y is equal to 1, and z is equal to 1.

In another preferred embodiment of the proposed method, in the above compound, m is equal to 1; E represents O; X ² represents O; and X ³ represents NH.

In another preferred embodiment of the proposed method, in the above compound, X ⁴ represents CR4R ⁵ , where each of R ⁴ and R ⁵ independently represents methyl.

In another preferred embodiment of the proposed method in the above compound R ⁶

- 2 046304 represents N.

In another preferred embodiment of the proposed method, in the above compound, R ¹ represents hydrogen or methyl.

In another preferred embodiment of the proposed method, in the above compound, X ⁴ represents a direct bond.

In another preferred embodiment of the proposed method in the above compound A ¹ represents (C2-C9)heteroaryl selected from isothiazole, furan, oxazole, isoxazole, pyrrole, imidazole, pyrazole, triazole, pyridine, pyrimidine, pyridazine, indole, benzothiazole, benzoisoxazole , benzopyrazole, benzoimidazole, benzofuran and benzooxazole.

In another preferred embodiment of the proposed method, in the above compound, X ⁵ represents a direct link.

In another preferred embodiment of the proposed method, the lysosomal storage disease is Fabry disease.

In another preferred embodiment of the proposed method, the lysosomal storage disease is Gaucher disease type 2 or Gaucher disease type 3.

The present invention also relates to the use of a compound represented by formula (I) as defined above for the preparation of a medicament for treating a lysosomal storage disease in a subject, wherein the lysosomal storage disease is selected from the group consisting of Gaucher disease, Fabry disease, G _M1 - gangliosidosis, G _M2 -activator deficiency, Tay-Sachs or Sandhoff disease. Preferably, the lysosomal storage disease is Gaucher disease or Fabry disease.

The present invention also relates to the use of a compound represented by formula (I) as defined above for the treatment of a lysosomal storage disease in a subject, wherein the lysosomal storage disease is selected from the group consisting of Gaucher disease, Fabry disease, G _M1 gangliosidosis, G _M2 deficiency - activator, Tay-Sachs or Sandhoff disease.

Preferably, the lysosomal storage disease is Gaucher disease or Fabry disease.

The present invention also relates to a compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, where n is 1, 2;

m is equal to 1;

p is equal to 1;

t is 0 or 1;

y is 1;

z is 0 or 1;

E represents O;

X ¹ represents CR ¹ ;

X ² represents O or -NH;

X ³ represents -NH;

X ⁴ represents a direct link or CR ⁴ R ⁵ ;

X ⁵ represents a direct connection or O;

R ¹ represents H or (C^C^alkyl;

R ⁴ and R ⁵ are selected independently from (C ₁ -C ₆ )alkyl or, taken together with the carbon atom to which they are attached, form a spiro(C ₃ -C ₁₀ )cycloalkyl ring;

R ⁶ represents -H or (C ₁ -C ₆ )alkyl;

And ¹ is (C6-C12)aryl or (C2-C9)heteroaryl selected from isothiazole, furan, oxazole, isoxazole, pyrrole, imidazole, pyrazole, triazole, pyridine, pyrimidine, pyridazine, indole, benzothiazole, benzisoxazole, benzopyrazole, benzoimidazole, benzofuran and benzooxazole, wherein A ¹ is optionally substituted with one or more substituents selected from the group consisting of halogen, (C1-C6)alkyl, optionally substituted with one to three halogen atoms;

(C1- _C6 )alkoxy, -OH;

A ² is (C6-C12)aryl or (C2-C9)heteroaryl, wherein A ² is substituted with one or more substituents selected from the group consisting of halogen, (C3-C6)cycloalkyl and (C2-C9)hetero

- 3 046304 cycloalkyl;

R ⁸ R ⁹ N-CO-, wherein each of R ⁸ and R ⁹ is selected independently from the group consisting of hydrogen and (C1-C6)alkyl, or R ⁸ and R ⁹ can be taken together with the nitrogen atom to which they attached to form a (C2-C9)heterocycloalkyl group, optionally substituted with one to three halogen groups;

(C ₁ -C ₆ )alkylsulfonyl, optionally substituted with one or two groups selected from (C'rCZalkoxy and (C ₃ -C ₁₀ )cycloalkyl;

(C^C^alkyl substituted with one to four substituents selected from the group consisting of hydroxy, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy (C ₁ -C ₆ )alkoxy, (C2- C ₉ )heterocycloalkyl and (C 2 -C ₉ )heteroaryl; and (C 1 -C ₆ )alkyloxy substituted with one to four substituents selected from the group consisting of cyano, (C ₁ -C ₆ )alkoxy, (C 2 -C ₉ )heterocycloalkyl and (C2- _C9 )heteroaryl;

with the proviso that when X ⁴ is CR4R ⁵ then A ² must be substituted with one or more substituents selected from the group consisting of (C2-C9) heterocycloalkyl;

R ⁸ R ⁹ N-CO-, wherein each of R ⁸ and R ⁹ is independently selected from the group consisting of hydrogen and (C1-C6)alkyl, or R ⁸ and R ⁹ may be taken together with the nitrogen atom to which they attached to form a (C2- _C9 )heterocycloalkyl group, optionally substituted with one to three halogen groups;

(C ₁ -C ₆ )alkylsulfonyl group, optionally substituted by one or two groups selected from (C ₁ -C ₆ )alkoxy and (C ₃ -C ₁₀ )cycloalkyl;

(C ₁ -C ₆ )alkyl substituted with one to four substituents selected from the group consisting of hydroxy, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy, ( C ₂ -C ₉ )heterocycloalkyl and (C ₂ -C ₉ )heteroaryl; and (C1- _C6 )alkyloxy substituted with one to four substituents selected from the group consisting of cyano, ( _C1 - _C6 )alkoxy, ( _C2 - _C9 )heterocycloalkyl and ( _C2 - _C9 )heteroaryl; and provided that the compound is not 1-{2-[4'-(2-methoxyethoxy)biphenyl-4yl]propan-2-yl}-3-(3-methyl-1-azabicyclo [2.2.2] oct-3-yl)urea, wherein in each case, (C ₂ -C ₉ )heterocycloalkyl contains from 3 to 10 ring atoms, where from 2 to 9 ring atoms are carbon atoms and the remaining ring atoms are selected from the group consisting of nitrogen , sulfur and oxygen; and wherein in each case (C ₂ -C ₉ )heteroaryl contains 5-10 ring atoms, where 2-9 ring atoms are carbon atoms and the remaining ring atoms are selected from the group consisting of nitrogen, sulfur and oxygen.

In a preferred embodiment of the proposed connection, n is 1; t is 0; y is equal to 1, and z is equal to 1.

In a preferred embodiment of the proposed connection, m is equal to 1; E represents O; X ² represents O; and X ³ represents NH.

In a preferred embodiment of the present compound, X ⁴ is CR4R ⁵ where R ⁴ and R ⁵ are each independently methyl.

In a preferred embodiment of the proposed compound, R ⁶ represents H.

In a preferred embodiment of the proposed compound, R ¹ represents hydrogen or methyl.

In a preferred embodiment of the proposed compound A ² represents (C ₆ -C ₁₂ )aryl.

In a preferred embodiment of the proposed connection, X ⁴ is a direct connection.

The present invention also relates to a pharmaceutical composition containing the specified compound in at least one pharmaceutically acceptable carrier.

The present invention also relates to the use of the said compound as a medicine.

The present invention also relates to the use of said compound for the preparation of a medicament.

The present invention also provides a method of treating a disease or disorder mediated by glucosylceramide synthase (GCS), or a disease or disorder involving GCS, in a subject in need of such treatment, comprising administering to the subject an effective amount of said compound, wherein the disease or disorder is a cancer, metabolic disorder, neuropathic disease.

In a preferred embodiment, the neuropathic disease is Alzheimer's disease or Parkinson's disease.

The present invention also relates to the use of a compound represented by formula (I) as defined above for the preparation of a medicament for the treatment of a disease or disorder mediated by glucosylceramide synthase (GCS), or a disease or disorder in which GCS is involved, wherein the disease or disorder represents cancer, metabolic disorder, neuropathic disease.

Preferably, the neuropathic disease is Alzheimer's disease or Parkinson's disease.

The present invention also relates to the use of a compound represented by formula (I),

- 4 046304 as defined above, for the treatment of a disease or disorder mediated by glucosylceramide synthase (GCS), or a disease or disorder that involves GCS, where the disease or disorder is a cancer, a metabolic disorder, a neuropathic disease.

In a preferred embodiment, the neuropathic disease is Alzheimer's disease or Parkinson's disease.

Definitions.

As used herein, the term pharmaceutically acceptable salt means either a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable base addition salt of a compound disclosed herein that can be administered without any subsequent significant undesirable biological (their) action(s) or subsequent harmful interaction(s) with any other component of the pharmaceutical composition in which it may be contained.

As used herein, the term prodrug refers to a pharmacological derivative of a parent drug molecule that requires biotransformation, either spontaneous or enzymatic, in the body to release the active drug. For example, prodrugs are various variants or derivatives of compounds of formula I that have groups capable of being cleaved under certain metabolic conditions, and which, when cleaved, become compounds of formula I. Such prodrugs are then pharmaceutically active in vivo when they are solvolyzed under physiological conditions or subjected to enzymatic decomposition. Prodrugs herein may be referred to as single, double, ternary, etc., depending on the number of biotransformation steps required to release the active drug in the body and the number of functional groups present in the precursor form. Prodrug forms often offer advantages of solubility, histocompatibility, or delayed release in the mammalian body (see Bundgard, Design of Drugs, pp. 7-9, 21-24, Elsevier, Amsterdam, 1985, and Silverman, The Organic Chemistry of Drug Design and Drug Action, pp. 352-401, Academic Press, San Diego, Calif., 1992). Prodrugs commonly known in the art include well-known acid derivatives, such as, for example, esters prepared by reacting parent acids with a suitable alcohol, amides prepared by reacting a parent acid compound with an amine, basic groups reacting to form acylated base derivatives, etc. .d. Of course, other prodrug derivatives can be combined with other features disclosed herein to enhance bioavailability. As such, those skilled in the art will appreciate that some of the compounds disclosed herein having free amino, amido, hydroxy or carboxyl groups may be converted into prodrugs. Prodrugs include compounds having an amino acid residue or polypeptide chain of two or more (eg, two, three, or four) amino acid residues that are covalently linked via peptide bonds to the free amino, hydroxy, or carboxyl groups of the compounds disclosed herein. Amino acid residues include 20 naturally occurring amino acids, usually designated by three-letter symbols, and also include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Prodrugs also include compounds having a carbonate, carbamate, amide or alkyl ether moiety covalently linked to any of the above substituents disclosed herein.

As used herein, the term (C1- _C6 )alkyl means a saturated linear or branched free radical consisting essentially of 1-6 carbon atoms and the corresponding number of hydrogen atoms. Examples of ^-^alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc. Of course, other ^-^alkyl groups will be readily apparent to those skilled in the art as determined by the benefit of the present disclosure.

As used herein, the term (C ₃ -C ₁₀ )cycloalkyl means a non-aromatic free radical forming at least one ring consisting of essentially 3-10 carbon atoms and an appropriate number of hydrogen atoms. As such, (C ₃ -C _{1 0} )cycloalkyl groups can be monocyclic or polycyclic. The individual rings of such polycyclic cycloalkyl groups may have various linkages, such as fused, bridged, spiro, etc., in addition to covalent bond substitution. Examples of (C ₃ -C ₁₀ )cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornanyl, bicyclo[3.2.1]octanyl, octahydropentalenyl, spiro[4.5]decanyl, cyclopropyl substituted with cyclobutyl, cyclobutyl substituted with cyclopentyl, cyclohexyl, ny cyclopropyl, etc. Of course, other (C ₃ -Cl ₀ )cycloalkyl groups will be readily apparent to those skilled in the art as determined by the benefit of the present disclosure.

As used herein, the term (C ₂ -C ₉ )heterocycloalkyl means a non-aromatic free radical with 3-10 atoms (i.e. ring atoms) that form at least one ring, with 2-9 ring atoms being carbon, and the remaining ring atom(s) (ie, ring heteroatom(s)) are selected from the group consisting of nitrogen, sulfur and oxygen. As such, (C ₂ -C ₉ )hetero

- 5 046304 cycloalkyl groups can be monocyclic or polycyclic. The individual rings of such polycyclic heterocycloalkyl groups may have various bonds, for example, fused, bridged, spiro, etc., in addition to covalent bond substitution. Examples of (C ₂ -C ₉ )heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, azetidinyl, oxiranyl, methylenedioxyl, chromenyl, barbituryl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, il, 1 ,3-thiazolidin-3-yl, 1,2-pyrazolidin2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl , tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl, piperisin-2-onyl, piperisin-3-onyl, chromanyl, 2pyrrolinyl, 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]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[4.1.0]heptanyl, 3azabicyclo[3.1.0]hexanyl, 2 -azaspiro[4.4]nonanyl, 7-oxa-1-azaspiro[4.4]nonanyl, 7-azabicyclo[2.2.2]heptanyl, octahydro-III-indolyl, etc. In general, a (C ₂ -C ₉ )heterocycloalkyl group is typically attached to the main structure via a carbon atom or a nitrogen atom. Of course, other (C ₂ -C ₉ )heterocycloalkyl groups will be readily apparent to those skilled in the art as determined by the benefit of the present disclosure.

As used herein, the term (C ₂ -C ₉ )heteroaryl refers to the aromatic free radical GCS. As such, (C ₂ -C ₉ )heteroaryl groups can be monocyclic or polycyclic. The individual rings of such polycyclic heteroaryl groups may have various linkages, such as fused, bridged, spiro, etc., in addition to covalent bond substitution. Examples of (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-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3 -triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H-[1]pyridinyl, benzo[b]thiophenyl, 5,6, 7,8-tetrahydroquinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl and benzoxazinil, etc. d. In general, a (C ₂ -C ₉ )heteroaryl group is typically attached to the backbone via a carbon atom, however one skilled in the art will appreciate when certain other atoms, such as ring heteroatoms, may be added to the backbone. Of course, other (C2-C9)heteroaryl groups will be readily apparent to those skilled in the art as determined by the benefit of the present disclosure.

As used herein, the term (C ₆ -Ciu)aryl means phenyl or naphthyl.

As used herein, the term halogen refers to fluorine, chlorine, bromine or iodine.

As used herein, the term amino denotes a radical having a nitrogen atom and 1-2 hydrogen atoms. As such, the term amino generally refers to primary and secondary amines. In this regard, as used in the specification and appended claims, the term tertiary amine is represented by the general formula RR'N-, wherein R and R' are carbon radicals which may or may not be identical. However, the term amino may generally be used herein to describe a primary, secondary or tertiary amine, and one skilled in the art will readily be able to identify the amine given the context in which the term is used in the present disclosure.

As used herein, the term combination therapy refers to treating a patient with two or more therapeutic platforms (eg, enzyme replacement therapy and small molecule therapy) in intermittent, alternating and/or simultaneous treatment programs. Examples of treatment programs may include, but are not limited to: (1) enzyme replacement therapy followed by small molecule therapy; (2) small molecule therapy followed by enzyme replacement therapy; (3) enzyme replacement therapy concurrently with small molecule therapy and (4) any combination of the options mentioned above. Combination therapy may provide a temporary overlay 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 therapy or ERT refers to the administration of an exogenously produced natural or recombinant enzyme to a patient in need. In the case of lysosomal storage disease, for example, the patient accumulates dangerous levels of substrate (i.e., stored material) in the lysosomes due to a deficiency or disorder in the enzyme responsible for metabolizing the substrate, or due to a lack of an enzyme activator required for its own enzyme function. functions. Enzyme replacement therapy is offered to the patient to reduce the levels (ie, reduce the mass) of accumulated substrate in the affected tissues. Table 1 provides a list of lysosomal storage diseases and identifies deficiency of the corresponding

- 6 046304 active enzymes and accumulated substrate for each disease. Enzyme replacement therapies for the treatment of lysosomal storage diseases are well known in medicine. In accordance with the combination therapy of the invention, the lysosomal enzymes identified in table. 1 may be used for enzyme replacement therapy to reduce levels of the corresponding substrate in a patient diagnosed with a corresponding lysosomal storage disease.

As used herein, an effective amount of an enzyme or small molecule, when delivered to a subject in a combination therapy of the invention, is an amount sufficient to improve the clinical course of a lysosomal storage disease, wherein clinical improvement is measured by any of a variety of established parameters well known to those skilled in the art. field of technology.

Abbreviations

ACN stands for acetonitrile.

DMF stands for KH-dimethylformamide.

DMSO stands for dimethyl sulfoxide.

EtOAc stands for ethyl acetate.

EtOH stands for ethanol.

Hunig's base stands for diisopropylethylamine (DIPEA).

MeOH stands for methanol.

NaOH stands for sodium hydroxide.

THF stands for tetrahydrofuran.

TFA stands for trifluoroacetic acid.

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

Brief description of drawings

Fig. 1 represents the metabolic pathway for the possible synthesis of Gb3 and lyso-GbS. Documented synthesis pathways are shown with black arrows, and undocumented (possible) pathways are shown with gray arrows;

fig. 2 represents the chemical structure of (b)-quinuclidin-3-yl(2-(4-(4'-(2-methoxyethoxy)|1.1biphenyl]-4-yl)propan-2-yl)carbamate;

fig. 3 represents the effect of the GCS inhibitor ^)-quinuclidin-3-yl(2-(4-(4'-(2-methoxyethoxy)[1,1biphenyl]-4-yl)propan-2-yl)carbamate in a mouse model of polycystic kidney disease - jck mice - at several dose levels.

Detailed description

Although specific embodiments of the present disclosure will now be described with reference to methods of preparation and designs, it should be understood that such embodiments are only examples and only illustrative of only a small number of the many possible specific embodiments that may represent applications of the principles of the present disclosure. Various changes and modifications will be apparent to those skilled in the art having benefited from the present disclosure, and are described as falling within the spirit and scope of the present disclosure as further defined in the appended claims.

Unless otherwise specified, technical and scientific terms used in this specification have the meanings commonly given to them by one skilled in the art to whom this disclosure pertains. Although other compounds or methods may be used in practice and testing, certain preferred methods are now described in the context of the following preparation methods and schemes.

- 7 046304

Method of obtaining A

Method of obtaining B

- 8 046304

Method for obtaining C

h ₂ n X— ^Αι — ^x s-1 ¹ / HO ₂ C 4 ' D-3 2 H _? N L D-1 NC----A ₁ ----X С-4 1 NC-----А-,----Х ₅ ----А ₂ с-з h ₂ n 5---- ^А 2 'V-----A _d ----X ₅ ----A ₂ ^R 4 ^R 5 _C -2 Method of obtaining D ----x D-5 X, but ₂ s /T- ^x D- 4 4 H ₂ N * L.' ^x D-2 Method of obtaining E H ₃ CO ₂ C----A ₁ ----X E-2 1 HO E-1 2 D-2

- 9 046304

Method for obtaining F

X---Xs--No. 1 ,χ---a ₂ 2''--^ Eyu^zX^— NOzSKHzKhdAi— F-1 X---XS—χ· I ¹ EtO ₂ CX ₃ X4A5 X ₅ — X· -x ₆ —a ₂ ^— x<. a ₂

0 L ^-X ₃ X ₄ Ar G-1 i A Method of obtaining G X3X4A1----X:..—X I' ХзХдА^----X ₅ --A ₂ ^{G 3} ^'x 0 ----¾ Az QX ₃ x ₄ Aj Χ _δ A ₂ G- 2 Scheme 1 A-1 or A-2 1 H 'Т4Г' - “ II or H >ТДГ ^{X5 A2} III

- 10 046304

Scheme 2

Scheme 3

- 11 046304

Scheme 4

A-1 ^and ™ A-2

O

XI

In Reaction 1 of Preparation Method A, a compound of formula A-7 is converted to the corresponding compound of formula A-1, in which X is OH, by reducing A-7 with a reducing agent, preferably lithium aluminum hydride, in an aprotic solvent such as tetrahydrofuran. The reaction mixture is stirred at 0°C to room temperature for a period of 15 minutes to about 2 hours, preferably about 30 minutes. Alternatively, a compound of formula A-7 is converted to the corresponding compound of formula A-1, in which X is OH, by reducing A-7 with hydrogen at a pressure of about 1 atmosphere in the presence of a catalyst, preferably platinum oxide, and a polar solvent such as methanol or ethanol, for a period of 2 to 6 hours, preferably 4 hours. On the other hand, the compound of formula A-7 is converted into the corresponding compound of formula A-1, in which X is NH, by reducing A-7 with hydrochloride hydroxylamine and sodium acetate in a polar solvent such as ethanol, methanol, isopropanol, preferably isopropanol. The reaction mixture is stirred at a temperature of 50-80°C for a period of time from 2 to 7 hours, preferably 3 hours. The compound formed as described above is then converted into the compound of formula A-1 using a reducing agent, preferably sodium metal, in polar a protic solvent such as ethanol, methanol, propanol, preferably n-propanol. The reaction mixture is stirred overnight at 5080°C, preferably at the reflux temperature of the solvent.

In Reaction 2 of Preparation Method A, a compound of formula A-7 is converted to the corresponding compound of formula A-5, in which R1, n and z are as defined above, by adding a solution of R1 magnesium bromide in ether to a solution of A-7 in an aprotic solvent such as ether , at a temperature of from about -60°C to about -90°C, preferably about -78°C, for a period of time from about 1 hour to about 4 hours, preferably about 2 hours. On the other hand, a compound of formula A-7 can be reacted with Ri-lithium to obtain a compound of formula A-5.

In Reaction 3 of Preparation Method A, a compound of formula A-5 is converted to the corresponding compound of formula A-4, in which R1, n and z are as defined above, by treating A-5 with a strong acid, preferably sulfuric acid, in the presence of acetonitrile. The reaction mixture is stirred overnight at room temperature.

In Reaction 4 of Preparation Method A, a compound of formula A-4 is converted to the corresponding compound of formula A-3, in which R1, n and z are as defined above, by treating A-4 with an acid, preferably hydrochloric acid. The reaction mixture is stirred at reflux for a period of 18 to 72 hours, preferably 24 hours, and made alkaline to pH=8 by treatment with an inorganic base in aqueous solution such as sodium hydroxide.

In Reaction 5 of Preparation Method A, a compound of formula A-7 is converted to the corresponding compound of formula A-6, in which R1, n and z are as defined above, by reacting A-7 with triphenylphosphonium ylide to form the corresponding alkene of formula A-6. The reaction mixture is stirred at room temperature overnight.

In reaction 6 of Preparation A, a compound of formula A-6 is converted to the corresponding compound of formula A-3, in which R1, n and z are as defined above, by reducing A-6 with hydrogen at a pressure of approximately 1 atmosphere in the presence of a catalyst, preferably palladium on carbon, and a polar solvent such as methanol, ethanol or ethyl acetate. The reaction mixture is stirred at room temperature for a period of time from about 2 hours to about 24 hours, preferably about 18 hours. The compound thus obtained is then treated with a base, preferably lithium hydroxide, in a mixture of solvents such as tetrahydrofuran, methanol and water, and compound A-3 is obtained. The reaction mixture is stirred overnight at room temperature.

In Reaction 1 of Preparation Method B, a compound of formula B-2 is converted to the corresponding compound of formula B-1 by reducing B-2 with a reducing agent, preferably lithium aluminum hydride, to

- 12 046304 aprotic solvent such as tetrahydrofuran. The reaction mixture is stirred at 0°C to room temperature for a period of about 15 minutes to about 2 hours, preferably about 30 minutes.

In Reaction 1 of Preparation Method C, compound C-4 is converted to the corresponding compound of formula C-3, in which X is bromine or chlorine, by reducing C-4 with boronic acid in the presence of a catalyst, preferably 1,1'-bis(diphenylphosphino) dichloride ferrocene palladium(P), and potassium carbonate. The reaction mixture is irradiated with microwaves in a mixture of dimethoxyethane and water at a temperature of from about 130°C to about 170°C, preferably about 150°C, for a period of time from about 15 minutes to about 1 hour, preferably about 30 minutes. Alternatively, the reaction can be carried out using a solvent such as dioxane with stirring overnight at 100°C under normal heating.

In Reaction 2 of Preparation Method C, compound C-3 is converted to the corresponding compound of formula C-1 in which f is 1-8 and A1, X5 and A2 are as defined above by adding dropwise a solution of ethyl magnesium bromide to a mixture of C-3 and isopropoxide titanium on the air. The reaction mixture is stirred at a temperature of from about -50°C to about -90°C, preferably about -70°C. The resulting reaction mixture is heated to about 20°C to about 30°C, preferably about 25°C, and stirred for a further period of about 30 minutes to about 2 hours, preferably about 1 hour. Boron trifluoride diethyl ether is then added dropwise to the mixture. at a temperature of from about 20°C to about 30°C, preferably about 25°C.

In Reaction 3 of Preparation Method C, compound C-3 is converted to the corresponding compound of formula C-2, in which A1, X5 and A2 are as defined above, by first stirring a suspension of cerium(III) chloride in an aprotic solvent such as tetrahydrofuran at room temperature for a period of time from about 30 minutes to about 2 hours, preferably about 1 hour. The resulting suspension is cooled to a temperature of from about -60°C to about -90°C, preferably about -78°C, and an organolithium compound is added, preferably methyllithium, in solution in ether. The resulting organocerium complex is allowed to form for a period of about 30 minutes to about 2 hours, preferably about 1 hour, and then C-3 in an aprotic solvent such as tetrahydrofuran is added. The resulting reaction mixture is then warmed to room temperature and stirred for a period of about 16 hours to about 20 hours, preferably about 18 hours.

In Reaction 1 of Preparation Method D, compound D-5, in which R is CO2Et or CN, and X is bromine or chlorine, is converted to the corresponding compound of formula D-3 by reacting D-5 with an alkyl dihalide such as 1,2- dibromoethane. The compound thus obtained is then treated with an inorganic base such as lithium hydroxide or potassium hydroxide in a mixture of solvents such as tetrahydrofuran, methanol, glycol and water to obtain compound D-3, in which f is 1-8. The reaction mixture is stirred overnight at a temperature of from 25°C to 130°C. On the other hand, to form the corresponding compound of formula D-3 in which X is X5-A2, D-5 must first be reacted according to the procedure described above in Reaction 1 of Method C.

In Reaction 2 of Preparation Method D, compound D-3 is converted to the corresponding compound of formula D-1 by reacting D-3 with a base such as diphenylphosphoryl azide in an aprotic solvent such as toluene. The reaction mixture is heated at a temperature in the range of 80-110°C, preferably at 110°C, for 15 minutes - 1 hour, preferably 30 minutes. The intermediate thus formed is then treated with tert-butyl alcohol overnight at 60-110°C, preferably 90°C. The carbamate thus formed is then converted to the corresponding compound of formula D-1, in which f is 1-8, by acidic treatment using preferably trifluoroacetic acid in dichloromethane at room temperature for a period of 30 minutes to 5 hours, preferably 2 h.

In Reaction 3 of Preparation Method D, compound D-5, in which R is CO2Et or CN, and X is bromine or chlorine, is converted to the corresponding compound of formula D-4 by reacting D-5 with an alkyl halide such as MeI. Then, the compound thus obtained is treated with an inorganic base such as lithium hydroxide or potassium hydroxide in a mixture of solvents such as tetrahydrofuran, methanol, glycol and water to obtain compound D-4. The reaction mixture is stirred overnight at a temperature of from 25 to 130°C. On the other hand, to form the corresponding compound of formula D-4 in which X is X5-A2, D-5 must first be reacted according to the procedure described above in Reaction 1 of Method C.

In Reaction 4 of Preparation Method D, compound D-4 is converted to the corresponding compound of formula D-2 by reacting D-4 with a base such as triethylamine and diphenylphosphoryl azide in an aprotic solvent such as toluene. The reaction mixture is heated at a temperature in the range of 80-110°C, preferably at 110°C, for 15 minutes - 1 hour, preferably 30 minutes. The intermediate thus formed is then treated with tert-butyl alcohol for

- 13 046304 nights at 60-110°C, preferably at 90°C. The carbamate thus formed is then converted into the corresponding compound of formula D-1 by acid treatment using preferably trifluoroacetic acid in dichloromethane at room temperature for a period of 30 minutes to 5 hours, preferably 2 hours.

In Reaction 1 of Preparation Method E, a compound of formula E-2 in which X is a bromide or chloride is converted to the corresponding compound of formula E-1 by reacting E-2 with methyl magnesium bromide in ether at a temperature of from about -60° C. to about -90 °C, preferably about -78°C, for a period of time from about 30 minutes to about 3 hours, preferably about 2 hours. Alternatively, to form the corresponding compound of formula E-1 in which X is X5-A2, E-2 must first be reacted according to the procedure discussed above in Reaction 1 of Method C.

In Reaction 2 of Preparation Method E, a compound of formula E-1 is converted to the corresponding compound of formula D-2 by treating E-1 with a strong acid, preferably sulfuric acid, in the presence of chloroacetonitrile. The reaction mixture is stirred overnight at room temperature. The compound thus formed is then treated with thiourea in a polar protic solvent such as ethanol overnight at 80° C. to form the corresponding compound of formula D-2. On the other hand, E-1 is treated with sodium azide and trifluoroacetic acid in an aprotic solvent such as dichloromethane at a temperature ranging from -10°C to room temperature, preferably at 0°C. The compound thus formed is reduced in the presence of triphenylphosphine in solution in tetrahydrofuran and water to form the corresponding compound of formula D-2. The reaction mixture is stirred at a temperature in the range of 25-80°C, preferably at room temperature, for 2 hours - 24 hours, preferably 18 hours.

In Reaction 1 of Preparation Method F, an arylboronate or arylboronic acid, sodium carbonate, and a catalyst such as [1,G-bis(diphenylphosphino)ferrocene]dichloropalladium(P) are added to a solution of the aryl halide component in a 5:1 (v/v) mixture .) dioxane/water (~0.15M) or 5:1 (v/v) N,Ndimethylformamide. The mixture thus formed is heated at a temperature of from about 80°C to about 100°C, preferably at about 90°C, for a period of from 8 hours to about 16 hours, preferably about 14 hours.

In Reaction 2 of Preparation Method F, the thus formed compound of formula X-X5-A2 is converted to the corresponding compound of formula EtO2CX3X3X4A1-X5-A2 by (1) transition metal-catalyzed coupling or (2) a nucleophilic aromatic substitution reaction between an aryl halide and an amine.

In Reaction 3 of Preparation Method F, the thus formed compound of formula X-X5-A2 is converted to the corresponding compound of formula EtO2CX3X3X4A1-X5-X' by (1) transition metal-catalyzed coupling or (2) a nucleophilic aromatic substitution reaction between an aryl halide and an amine.

In Reaction 4 of Preparation Method F, an arylboronate or arylboronic acid, sodium carbonate, and a catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) are added to a solution of the aryl halide component in a 5:1 (v/v) mixture. v/v) dioxane/water (~0.15M) or 5:1 (v/v) N, Ndimethylformamide. The mixture thus formed is heated at a temperature of from about 80°C to about 100°C, preferably at about 90°C, for a period of from 8 hours to about 16 hours, preferably about 14 hours.

In Reaction 5 of Preparation Method F, the thus formed compound of formula EtO2CX3X3X4A1-X5-A2 is converted into the corresponding compound of formula F-1 by ester hydrolysis reaction.

In Reaction 1 of Preparation Method G, a 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,G-bis(diphenylphosphino)ferrocene]dichloropalladium(P ), to a solution of the aryl halide component in a 5:1 (v/v) dioxane/water (~0.15M) or 5:1 (v/v) N,Ndimethylformamide mixture. The mixture thus formed is heated at a temperature of from about 80°C to about 100°C, preferably at about 90°C, for a period of from 8 hours to about 16 hours, preferably about 14 hours.

In Reaction 2 of Preparation Method G, a compound of formula G-3 is converted to the corresponding compound of formula G-1 by cooling (0° C.) a solution of the secondary amine component and triethylamine in methylene chloride and adding methyl chloroformate. The reaction mixture is then warmed to room temperature and stirred for a period of from 4 hours to about 8 hours, preferably about 6 hours. The reaction solution is then washed with aqueous sodium bicarbonate and brine, dried (Na ₂ SO ₄ ) and concentrated. Crude, without purification, methyl carbamate is used in the next step. To a solution of such an intermediate in toluene are added, in order, the activated molecular sieves 4A, the alcohol component and the sodium hydride. The reaction mixture is refluxed overnight, filtered and concentrated.

In reaction 2 of the preparation method G, a compound of formula G-3 is converted into the corresponding compound

- 14 046304 formula G-2 by adding thiophosgene in toluene to a solution of the amine component in chloroform. The reaction mixture is stirred for a period of about 1 hour to about 4 hours, preferably 2 hours, and then concentrated. The residue is dissolved in chloroform and cooled (0°C). While stirring, add the second amine component and triethylamine (2 equivalents) in order. The reaction mixture is stirred overnight at room temperature and then concentrated.

In reaction 1 in Scheme 1, compounds of formula A-1 or A-2 are converted to the corresponding compounds of formula II, in which f is 1-8, or III, respectively, by adding triphosgene to a suspension of C-1 or C-2 and triethylamine in aprotic a solvent such as tetrahydrofuran. The reaction mixture is stirred at room temperature for a period of about 5 minutes to about 20 minutes, preferably about 15 minutes, and a small amount of ether is added. The resulting triethylammonium salt is filtered off. Separately, sodium hydride is added to a suspension of A-1 or A-2, wherein X is OH or NH, in an aprotic solvent such as tetrahydrofuran at 0° C. or room temperature. The reaction mixture is stirred at room temperature for a period of about 5 minutes to about 20 minutes, preferably about 15 minutes, and the tetrahydrofuran/ether solution of the isocyanate obtained above is added dropwise. Alternatively, compounds of formula II and III can be formed by reacting compounds D3 or D4 with A-1 and A-2 in the presence of a base such as triethylamine and diphenylphosphoryl azide in an aprotic solvent such as toluene, as described in the procedure discussed above in the reaction there are 4 ways to obtain D.

In reaction 1 in Scheme 2, compounds of formula A-1, A-2 or B-1 are converted to the corresponding compounds of formulas IV, V, VI and VII, in which f is 1-8, respectively, by adding triphosgene to suspension C-1, C-2, D-1 or D-2 and triethylamine in an aprotic solvent such as tetrahydrofuran or toluene. The reaction mixture is stirred at room temperature for a period of about 5 minutes to about 20 minutes, preferably about 15 minutes, and a small amount of ether is added. Then A-1 or A-2, in which X represents NH, is added to the solution of the isocyanate obtained above, and the reaction mixture is stirred at a temperature in the range of 25-100°C, preferably at room temperature, for a period of time from about 2 up to 24 hours, preferably about 18 hours.

In reaction 1 in Scheme 3, a compound of formula A-3 is converted to the corresponding compounds of formula VIII, in which f is 1-8, and IX, respectively, by reacting A3 with C-1, C-2, D-1 or D-2 via peptide coupling using a carbodiimide coupling agent such as 1-ethyl-3-(3dimethylaminopropyl)carbodiimide, and 1-hydroxybenzotriazole or 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-hexafluorophosphate tetramethyluronium in a solvent such as tetrahydrofuran or dimethylformamide. The reaction mixture is stirred at room temperature overnight.

In reaction 1 in Scheme 4, a compound of formula A-2 is converted to the corresponding compound of formula XI by reacting, via amide coupling, a compound of formula A-2 and a compound of formula F-1. Specifically, 4-dimethylaminopyridine (0.1 equivalent) and di-tert-butyl dicarbonate are added to a solution of the primary amine component in chloroform. The mixture is stirred for 1 hour and then the secondary amine component is added and the mixture is refluxed overnight.

In reaction 1 in Scheme 4, a compound of formula A-2 with a protecting tert-butoxycarbonyl group is converted to the corresponding compound of formula XI by reacting, via a condensation reaction, a compound of formula A-2 and a compound of formula G-3. Specifically, 4-dimethylaminopyridine and di-tert-butyl dicarbonate are added to a solution of the primary amine component in chloroform (concentration ~0.1 M). The mixture is stirred for 1 hour and then the secondary amine component is added and the mixture is refluxed overnight.

In reaction 1 in Scheme 4, a compound of formula A-1 is converted to the corresponding compound of formula XI by reacting, via an acylation reaction, a compound of formula A-1 and a compound of formula G-1 while cooling (0° C.) a solution of the secondary amine component and triethylamine in methylene chloride and adding methyl chloroformate. The reaction mixture is then warmed to room temperature and stirred for a period of about 4 hours to about 8 hours, preferably about 6 hours. The reaction solution is then washed with aqueous sodium bicarbonate and brine, dried (Na ₂ SO ₄ ) and concentrated. Crude methyl carbamate, without purification, is used in the next step. To a solution of such an intermediate in toluene are added, in order, the activated molecular sieves 4A, the alcohol component and the sodium hydride. The reaction mixture is refluxed overnight, filtered and concentrated.

In reaction 1 in Scheme 4, a compound of formula A-2 is converted to the corresponding compound of formula XI by reacting, via an acylation reaction, a compound of formula A-2 and a compound of formula G-2 by adding thiophosgene in toluene to a solution of the amine component in chloroform. The reaction mixture is stirred for a period of about 1 hour to about 4 hours, preferably 2 hours, and then concentrated. The residue is dissolved in chloroform and cooled (0°C). While stirring, add the secondary amine and triethylamine components (2 equivalents) in order. The reaction mixture is stirred at room temperature overnight and then concentrated.

- 15 046304

Although specific embodiments of the present disclosure will now be described with reference to methods of preparation and designs, it is understood that such embodiments are only examples and only illustrative of only a small number of the many possible specific embodiments that may represent applications of the principles of the present disclosure. Various changes and modifications will be apparent to those skilled in the art having the benefit of the present disclosure, and are intended to be within the spirit and scope of the present disclosure as set forth also in the appended claims.

Unless otherwise specified, all technical and scientific terms used in this specification have the meanings commonly given to them by those skilled in the art to which this disclosure pertains. Although other compounds or methods may be used in practice or testing, certain preferred methods are now described in the context of the preparation methods and schemes described below.

All pharmaceutically acceptable salts, prodrugs, tautomers, hydrates and solvates of the compounds disclosed herein are also included within the scope of the present disclosure.

The compounds disclosed herein, which are basic in nature, are generally capable of forming a variety of different salts with various inorganic and/or organic acids. Although such salts are generally pharmaceutically acceptable for administration to animals and humans, in practice it is often desirable to first isolate the compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base by treatment with an alkaline reagent and then convert the free base to a pharmaceutically acceptable salt addition of acid. Acid addition salts of basic compounds can be readily prepared using conventional methods, for example by treating the basic compound with a substantially equivalent amount of the selected inorganic or organic acid in an aqueous solvent medium or a suitable organic solvent such as, for example, methanol and ethanol. After careful evaporation of the solvent, the desired solid salt is obtained.

Acids that can be used to prepare pharmaceutically acceptable acid addition salts of basic compounds are acids that 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, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [i.e. 1,1'-methylenebis(2-hydroxy-3-naphthoate)].

Compounds disclosed herein that are acidic in nature, for example containing COOH or a tetrazole group, are generally capable of forming a variety of different salts with various inorganic and/or organic bases. Although such salts are generally pharmaceutically acceptable for administration to animals and humans, in practice it is often desirable to first isolate the compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free acid by treatment with an acid reagent and then convert the free acid to a pharmaceutically acceptable salt connecting the base. Such base addition salts of acidic compounds can be readily prepared using conventional methods, for example by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations and then evaporating the resulting solution to dryness, preferably under reduced pressure. On the other hand, they can also be prepared by mixing solutions in lower alcohols of acidic compounds and the alkoxide of the desired alkali metal, and then evaporating the resulting solution to dryness in the same manner as before. In any case, it is preferable to use stoichiometric amounts of reactants in order to ensure completeness of the reaction and maximum yield of the reaction product of the desired solid salt.

Bases that can be used to prepare pharmaceutically acceptable base addition salts of acidic compounds are bases that can form non-toxic base addition salts, i.e., salts containing pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) , as cations of alkaline earth metals (for example, calcium and magnesium), ammonium and other water-soluble addition salts of amines, such as N-methylglucamine (meglumine), lower alkanolammonium and other such bases from organic amines.

In the compounds disclosed herein, one or more atoms may be replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature to form the isotopically labeled compound. Examples of isotopes that may be introduced into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ^2H , ^3H , ^13C , ^14C , ^15N , ¹⁸⁰ , ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl, respectively.

The isotopically labeled compounds disclosed herein can be used in drug and/or substrate tissue distribution assays. Tritium ( ^3H ) and carbon14 ( ^14C ) labeled compounds are particularly preferred due to their ease of preparation and detection

- 16 046304 nia. In addition, substitution with heavier isotopes such as deuterium ( ^2H ) may confer some therapeutic benefits resulting from greater metabolic stability, such as increased in vivo half-life, or reduced dosage requirements, and may therefore be preferred in some cases. circumstances. The isotopically labeled compounds disclosed herein, including their pharmaceutical salts and prodrugs, can be prepared by any methods known in the art.

The compounds disclosed herein can be isolated as stereoisomers (eg, cis- and trans-isomers) and all optical isomers of the compound (eg, R- and S-enantiomers), as well as racemic, diastereomeric and other mixtures of such isomers.

The compounds, salts, prodrugs, hydrates and solvates disclosed herein may exist in several tautomeric forms, including enol and imine form, and keto and enamine form and geometric isomers and mixtures thereof. Tautomers exist as mixtures of a collection of tautomers in solution. In solid form, one tautomer usually predominates. Even though one tautomer may be disclosed, all tautomers are included within the scope of the present disclosure.

The compounds disclosed herein can be isolated as atropisomers. Atropisomers include compounds that can be divided into rotationally limited isomers.

The present disclosure also relates to pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier can be any such carrier known in the art, including those described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A.R. Gennaro edit., 1985). Pharmaceutical compositions of the compounds disclosed herein can be prepared by conventional methods known in the art, including, for example, mixing at least one compound disclosed herein with a pharmaceutically acceptable carrier.

The pharmaceutical compositions disclosed herein can be used in animals or humans. Thus, a compound disclosed herein may be formulated as a pharmaceutical composition for oral, buccal, parenteral (e.g., intravenous, intramuscular, or subcutaneous), topical, rectal, or intranasal administration, or in a form suitable for administration by inhalation or insufflation . The compounds disclosed herein can also be formulated for sustained delivery according to methods well known to those skilled in the art. Examples of such preparations can be found in United States Patents 3119742, 3492397, 3538214, 4060598 and 4173626.

For oral administration, the pharmaceutical composition may take the form of, for example, a tablet or capsule prepared by conventional methods comprising pharmaceutically acceptable excipient(s) such as a binder (eg, pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); filler (eg lactose, microcrystalline cellulose or calcium phosphate); lubricant (for example, magnesium stearate, talc or silicon dioxide); a disintegrant (eg potato starch or sodium starch glycolate) and/or a wetting agent (eg sodium lauryl sulfate). The tablets can be coated by methods known in the art. Liquid preparations for oral administration may take the form of, for example, a solution, syrup or suspension, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional methods with the addition of pharmaceutically acceptable additive(s), such as a suspending agent (eg, sorbitol syrup, methylcellulose or hydrogenated edible fats); an emulsifier (for example, lecithin or acacia); a non-aqueous vehicle (eg almond oil, oily esters or ethyl alcohol) and/or a preservative (eg methyl or propyl p-hydroxybenzoates or sorbic acid).

For buccal administration, the composition may take the form of tablets or lozenges prepared in a conventional manner.

The compounds disclosed herein can be formulated for parenteral administration by injection, including the use of conventional catheterization or infusion methods.

Injectable preparations may be presented in unit dosage form, such as ampoules or multi-dose containers, with an added preservative. The compositions may take forms such as suspensions, solutions or emulsions in oily or aqueous media, and may contain a constituent agent such as a suspending agent, stabilizer and/or dispersant known to those skilled in the art. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable medium, such as sterile pyrogen-free water, before use.

For topical administration, the compound disclosed herein may be formulated in an ointment or cream.

The compounds disclosed herein can be administered in rectal compositions such as suppositories or retention enemas, for example containing conventional suppository bases such as cocoa butter or other glycerides.

- 17 046304

For intranasal or inhalation administration, the compounds disclosed herein can be delivered typically in the form of a solution or suspension from a pump nebulizer container that is compressed or pumped by the patient, or as an aerosol spray from a pressurized container or nebulizer, using a suitable a propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a compressed aerosol, the unit dose can be determined by providing a valve to deliver the metered amount. The pressurized container or nebulizer may contain a solution or suspension of a compound disclosed herein. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may contain a powder mixture of a compound disclosed herein and a suitable powder base, such as lactose or starch.

The intended dose of a compound disclosed herein for oral, parenteral or buccal administration to an average adult human for the treatment or prevention of a TPO-related disease state is from about 0.1 mg to about 2000 mg. In some embodiments, the intended dosage is from about 0.1 mg to about 200 mg of active ingredient per unit dose. Regardless of the amount of the intended dose, administration of the compound may occur, for example, 1-4 times a day.

Aerosol formulations for the treatment or prevention of the conditions mentioned above for the average adult are preferably formulated such that each metered dose or puff of aerosol contains from about 20 mg to about 10,000 mg, preferably from about 20 mg to about 1000 mg of the compound disclosed in this description. The total daily aerosol dose will range from about 100 mg to about 100 mg. In some embodiments, the total daily dose of the aerosol will generally be in the range of from about 100 mg to about 10 mg. The administration can be carried out several times a day, for example, 2, 3, 4 or 8 times, giving 1, 2 or 3 doses each time.

Aerosol combination formulations for the treatment or prevention of the conditions mentioned above for the average adult are preferably formulated such that each metered dose or puff of aerosol contains from about 0.01 mg to about 1000 mg of a combination comprising a compound disclosed herein. In some embodiments, each metered dose or puff of aerosol contains from about 0.01 mg to about 100 mg of a combination comprising a compound disclosed herein. In some embodiments, each metered dose or puff of aerosol contains from about 1 mg to about 10 mg of a combination comprising a compound disclosed herein. The administration can be carried out several times a day, for example, 2, 3, 4 or 8 times, giving 1, 2 or 3 doses each time.

Pharmaceutical compositions and methods of treatment or prevention, including the administration of prodrugs of at least one compound disclosed herein, are also included within the scope of the present disclosure.

Glucosylceramide synthase assays.

Inhibition of glucosylceramide synthase activity can be measured using one or more assays. The first assay is a microsomal assay that directly measures the conversion of ceramide to glucosylceramide by HPLC. Microsomes are the source of glucosylceramide synthase activity in microsomal assays. The second assay is a cell phenotypic assay that monitors cell surface expression of the downregulated lipid GM3 by antibody-mediated immunofluorescence. Specific protocols are provided below.

Microsomal analysis of glucosylceramide synthase activity. Enzyme assay using microsomes as a source of glucosylceramide synthase activity. The fluorescent ceramide substrate is delivered to the membrane-bound enzyme as a complex with albumin. After the reaction, ceramide and glucosylceramide are separated and quantified by reverse phase HPLC with fluorescence detection. Enzyme activity is assessed using a fluorescently labeled substrate and microsomes as a source of glucosylceramide synthase activity. The CgNBD-ceramide-albumin complex is prepared for delivery to microsomes, which are isolated according to the procedure described below. The final concentration of CgNBD-ceramide in the initial mixture is 0.5 mM; the final concentration of BSA is 0.5 mM.

Separations and quantitation of substrate and product (glucosylceramide) are achieved by reverse phase HPLC with fluorescence detection.

Procedure.

Preparation of microsomes from human melanoma cells A375.

Microsomes are isolated from human melanoma A375 cells. Eight to ten million cells are collected by trypsinization and washed with ice-cold PBS. Cells are resuspended in ice-cold lysis buffer containing protease inhibitors. The cell lysate is sonicated on ice using a probe ultrasonic disintegrator. After ultrasonic treatment

- 18 046304 com The cell lysate is separated from debris by centrifugation at 10,000 g for 10 minutes at 4°C. The supernatant is removed and clarified by further centrifugation at 100,000 g for 1 hour at 4°C. The pellet is then resuspended in lysis buffer, aliquoted and stored at -80°C until use.

Glucosylceramide synthase assay.

To determine inhibition of glucosylceramide synthase, substrates at 2x their Km (fluorescent ceramide and UDP-glucose, 3 μM and 4 μM, respectively) and microsomes (1:50 dilution) were combined 1:1 and incubated at room temperature for 1 h in the dark on a tablet shaker. The reaction is stopped by adding 150 μl of 100 μM ceramide C ₈ in 50% aq. isopropanol; 10 µl of the final mixture is analyzed by HPLC (with fluorescence detector). The mobile phase of 1% formic acid in 81% methanol, 19% water is carried out at a flow rate of 0.5 ml/min. Fluorescence is detected at /.„ = 470 nm and /. _em = 530 nm. Under these conditions, NBD C ₆ GluCer has a retention time of approximately 1.7 minutes, NBD C ₆ Cer elutes from the column after approximately 2.1 minutes. Both peaks are separated from each other and the baseline and integrated automatically using HPLC software. The percentage conversion of substrate to product is used as a reference for screening inhibitors.

Fluorescence-linked immunosorbent assay (FLISA) GM3. This is a phenotypic assay that measures GM3 expression in conjugation with B16 or C32 cell viability following treatment with compounds. Cell surface expression of GM3 is detected by antibody-mediated fluorescence, and viability in each cell is assessed.

Procedure.

Compounds are diluted in media and added to 384-well plates in DMSO. B16 and C32 cells were assayed at a density of 20,000 cells/ml, respectively, per well. Each titration curve contains 10 points, at which the analysis is carried out twice in each test. The plates are incubated for 48 hours at 37°C, 5% CO ₂ and then washed once with TBS. Anti-GM3 antibodies are added to each well and the plates are then incubated for an additional hour at room temperature. The plates are then washed twice and incubated for an additional hour with labeled secondary antibodies. After the last incubation, the plates are washed twice, and fluorescence is detected on a fluorescence plate reader at /.„ = D640/20 nm and /. _em = 657 nm. After GM3 fluorescence detection, cell viability was assessed using the ATPlite assay (Perkin Elmer) according to the manufacturer's instructions.

Analysis results.

Selected analytical results for some example compounds in these assays are given in Table 1. 1. Microsomal assay results are expressed as GCS IC ₅₀ , which represents the concentration of compound causing 50% inhibition of glucosylceramide synthase activity. The results of cell-based assays (performed on two different cell systems, i.e., B16 mouse melanoma or C32 human melanoma cells) are expressed as GM3 B16 IC ₅₀ or GM3 C32 IC ₅₀ for the B16 assay and the C32 assay, respectively. These results are represented by the concentration of the compound causing 50% inhibition of GM3 expression on the cell surface.

Inhibition of glucosylceramide synthase in a model of polycystic kidney disease.

Mice homozygous for the Nek8jck mutation develop polycystic kidney disease (jck mice). Histology shows that some 3-day-old pups of heterozygous parents have small, discrete cysts outlined by cuboidal epithelial cells, and 15-day-old pups have cysts outlined by flattened epithelium. The disease progresses, but is not detected by palpation of the kidneys until at least 4-5 weeks of age. Homozygotes typically remain active until almost death and usually die between 20 and 25 weeks of age. Homozygous females are fertile, but subsequently do not care for their offspring; homozygous males are fertile, but fertility is reported to decline after 15 weeks of age. No histological abnormalities were found in the liver, spleen or pancreas (Atala et al., 1993).

In order to evaluate the effect of a GCS inhibitor on polycystic disease, the compound of interest can be administered to the jck mouse in one or two doses. Administration of the compound can begin at any time after birth, for example starting at 3 to 4 weeks of age, and can be continued for as long as required. The effect of a compound on disease phenotype can be assessed by measuring body weight, blood urea nitrogen (BUN) and serum GL1 during the life phase. Additional effects on kidney/body weight (K/BW), cyst volume, BUN, renal GL1 and serum GL1 can be measured at the end of life at the end of the study.

Inhibition of glucosylceramide synthase in a mouse model of Fabry disease.

A study may be designed to evaluate whether substrate inhibition (ie, substrate reduction therapy or SRT) using the compounds of the invention can reduce the accumulation of stored globotriaosylceramide (Gb3) and lysoglobotriaosylceramide (lysoGb3) material. The Fabry disease mouse model can be used to evaluate substrate reduction therapy (SRT) with GCS inhibitor compounds in reducing plasma levels of both Gb3 and lyso-Gb3.

- 19 046304 kidneys and urine of Fabry mice. It has recently been suggested that urinary lyso-C3 may represent a reliable biomarker of clinical relevance for Fabry disease (Aerts et al., PNAS USA, 105: 28122817 (2008); and Auray-Blais et al., Clin. Chem. Acta, 411 : 1906-1914 (2010)). The metabolic origin of lyso-Cb3 is unknown and it may be either deacylation of Gb3 or anabolic synthesis from glucosylsphingosine.

In fig. 1, black arrows show demonstrated pathways, gray arrows indicate proposed pathways. Enzyme replacement therapy is known to destroy both Gb3 and lyso-Gb3. Accordingly, SRT using a GCS inhibitor may be most effective in limiting lyso-Cl3 accumulation if lyso-Cl3 is generated predominantly through Gb3 deacylation in a GCS-dependent pathway. Such experiments can be used to demonstrate that SRT using GCS inhibitors in a mouse model of Fabry disease reduces both Gb3 and lyso-G3. which provides support for the use of the compounds of the invention as viable therapeutic options for patients with Fabry disease.

Experimental part.

Several approaches are used or followed to treat LSD, most of which focus on enzyme replacement therapy for use only when the disease is eliminated. Many approved enzyme replacement therapies for the treatment of LSD are commercially available (eg, Myozyme® for Pompe disease, Aldurazyme® for mucopolysaccharidosis I, Cerezyme® for Gaucher disease, and Fabrazyme® for Fabry disease). In addition, the inventors have identified a number of small molecules for use only in the treatment of LSD. The therapeutic methods of the invention described herein provide treatment options for practitioners to address various lysosomal storage diseases, as described in detail below.

In some aspects of the invention, the compounds of the present invention can be used to treat a metabolic disease, such as lysosomal storage disease (LSD), either alone or in combination therapy with enzyme replacement therapy. In other aspects of the invention, the compounds of the present invention can be used to inhibit or reduce GCS activity in a subject diagnosed with a metabolic disease such as LSD, either alone or in combination therapy with enzyme replacement therapy. In other aspects of the invention, the compounds of the present invention can be used to reduce and/or inhibit the accumulation of stored material (eg, lysosomal substrate) in a subject diagnosed with a metabolic disease, such as LSD. In some embodiments of the above aspects, LSD is Gaucher disease (type 1, type 2, or type 3), Fabry disease, GMj gangliosidosis, or G _M2 gangliosidosis (eg, GM2 activator deficiency, Tay-Sachs and Sandhoff disease). In table 1 lists a number of LSDs and identifies the corresponding missing enzymes that can be used as ERTs in the above aspects of the invention.

In other cases, SMT may be required for a patient whose condition requires reduction of brain substrates and thus cannot be treated with systemic ERT. While direct intracerebrovascular or intrathecal administration may reduce substrate levels in the brain, systemic administration of ERT is not tolerated in LSD involving the central nervous system (CNS) due to its inability to cross the blood-brain barrier (BBB), and SMT may be beneficial effect on patients with residual enzymatic activity in the central nervous system.

According to the present invention, SMTs are provided to a patient for the treatment of cancer and/or a metabolic disease such as a lysosomal storage disease. SMT may include one or more small molecules. SMT involves administering to a patient the compounds of the present invention. In certain embodiments, the compound is ^)-quinuclidin-3-yl(2-(2-(4-fluorophenyl)thiazol-4yl)propan-2-yl)carbamate or quinuclidin-3-yl(2-(4'-fluoro) [1,1'-biphenyl]-3-yl)propan-2-yl)carbamate or combinations thereof.

In some embodiments, compounds of the invention, such as ^)-quinuclidin-3-yl(2-(2-(4fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate and quinuclidin-3-yl(2-(4 '-fluoro[1,1'-biphenyl]-3-yl)propan2-yl)carbamate can be used to treat virtually any storage disease resulting from disruption of the glycosphingolipid pathway (eg, Gaucher disease (type 1, type 2 or type 3 ), Fabry, GMj gangliosidosis or G _M2 gangliosidosis (eg, GM2 activator deficiency, Tay-Sachs disease and Sandhoff disease)). In a particularly preferred embodiment, ^)-quinuclidin-3-yl(2-(2(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate or a pharmaceutically acceptable salt or prodrug thereof is used to inhibit and/or reduce accumulation Gb3 and/or lyso-Gb3 in a patient with Fabry disease, either alone or in combination therapy with enzyme replacement therapy (see examples). In a preferred embodiment, enzyme replacement therapy comprises administering alpha-galactosidase A to a patient with Fabry disease. Indeed, the examples below show that in a mouse model of Fabry disease, the GCS inhibitor of the invention effectively reduces the accumulation of Gb3 and lyso-Cl3. thus supporting its use as a viable approach for the treatment of Fabry disease. Moreover, the in vivo combination therapy data provided in the examples are re

- 20 046304 strongly suggest that the combined therapeutic approach can be either additive or complementary.

In some embodiments, compounds of the invention, such as ^)-quinuclidin-3-yl(2-(2-(4fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate and quinuclidin-3-yl(2-(4 '-fluoro[1,1'-biphenyl]-3-yl)propan2-yl)carbamate, can be used to reduce the level of GluCer or GluSph in the brain of a subject diagnosed with neuropathic Gaucher disease, either alone or in combination with ERT (eg, administration glucocerebrosidase).

Treatment regimens for the small molecule therapy component of the combination therapy of the invention will generally be determined by one skilled in the art and are expected to vary significantly depending on the particular storage disease being treated and the clinical status of the particular patient.

The general principles for determining a treatment regimen for a given SMT of the invention for the treatment of any storage disease are well known to those skilled in the art. Guidance on treatment regimens can be obtained from any of the many well-known literature sources on the topic. Guidance is also available from, among other things, a review of the specific references cited herein. In some 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, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 and 60 mg/kg) when administered intraperitoneally, orally or equivalent one to five times a day. 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, when administered orally, intraperitoneally, or the equivalent, one to five times daily. In one embodiment, dosages range from about 10 mg/day to about 500 mg/day (e.g., 10, 20, 30, 40, 50, 60, 70, 80 mg/day, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300 mg/day). A particularly preferred oral dosage ranges from about 50 mg to about 100 mg, administered twice daily. A particularly preferred oral dosage range for a compound of the present invention is from about 5 mg/kg/day to about 600 mg/kg/day. Specifically, the oral dosage range for a compound of the present invention is from about 1 mg/kg/day to about 120, such as 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60 , 65, 70, 75, 80, 85 or 90, 95, 100, 105, 110, 115 or 120 mg/kg/day.

In some embodiments, the invention relates to combination SMT therapies using compounds of the invention and ERT therapy for the treatment of lysosomal storage diseases. A partial list of known lysosomal storage diseases that can be treated according to the invention is given in table. 1, including the common name of the disease, the material stored, and the deficiency of the corresponding enzyme (adapted from Table 38-4 of Kolodny et al., 1988, cited above).

Table 1

Lysosomal storage diseases

Disease Accumulated material Missing enzyme

Sphingolipidoses

Gaucher Glucocerebroside, Glucocerebrosidase glucosylsphingosine A Niemann-Pick Sphingomyelin Sphingomyelinase Niemann-Pick B Sphingomyelin Sphingomyelinase Farber Ceramide Ceramidase G _M1 - gangliosidosis G _M1 -ganglioside, glycoprotein 6 _m1 -ganglioside-p-galactosidase 6 _m2 - gangliosidosis G _M; (disease ^-ganglioside, globoside Hexosaminidase A and B Sandhoff) Tay-Sachs G _M2 -ganglioside Hexosaminidase A Krabbe Galactosylceramide β- Galactocerebroside aza Mucopolysaccharidoses Gurler-Scheie (MPS I) Dermatan sulfate, heparin sulfate oc-L-Iduronidase Gunther (MPS II) Dermatan sulfate, heparin sulfate Iduronate sulfatase A

- 21 046304

Sanfilippo (MPS III)

Type A Heparan sulfate Heparin-N- sulfatase Type B Heparan sulfate N-Acetyl-os- glucosaminidase Type C Heparan sulfate Acetyl CoA:aglkosaminidacetyl-transferase Type D Heparan sulfate N-Acetyl-os- glucosamine-6sulfatase Morquio (MPS IV) Type A Keratan sulfate Galactosamine-6sulfatase Type B Keratan sulfate β-Galactosidase Marotheau-Lami (MPS VI) Deramatan sulfate Galactosamine 4sulfatase (arylsulfatase B) Slya (MPS VII) Deramatan sulfate, heparan sulfate β-Glucuronide Mucosulfatidosis Sulfatides, mucopolysaccharides Arylsulfatase A, B and C, other sulfatases Mucolipidoses Sialidoses Sialoligosaccharides, glycoproteins a-Neuraminidase Mucolipidosis II Sialyl oligosaccharides, glycoproteins, glycolipids High (active) serum, low (active) fibroblast enzymes; Acetylglucosamine-

1phosphate transferase

- 22 046304

Mucolipidosis III Glycoproteins, glycolipids

Mucolipidosis IV Glycolipids, glycoproteins

Same as above Mcolnl transmprotein

Other diseases of complex carbohydrate metabolism

Fabry Schindler Globotriaosylceramide (Gb3), lyso-C3 O-related α-Galactosidase A OC-N- glycopeptides Acetylgalactoses nidaza Pompe Glycogen a-Glucosidase Sialic acid storage disease Free sialic acid Unknown Fucosidosis Fucoglycolipids, fucosyl oligosaccharides a-Fucosidase Mannosidosis Mannosyl oligosaccharides a-Mannosidase Aspartyl glucose Nuria Aspartylglucosamine Aspartyl glucose n-amidase Wolman Cholesteryl ethers, triglycerides Acid lipase

Neuronal ceroid lipofuscinoses (NCL)*

Children's NCL Granular osmophilic deposits, saposin A and D thioesterases Palmitoylprotein -thioesterase (PPT1) Late children's Curvilinear profiles, Tripeptidylprotea form ATP synthase subunit With for 1 (TRP1) Finnish Variation Fingerprint/Straight Line Profiles, ATP Synthase Subunit with CLN5 Option Fingerprint/Straight Line Profiles, ATP Synthase Subunit with CLN6 Juvenile form Fingerprint profile, ATP synthase subunit with CLN3 Adult form Variables Unknown Northern Straight profiles, CLN8 epilepsy ATP synthase subunit With Turkish version Fingerprint/Straight Line Profiles components unknown Unknown

Lysosomal diseases of cholesterol transport and metabolism

Niemann-Pick type Non-esterified NPC1 or NPC2

C cholesterol * Davidson et al., The Neuronal Ceroid Lipofuscinosis, Clinical Features and Molecular Basis of Disease. In Barranger J.A. and Caberra-Salazar M.A. (Eds). Lisosomal Storage Disorders, 2007, pp. 371-388, Springer, New York, U.S.A.

- 23 046304

Any method known to those skilled in the art can be used to monitor disease status and the effectiveness of the combination therapy of the invention. Clinical monitoring parameters of disease state may include, but are not limited to, organ volume (eg, liver, spleen), hemoglobin, red blood cell count, hematocrit, thrombocytopenia, cachexia (wasting), and plasma chitinase levels (eg, chitotriosidase). The chitinase family enzyme chitotriosidase is known to be produced at high levels by macrophages in subjects with lysosomal storage diseases (see Guo et al., 1995, J. Inherit. Metab. Dis. 18, 717-722; den Tandt et al., 1996, J Inherit. Dis. 19, 344-350; Medicina (Buenos Aires) 57, 677-684; Clin. Biochem. 33, 147-149; al, 1998, Clin. Biochem. 31, 417-420; Baillieres Clin. 10, 817-838; J. Inherit. ; Hollak et al, 1994, J. Clin. Invest. 93, 1288-1292).

Chitotriosidase is preferably tested conjugated to angiotensin converting enzyme and tartrate labile acid phosphatase to test the response to treatment of patients with Gaucher disease.

Methods and compositions for administration in the combination therapies of the invention include all methods and compositions well known in the art (see, for example, Remington's Pharmaceutical Sciences, 1980 et seq., 16th et seq., ed. A. Oslo, Easton Pa. ; Controlled Drug Delivery, 1987, ^2nd rev., Joseph R. Robinson & Vincent H. L. Lee, eds., Marcel Dekker, ISBN: 0824775880; Encyclopedia of Controlled Drug Delivery, 1999, Edith Mathiowitz, John Wiley & Sons, ISBN: 047114288 ; US Pat. No. 6066626 and the references cited therein; see also the references cited in the sections below).

The invention provides the following general approaches for combination therapy in the treatment of lysosomal storage diseases. Each general approach involves combining enzyme replacement therapy with small molecule therapy in a manner consistent with optimizing clinical benefit while minimizing the disadvantages associated with the use of either therapy alone.

In one embodiment of the invention, enzyme replacement therapy (alone or in combination with small molecule therapy) is administered to initiate treatment (i.e., to debulk the subject), and small molecule therapy is given after the debulking phase to achieve and maintain sustained long-term therapeutic effect without the need for frequent intravenous injections of ERT. For example, enzyme replacement therapy may be administered intravenously (eg, over one to two hours) once, weekly, once every two weeks, or once every two months, for several weeks or months or longer (eg, until included indicator organ such as the spleen or liver will not show a decrease in size). Moreover, the initial debulking phase of ERT treatment can be performed alone or in combination with small molecule therapy. The therapeutic component of small molecules is particularly advantageous when the small molecules are compatible with oral administration, thereby also reducing frequent intravenous intervention.

Alternating ERT and SMT, or adding SMT to ERT as required, provides a strategy for simultaneously obtaining the efficacy benefits and weakness targeting associated with each therapy when used alone. The benefit of ERT, whether used for debulking and/or longer-term treatment, is much greater than the clinical experience available to inform the practitioner's decisions. Moreover, the subject can be effectively monitored for ERT during the volume depletion phase, for example, by titrating biochemical metabolites in urine or other body samples or by measuring the volume of the affected organ. However, a disadvantage of ERT is the required frequency of administration, typically involving weekly or biweekly intravenous injection, due to the constant reaccumulation of substrate. The use of small molecule therapy to reduce or inhibit substrate accumulation in a patient may, in turn, reduce the frequency of ERT administration. For example, a biweekly ERT holiday enzyme replacement therapy dosing regimen (eg, using SMT) may be suggested so that frequent enzyme injections are not a necessary therapy. In addition, treatment of lysosomal storage disease with combination therapy may provide complementary therapeutic approaches. Indeed, as demonstrated in the examples below, combination therapy of SMT and ERT can provide significant improvements over any single therapeutic platform. Such results suggest that combination therapy using SMT and ERT may be either additive or complementary. In one embodiment, ERT can be used as a debulking strategy (ie, treatment initiation) followed by or simultaneous addition of SMT using a compound of the present invention. In another embodiment, the patient is first treated with SMT using a compound of the present invention followed by or concurrently with ERT. In other embodiments, SMT is used to inhibit or reduce also substrate accumulation (or substrate reaccumulation if used after ERT debulking) in a patient with a lysosomal storage disease, and optionally provide ERT as necessary to reduce the accumulation of any other substrate. In one embodiment of this invention

- 24 046304 This relates to a method of combination therapy for treating a subject diagnosed with a lysosomal storage disease, including alternating administration of enzyme replacement therapy and small molecule therapy. In another embodiment, the present invention provides a method of combination therapy for treating a subject diagnosed with a lysosomal storage disease, comprising simultaneous administration of enzyme replacement therapy and small molecule therapy. It will be understood that in the various combination therapies of the invention, the administration of the small molecule therapy may occur before, simultaneously with, or after the administration of the enzyme replacement therapy. Likewise, administration of enzyme replacement therapy may occur before, simultaneously with, or after the administration of small molecule therapy.

In any embodiment of the invention, the lysosomal storage disease is selected from the group consisting of Gaucher diseases (types 1, 2 and 3), Niemann-Pick, Farber, GMi gangliosidosis, G _M2 gangliosidosis (for example, GM2 activator deficiency, Tay-Sachs and Sandhoff disease ), Krabbe disease, HurlerScheie (MPS I), Gunther (MPS II), Sanfilippo (MPS III) type A, Sanfilippo (MPS III) type B, Sanfilippo (MPS III) type C, Sanfilippo (MPS III) type D, Morquio (MPS IV) type A, Morquio (MPS IV) type B, Maroto-Lamy (MPS VI), Sly (MPS VII), mucosulfatidosis, sialidosis, mucolipidosis II, mucolipidosis III, mucolipidosis IV, Fabry disease, Schindler disease, Pompe disease, disease sialic acid accumulation, fucosidosis, mannosidosis, aspartylglucosaminuria, Wolman's disease and neural ceroidlipofuscinoses.

In addition, ERT provides an effective amount of at least one of the following enzymes: glucocerebrosidase, sphingomyelinase, ceramidase, GMganglioside-beta-galactosidase, hexosaminidase A, hexosaminidase B, beta-galactocerebrosidase, alpha-b-iduronidase, iduronate sulfatase, heparan -N-sulfatases, N-acetyl-alpha-glucosaminidase, acetylCoA:alpha-glucosaminidacetyl-transferase, N-acetyl-alpha-glucosamine-b-sulfatase, galactosamine-6-sulfatase, beta-galactosidase, galactosamine-4-sulfatase (arylsulfatase B), beta-glucuronidase, arylsulfatase A, arylsulfatase C, alpha-neuraminidases, N-acetylglucosamine-1-phosphate transferase, alpha-galactosidase A, alpha-N-acetylgalactosaminidase, alpha-glucosidase, alpha-fucosidase, alphamannosidase, aspartylglucosaminamidase, acid lipase , palmitoylprotein thioesterase (CLN-1), PPT1, TPP1, CLN3, CLN5, CLN6, CLN8, NPC1 or NPC2.

In accordance with the invention, SMT and/or ERT causes a decrease in at least one of the following accumulated materials: glucocerebroside, sphingomyelin, ceramide, G _M1 -ganglioside, G _M 2-ganglioside, globoside, galactosylceramide, dermatan sulfate, heparan sulfate, keratan sulfate, sulfatides, mucopolysaccharides, sialyl oligosaccharides, glycoproteins, sialyl oligosaccharides, glycolipids, globotriaosylceramide, O-linked glycopeptides, glycogen, free sialic acid, fucoglycolipids, fucosyl oligosaccharides, mannosyl oligosaccharides, aspartyl glucosamine, cholesterol esters a, triglycerides, granular osmolytic deposits - saposins A and D, subunits ATP synthase c, NPC1 or NPC2.

In some embodiments of the invention, the small molecule therapy comprises administering to a subject an effective amount of ^)-quinuclidin-3-yl(2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2yl)carbamate. In other embodiments of the invention, the small molecule therapy comprises administering to a subject an effective amount of quinuclidin-3-yl(2-(4'-fluoro[1,1'-biphenyl]-3-yl)propan-2yl)carbamate. In some embodiments, at least one of the compounds is a compound of the present invention. Enzyme replacement therapy may provoke unwanted immune reactions. Accordingly, immunosuppressants can be used together with the enzyme replacement therapy component of the combination therapy of the invention. Such agents can also be used with a small molecule therapy component, but the need for intervention is usually less likely. Any immunosuppressant known to those skilled in the art can be used in conjunction with the combination therapy of the invention. Such immunosuppressants include, but are not limited to, cyclosporine, FK506, rapamycin, CTLA4-Ig and anti-TNF agents such as etanercept (see Moder, 2000, Ann. Allergy Asthma Immunol. 84, 280-284; Nevins, 2000, Curr. Opin. 12, 146-150; Scand. J. Immunol. 51, 224-230; Neuroscience 95, 217-226; N.Y. Acad. Sci. 875, 159-174; Immunol. Res. 1999, Bone Marrow Transplant. Transplant. 13, 209-220; J. Am. Nephrol. 10, 1366-1380; Transplantation 69, 1275-1283. Antibodies against the IL-2 receptor (alpha subunit) daclizumab (eg, Zenapax.TM.), which have been shown to be effective in transplant patients, can also be used as an immunosuppressant (see, for example, Wiseman et al, 1999, Drugs 58, 1029 -1042; Beniaminovitz et al, 2000, N. Engl J. Med. 342, 613-619; Ponticelli et al, 1999, Drugs R. D. 1, 55-60; et al, 2000, Transplantation 69, 1867-1872; Ekberg et al, 2000, Transpl. 13, 151-159). Other immunosuppressants include, but are not limited to, anti-CD2 antibodies (Branco et al., 1999, Transplantation, 68, 1588-1596; Przepiorka et al., 1998, Blood, 92, 4066-4071), anti-C42 (Marinova -Mutafchieva et al., 2000, Arthritis Reum., 43, 638-644; Fishwid et al., 1999, Clin. Immunol., 92, 138-152) and anti-CD40 ligand (Hong et al., 2000, Semin Nephrol., 20, 108-125; Chirmule et al., 2000, J. Virol., 74, 3345-3352; Ito et al., 2000, J. Immunol., 164, 1230-25 046304

1235).

Any combination of immunosuppressive agents known to those skilled in the art can be used in conjunction with the combination therapy of the invention. One particularly useful combination of immunosuppressants is tacrolimus (FK506) plus sirolimus (rapamycin) plus daclizumab (antibodies against the alpha subunit of the IL-2 receptor). This combination has proven effective as an alternative to steroids and cyclosporine, and when specifically targeting the liver. Moreover, this combination has recently been shown to allow successful transplantation of pancreatic islet cells. See Denise Grady, The New York Times, Saturday, May 27, 2000, pages A1 and A11. See also A.M. Shapiro et al., Jul. 27, 2000, Islet Transplantation In Seven Patients With Type 1 Diabetes Mellitus Using A Glucocorticoid-Free Immunosuppressive Regimen, N. Engl. J. Med., 343, 230-238; Ryan et al., 2001, Diabetes, 50, 710-719. Plasmaphoresis by any method known in the art can also be used to remove or purify antibodies that may be produced against the various components of the combination therapy.

Indicators of immune status for use with the invention include, but are not limited to, antibodies and any cytokines known to those skilled in the art, such as interleukins, CSF and interferons (for a general overview, see Leonard et al., 2000, J. Allergy Clin . Immunol., 105, 877-888; Oberholzer et al., 2000, Crit. Care Med., 28 (4 Suppl.), N3-N12; -181). For example, antibodies that are immunoreactive with the replacement enzyme can be specifically monitored to determine the immune status of a subject. Of the two dozen or so known interleukins, IL-1 alpha, IL-2, IL-4, IL-8 and IL-10 are particularly preferred indicators of immune status. Among the colony stimulating factors (CSFs), particularly preferred indicators of immune status are G-CSF, GM-CSF and MCSF. Among interferons, one or more of alpha, beta or gamma interferons are preferred as indicators of immune status.

The sections that follow outline the various components that can be used for eight specific lysosomal storage diseases (i.e. Gaucher diseases (including types 1,2 and 3), Fabry, Niemann-Pick B, Gunther, Morquio, Maroto- Lamy, Pompe and Gurler-Scheie). The following sections provide other possible disclosures of the enzyme replacement therapy and small molecule combination therapy components of the invention.

Gaucher's disease.

As noted above, Gaucher's disease is caused by a deficiency of the enzyme glucocerebrosidase (betaD-glucosyl-N-acylsphingosine glucohydrolase, EC 3.2.1.45) and the accumulation of glucocerebroside (glucosylceramide). For the enzyme replacement therapy component of the combination therapy of the invention for the treatment of Gaucher's disease, a number of references are available that indicate satisfactory dosage regimens and other useful information regarding treatment (see Morales, 1996, Gaucher's Disease: A Review, The Annals of Pharmacotherapy 30, 381 -388; Rosenthal et al., 1995, Enzyme Replacement Therapy for Gaucher Disease: Skeletal Responses to Macrophage-targeted Glucocerebrosidase, Pediatrics 96, 629-637; Gaucher's Disease, New England Journal of Medicine 324, 1464-1470; Grabowski et al., 1995, Enzyme Therapy in Type 1 Gaucher Disease: Comparative Efficacy of Mannose-terminated Glucocerebrosidase from Natural and Recombinant Sources, Annals of Internal Medicine 122, 33- 39; Pastores et al, 1993, Enzyme Therapy in Gaucher Disease Type 1: Dosage Efficacy and Adverse Effects in 33 Patients treated 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 regimen of 2.5 units per kilogram (U/kg) three times a week to 60 U/kg once every two weeks is given, where the enzyme is administered by intravenous infusion over 1-2 hours. A unit of glucocerebrosidase is defined as the amount of enzyme that catalyzes the hydrolysis of one micromole of the synthetic substrate p-nitrophenyl-p-E-glucopyranoside per minute at 37°C. In another embodiment, a dosage regimen of 1 U/kg three times a week to 120 U/kg once every two weeks is given. In yet another embodiment, a dosage regimen of 0.25 U/kg daily or three times a week up to 600 U/kg once every two to six weeks is provided.

Alglucerase (ceredase®) has been available since 1991 from Genzyme Corporation. Alglucerase is a placenta-derived modified form of glucocerebrosidase. In 1994, imiglucerase (Cerezim®) also became available from Genzyme Corporation. Imiglucerase is a modified form of glucocerebrosidase obtained by expressing recombinant DNA in a cultured mammalian cell system (Chinese hamster ovary cells). Imiglucerase is a 497 amino acid monomeric glycoprotein containing 4 N-linked glycosylation sites. Imiglucerase has the advantages of theoretically unlimited addition and reduced potential for biological contamination relative to placenta-derived alglucerase. These enzymes are modified at their glycosylation sites to expose mannose residues, a maneuver that improves lysosomal targeting via the mannose 6-phosphate receptor. Imiglucerase differs from placental glucocerebrosidase by one amino acid at position 495, where histidine

- 26 046304 replaced with arginine. Several effective regimens for these products are known (see Morales, 1996, op. cit.; Rosenthal et al., 1995, op. cit.; Barton et al., 1991, op. cit.; Grabowski et al., 1995, op. cit. ; Pastores et al., 1993, cited above). For example, a clinically beneficial dosing regimen for subjects with moderate to severe disease is 60 U/kg once every two weeks. Practitioners should refer to the references cited above and package inserts for such products for other dosage schedules and administration information. See also Pat. US No. 5236838 and 5549892, Genzyme Corporation.

As noted above, Gaucher disease results from a deficiency of the lysosomal enzyme glucocerebrosidase (GC). In the most common phenotype of Gaucher disease (type 1), pathology is limited to the reticuloendothelial and skeletal systems and there are no neuropathic symptoms. See Barranger, Glucosylceramide lipidosis: Gaucher disease. In Seriver CR BA, Sly WS, Valie D, editor. The Metabolic Basis of Inherited Disease. New York: McGraw-Hill, pp. 3635-3668 (2001). In neuropathic Gaucher disease (nGD), subdivided into Gaucher disease type 2 and type 3, glucocerebrosidase (GC) deficiency causes accumulation of glucosylceramide (GluCer; GL-1) and glucosylsphingosine (GluSph) in the brain, leading to neurological deterioration. Gaucher disease type 2 is characterized by early onset, rapid progression, extensive pathology in the viscera and central nervous system, and usually death by age 2 years. Gaucher disease type 3, also known as subacute nGD, is an intermediate phenotype with onset at varying ages and varying degrees of severity and rates of progression. Goker-Alpan et al., The Journal of Pediatrics, 143: 273-276 (2003). Recently, a K14 Inl/Inl mouse model of Gaucher disease type 2 (hereinafter referred to as the K14 mouse) has been developed; this mouse model closely recapitulates the human disease, showing ataxia, paroxysms, muscle spasticity and a reduced average lifespan of only 14 days. Enquist et al., PNAS, 104: 17483–17488 (2007).

Like nGD patients, some mouse models of the disease have elevated levels of GluCer and GluSph in the brain due to a deficiency in GC activity. Liu et al., PNAS, 95: 2503-2508 (1998), and Nilsson, J. Neurochem., 39: 709-718 (1982). K14 mice display a neuropathic phenotype that shares many of the pathological features of Gaucher disease type 2, such as neurodegeneration, astrogliosis, microglial proliferation, and elevated levels of GluCer and GluSph in specific brain regions. Enquist et al. (2007).

Clinical management of patients affected by nGD requires the efforts of treating physicians, both due to the severity of type 2 disease and the inability of existing therapies to cross the blood-brain barrier (BBB). Current treatment for non-nGD relies on intravenous delivery of recombinant human glucocerebrosidase (imiglucerase; Cerezyme™) to replace the missing enzyme or administration of glucosylceramide synthase inhibitors to attenuate substrate (GL-1) production. However, such drugs do not cross the blood-brain barrier and thus are not expected to provide beneficial therapeutic effects for nGD patients. Current small molecule glucosylceramide synthase inhibitors cannot be targeted to treat neuropathic nGD phenotypes. Evaluation of the compound of the present invention, quinuclidin-3-yl(2-(4'-fluoro[1,1'biphenyl]-3-yl)propan-2-yl)carbamate (hereinafter Gz161) in the K14 mouse model of Gaucher disease type 1 shows that it is indeed possible to reduce GluCer and GluSph in the brain (see examples 122-125). Neuropathology of the brain is also reduced and the life expectancy of this model is extended. Additionally, a combination approach using both enzyme replacement and substrate reduction with small molecules may provide superior therapy for Gaucher disease type 2.

Fabry disease.

As previously noted, Fabry disease is caused by a deficiency of the lysosomal enzyme alpha-galactosidase A. Enzyme deficiency leads to systemic deposition of alpha-galactosyl-terminated glycosphingolipids, predominantly globotriaosylceramide (GL3 or Gb3) and to a lesser extent galabiosylceramide and blood group B glycosphingolipids.

Several tests are available to monitor the progression of the disease and to determine when to switch from one therapeutic modality to another. In one embodiment, the assay can be used to determine the specific activity of alpha-galactosidase A in a tissue sample. In another embodiment, the assay can be used to determine Gb3 accumulation. In another embodiment, a physician may analyze the deposition of glycosphingolipid substrates in body fluids and in liposomes in vascular endothelial, perithelial, and smooth muscle cells of blood vessels. Other clinical manifestations that may be useful indicators in disease management include proteinuria or other signs of renal deterioration, such as red blood cells or lipid globules in the urine, and an elevated erythrocyte sedimentation rate. The disease can also be monitored by anemia, low serum iron concentration, high beta thromboglobulin concentration, and increased reticulocyte count or platelet aggregation. Indeed, any approach to control disease progression that is known to those skilled in the art can be used (for an overview, see Desnick R. J. et al., 1995, alpha-Galactosidase A

- 27 046304

Deficiency: Fabry Disease, In The Metabolic and Molecular Bases of Inherited Disease, Servier et al., eds., McGraw-Hill, N.Y., 7.sup.th ed., pages 2741-2784).

The preferred replacement marker for monitoring in the management of Fabry disease is pain. Other preferred methods include measuring the total clearance of the enzyme and/or substrate from a body fluid sample or biopsy sample. The preferred dosage regimen for enzyme replacement therapy for Fabry disease is 1-10 mg/kg, i.v., every other day. Dosing regimens ranging from 0.1 to 100 mg/kg, i.v., can be used at a frequency ranging from every other day to once a week or every two weeks.

Niemann-Pick disease B.

As previously noted, Niemann-Pick B disease is caused by decreased activity of the lysosomal enzyme acid sphingomyelinase and the accumulation of membrane lipid, mainly sphingomyelin. The effective dosage of acid sphingomyelinase replacement enzyme that is delivered can range from about 0.01 mg/kg to about 10 mg/kg body weight at a frequency of every other day to weekly, once every two weeks, or once every two months. In other embodiments, the 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 from about 0.3 mg/kg to about 0.6 mg/kg. In a particular embodiment, the patient is administered acid sphingomyelinase on an escalating schedule in 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 twice, and each dose is administered at two-week intervals, and the patient is monitored for toxicity before increasing the dose to the next level (See US Patent Application Publication No. 2011/0052559).

Hurler-Scheie disease (MPS I).

Hurler, Scheie and Hurler-Scheie disease, also known as MPS I, is caused by inactivation of alphaiduronidase and accumulation of dermatan sulfate and heparan sulfate. Several assays are available to monitor the progression of MPS I disease. For example, alpha-iduronidase enzyme activity can be monitored in tissue biopsy specimens or cultured cells obtained from peripheral blood. In addition, a useful measure of disease progression in MPS I is the urinary excretion of the glycosaminoglucans dermatan sulfate and heparan sulfate (see Neufeld et al., 1995, cited above). In a particular embodiment, the alpha-iduronidase enzyme is administered once a week as an intravenous infusion at a dosage of 0.58 mg/kg body weight.

Gunther's disease (MPS II).

Gunther's disease (also known as MPS II) is caused by inactivation of iduronate sulfatase and accumulation of dermatan sulfate and heparan sulfate. Gunther's disease is clinically presented in severe and moderate forms. The preferred therapeutic enzyme dosage regimen ranges from 1.5 mg/kg every two weeks to 50 mg/kg every week.

Morquio's disease (MPS IV).

Morquio syndrome (also known as MPS IV) results from the accumulation of keratan sulfate due to inactivation of either of the two enzymes. In MPS IVA, the inactivated enzyme is galactosamine-6-sulfatase, and in MPS IVB, the inactivated enzyme is beta-galactosidase. The preferred therapeutic enzyme dosage regimen ranges from 1.5 mg/kg every two weeks to 50 mg/kg every week.

Maroteaux-Lamy disease (MPS VI).

Maroteaux-Lamy syndrome (also known as MPS VI) is caused by inactivation of galactosamine 4sulfatase (arylsulfatase B) and accumulation of dermatan sulfate. The preferred dosing interval for the therapeutic enzyme offered by ERT is a dosing regimen of 1.5 mg/kg every two weeks to 50 mg/kg every week. Optionally, the dosage used is less than or equal to 10 mg/kg per week. The preferred replacement marker for MPS VI disease development is proteoglycan levels.

Pompe disease.

Pompe disease is caused by inactivation of the enzyme alpha-acid glucosidase and accumulation of glycogen. The gene for acid alpha-glucosidase is located on human chromosome 17 and is designated GAA. H.G. Hers first proposed the concept of congenital lysosomal disease based on his studies of the disease, which he classified as glycogen storage disease type II (GSD II), and which is now also called acid maltase deficiency (AMD) (see Hers, 1965, Gastroenterology, 48 , 625). In a particular embodiment, GAA is administered every 2 weeks as an intravenous infusion at a dosage of 20 mg/kg body weight.

Several tests are available to monitor the progression of Pompe disease. Any assay known to those skilled in the art may be used. For example, this could be an assay for intralysosomal accumulation of glycogen granules, particularly in the myocardium, liver, and biopsied skeletal muscle fibers. Alpha-glucosidase enzyme activity can also be monitored in biopsy specimens or cultured cells obtained from peripheral blood. An increase in serum creatine kinase (CK) can be monitored as an indicator of disease progression. Syvoro

- 28 046304 exact CK can increase up to tenfold in affected infants and usually increases to a lesser extent in affected adults. See Hirschhorn R., 1995, Glycogen Storage Disease Type II: Acid alpha-Glucosidase (Acid Maltase) Deficiency, In The Metabolic and Molecular Bases of Inherited Disease, Servier et al., eds., McGraw-Hill, N.Y., 7. sup.th ed., pages 2443-2464).

Enzyme replacement therapy.

The following sections provide specific disclosure and alternative embodiments suitable for the combination therapy component of the enzyme replacement therapy invention. In general, dosage regimens for the enzyme replacement therapy component of the combination therapy of the invention are generally determined by the medical practitioner. Some examples of dosage regimens for the treatment of Gauche disease with glucocerebrosidase are given above. The general principles for determining the dosage regimen for any given ERT component of the combination therapy of the invention for the treatment of LSD will be apparent to one skilled in the art from publicly available information, such as, for example, a review of the specific references cited in the sections on each specific LSD. ERT agents can be administered to the patient by intravenous infusion. Intracerebroventricular and/or intrathecal infusion can be used to administer ERT to a patient diagnosed with a lysosomal storage disease with CNS manifestations.

Any method known in the art can be used to make the enzymes used in the combination therapy component of the enzyme replacement therapy invention. Many such methods are known and include, but are not limited to, gene activation technology developed by Shire plc (see US Pat. No. 5,968,502 and 5,272,071).

Renal cysts occur in one third of the population over 50 years of age. Although the majority are simple cysts, cystic kidney disease has many etiologies. Broad categories of cystic disease include the following:

congenital - congenital cystic dysplasia;

genetic - autosomal recessive polycystic kidney disease (ARPKD), autosomal dominant polycystic kidney disease (ADPKD), nephronophthisis-medullary complex polycystic kidney disease (NMCD);

acquired - simple cysts, acquired cystic disease;

cysts associated with systemic disease - von Hippel-Lindau syndrome (VHLS), tuberous sclerosis (TS); and malignant - renal cell carcinoma (RCC).

The most common larger cysts are acquired cysts, simple cysts, and ADPKD cysts. Smaller cysts are associated with ARPKD, NMCD, and medullary spongiform kidney (MSK). In adults, renal angiomyolipomas and RCC may also show cystic lesions.

Polycystic kidney disease (PKD).

Polycystic kidney disease (PKD) describes some conditions in which fluid-filled cysts form in the kidneys. Cysts usually develop in weak segments of the tubules that carry urine from the glomeruli. Growing cysts crowd out healthy kidney tissue. The kidneys enlarge to accommodate the cyst, which can weigh ~9 kg (20 lb). There are several forms of PKD—both hereditary forms and non-hereditary forms.

Autosomal dominant PKD (ADPKD) is the most common inherited form. Symptoms of ADPKD usually develop between ages 30 and 40, but they can appear earlier, even during childhood. In approximately 90 percent of all cases, PKD is autosomal dominant PKD. ADPKD results from a mutation in the PKD1 gene, which encodes polycystin-1 (85% of cases), or the PKD2 gene, which encodes polycystin-1 (15% of cases).

Autosomal recessive PKD (ARPKD) is a rare inherited form. Symptoms of autosomal recessive PKD appear in the very first months of life, even in the uterus.

Acquired cystic kidney disease (ACKD) develops due to long-term kidney problems, especially in patients with kidney failure who have been on dialysis for a long time. Therefore, it tends to appear at a later age. It is not an inherited form of PKD.

Cystic kidney diseases include, but are not limited to, cystic kidney diseases such as acquired cystic kidney disease (ACKD), dialysis-associated cystic disease, autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), congenital polycystic kidney disease (CPKD) , polycystic dysplastic kidney, end-stage renal disease (ESRD), medullary sponge kidney MSK, nephronophthisnomedullary complex polycystic kidney disease (NMCD), nephronophthisno-uremic medullary complex cystic disease, juvenile nephronophthisis, medullary cystic disease, renal cell carcinoma (RCC), tuberous s sclerosis ( TS), von Hippel-Lindau syndrome (VHLS).

When PKD causes kidney failure, which usually occurs after a few years, the patient requires dialysis or a kidney transplant. In about half of patients with the main type of PKD, the disease progresses to kidney failure. PKD can cause cysts in the liver and problems with

- 29 046304 other organs such as the heart and blood vessels in the brain. Such complications distinguish PKD from the usually harmless simple cysts that often form in the kidneys later in life.

In the United States, approximately 600,000 people, and approximately 12.5 million people worldwide, have PKD, and it is a leading cause of kidney failure. Three factors determine the classification of cysts: their cause (acquired, hereditary), their features (complex, simple, multiple, isolated) and their location (external (cortical) or internal (medullary) tissue of the kidney).

There is no cure for PKD at this time. Treatment for PKD includes drugs and surgery to relieve pain, antibiotics to clear infections, dialysis to replace weak kidney function, and a kidney transplant. Therefore, there is a need to develop more effective treatments for PKD.

Conclusion.

In one embodiment, this disclosure provides methods for treating, alleviating, or preventing polycystic diseases. Cystic diseases include, but are not limited to, cystic kidney diseases such as acquired cystic kidney disease (ACKD), dialysis-associated cystic disease, autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), congenital polycystic kidney disease (CPKD), polycystic dysplastic kidney, end-stage renal disease (ESRD), medullary spongiform kidney (MSK), nephronophthisis-medullary complex polycystic kidney disease (NMCD), nephronophthisis-uremic medullary complex cystic disease, juvenile nephronophthisis, medullary cystic disease, renal cell carcinoma (RCC), tuberous sclerosis (TS), von Hippel-Lindau syndrome (VHLS). In one embodiment, methods are provided for treating, ameliorating, or preventing polycystic kidney disease.

Small molecule therapy.

The following section also provides specific disclosures and alternative embodiments suitable for the combination therapy component of the small molecule therapy invention. Drug dosage regimens for the small molecule therapy component of the combination therapy of the invention are typically determined by the attending physician and are expected to vary substantially depending on the particular storage disease being treated and the clinical condition of the particular disease-affected individual. The general principles for determining dosage regimens for a given SMT component of any combination therapy of the invention for the treatment of any storage disease are well known to one skilled in the art. Guidance on dosage regimens can be obtained from any of the many well-known literature sources on the topic. Guidance is also available from, among other things, a review of the specific references cited herein.

In general, the compounds of the present invention, such as, for example, (b)-quinuclidin-3-yl(2(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate and quinuclidin-3 - yl(2-(4'-fluoro[1,1'-biphenyl]-3 yl)propan-2-yl)carbamate can be used in the combination therapies of the invention to treat virtually any storage disease resulting from damage in the glycosphingolipid metabolic pathway (eg Gaucher disease, Fabry disease, GMj gangliosidosis and G _M2 gangliosidosis (eg activator deficiency, Tay-Sachs and Sandhoff disease)). Likewise, the combination therapies of the invention can use aminoglycosides (eg, gentamicin, G418) for an individual with any storage disease having an early stop codon mutation (ie, a nonsense mutation). Such mutations are especially prevalent in Hurler syndrome. The small molecule therapy component of the combination therapy of the invention is particularly preferred when there is a manifestation of the storage disease being treated in the central nervous system (eg, Sandhoff, Tay-Sachs, Niemann-Pick type A and Gaucher diseases types 2 and 3), as small molecules can generally cross the blood-brain barrier more easily compared to other therapies.

Preferred dosages of substrate inhibitors used in the combination therapy of the invention are readily determined by those skilled in the art. In some 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, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 and 60 mg/kg) when administered intraperitoneally, orally or equivalent one to five times a day. 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, when administered orally, intraperitoneally, or the equivalent, one to five times daily. In one embodiment, doses range from about 10 mg/day to about 500 mg/day (e.g., 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150 , 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300 mg/day). A particularly preferred oral dosage ranges from about 50 mg to about 100 mg, administered twice daily. A particularly preferred oral dosage range for a compound of the present invention is from about 5 mg/kg/day to about 600 mg/kg/day. In particular, the interval of oral

- 30 046304 doses for a compound of the present invention are from about 1 mg/kg/day to about 100 mg/kg/day, for example 1 mg/kg/day, 5, 10, 15, 20, 25, 30, 35, 40 , 45, 50, 55 or 60, 65, 70, 75, 80, 85, 90, 95 or 100 mg/kg/day.

An alternating combination of therapeutic platforms (ie, enzyme replacement therapy and small molecule therapy) is preferred. However, subjects can be treated when both approaches overlap if necessary, as determined by the treating physician. Examples of treatment regimens may include, but are not limited to, (1) SMT followed by ERT; (2) ERT followed by SMT; and (3) ERT and SMT performed at approximately the same time. As noted previously, time-overlapping therapeutic platforms can also be performed if necessary, depending on the clinical course of a given storage disease in a given subject.

Treatment intervals for different combination therapies can vary widely and may generally differ for different storage diseases and different individuals, depending on how aggressively the stored products accumulate. For example, storage product accumulation in Fabry disease may be slow compared to the rapid storage product accumulation in Pompe disease. Titration for a particular storage disease in a particular individual is performed by one skilled in the art by monitoring clinical signs of disease progression and treatment success.

The various macromolecules that accumulate in lysosomal storage diseases are not uniformly distributed but instead settle at certain preferred anatomical sites in each disease. However, an exogenously supplied enzyme is usually taken up by cells of the reticuloendothelial system and stored in the lysosomal compartment, where it acts to hydrolyze the accumulated substrate. In addition, cellular uptake of a therapeutic enzyme can be enhanced by certain techniques that enhance lysosomal targeting (see, for example, US Pat. No. 5,549,892, Fridman et al., assigned to Genzyme Corporation, which describes a recombinant glucocerebrosidase with improved pharmacokinetics due to the advantage of remodeled oligosaccharide side chains , recognized by cell surface mannose receptors, which undergo endocytosis and are transferred to liposomes).

With some treatments, some affected organs are better targets than others. In Fabry disease, for example, if ERT does not reach the kidneys sufficiently for satisfactory clinical outcome, SMT can be used to reduce substrate levels in the kidneys. As shown in Example 112 and FIG. 6B, SMT effectively reduces urinary levels of Gb3 (i.e., a substrate accumulated in Fabry disease patients) to a greater extent than ERT. It is believed that the kidneys are the main source of Gb3 in urine. On the contrary, Fig. 6B shows that ERT effectively reduces plasma Gb3 levels to a greater extent than SMT. Such results indicate that combination therapy of ERT and SMT provides a complementary therapeutic strategy that has an advantage in effectiveness and targets weaknesses associated with each therapy used separately. SMT also overcomes VVA, providing a potent approach when combined with ERT to treat LSD with CNS manifestations, such as NiemannPick disease type A and neuropathic Gaucher disease (nGD). In addition, SMT substrate reduction combined with enzyme replacement addresses the problem of storage at separate and distinct sites in the veins, which may enhance clinical outcome.

It should be understood that reference to the co-administration or simultaneous administration of agents of two or more therapies does not require that they be administered at the same time, but only that they act in the body of the subject at the same time.

General procedure A. Preparation of trisubstituted urea through a primary amine component with an Nbutoxycarbonyl group

To a solution of the primary amine component (1 equivalent) in chloroform (concentration ~0.1 M), 4-dimethylaminopyridine (0.1 equivalent) and di-tert-butyl dicarbonate (1 equivalent) are added with stirring. The mixture is stirred for 1 hour and then the secondary amine component (1 equivalent) is added and refluxed overnight. The reaction mixture is then concentrated and the residue is purified by preparative HPLC.

General procedure B. Preparation of tetrasubstituted urea with phosgene.

To a solution of triphosgene (0.7 equivalent) in toluene (~0.7 M), a solution of the first amine component (1 equivalent) in chloroform (~0.5 M) is added with stirring. The reaction mixture is stirred for 2 hours and then concentrated. The residue is dissolved in chloroform (~0.3 M) and the solution is cooled (0°C). While stirring, add the second amine component (1.1 equivalents) and triethylamine (2 equivalents) in order. The reaction mixture is stirred overnight and then concentrated. The residue is dissolved in an aqueous sodium carbonate solution and extracted with chloroform. The combined extracts are dried (Na ₂ SO ₄ ) and concentrated. The crude material is purified by preparative HPLC or reverse phase flash chromatography on C18 silica.

General Procedure C. Preparation of a tricarbamate via an amine component with an Nbutoxycarbonyl group.

- 31 046304

Methyl chloroformate (3 equivalents) is added to a solution of the secondary amine component (1 equivalent) and triethylamine (4 equivalents) in methylene chloride (~0.2 M) with stirring and cooling (0°C). The reaction mixture is warmed to room temperature and stirred for 6 hours. The reaction solution is then washed with aqueous sodium bicarbonate, dried (Na ₂ SO ₄ ) and concentrated. The crude methyl carbamate is used without purification in the next step. To a solution of this intermediate (1 equivalent) in toluene (~0.2 M) add in order 4A activated molecular sieves, alcohol component (1.4 equivalents) and sodium hydride (60% dispersion in mineral oil; 0.25 equivalents) . The reaction mixture is refluxed overnight, filtered and concentrated. The residue is purified by flash reverse phase chromatography on C18 silica.

General Procedure D. Preparation of amide using N(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride.

To a solution of the carboxylic acid component (1 equivalent) in N,N-dimethylformamide (~0.1 M), with stirring, add the amine component (1.1 equivalents), N,N-diisopropylethylamine (2.2 equivalents), hydrochloride No. (3 -dimethylaminopropyl)-N-ethylcarbodiimide (1.1 equivalents) and 1-hydroxybenzotriazole hydrate (1.1 equivalents). Stirring is continued overnight, and then the reaction solution is diluted with water and extracted with chloroform. The combined extracts are dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by preparative HPLC.

General procedure E. Preparation of amide using O-(7-azabenzotriazol1 -yl)-KKH'.H'-tetramethyluronium hexafluorophosphate.

To a solution of the carboxylic acid component (1.1 equivalents) in N,N-dimethylformamide (~0.25 M) with stirring, add the amine component (1 equivalent) and hexafluorophosphate O-(7-azabenzotriazol-1-yl)-H,H ^,N-tetramethyluronium (1.1 equivalents). The mixture is cooled (0°C) and treated by adding triethylamine (2.2 equivalents) dropwise. The reaction mixture is warmed to room temperature, stirred overnight and then concentrated. The residue is dissolved in an aqueous sodium carbonate solution and extracted with ethyl acetate. The combined organic layers are dried (Na ₂ SO ₄ ) and concentrated, and the crude material is purified by flash chromatography on silica using chloroform/methanol/ammonia eluent.

General Procedure F. Biaryl coupling using Suzuki conditions.

To a solution of the aryl halide component (1 equivalent) in a mixture of 5:1 (v/v) dioxane/water (~0.15 M) or 5:1 (v/v) dioxane/Ni-dimethylformamide (~0. 15 M) with stirring, add the arylboronate or arylboronic acid component (1-1.5 equivalents), sodium carbonate (2-3 equivalents) and [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(11) (0.05 equivalents) . The mixture is heated (90°C) overnight and then filtered through a pad of celite. The celite is washed with ethyl acetate and the combined filtrate is washed with brine, dried (Na2SO4) and concentrated. The residue is purified by flash chromatography on silica.

General Procedure G. Deprotection of the tert-butoxycarbonylamino group with trifluoroacetic acid.

Trifluoroacetic acid (20-50 equivalents) is added to a solution of the starting material with a tert-butoxycarbonyl-protected amino group in dichloromethane (~0.15 M) with stirring. The reaction mixture is stirred at room temperature until TLC monitoring indicates completion of the reaction (usually 30-120 minutes). The reaction mixture is concentrated and the residue is dissolved in an aqueous sodium hydroxide solution and extracted with ethyl acetate. The combined extracts are washed with brine, dried (Na ₂ SO ₄ ) and concentrated to provide a product that can be used without purification, or optionally subjected to flash chromatography on silica.

General Procedure H. Preparation of urea/carbamate using isocyanate prepared by the mixed anhydride/Curtius rearrangement process.

Triethylamine (2 equivalents) is added to a solution of the carboxylic acid component (1 equivalent) in tetrahydrofuran (~0.1 M) with stirring. The reaction mixture is cooled (0°C) and treated with isobutyl chloroformate (1.5 equivalents). After 1 hour at 0°C, a solution of sodium azide (2 equivalents) in water (~1 M) is added and the reaction mixture is warmed to room temperature. After stirring overnight, the reaction mixture is diluted with water and extracted with ethyl acetate. The combined extracts are washed with aqueous sodium bicarbonate, dried (Na ₂ SO ₄ ) and concentrated. The crude acyl azide is further dried by co-evaporation with toluene and then dissolved in toluene (~0.1 M). The solution, while stirring, is refluxed for 2-2.5 hours, cooled and treated with either an amine component (1-1.5 equivalents) or an alcohol component (1.25-2 equivalents). The reaction mixture is refluxed overnight and then concentrated. The residue is dissolved in either ethyl acetate or chloroform and washed with aqueous sodium carbonate solution, dried (Na2SO4) and concentrated. The crude product is purified by silica flash chromatography using gradient solvent mixtures of chloroform/methanol (less polar carbamates) or chloroform/methanol/ammonia (more polar carbamates).

General Procedure I. Preparation of Urea/Carbamate Using Isocyanate Prepared

- 32 046304 by the diphenylphosphoryl azide/Curtius rearrangement method.

Triethylamine (2.5 equivalents) and diphenylphosphoryl azide (1.25 equivalents) are added to a solution of the carboxylic acid component (1 equivalent) in toluene (~0.25 M) with stirring. The mixture is refluxed for 30 minutes and then cooled to room temperature. The amine or alcohol component (1.2-1.5 equivalents) is added and the reaction mixture is refluxed for a further 3-18 hours (less time for ureas, more time for carbamates). At the end of the specified time, the reaction mixture is concentrated and the residue is treated with ethyl acetate and an aqueous solution of sodium carbonate. The organic layer is dried (Na ₂ SO ₄ ) and concentrated, and the resulting crude product is purified by reverse phase flash chromatography on silica using a water/acetonitrile solvent gradient.

General Procedure J. Preparation of urea/carbamate using isocyanate prepared with phosgene.

To a solution of the benzylamine component (1 equivalent) in toluene (~0.2 M), a 1.9 M solution of phosgene in toluene (4 equivalents) is added with stirring. The reaction mixture is refluxed for 4 hours and then concentrated. When the target is urea, the crude isocyanate is dissolved in chloroform (~0.2 M), treated with the secondary amine component and stirred overnight at room temperature. In the case where the target is a carbamate, the crude isocyanate is dissolved in toluene (~0.2 M), treated with the alcohol component and refluxed overnight. The urea or carbamate reaction solution is then concentrated and the residue is treated with an aqueous solution of sodium carbonate and chloroform. The organic solution is dried (Na2SO4) and concentrated. The crude product is purified by flash silica chromatography using gradient solvent mixtures of chloroform/methanol (less polar carbamates) or chloroform/methanol/ammonia (more polar carbamates).

Preparative example A.

Intermediate connection 1.

-Methylquinuclidine-3-amine.

With thorough stirring, a 3.0 M solution of methyllithium in diethyl ether (67.0 ml, 201 mmol) is diluted with more diethyl ether (150 ml), cooled to -78°C and treated by dropwise adding a solution of quinuclidin-3-one (12 .5 g, 100 mmol) in diethyl ether (100 ml). The resulting solution was kept at -78°C for 1 hour and then warmed to room temperature. After stirring overnight, the reaction solution is cooled again (0°C) and worked up by adding water (60 ml) dropwise. The mixture was concentrated and the resulting residue was purified by flash chromatography on neutral alumina using a chloroform/methanol gradient (0-20% methanol) to give 3-methylquinuclidin-3-ol (10.0 g, 71%) as light yellow solid matter. Concentrated sulfuric acid (100 ml) is gradually added to acetonitrile (250 ml) at 0°C with stirring. The resulting solution at 0°C was added dropwise to a mixture of 3-methylquinuclidin-3-ol (9.10 g, 64.5 mmol) and acetonitrile (250 ml). The reaction mixture is stirred at room temperature for 60 hours, cooled (0°C) and then made alkaline (pH~10) with an aqueous solution of sodium hydroxide. The mixture was extracted with chloroform/isopropanol 5:1 (v/v). The combined organic layers are concentrated and the residue is diluted with 2N. hydrochloric acid, after washing with a mixture of chloroform/isopropanol, 5:1 (v/v), the aqueous layer is made alkaline with 2N. aqueous sodium hydroxide solution and extracted with a mixture of chloroform/isopropanol, 5:1 (v/v). The combined organic layers were washed with water, dried (Na ₂ SO ₄ ) and concentrated to give N(3-methylquinuclidin-3-yl)acetamide as a light yellow oil (9.59 g, 82%). A solution of the acetamide intermediate obtained above (9.50 g, 52.0 mmol) in concentrated hydrochloric acid (100 ml) was refluxed for 3 days. After cooling in an ice bath, the reaction mixture is treated with an aqueous solution of sodium hydroxide in an amount sufficient to achieve a pH of ~1. The mixture is washed with chloroform/isopropanol, 5:1 (v/v). Then the aqueous layer is made alkaline with 2N. aqueous sodium hydroxide solution and extracted with a mixture of chloroform/isopropanol, 5:1 (v/v). The combined extracts were washed with water, dried (Na ₂ SO ₄ ) and concentrated to give the title compound as a light yellow semi-solid (5.00 g, 69%). ^1H NMR (500 MHz, DMSO-De) δ 2.72-2.39 (m, 6H), 2.01-1.96 (m, 1H), 1.671.61 (m, 1H), 1.43 -1.36 (m, 2H), 1.23-1.17 (m, 1H), 1.09 (s, 3H) ppm ¹³ C NMR (125 MHz, DMSO-D6) δ 65.3, 48.3, 46.6, 46.4, 34.2, 30.0, 24.8, 22.8 ppm.

Preparative example B.

Intermediate 2.

-Ethylquinuclidine-3-amine.

A cooled (0°C) 0.5 M solution of ethyl lithium in a benzene/cyclohexane mixture (100 ml, 50 mmol), with thorough stirring, is diluted with tetrahydrofuran (50 ml) and treated by adding a solution of quinuclidin-3-one ( 3.13 g, 25.0 mmol) in tetrahydrofuran (20 ml). After 2 hours, the cooling bath is removed and the reaction mixture is stirred overnight. The reaction is quenched by gradually adding water (10 ml). The resulting mixture is concentrated on silica and purified

- 33 046304 flash chromatography on silica using chloroform/methanol/ammonia as an eluent to obtain 3-quinuclidin-3-ol as an amber waxy solid (2.43 g, 63%). To a solution of the resulting product (2.31 g, 14.9 mmol) in acetonitrile (20 ml) with stirring and cooling (0°C) was added dropwise concentrated sulfuric acid (40 ml) over ~20 min. The mixture is stirred overnight and gradually warmed to room temperature. The reaction mixture is then poured into crushed ice. While stirring, concentrated ammonium hydroxide (~110 ml) is gradually added (final pH ~10). The solution is extracted with chloroform/isopropanol 4:1 (v/v) and the combined extracts are dried (Na ₂ SO ₄ ) and concentrated on silica. The crude product was purified by flash chromatography using a chloroform/methanol/ammonia gradient to give N(3-ethylquinuclidin-3-yl)acetamide as an amber waxy solid (2.16 g, 74%). A solution of the resulting product (5.48 g, 28.0 mmol) in a mixture of water (60 ml) and concentrated hydrochloric acid (60 ml) was refluxed for 3 days. At the end of this time, the solution was concentrated to give the dihydrochloride of the title compound as a light brown solid (4.75 g, 75%) which was used without purification. ¹ H NMR (400 MHz, CD3OD) δ 3.65-3.55 (m, 2H), 3.52-3.27 (m, 4H), 2.51-2.45 (m, 1H), 2 .27-2.00 (m, 6H), 1.06 (t, J=7.5 Hz, 3H) ppm. In the reaction where liberation of the free base is required, triethylamine is added to the dihydrochloride salt in an equimolar amount. Alternatively, the product can be isolated as the free base by dissolving the dihydrochloride in aqueous sodium hydroxide and extracting with chloroform/isopropanol 4:1 (v/v). After drying (Na ₂ SO ₄ ), the combined extracts are concentrated to give the product as a pale amber oil. 1H NMR (400 MHz, CD3OD) δ 2.94-2.84 (m, 1H), 2.83-2.55 (m, 5H), 2.05-1.94 (m, 1H), 1, 83-1.73 (m, 1H), 1.73-1.60 (m, 2H), 0.91 (t, J=7.4 Hz, 3H) ppm.

Preparative example C.

Intermediate 3.

- Azabicyclo [3.2.2] nonan-4-ol.

A cooled (0°C) 2.0 M solution of trimethylsilyldiazomethane in hexane (43.9 ml, 87.9 mmol) was treated with stirring by adding dropwise a solution of 3-quinuclidinone (10.0 g, 79.9 mmol) in THF (80 ml). Methanol (44 ml) was added and the reaction mixture was stirred overnight and allowed to warm to room temperature. The reaction mixture is then treated with acetic acid (1.0 ml). After a few minutes, saturated aqueous sodium carbonate (40 ml) was added and the layers were separated. The organic layer is combined with the other ethyl acetate extracts, dried (Na ₂ SO ₄ ) and concentrated. The resulting yellow oil was purified by flash chromatography on neutral alumina using methylene chloride/methanol as eluent to give 1-azabicyclo[3.2.2]nonan-4-one as a white solid (6.80 g, 61%). To a solution of the resulting product (6.80 g, 48.8 mmol) in tetrahydrofuran (100 ml) was added portionwise lithium aluminum hydride (1.85 g, 48.8 mmol) with stirring and cooling (0°C). After the rapid evolution of hydrogen gas has stopped, the reaction mixture is heated to room temperature and then refluxed for 1 hour. Then the solution is cooled (0°C) and quenched by sequentially adding dropwise water (1.8 ml), 10% hydroxide solution sodium (1.8 ml) and again water (5.5 ml). The colorless precipitated substance is removed by filtration through celite, which is then washed with tetrahydrofuran. The combined filtrate was dried (Na ₂ SO ₄ ) and concentrated to give the title compound as a white solid (5.60 g, 81%). ^1H NMR (400 MHz, CDCl3) δ 3.90-3.86 (m, 1H), 3.09-3.03 (m, 1H), 2.96-2.91 (dd, J=9, 2, 6.8 Hz, 1H), 2.86-2.75 (m, 3H), 2.71-2.64 (m, 1H), 2.34-2.27 (br.s, 1H) , 1.98-1.86 (m, 3H), 1.71-1.59 (m, 3H), 1.51-1.35 (m, 1H) ppm.

Preparative example D.

Intermediate 4.

1-Azabicyclo[3.2.2]nonane-4-amine.

To a solution of 1-azabicyclo[3.2.2]nonan-4-one (Preparative Example C) (10.0 g, 71.8 mmol) in isopropanol (50 ml) add sodium acetate (11.80 g, 143, 7 mmol) and hydroxylamine hydrochloride (5.50 g, 79.1 mmol). The mixture is refluxed for 3 hours and then cooled to room temperature. The reaction mixture was filtered and concentrated to give the oxime intermediate as a white solid (11.00 g, 99%), which was used in the next step without purification. A solution of the resulting product (11.0 g, 71.3 mmol) in n-propanol (120 ml) is heated to reflux temperature with stirring, and sodium metal (16.5 g, 718 mmol) is added in portions over 30 min. Boiling is continued overnight and then the reaction mixture is cooled to room temperature and treated with brine (20 ml). The mixture is extracted with npropanol (2x50 ml) and the combined organic layers are concentrated. The residue is diluted with chloroform and the remaining solid is filtered off. The filters were dried (Na ₂ SO ₄ ) and concentrated to give the title compound as a light yellow semi-solid (6.70 g, 74%). 1H NMR (500 MHz, CDC'h) δ 3.17-3.13 (m, 1H), 3.10-3.07 (m, 1H), 3.05-3.01 (m, 1H), 2.91-2.88 (m, 3H), 2.772.70 (m, 1H), 1.92-1.87 (m, 1H), 1.83-1.80 (m, 1H), 1. 71-1.68 (m, 3H), 1.59-1.48 (m, 2H), 1.33 (brs, 2H) ppm.

- 34 046304

Preparative example E.

Intermediate 5.

4-Methyl-1-azabicyclo[3.2.2]nonane-4-amine.

The title compound was prepared from 1-azabicyclo[3.2.2]nonan-4-one (Preparative Example C) by the same procedure used to convert quinuclidin-3-one to 3methylquinuclidin-3-amine in Preparative Example A. 1H NMR (500 MHz, DMSO-d ₆ ) δ 2.84-2.65 (m, 6H), 2.01-1.97 (m, 1H), 1.69-1.24 (m, 8H), 1 .09 (s, 3H) ppm

Preparative example F.

Intermediate 6.

1,4-Diazabicyclo[3.2.2]nonane.

Lithium aluminum hydride was added to a solution of 1,4-diazabicyclo[3.2.2]nonan-3-one (1.00 g, 7.13 mmol) in 1,4-dioxane (7.2 ml) with stirring at room temperature [2 .0 M/THF] (4.1 ml, 8.2 mmol). Then the reaction mixture is refluxed for 6 hours. After cooling to room temperature, the reaction is quenched by successively adding water (200 ml), 15% aq.

The mixture is filtered through celite, which is then washed with ethyl acetate. The combined filtrate was concentrated to give the title compound as a light brown solid (0.82 g, 90%) which was used without purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.28-3.25 (m, 1H), 2.99-2.95 (m, 8H), 1.86-1.80 (m, 3H), 1.69-1.64 (m, 2H) ppm

Preparative example G.

Intermediate 7.

- Azabicyclo [3.2.2] nonan-3-ol.

To a solution of ethyl 2-hydroxyacetate (20.0 g, 19.0 mmol) in tetrahydrofuran (250 ml) add tetrabutylammonium iodide (7.01 g, 19.0 mmol) and sodium hydride with stirring and cooling (0°C). (60% in mineral oil, 7.00 g, 19.0 mmol). The mixture was stirred at 0°C for 30 min and then benzyl bromide (32.3 g, 19.0 mmol) was added. The reaction mixture is stirred overnight and warmed to room temperature. The mixture is then cooled (0°C), quenched with aqueous ammonium chloride (100 ml) and extracted with ethyl acetate. The combined organic layers are washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash silica chromatography using hexane/ethyl acetate to give ethyl 2-(benzyloxy)acetate as a yellow oil (14.7 g, 57%). To a solution of the resulting product (13.6 g, 70.0 mmol) in tetrahydrofuran (150 ml), dimethyl methylphosphonate (11.3 g, 91.1 mmol) was added with stirring and cooling (0°C), followed by a 2.0 M solution lithium diisopropylamide in tetrahydrofuran/heptane/ethylbenzene (74.0 ml, 148 mmol). The reaction mixture is stirred at 0°C for 3 hours and then quenched with 5.0 M hydrochloric acid in an amount sufficient to bring it to pH ~ 4. The resulting mixture is then extracted with ethyl acetate. The combined organic layers are washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash silica chromatography using hexane/ethyl acetate to give dimethyl (3-(benzyloxy)-2-oxopropyl)phosphonate as a light yellow oil (10.1 g, 54%). To a solution of the resulting intermediate (9.89 g, 36.4 mmol) in tetrahydrofuran (100 ml) was added sodium hydride (60% in mineral oil, 1.60 g, 40.0 mmol) with stirring and cooling (0°C). ). The mixture was stirred at 0°C for 30 minutes and then a solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.79 g, 29.1 mmol) in tetrahydrofuran (50 ml) was added dropwise. 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 are washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography on silica using hexane/ethyl acetate to give tert-butyl 4-(3-(benzyloxy)-2oxopropylidene)piperidine-1-carboxylate as a light yellow oil (6.50 g, 52 %). The resulting material (6.50 g, 18.8 mmol), 10% Pd/C (1.00 g) and ethyl acetate (50 ml) were placed in a Parr flask and hydrogenated for 5 hours at room temperature. The mixture was filtered through celite and concentrated to give tert-butyl 4-(3-(hydroxy-2-oxopropyl)piperidine-1-carboxylate as a yellow oil (4.80 g, 99%). To a solution of the resulting product (4, 80 g, 18.7 mmol) in methylene chloride (8 ml), carbon tetrabromide (12.4 g, 37.4 mmol) and triphenylphosphine (9.80 g, 37.4 mmol) are added with stirring. After 3 hours, the reaction mixture is concentrated. The residue was purified by flash chromatography on silica using hexane/ethyl acetate to give tert-butyl 4-(3-bromo-2-oxopropyl) piperidine 1-carboxylate as a white solid (3.30 g, 56%) Trifluoroacetic acid (12.0 ml, 145 mmol) was added to a solution of the resulting product (3.30 g, 10.3 mmol) in methylene chloride (50 ml) with stirring and cooling (0°C). The mixture was stirred at 0°C. for 30 min and then concentrated to give crude 1-bromo-3-(piperidin-4-yl)acetone trifluoroacetate, which was used in the next step without purification. To a solution of diisopropylethylamine (20 ml) in acetonitrile (800 ml) with stirring. While refluxing, add a solution of the crude intermediate in acetonitrile (150 ml) dropwise over 4 hours (syringe pump). Refluxing is continued overnight and the mixture is then concentrated. Resulting balance

- 35 046304 is treated with an aqueous solution of potassium carbonate and a mixture of chloroform/methanol, 9:1 (v/v). The organic layer is combined with the second extract using the same solvent mixture, dried (Na ₂ SO ₄ ) and concentrated. The crude material is purified by flash chromatography on silica using chloroform/methanol/ammonium hydroxide, 95/4.5/0.5 (v/v) to give 1azabicyclo[3.2.2]nonan-3-one in as a brown solid (770 mg, 54%). To a solution of the resulting intermediate (770 mg, 5.54 mmol) in tetrahydrofuran (10 ml) was added portionwise lithium aluminum hydride (211 mg, 5.54 mmol) with stirring and cooling (0°C). After the rapid evolution of hydrogen gas has stopped, the reaction mixture is heated to room temperature and then refluxed for 1 hour. The solution is cooled to 0°C and quenched by sequentially adding dropwise water (0.2 ml), 10% aqueous sodium hydroxide solution (0.2 ml) and again water (0.6 ml). The precipitated colorless substance is removed by filtration through celite, which is then washed with tetrahydrofuran. The combined filtrate was dried (Na2SO4) and concentrated to give the title compound as a yellow solid (770 mg, 99%).

Preparative example N.

Intermediate 8.

- Azabicyclo[3.2.2]nonane-3-amine.

The title compound is prepared from 1-azabicyclo[3.2.2]nonan-3-one (Preparative Example G) by the same procedure used to convert 1-azabicyclo[3.2.2]nonan-4-one to 1-azabicyclo[ 3.2.2]nonane-4-amine in Preparative Example D.

Preparative example I.

Intermediates 9, 10.

Enantiomers of 4-methyl-1-azabicyclo[3.2.2]nonane-4-amine.

Racemic N(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)acetamide (Preparative Example E) is resolved into its constituent enantiomers using a Thar SFC Prep 80 instrument and the following separation conditions: CHIRALCEL OZ-H column ( 30x250 mm, particle size 5 mm) with a mobile phase carbon dioxide/acetonitrile/isopropanol/diethylamine (55/30/15/0.2) and a flow rate of 60 g/min. Enantiomers elute at 6.34 and 9.55 minutes. Using the acetamide hydrolysis conditions described in Preparation A, the early eluting isomer was deacetylated to yield intermediate 9 and the later eluting isomer was deacetylated to yield intermediate 10. The absolute stereochemistry of the enantiomers was not determined.

Preparative example J.

Intermediates 11, 12.

Enantiomers of 3-methylquinuclidine-3-amine.

Racemic N(3-methylquinuclidin-3-yl)acetamide (Formulation A) is resolved into its constituent enantiomers using a Thar SFC Prep 80 instrument and the following separation conditions: CHIRALCEL IC-H column (30x250 mm, particle size 5 μm) with a moving carbon dioxide/isopropanol/diethylamine phase (50/50/0.1) and a flow rate of 60 g/min. Enantiomers elute at 3.12 and 8.17 min. Using the acetamide hydrolysis conditions described in Preparation A, the early eluting isomer was deacetylated to yield intermediate 11 and the late eluting isomer was deacetylated to yield intermediate 12. Intermediate 12 was then amide coupled (general procedure D) with ^)- (+)-2-phenylpropionic acid to obtain the separate enantiomer (2S)-N-(3-methylquinuclidin-3-yl)-2-phenylpropanamide. A crystal of such a compound is obtained and subjected to X-ray diffraction and the amide is found to be in the (2'R,3S) configuration. Thus, intermediate 11 is determined to be (S)(3-methylquinuclidine-3-amine and intermediate 12 is (R)-(3methylquinuclidine-3-amine.

Preparative example K.

Intermediates 13, 14.

Enantiomers of 3-ethylquinuclidine-3-amine.

Racemic Na(3-ethylquinuclidin-3-yl)acetamide (Formulation B) is resolved into its constituent enantiomers using a Thar SFC Prep 80 instrument and the following separation conditions: CHIRALCEL IC-H column (30x250 mm, particle size 5 μm) with a moving carbon dioxide/ethanol/diethylamine phase (60/40/0.2) and a flow rate of 80 g/min. Enantiomers elute at 3.31 and 4.70 minutes. Using the acetamide hydrolysis conditions described in Preparation A, the earlier eluting isomer was deacetylated to yield intermediate 13 and the later eluting isomer was deacetylated to yield intermediate 14. The absolute stereochemistry of the enantiomers was not determined.

Preparative example L.

Intermediates 15, 16.

Enantiomers of 1-azabicyclo[3.2.2]nonan-4-ol.

Racemic 1-azabicyclo[3.2.2]nonan-4-ol solution (Preparative Example C; 23.0 g, 16.3

- 36046304 mmol) in acetic anhydride (100 ml) is refluxed with stirring for 1 hour. The mixture is concentrated and the residue is dissolved in aqueous sodium bicarbonate and extracted with a mixture of chloroform/isopropanol, 5:1 (v/v) . The combined extracts are washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give 1-azabicyclo[3.2.2]nonan-4-ylacetate. The resulting material is resolved into its constituent enantiomers using a Thar SFC Prep 80 instrument and the following separation conditions: CHIRALCEL OZ-H column (30x250 mm, particle size 5 μm) with a mobile phase (carbon dioxide/acetonitrile/isopropanol/)diethylamine (55/30 /15/0.2) and a flow rate of 60 g/min. The acetate enantiomer, eluted later (11.0 g, 60.0 mmol), is dissolved in 2N. aqueous sodium hydroxide solution. The mixture is heated with stirring at 50°C for 1 hour, then cooled and extracted with a mixture of chloroform/isopropanol, 5:1 (v/v). The combined extracts were washed with brine, dried (Na2SO4) and concentrated to give intermediate 16 as a light yellow solid (8.00 g, 94%).

The previously eluted acetate isomer is deprotected in the same manner to yield intermediate 15. The absolute stereochemistry of the enantiomers is not determined.

Preparative example M.

Intermediate 17.

3-Propylquinuclidin-3-amine dihydrochloride.

With stirring and cooling (0°C), a 2.0 M solution of propylmagnesium chloride in diethyl ether (100 ml, 200 mmol) is diluted with tetrahydrofuran (150 ml) and treated by adding a solution of quinuclidin-3-one (13, 45 g, 107.5 mmol) in tetrahydrofuran (90 ml). The cooling bath allows gradual warming to room temperature and the mixture is stirred overnight. Then the reaction mixture is refluxed for 30 minutes, cooled (0°C) and quenched by gradually adding water (60 ml). The mixture was concentrated to remove the organic solvent, diluted with aqueous ammonium chloride (250 ml) and extracted with chloroform/isopropanol 4:1 (v/v). The combined extracts are dried (Na ₂ SO ₄ ) and concentrated on silica. Flash silica chromatography using a chloroform/methanol/ammonia gradient gave 3-propylquinuclidin-3-ol as a white solid (5.57 g, 31%). To a solution of the resulting product (5.55 g, 32.8 mmol) in acetonitrile (30 ml) was added dropwise concentrated sulfuric acid (40 ml) over 15 min with stirring and cooling (0°C). The cooling bath allows gradual warming to room temperature and the mixture is stirred overnight. The reaction mixture is then poured into crushed ice. The resulting slurry with ice is stirred and concentrated ammonium hydroxide (100 ml) is gradually added. After the ice has completely melted, the mixture is extracted with chloroform/isopropanol, 4:1 (v/v). The combined extracts are dried (Na2SO4) and concentrated on silica. Flash chromatography using a chloroform/methanol/ammonia gradient gave N-(3propylquinuclidin-3-yl) acetamide as a faint amber resin (6.94 g, 100%). A solution of the resulting product (6.94 g, 32.8 mmol) in a mixture of water (90 ml) and concentrated hydrochloric acid (90 ml) was refluxed for 4 days. At the end of this time, the solution was concentrated to give the title compound as a white solid (6.44 g, 81%) which was used without purification. In reactions where liberation of the free base is required, triethylamine is added in an equimolar amount to the dihydrochloride salt. 1H NMR (400 MHz, DMSO-de) δ 11.27 (brs, 1H), 8.91 (brs, 3H), 3.52-3.30 (m, 2H), 3.28- 3.06 (m, 4H), 2.35-2.24 (m, 1H), 2.24-2.08 (m, 1H), 1.97-1.71 (m, 5H), 1. 48-1.21 (m, 2H), 0.89 (t, J=7.1 Hz, 3H) ppm

Example 1.

4-([1,1'-Biphenyl]-4-yl)-I-(3-methylquinuclidin-3-yl)piperazin-1-carboxamide.

Using General Procedure A and reacting 1-([1,1'-biphenyl]-4yl)piperazine and intermediate 1, the title compound was obtained. 1H NMR (500 MHz, DMSO-d ₆ ) δ 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, J=7.5 Hz, 1H), 7.05 (d, J=8.5 Hz, 2H), 5.99 (s, 1H) , 3.44 (t, J=5.0 Hz, 4H), 3.15 (t, J=5.0 Hz, 4H), 2.96-2.93 (m, 1H), 2.67- 2.57 (m, 5H), 2.12-2.11 (m, 1H), 1.75-1.64 (m, 2H), 1.41-1.23 (m, 5H) ppm . ¹³ C NMR (125 MHz, CDC'h) 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. LCMS purity >99% (214 and 254 nm); retention time 1.99 min; (M+H+) 405.3.

Example 2.

4-([1,1'-Biphenyl]-4-yl)-N-(quinuclidin-3-yl)piperazin-1-carboxamide.

Using General Procedure A and reacting 1-([1,1'-biphenyl]-4yl)piperazine and quinuclidine-3-amine, the title compound was obtained. 1H NMR (500 MHz, CDCl3) δ 7.57-7.52 (m, 4H), 7.41 (t, J=8.0 Hz, 2H), 7.29 (t, J=7.5 Hz , 1H), 7.00 (d, J=8.5 Hz, 2H), 4.61 (s, 1H), 3.88 (m, 1H), 3.57 (t, J=5.0 Hz , 4H), 3.41-3.36 (m, 1H), 3.26 (t, J=5.0 Hz, 4H), 2.90-2.80 (m, 4H), 2.53- 2.50 (m, 1H), 1.95-1.94 (m, 1H), 1.74-1.66 (m, 3H), 1.49 (m, 1H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) 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. LCMS purity >99% (214 and 254 nm); retention time 1.44 min; (M+H+) 391.2.

- 37 046304

Example 3.

4-([1.1'-Biphenyl|-4-yl)^-(1-azabicyclo[3.2.2|nonan-4-yl)piperazin-1-carboxamide.

Using General Procedure A and reacting 1-([1,1'-biphenyl]-4yl)piperazine and intermediate 4, the title compound was obtained. 1H NMR (500 MHz, CDCl ₃ ) 7.56-7.52 (m, 4H), 7.41 (t, J=8.0 Hz, 2H), 7.29 (t, J=8.0 Hz , 1H), 7.00-6.98 (d, J=9.0 Hz, 2H), 4.50 (d, J=7.0 Hz, 1H), 4.01-3.96 (m, 1H), 3.55 (t, J=5.0 Hz, 4H), 3.25 (t, J=5.0 Hz, 4H), 3.19-2.76 (m, 6H), 2, 05-1.57 (m, 7H) ppm ¹³ C NMR (125 MHz, CDCl ₃ ) 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. LCMS purity >98% (214 and 254 nm); retention time 1.45 min; (M+H+) 405.2.

Example 4.

4-([1,G-Biphenyl]-4-yl)-N(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperazin-1-carboxamide.

Using General Procedure A and reacting 1-([1,1'-biphenyl]-4yl)piperazine and intermediate 5, the title compound was obtained. ¹ H NMR (500 MHz, CDCl3) δ 7.56-7.52 (m, 4H), 7.41 (t, J=7.5 Hz, 2H), 7.29 (t, J=7.5 Hz, 1H), 7.00-6.98 (d, J=8.5 Hz, 2H), 4.40 (s, 1H), 3.54-3.26 (m, 4H), 3.25 -3.02 (m, 4H), 3.00-2.81 (m, 6H), 2.39-2.37 (m, 1H), 2.17 (m, 1H), 1.96-1 .51 (m, 8H) ppm ¹³ C NMR (125 MHz, CDCl3) 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. LCMS purity >98% (214 and 254 nm); retention time 1.29 min; (M+H+) 419.2.

Example 5.

4-([1,1'-Biphenyl]-4-yl)piperazin-1-yl)(1,4-diazabicyclo[3.2.2]nonan-4-yl)methanone.

Using General Procedure B and reacting 1-([1,1'-biphenyl]-4yl)piperazine and intermediate 6, the title compound was obtained. 'H NMR (400 MHz, CDCl ₃ ) δ 7.57-7.52 (m, 4H), 7.40 (t, J=8.0 Hz, 2H), 7.28 (t, J=7, 2 Hz, 1H), 7.01-6.98 (d, J=8.8 Hz, 2H), 4.12-4.11 (m, 1H), 3.52 (t, J=6.0 Hz, 2H), 3.38-3.36 (m, 4H), 3.25-3.23 (m, 4H), 3.07-2.96 (m, 6H), 2,072.00 (m, 2H), 1.80-1.72 (m, 2H) ppm. ¹³ C NMR (100 MHz, CDCl ₃ ) δ 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. LCMS purity >99% (214 and 254 nm); retention time 1.26 min; (M+H+) 391.2.

Example 6.

Quinuclidin-3 -yl-4 -([1,1'-biphenyl]-4 -yl)piperazine-1-carboxylate.

Using General Procedure C and reacting 1-([1,1'-biphenyl]-4yl)piperazine and quinuclidin-3-ol, the title compound was obtained. 'H NMR (500 MHz, CDC13) δ 7.58-7.54 (m, 4H), 7.43 (t, J=7.5 Hz, 2H), 7.31 (t, J=7.5 Hz, 1H), 7.02 (d, J=8.0 Hz, 2H), 4.81 (m, 1H), 3.68 (t, J=4.5 Hz, 4H), 3.31- 3.24 (m, 5H), 2.95-2.78 (m, 5H), 2.11-2.10 (m, 1H), 1.87-1.46 (m, 4H) ppm . ¹³ C NMR (125 MHz, CDC13) 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. LCMS purity >99% (214 and 254 nm); retention time 1.32 min; (M+H+) 392.2.

Example 7.

4-Phenyl-N-(quinuclidin-3-yl)piperazine-1-carboxamide.

Using General Procedure A and reacting 1-phenylpiperazine with quinuclidine-3-amine, the title compound was obtained. 'H NMR (500 MHz, CDCl ₃ ) δ 7.31-7.28 (m, 2H), 6.95-6.89 (m, 3H), 4.74-4.72 (m, 1H), 3.91-3.89 (m, 1H), 3.56 (t, J=5.0 Hz, 4H), 3.38-3.37 (m, 1H), 3.21 (t, J= 5.0 Hz, 4H), 2.87-2.82 (m, 4H), 2.60-2.59 (m, 1H), 1.97-1.96 (m, 1H), 1.72 -1.25 (m, 4H) ppm ¹³ C NMR (125 MHz, CDCl ₃ ) δ 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 LCMS purity >98% (214 and 254 nm); retention time 1.04 min; (M+H+) 315.1.

Example 8.

N(1-Azabicyclo[3.2.2]nonan-4-yl)-4-phenylpiperazine-1-carboxamide.

Using General Procedure A and reacting 1-phenylpiperazine with intermediate 4, the title compound was obtained. 'H NMR (500 MHz, CDCl ₃ ) δ 7.317.28 (m, 2H), 6.95-6.90 (m, 3H), 4.58 (d, J=7.0 Hz, 1H), 4 .04-3.99 (m, 1H), 3.55-3.53 (m, 4H), 3.28-3.19 (m, 5H), 3.11-3.05 (m, 1H) , 2.99-2.96 (m, 3H), 2.87-2.81 (m, 1H), 2.09-1.59 (m, 7H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity >96% (214 and 254 nm); retention time 1.60 min; (M+H+) 329.3.

Example 9.

N-(3-Methylquinuclidin-3-yl)-4-phenylpiperazine-1-carboxamide.

Using General Procedure A and reacting 1-phenylpiperazine with intermediate 1, the title compound was obtained. 'H NMR (500 MHz, CDCl ₃ ) δ 7.307.27 (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, 1H), 1.86-1.78 (m, 2H), 1.56-1.44 (m, 5H) ppm. ¹³ C NMR (100 MHz, CDCl ₃ ) 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. LCMS purity >98% (214 and 254 nm); retention time 1.63 min; (M+H+) 329.3.

Example 10.

- 38 046304

H-(4-Me'thyl-1-azabic.to[3.2.2|nonan-4-yl)-4-(|)enylpiperazine-1-carboxamide.

Using General Procedure A and reacting 1-phenylpiperazine with intermediate 5, the title compound was obtained. 1H NMR (500 MHz, CDCl ₃ ) δ 7.317.26 (m, 2H), 6.95-6.89 (m, 3H), 4.42 (s, 1H), 3.54-3.51 (m , 4H), 3.22-3.20 (m, 4H), 3.07-2.96 (m, 4H), 2.90-2.84 (m, 2H), 2.42-2.40 (m, 1H), 1.97-1.92 (m, 1H), 1.88-1.82 (m, 2H), 1.73-1.50 (m, 6H) ppm. ¹³ C NMR (125 MHz, CDCl3) 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 LCMS purity >99% (214 and 254 nm); retention time 1.63 min; (M+H+) 343.3.

Example 11.

1,4-Diazabicyclo[3.2.2] nonan-4 -yl(4-phenylpiperazin-1 -yl)methanone.

Using general procedure B and reacting 1-phenylpiperazine with intermediate 6, the title compound was obtained. ^1H NMR (500 MHz, CDCl3) 7.25 (t, J=8.0 Hz, 2H), 6.92 (d, J=8.0 Hz, 2H), 6.86 (t, J=7 .5 Hz, 1H), 4.09 (m, 1H), 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. ¹³ C NMR (100 MHz, CDCl3) δ 163.7, 151.2, 129.1, 120.1, 116.3, 56.4, 49.1, 47.2, 46.3, 45.6, 27.2 ppm LCMS purity >99% (214 and 254 nm); retention time 1.70 min; (M+H+) 315.3.

Example 12.

Quinuclidin-3-yl-4-phenylpiperazine-1-carboxylate.

Using General Procedure C and reacting 1-phenylpiperazine with quinuclidin-3-ol, the title compound was obtained. ^1H NMR (500 MHz, CDCl3) δ 7.31-7.28 (m, 2H), 6.96-6.90 (m, 3H), 4.79-4.78 (m, 1H), 3 .66 (t, J=5.0 Hz, 4H), 3.28-3.25 (m, 1H), 3.17 (m, 4H), 2.93-2.74 (m, 5H), 2.08-2.07 (m, 1H), 1.85-1.44 (m, 4H) ppm ¹³ C NMR (125 MHz, CDCl3) 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 LCMS purity >99% (214 and 254 nm); retention time 1.11 min; (M+H+) 316.1.

Example 13.

4-([1,1'-Biphenyl]-3-yl)-N-(quinuclidin-3-yl)piperazin-1-carboxamide.

Using General Procedure A and reacting 1-[1,1'-biphenyl]-3yl)piperazine with quinuclidine-3-amine, the title compound was obtained. ^1H NMR (500 MHz, CDC13) 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), 6.956.93 (m, 1H), 4.62 (d, J=6.0 Hz, 1H), 3.89-3.88 (m, 1H), 3.58 (m, J=5.5 Hz, 4H), 3.42-3.38 (m, 1H), 3.28 (t, J= 5.5 Hz, 4H), 2.89-2.81 (m, 4H), 2.53-2.50 (m, 1H), 1.96-1.94 (m, 1H) 1.70- 1.48 (m, 4H) ppm ¹³ C NMR (125 MHz, CDCl ₃ ) δ 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. LCMS purity >99% (214 and 254 nm); retention time 1.27 min; (M+H+) 391.3.

Example 14.

4-([1,G-Biphenyl]-3-yl)-N-(1-azabicyclo[3.2.2]nonan-4-yl)piperazin-1-carboxamide.

Using General Procedure A and reacting 1-[1,1'-biphenyl]-3yl)piperazine with intermediate 4, the title compound was obtained. ¹ H NMR (500 MHz, CDC13) δ 7.59-7.57 (d, J=8.5 Hz, 2H), 7.45 (t, J=7.5 Hz, 2H), 7.36 ( t, J=8.0 Hz, 2H), 7.14-7.13 (m, 2H), 6.94-6.92 (m, 1H), 4.57-4.55 (d, J= 7.0 Hz, 1H), 4.01-3.98 (m, 1H), 3.56 (t, J=5.0 Hz, 4H), 3.27 (t, J=5.0 Hz, 4H), 3.20-3.17 (m, 1H), 3.07-3.04 (m, 1H), 2.97-2.78 (m, 4H), 2.11-1.58 ( m, 7H) ppm ¹³ C NMR (125 MHz, CDC13) δ 156.8, 151.4, 42.5, 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. LCMS purity >98% (214 and 254 nm); retention time 1.27 min; (M+H+) 405.2.

Example 15.

4-([1,1'-Biphenyl]-3-yl)-K-(3-methylquinuclidin-3-yl)piperazin-1-carboxamide.

Using General Procedure A and reacting 1-[1,1'-biphenyl]-3yl)piperazine and intermediate 1, the title compound was obtained. ^1H NMR (500 MHz, CDCl3) δ 7.59-7.58 (dd, J=7.5, 1.5 Hz, 2H), 7.44 (t, J=7.5 Hz, 2H), 7.36 (t, J=7.5 Hz, 2H), 7.14-7.12 (m, 2H), 6.94 (m, 1H), 4.44 (s, 1H), 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, 1H) , 1.85-1.83 (m, 2H), 1.57-1.45 (m, 5H) ppm ¹³ C NMR (125 MHz, CDCl3) δ 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. LCMS purity >96% (214 and 254 nm); retention time 1.97 min; (M+H+) 405.3.

Example 16.

4-([1,G-Biphenyl]-3-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperazin-1-carboxamide.

Using General Procedure A and reacting 1-[1,1'-biphenyl]-3yl)piperazine with intermediate 5, the title compound was obtained. ^1H NMR (500 MHz, CDC13) δ 7.60-7.35 (m, 6H), 7.14-7.13 (m, 2H), 6.94-6.93 (m, 1H), 4 .41 (s, 1H), 3.56-3.54 (m, 4H), 3.29-3.27 (m, 4H), 3.02-2.85 (m, 6H), 2.42 -2.40 (m, 1H), 1.98-1.53 (m, 9H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) δ 157.0, 151.4, 142.4, 141.6, 129.6, 128.7, 127.3, 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. LCMS purity >99% (214 and 254 nm); retention time 1.29 min; (M+H+) 419.2.

Example 17.

- 39 046304

4-([1,1 '-Biphenyl]-3 -yl)piperazin-1 -yl)(1,4-diazabicyclo[3.2.2]nonan-4-yl)methanone.

Using General Procedure B and reacting 1-[1,1'-biphenyl]-3yl)piperazine and intermediate 6, the title compound was obtained. 1H NMR (500 MHz, CDCl ₃ ) 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, 1H), 4.14-4.13 (m, 1H), 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. ¹³ C NMR (125 MHz, CDCl ₃ ) 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. LCMS purity >99% (214 and 254 nm); retention time 2.01 min; (M+H+) 391.3.

Example 18.

Quinuclidin-3 -yl-4 -([1,1'-biphenyl]-3 -yl)piperazine-1-carboxylate.

Using General Procedure C and reacting 1-([1,1'-biphenyl]-3yl)piperazine and quinuclidin-3-ol, the title compound was obtained. 1H NMR (500 MHz, CDCl ₃ ) 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, 1H), 4.80-4.78 (m, 1H), 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, 1H), 1.851 .44 (m, 4H) ppm ¹³ C NMR (125 MHz, CDCl ₃ ) δ 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. LCMS purity >99% (214 and 254 nm); retention time 1.33 min; (M+H+) 392.2.

Example 19.

- Azabicyclo[3.2.2]nonan-4-yl-4-([1,1'-biphenyl]-3-yl)piperazin-1-carboxylate.

Using General Procedure C and reacting 1-([1,1'-biphenyl]-3yl)piperazine and intermediate 3, the title compound was obtained. 1H NMR (500 MHz, CDCl3) δ 7.59-7.58 (d, J=7.5 Hz, 2H), 7.45 (t, J=7.5 Hz, 2H), 7.36 (t , J=7.5 Hz, 2H), 7.15-7.13 (m, 2H), 6.95-6.93 (m, 1H), 4.96 (m, 1H), 3.68- 3.66 (m, 4H), 3.23-2.86 (m, 10H), 2.17-1.55 (m, 7H) ppm. ¹³ C NMR (100 MHz, CDCl ₃ ) δ 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. LCMS purity >99% (214 and 254 nm); retention time 1.16 min; (M+H+) 406.2.

Example 20.

- Azabicyclo[3.2.2]nonan-3-yl-4-([1,1'-biphenyl]-3-yl)piperazin-1-carboxylate.

Using General Procedure C and reacting 1-([1,1'-biphenyl]-3yl)piperazine and intermediate 7, the title compound was obtained. 1H NMR (500 MHz, CDCl3) δ 7.60 (d, J=8.0 Hz, 2H), 7.46 (t, J=7.5 Hz, 2H), 7.37 (t, J=8 ,0 Hz, 2H), 7.15 (m, 2H), 6.95 (dd, J=9.0 Hz, 1.5 Hz, 1H), 5.15 (m, 1H), 3.67 ( m, 4H), 3.50 (m, 1H), 3.24-2.83 (m, 9H), 2.35 (m, 1H), 2.13 (m, 1H), 1.80-1 .72 (m, 5H) ppm ¹³ C NMR (125 MHz, CDCl ₃ ) δ 154.9, 151.6, 142.4, 141.6, 129.6, 128.7, 127.3, 127.2, 119.5, 115.8 , 72.1, 61.2, 49.5, 48.5, 45.4, 43.7, 39.1, 28.9, 26.9, 24.2 ppm. LCMS purity >99% (214 and 254 nm); retention time 1.40 min; (M+H+) 406.2.

Example 21.

4-([1,1'-Biphenyl]-3-yl)-K-(3-ethylquinuclidin-3-yl)piperazin-1-carboxamide.

Using General Procedure A and reacting 1-[1,1'-biphenyl]-3yl)piperazine with intermediate 2, the title compound was obtained. 1H NMR (500 MHz, CDCl ₃ ) δ 7.59-7.58 (d, J=7.5 Hz, 2H), 7.45 (d, J=7.5 Hz, 2H), 7.37- 7.35 (m, 2H), 7.14-7.12 (m, 2H), 6.94-6.92 (m, 1H), 4.43 (s, 1H), 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. ¹³ C NMR (125 MHz, CDCl ₃ ) δ 156.8, 151.4, 142.4, 141.6, 129.6, 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 m. d. LCMS purity >99% (214 and 254 nm); retention time 1.51 min; (M+H+) 419.3.

Example 22.

4-(4'-Fluoro-[1,G-biphenyl]-3-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperazin-1-carboxamide.

Using General Procedure F and reacting 1-(3-bromophenyl)piperazine with 4-fluorophenylboronic acid, 1-(4'-fluoro-[1,1'-biphenyl]-3-yl)piperazine is obtained.

This compound is reacted with intermediate 5 using General Procedure A to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 9.22 (s, 1H), 8.94 (s, 2H), 7.44 (t, J=7.5 Hz, 1H), 7.10-7, 02 (m, 3H), 4.43 (s, 1H), 3.58-3.56 (m, 4H), 3.31-3.29 (m, 4H), 3.06-2.85 ( m, 6H), 2.42 (m, 1H), 1.95-1.57 (m, 9H) ppm. ¹³ C NMR (100 MHz, CDCl ₃ ) δ 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. LCMS purity >99% (214 and 254 nm); retention time 1.01 min; (M+H+) 421.3.

Example 23.

N-(3-Ethylquinuclidin-3 -yl)-4-(4'-fluoro-[1,1'-biphenyl]-3 -yl)piperazin-1-carboxamide.

Using General Procedure A and reacting 1-(4'-fluoro-[1,1'-biphenyl]-3yl)piperazine (prepared as described in Example 22) and intermediate 2, the title compound was obtained. 1H NMR (500 MHz, CDCl ₃ ) δ 7.54-7.52 (m, 2H), 7.35-7.33 (m, 1H), 7.147.06 (m, 4H), 6.93-6 .91 (d, J=8.0 Hz, 1H), 4.39 (s, 1H), 3.55 (m, 4H), 3.28-3.26 (m, 4H), 2.99- 2.83 (m, 6N), 2.18

- 40 046304

2.08 (m, 2H), 1.89-1.73 (m, 3H), 1.52-1.46 (m, 2H), 0.81 (t, J=7.5 Hz, 3H) m.d. ¹³ C NMR (125 MHz, CDCl ₃ ) δ 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 LCMS purity >99% (214 and 254 nm); retention time 1.54 min; (M+H+) 437.3.

Example 24.

- Azabicyclo[3.2.2] nonan-4 -yl-4-(4'-fluoro-[1,1'-biphenyl]-3 -yl)piperazin-1-carboxylate.

Using General Procedure C and reacting 1-(4'-fluoro-[1,1'-biphenyl]-3yl)piperazine (prepared as described in Example 22) and intermediate 3 afforded the title compound. ^1H NMR (500 MHz, CDCl3) δ 7.55-7.52 (m, 2H), 7.35 (t, J=8.5 Hz, 1H), 7.14-7.07 (m, 4H ), 6.94-6.92 (m, 1H), 4.96 (m, 1H), 3.67 (t, J=5.0 Hz, 4H), 3.23-2.80 (m, 10H), 2.16-1.53 (m, 7H) ppm. ¹³ C NMR (125 MHz, CDCl3) δ 162.5 (d, J=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. LCMS purity >95% (214 and 254 nm); retention time 1.27 min; (M+H+) 424.2.

Example 25.

- Azabicyclo[3.2.2]nonan-3-yl-4-(4'-fluoro-[1,1'-biphenyl]-3-yl)piperazin-1-carboxylate.

Using General Procedure C and reacting 1-(4'-fluoro-[1,1'-biphenyl]-3yl)piperazine (prepared as described in Example 22) and intermediate 7 afforded the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 7.57-7.47 (m, 6H), 7.13 (t, J=8.5 Hz, 2H), 5.11 (br s, 1H), 5.00 (m, 1H), 3.43-2.75 (m, 6H), 2.35-2.05 (m, 2H), 1.71-1.56 (m, 11H) ppm . ¹³ C NMR (100 MHz, CDCl ₃ ) 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. LCMS purity >93% (214 and 254 nm); retention time 1.42 min; (M+H+) 397.2.

Example 26.

N(4-Methyl-1-azabicyclo[3.2.2]nonan-4-yl)-4-(3-(pyrimidin-2-yl)phenyl)piperazin-1-carboxamide.

Using general procedure F and reacting 2-chloropyrimidine with tert-butyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate tert-butyl 4-(3-(pyrimidin-2-yl)phenyl)piperazine-1-carboxylate is obtained. The N-tert-butoxycarbonyl protecting group was removed from the resulting compound using General Procedure G to give 2-(3(piperazin-1-yl)phenyl)pyrimidine. This product is in turn reacted with intermediate 5 using general procedure A to give the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 8.82-8.81 (d, J=4.5 Hz, 2H), 8.07-8.06 (d, J=2.0 Hz, 1H), 8.00-7.98 (d, J=7.5 Hz, 1H), 7.42 (t, J=7.5 Hz, 1H), 7.20 (t, J=4.5 Hz, 1H ), 7.08-7.06 (m, 1H), 4.40 (s, 1H), 3.56-3.54 (m, 4H), 3.33-3.31 (m, 4H), 3.00-2.86 (m, 6H), 2.39 (m, 1H), 1.97-1.54 (m, 9H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) 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. LCMS purity >99% (214 and 254 nm); retention time 1.30 min; (M+H+) 421.3.

Example 27.

N(4-Methyl-1-azabicyclo[3.2.2]nonan-4-yl)-4-(3-(pyrimidin-5-yl)phenyl)piperazine-1-carboxamide.

Using General Procedure F and reacting 5-bromopyrimidine with tert-butyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate tert-butyl-4-(3-(pyrimidin-5-yl)phenyl)piperazine-1-carboxylate is obtained. The tert-butoxycarbonyl protecting group was removed from the resulting compound using General Procedure G to give 5-(3(piperazin-1-yl)phenyl)pyrimidine. This product is in turn reacted with intermediate 5 using general procedure A to give the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 9.20 (s, 1H), 8.93 (s, 2H), 7.39 (t, J=8.0 Hz, 1H), 7.07-7, 02 (m, 3H), 5.41 (s, 1H), 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. ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity >99% (214 and 254 nm); retention time 0.90 min; (M+H+) 420.2.

Example 28.

4-(3-Isopropylphenyl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperazine-1-carboxamide.

Using general procedure F and reacting 1-(3-bromophenyl)piperazine and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane, 1-(3-(prop-1-en-2-yl)phenyl)piperazine. A suspension of the resulting compound (0.500 g, 2.50 mmol) and 10% palladium on carbon (0.100 g) in ethyl acetate (30 ml) was pumped out several times with stirring and purged with nitrogen. After the last pumping, the reaction mixture is again filled with hydrogen gas. The mixture is stirred overnight and then filtered through celite. The filtrate is combined with ethyl acetate, which has been washed with the Celite and concentrated to give 1-(3-isopropylphenyl)piperazine as a yellow oil (0.360 g, 72%). The resulting compound is reacted with intermediate 5 using General Procedure A to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 7.13 (t, J=8.0

- 41 046304

Hz, 1H), 6.73-6.66 (m, 3H), 4.36 (s, 1H), 3.46-3.42 (m, 4H), 3.41-3.10 (m, 4H), 2.97-2.75 (m, 7H), 2.31-2.30 (m, 1H), 1.87-1.72 (m, 3H), 1.63-1.42 ( m, 6H), 1.18-1.16 (d, J=7.0 Hz, 6H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) δ 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. LCMS purity 100% (214 and 254 nm); retention time 1.88 min; (M+H+) 385.4.

Example 29.

4-(3-Cyclohexylphenyl)-N(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperazine-1-carboxamide.

Replacing 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane with 2-(cyclohex-1-en-1-yl)4,4, 5,5-tetramethyl-1,3,2-dioxaborolane, the same reaction sequence as described in Example 28 was used to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 7.20 (t, J=8.0 Hz, 1H), 6.79-6.73 (m, 3H), 4.40 (s, 1H), 3, 53-3.47 (m, 4H), 3.19-3.18 (m, 4H), 3.06-2.83 (m, 6H), 2.482.39 (m, 2H), 1.95- 1.23 (m, 19H) ppm ¹³ C NMR (125 MHz, CDCl ₃ ) δ 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 m. d. LCMS purity >99% (214 and 254 nm); retention time 1.57 min; (M+H+) 425.4.

Example 30.

4-([1,G-Biphenyl]-3-yl)-2-methyl-N(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperazine-1-carboxamide.

To a solution of 3-bromobiphenyl (0.70 g, 3.00 mmol) in toluene (10 ml) add tert-butyl-2-methylpiperazine-1-carboxylate (0.720 g, 3.60 mmol), potassium tert-butoxide, with stirring (0.504 g, 4.50 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.090 g, 98.3 mmol) and tri-tert-butylphosphine (0.018 g, 89.0 mmol). The mixture is heated at 90°C for 5 hours. After this, the reaction mixture is cooled, diluted with water and extracted with ethyl acetate. The combined extracts are washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography on silica using hexane/ethyl acetate to give tert-butyl 4-([1,1'-biphenyl]-3-yl)-2-methylpiperazine-1-carboxylate (0.750 g, 71%) in the form of brown butter. The tert-butoxycarbonyl protecting group was removed from the resulting compound using General Procedure G to give 1-([1,1'biphenyl]-3-yl)-3-methylpiperazine. This intermediate is in turn reacted with intermediate 5 using the general procedure A to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 7.60-7.34 (m, 6H), 7.12-7.11 (m, 2H), 6.92-6.90 (m, 1H), 4 .40-4.39 (d, J=6.5 Hz, 1H), 4.19-4.14 (m, 1H), 3.87-3.33 (m, 4H), 3.09-2 .88 (m, 8H), 2.46-2.43 (m, 1H), 1.991.55 (m, 9H), 1.38 (t, J=7.0 Hz, 3H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) 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. LCMS purity >99% (214 and 254 nm); retention time 1.29 min; (M+H+) 433.3.

Example 31.

4-([1,G-Biphenyl]-3-yl)-3-methyl-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperazin-1-carboxamide.

Replacing tert-butyl-2-methylpiperazine-1-carboxylate with tert-butyl-3-methylpiperazine-1-carboxylate, the same reaction sequence as described in Example 30 was used to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) 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, 1H), 4.39-4.37 (d, J=9.0 Hz, 1H), 3.93-2.85 (m, 13H), 2.41 (m, 1H), 1.98-1.55 (m, 9H), 1.12-1.11 (m, 3H) ppm ¹³ C NMR (100 MHz, CDCl ₃ ) δ 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 LCMS purity >98% (214 and 254 nm); retention time 1.47 min; (M+H+) 433.3.

Example 32.

4-([1,G-Biphenyl]-3-yl)-3-methyl-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperazin-1-carboxamide.

Replacing tert-butyl-2-methylpiperazine-1-carboxylate with tert-butyl-3,3-dimethylpiperazine-1carboxylate, the same reaction sequence as described in Example 30 was used to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 7.59-7.57 (d, J=7.5 Hz, 2H), 7.45 (t, J=7.5 Hz, 2H), 7.37- 7.33 (m, 4H), 7.11-7.09 (m, 1H), 4.54 (s, 1H), 3.59-2.97 (m, 12H), 2.58 (m, 1H), 2.01-1.55 (m, 9H), 1.12 (s, 6H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity >99% (214 and 254 nm); retention time 1.00 min; (M+H+) 447.3.

Example 33.

-(4'-Fluoro-[1,1'-biphenyl]-3-ng)-N-(3-methylquinuclidin-3-yl)piperidin-4-carboxamide.

To a solution of ethylpiperidine-4-carboxylate (1.60 g, 10.0 mmol) in methylene chloride (50 ml) add 3-bromophenylboronic acid (4.10 g, 20.4 mmol), triethylamine (5.00 g, 49.4 mmol), copper(II) acetate (2.70 g, 1.49 mmol) and 4A molecular sieves (2.00 g). The mixture, which is left in air, is stirred at room temperature for 24 hours. The reaction mixture is then diluted with methylene chloride and filtered through a pad of celite. The filtrate is concentrated, the residue is purified

- 42 046304 flash chromatography on silica using hexane/ethyl acetate as eluent to give ethyl 1-(3-bromophenyl)piperidine-4-carboxylate as a yellow oil (0.930 g, 30%). Using general procedure F and the boronic acid component 4-fluorophenylboronic acid (0.420 g, 3.00 mmol), the resulting intermediate (0.642 g, 2.00 mmol) was subjected to Suzuki coupling to give ethyl-1-(4'-fluoro- [1,1'-biphenyl]-3-yl)piperidine-4-carboxylate as a dark oil (0.589 g, 90%). A solution of the resulting compound (0.589 g, 1.80 mmol) in methanol/water, 1:1 (v/v) was treated with solid sodium hydroxide (0.360 g, 9.00 mmol) with stirring.

After stirring overnight, the reaction mixture is concentrated. The residue is dissolved in water, acidified (pH~6) by adding 1N hydrochloric acid and extracted with ethyl acetate.

The combined organic layers are washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give 1-(4'-fluoro-[1,1'-biphenyl]-3-yl)piperidine-4-carboxylic acid as a white solid ( 0.520 g, 96%). Using General Procedure D and Intermediate 1, the resulting carboxylic acid was amide coupled to give the title white solid (0.33 g, 24%). ¹ H NMR (500 MHz, CDCl3) δ 7.54-7.52 (m, 2H), 7.32 (t, J=8.0 Hz, 1H), 7.13-6.92 (m, 5H ), 5.55 (s, 1H), 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 ¹³ C NMR (125 MHz, CDCl3) δ 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 LCMS purity >99% (214 and 254 nm); retention time 1.10 min; (M+H+) 422.2.

Example 34.

1-(4'-Fluoro-[1,G-biphenyl]-3-yl)-N(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin-4-carboxamide.

Using general procedure A and reacting 1-(4'-fluoro-[1,1'-biphenyl]-3yl)piperidine-4-carboxylic acid (prepared as described in Example 33) and intermediate 5, the title in the connection header. 1H NMR (500 MHz, CDCl ₃ ) δ 7.53-7.51 (m, 2H), 7.31 (t, J=8.0 Hz, 1H), 7.12-7.02 (m, 3H ), 7.02-7.00 (d, J=7.5 Hz, 1H), 6.93-6.91 (m, 1H), 5.48 (s, 1H), 3.80-3, 78 (m, 2H), 3.05-2.76 (m, 8H), 2.40 (m, 1H), 2.24-2.20 (m, 1H), 1.95-1.50 ( m, 13H) ppm ¹³ C NMR (125 MHz, CDCl ₃ ) δ 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, 53.1, 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 LCMS purity >99% (214 and 254 nm); retention time 1.97 min; (M+H+) 436.4.

Example 35.

1-([1,1'-Biphenyl]-3-yl)-N(3-methylquinuclidin-3-yl)piperidin-4-carboxamide.

Replacing 4-fluorophenylboronic acid with phenylboronic acid, the same reaction sequence as described in Example 33 was used to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) 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), 7.14 (s, 1H), 7.09-7.07 (d, J=7.5 Hz, 1H), 6.95-6.93 (m, 1H) , 5.85 (br.s, 1H), 3.82-3.79 (m, 2H), 3.21-3.18 (m, 1H), 3.032.79 (m, 7H), 2.34 -2.29 (m, 2H), 1.96-1.82 (m, 6H), 1.65-1.47 (m, 5H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) δ 174.4, 151.9, 142.3, 141.8, 129.4, 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. LCMS purity >99% (214 and 254 nm); retention time 1.08 min; (M+H+) 404.2.

Example 36.

1-([1,G-Biphenyl]-3-yl)-N(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin-4-carboxamide.

Replacing 4-fluorophenylboronic acid with phenylboronic acid and intermediate 1 with intermediate 5, the same reaction sequence as described in Example 33 was used to obtain the title compound. 1H NMR (400 MHz, CDCl ₃ ) 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, 1H), 7.10-7.08 (d, J=7.2 Hz, 1H), 6.96-6.94 (d, J= 8.0 Hz, 1H), 5.46 (s, 1H), 3.83-3.80 (m, 2H), 3.08-2.78 (m, 8H), 2.41 (m, 1H ), 2.24-2.21 (m, 1H), 2.01-1.52 (m, 13H) ppm. ¹³ C NMR (100 MHz, CDCl ₃ ) 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 LCMS purity >95% (214 and 254 nm); retention time 1.38 min; (M+H+) 418.3.

Example 37.

1-([1,1 '-Biphenyl]-4-yl)-N(3-methylquinuclidin-3-yl)piperidin-4-carboxamide.

Replacing 4-fluorophenylboronic acid with phenylboronic acid and 3-bromophenylboronic acid with 4-bromophenylboronic acid, the same reaction sequence as described in Example 33 was used to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 7.577.51 (m, 4H), 7.41 (t, J=7.5 Hz, 2H), 7.29 (t, J=7.5 Hz, 1H) , 7.02-7.00 (d, J=8.5 Hz, 2H), 5.75 (br.s, 1H), 3.813.79 (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. ¹³ C NMR (125 MHz, CDCl3) δ 174.5, 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, 29.9, 28.9, 28.8, 24.3, 22.6, 22.2 ppm. LCMS purity >98% (214 and 254 nm); retention time 1.97 min; (M+H+) 404.4.

Example 38.

1-([1,G-Biphenyl]-4-yl)-N(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin-4-carboxamide.

Replacing 4-fluorophenylboronic acid with phenylboronic acid, 3-bromophenylboronic acid

- 43 046304 slot for 4-bromophenylboronic acid and intermediate 1 for intermediate 5, use the same reaction sequence as described in example 33 to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 7.60-7.56 (m, 4H), 7.45 (t, J=7.5 Hz, 2H), 7.35 (t, J=7.5 Hz, 1H), 7.30-7.29 (d, J=8.0 Hz, 2H), 4.43 (s, 1H), 4.10-4.05 (m, 2H), 3.08 -2.85 (m, 8H), 2.76-2.71 (m, 1H), 2.44-2.42 (m, 1H), 1.97-1.53 (m, 13H) m. d. ¹³ C NMR (125 MHz, CDCl ₃ ) 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 m. d. LCMS purity >99% (214 and 254 nm); retention time 1.99 min; (M+H+) 418.4.

Example 39.

N(4-Methyl-1-azabicyclo[3.2.2]nonan-4-yl)-1-(3-(pyrimidin-2-yl)phenyl)piperidine-4-carboxamide.

To a solution of ethyl 1-(3-bromophenyl)piperidine-4-carboxylate (prepared as described in Example 33; 0.800 g, 2.68 mmol) in dioxane (10 ml) add bis(pinacolato)diboron (0.817) with stirring g, 3.22 mmol), potassium acetate (0.790 g, 8.04 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(P) (0.060 g, 73.5 mmol). The mixture is heated at 90°C overnight. After cooling, the reaction mixture is filtered through celite and concentrated. The residue is purified by flash chromatography on silica using hexane/ethyl acetate to give ethyl 1-(3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-4 -carboxylate as a yellow solid (0.84 g, 91%). Using general procedure F and the aryl halide moiety of 2chloropyrimidine (0.137 g, 1.20 mmol), the resulting intermediate (0.430 g, 1.20 mmol) was subjected to Suzuki coupling to yield ethyl-1-(3-(pyrimidin-2-yl) phenyl)piperidine-4-carboxylate as a colorless oil (0.200 g, 54%). To a solution of the resulting product (0.200 g, 0.642 mmol) in a mixture of methanol/water, 1:1 (v/v), solid sodium hydroxide (0.128 g, 3.20 mmol) was added with stirring. After stirring overnight, the reaction mixture is concentrated. The residue is dissolved in water, acidified (pH~6) by adding 1N hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give 1-(3-(pyrimidin2-yl)phenyl)piperidine-4-carboxylic acid as a white solid (0.150 g, 82%). Using General Procedure D and Intermediate 5, the resulting carboxylic acid was amide coupled to give the title compound as a white solid (0.060 g, 27%). 1H NMR (500 MHz, CDCl ₃ ) δ 8.80-8.79 (d, J=4.5 Hz, 2H), 8.06 (s, 1H), 7.94-7.92 (d, J =8.0 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.18 (t, J=5.0 Hz, 1H), 7.09-7.07 (dd , J=8.0 Hz and 2.0 Hz, 1H), 5.49 (s, 1H), 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. ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity >99% (214 and 254 nm); retention time 1.23 min; (M+H+) 420.3.

Example 40.

N(4-Methyl-1-azabicyclo[3.2.2]nonan-4-yl)-1-(3-(pyrimidin-5-yl)phenyl)piperidine-4-carboxamide.

Replacing 2-chloropyrimidine with 5-bromopyrimidine, the same reaction sequence as described in Example 39 was used to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 9.20 (s, 1H), 8.93 (s, 2H), 7.39 (t, J=8.0 Hz, 1H), 7.07-7, 02 (m, 3H), 5.41 (s, 1H), 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. ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity >99% (214 and 254 nm); retention time 0.90 min; (M+H+) 420.2.

Example 41.

1-(4-(4-Fluorophenyl)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin-4-carboxamide.

To a solution of 2,4-dichloropyrimidine (3.00 g, 20.1 mmol) in toluene (25 ml) add 4-fluorophenylboronic acid (2.82 g, 20.1 mmol), potassium carbonate (8.32 g) with stirring , 60.3 mmol), tetrakis(triphenylphosphine)palladium(0) (0.630 g, 0.545 mmol) and ethanol/water, 1:1 (v/v, 36 ml). The mixture is heated at 55°C for 12 hours and then concentrated. The residue is diluted with water and extracted with ethyl acetate. The combined extracts are washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by flash chromatography on silica using hexane/ethyl acetate to give 2-chloro-4-(4-fluorophenyl)pyrimidine as a yellow solid (2.50 g, 61%). To a solution of the resulting compound (1.27 g, 6.09 mmol) in N-dimethylformamide (8 ml), ethylpiperidine-4-carboxylate (0.959 g, 6.10 mmol) and cesium carbonate (2.10 g, 6 .44 mmol). The mixture is heated at 100°C for 12 hours and then concentrated. The residue is diluted with water and extracted with ethyl acetate. The combined extracts are washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by flash chromatography on silica using hexane/ethyl acetate to give ethyl 1-(4'-fluoro[1,1'-biphenyl]-3-yl)piperidine-4-carboxylate as a yellow oil. (1.60 g, 80%). To a solution of the resulting intermediate (1.60 g, 4.80

- 44046304 mmol) in a mixture of methanol/water, 1:1 (v/v, 20 ml) add solid sodium hydroxide (0.988 g, 24.2 mmol) with stirring. After 2 hours, the reaction mixture is concentrated. The residue is dissolved in water, acidified (pH~6) by adding 1N hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give 1-(4'-fluoro-[1,1'biphenyl]-3-yl)piperidin-4-carboxylic acid as a white solid (1 .40 g, 97%). Using General Procedure D and Intermediate 5, the resulting carboxylic acid was amide coupled to give the title compound as a white solid (0.118 g, 27%). ¹ H NMR (500 MHz, CDCl3) δ 8.37 (d, J=5.0 Hz, 1H), 8.07-8.04 (m, 2H), 7.15 (t, J=9.0 Hz, 2H), 6.89 (d, J=10.0 Hz, 1H), 5.38 (s, 1H), 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. ¹³ C NMR (100 MHz, CDCl3) δ 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 LCMS purity >96% (214 and 254 nm); retention time 1.44 min; (M+H+) 438.3.

Example 42.

1-(4-(4-Fluorophenyl)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin-4carboxamide (single enantiomer A).

Using general procedure D and reacting 1-(4'-fluoro-[1,1'-biphenyl]-3yl)piperidine-4-carboxylic acid (prepared as described in Example 41) and intermediate 9, the title the title compound appears as a single enantiomer of unknown absolute stereochemistry. NMR data consistent with product of Example 41. Purity by UPLCMS 96.9%, 97.2% (210 and 254 nm); retention time 0.78 min; (M+H+) 438.3.

Example 43.

1-(4-(4-Fluorophenyl)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin-4carboxamide (single enantiomer B).

Using general procedure D and reacting 1-(4'-fluoro-[1,1'-biphenyl]-3yl)piperidine-4-carboxylic acid (prepared as described in Example 41) and intermediate 10, the title the title compound appears as a single enantiomer of unknown absolute stereochemistry. NMR data consistent with product of Example 41. Purity by UPLCMS 100%, 99.4% (210 and 254 nm); retention time 0.78 min; (M+H+) 438.3.

Example 44.

1-(4-(4-Fluorophenyl)pyrimidin-2-yl)-N-(3-methylquinuclidin-3-yl)piperidin-4-carboxamide.

Using general procedure D and reacting 1-(4'-fluoro-[1,1'-biphenyl]-3yl)piperidine-4-carboxylic acid (prepared as described in Example 41) and intermediate 1, the title in the connection header. 1H NMR (500 MHz, CDCl ₃ ) δ 8.30 (d, J=4.5 Hz, 1H), 8.07-8.04 (m, 2H), 7.16 (t, J=8.5 Hz, 2H), 6.89 (d, J=5.0 Hz, 1H), 5.57 (s, 1H), 4.97-4.94 (m, 2H), 3.04-2.84 (m, 8H), 2.40-2.21 (m, 2H), 1.97-1.51 (m, 11H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) δ 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 LCMS purity >99% (214 and 254 nm); retention time 1.27 min; (M+H+) 424.2.

Example 45.

1-(4-(4-Fluorophenyl)pyrimidin-2-yl)-N-(quinuclidin-3-yl)piperidin-4-carboxamide.

Using General Procedure E and reacting 1-(4'-fluoro-[1,1'-biphenyl]-3yl)piperidine-4-carboxylic acid (prepared as described in Example 41) and quinuclidine-3-amine obtain the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.43 (d, J=5.0 Hz, 1H), 8.26-8.13 (m, 2H), 7.86 (d, J=7 ,1 Hz, 2H), 7.38-7.29 (m, 2H), 7.17 (d, J=5.1 Hz, 1H), 4.89-4.72 (m, 2H), 3 .75-3.62 (m, 1H), 3.09-2.87 (m, 3H), 2.85-2.72 (m, 1H), 2.72-2.36 (m, 5H) , 1.84-1.64 (m, 4H), 1.64-1.40 (m, 4H), 1.35-1.19 (m, 1H) ppm. ¹³ C NMR (100 MHz, DMSO46) δ 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, J=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. UP-LCMS purity 95.2%, 99.6% (210 and 254 nm); retention time 0.73 min; (M+H+) 410.3.

Example 46.

1-(6-(4-Fluorophenyl)pyraZin-2-yl)-H-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin-4-carboxamide.

To a solution of 2,6-dichloropyrazine (5.00 g, 33.6 mmol) in 1,4-dioxane (150 ml) add ethyl piperidine 4-carboxylate (5.54 g, 35.2 mmol) and triethylamine ( 5.2 ml, 37 mmol). The mixture is refluxed overnight and then concentrated. The residue is dissolved in aqueous sodium bicarbonate and extracted with ethyl acetate. The combined extracts are dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash silica chromatography using hexane/ethyl acetate to give ethyl 1-(6-chloropyrazin-2-yl)piperidine-4-carboxylate as a yellow oil (8.50 g, 94%). To a solution of the resulting compound (1.00 g, 3.71 mmol) in a mixture of 1,4dioxane/water, 10:1 (v/v, 11 ml), 4-fluorophenylboronic acid (0.622 g, 4.44 mmol), sodium carbonate (0.785 g, 7.41 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.136 g, 0.185 mmol). The mixture is refluxed overnight. After the chill

- 45 046304 While waiting, the reaction mixture is diluted with water and extracted with ethyl acetate. The combined extracts are washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography on silica using hexane/ethyl acetate to give ethyl 1-(6-(4fluorophenyl)pyrazin-2-yl)piperidine-4-carboxylate as a yellow oil (1.20 g, 98% ). To a solution of the resulting product in a mixture of tetrahydrofuran/methanol/water, 1:1:1 (v/v/v), solid sodium hydroxide (0.730 g, 18.3 mmol) was added with stirring. After stirring overnight, the reaction mixture is concentrated. The residue is dissolved in water, acidified (pH~6) by adding 1N hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give 1-(6-(4-fluorophenyl)pyrazin-2-yl)piperidine-4-carboxylic acid as a yellow solid (0.600 g, 54% ). Using General Procedure D and Intermediate 5, the resulting carboxylic acid was amide coupled to give the title compound as a white solid (0.100 g, 34%). ¹ H NMR (500 MHz, CDCl3) δ 8.25 (s, 1H), 8.07 (s, 1H), 7.98-7.95 (m, 2H), 7.13 (t, J=8 .0 Hz. 2H), 5.54 (s, 1H), 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. ¹³ C NMR (125 MHz, CDCl3) 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 LCMS purity >99% (214 and 254 nm); retention time 1.23 min; (M+H+) 438.0.

Example 47.

1-(6-(4-Fluorophenyl)pyrazin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin-4-carboxamide (single enantiomer A).

Using General Procedure D and reacting 1-(6-(4-fluorophenyl)pyrazin2-yl)piperidine-4-carboxylic acid (prepared as described in Example 46) and intermediate 9 afforded the title compound as of a single enantiomer with unknown absolute stereochemistry. NMR data consistent with product of Example 46. Purity by UPLCMS 100%, 98.6% (214 and 254 nm); retention time 0.79 min; (M+H+) 438.4.

Example 48.

1-(6-(4-Fluorophenyl)pyrazin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin-4carboxamide (single enantiomer B).

Using General Procedure D and reacting 1-(6-(4-fluorophenyl)pyrazin2-yl)piperidine-4-carboxylic acid (prepared as described in Example 46) and intermediate 10 afforded the title compound as of a single enantiomer with unknown absolute stereochemistry. NMR data consistent with product of Example 46. Purity by UPLCMS 100%, 100% (214 and 254 nm); retention time 0.79 min; (M+H+) 438.4.

Example 49.

1-(6-(4-Fluorophenyl)pyrazin-2-yl)-N-(3-methylquinuclidin-3-yl)piperidin-4-carboxamide.

Using General Procedure E and reacting 1-(6-(4-fluorophenyl)pyrazin-2yl)piperidine-4-carboxylic acid (prepared as described in Example 46) and Intermediate 1 afforded the title compound as light brown solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.41 (s, 1H), 8.29 (m, 1H), 8.16-8.08 (m, 2H), 7.47 (br.s , 1H), 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, 1H), 1.84-1.51 (m, 6H), 1.45-1.20 (m, 5H) ppm. ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 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. UP-LCMS purity 100%, 97.7% (214 and 254 nm); retention time 0.77 min; (M+H+) 424.2.

Example 50.

1-(4-(4-Fluorophenyl)-1,3,5-triazin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin-4carboxamide.

Replacing 2,6-dichloropyrazine with 2,4-dichloro-1,3,5-triazine, the same reaction sequence as described in Example 46 was used to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 8.60 (s, 1H), 8.43-8.40 (m, 2H), 7.12 (t, J=8.5 Hz, 2H), 5, 43 (s, 1H), 5.02-4.88 (m, 2H), 3.04-2.82 (m, 8H), 2.40-2.36 (m, 2H), 1.95- 1.48 (m, 13H) ppm ¹³ C NMR (125 MHz, CDCl ₃ ) δ 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 LCMS purity >98% (214 and 254 nm); retention time 1.20 min; (M+H+) 439.0.

Example 51.

1-(2-(4-Fluorophenyl)pyrimidin-4-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin-4-carboxamide.

To a solution of 2,4-dichloropyrimidine (2.00 g, 13.4 mmol) in methanol (30 ml) add ethylpiperidine-4-carboxylate (1.73 g, 12.1 mmol) and triethylamine (1.49 g) with stirring , 14.8 mmol). The mixture is heated at 65°C overnight. After cooling, the reaction mixture is filtered to remove solids and concentrated. The residue is purified by flash chromatography on silica using

- 46 046304 eluting with hexane/ethyl acetate to obtain ethyl 1-(2-chloropyrimidin-4-yl)piperidin-4-carboxylate as a yellow oil (2.50 g, 60%). To a solution of the resulting product in a mixture of N,Ndimethylformamide (15 ml) and water (8 ml), 4-fluorophenylboronic acid (0.780 g, 5.60 mmol), sodium carbonate (2.37 g, 22.4 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(P) (0.204 g, 0.279 mmol). The mixture is heated at 90°C for 6 hours and then concentrated. The residue was purified by flash chromatography on silica using methylene chloride/methanol as an eluent to give ethyl 1-(2-(4-fluorophenyl)pyrimidin-4-yl)piperidine-4-carboxylate as a white solid (0.500 g, 27 %). To a solution of the resulting intermediate in 1:1 methanol/water (v/v/v, 20 mL) was added solid sodium hydroxide (0.303 g, 7.58 mmol) with stirring. After 3 hours, the reaction mixture is concentrated. The residue is dissolved in water, acidified (pH~6) by adding 1N hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give 1-(2-(4-fluorophenyl)pyrimidin4-yl)piperidin-4-carboxylic acid as a white solid (0.430 g, 94%). Using General Procedure D and Intermediate 5, the resulting carboxylic acid was amide coupled to give the title compound as a white solid (0.096 g, 22%). 1H NMR (500 MHz, CDCl ₃ ) δ 8.37 (d, J=5.0 Hz, 1H), 8.07-8.04 (m, 2H), 7.15 (t, J=9.0 Hz, 2H), 6.89 (d, J=10.0 Hz, 1H), 5.38 (s, 1H), 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. ¹³ C NMR (125 MHz, CDCl ₃ ) δ 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 LCMS purity >96% (214 and 254 nm); retention time 1.44 min; (M+H+) 438.3.

Example 52.

4-([1,G-Biphenyl]-3-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin-1-carboxamide.

To a solution of tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)carboxylate (1.05 g, 3 .40 mmol) in a mixture of 1,4-dioxane/water, 5:1 (v/v, 30 ml) add 3-bromobiphenyl (0.660 g, 2.80 mmol), potassium carbonate (1.16 g) with stirring , 8.39 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(P) (0.102 g, 0.139 mmol). The mixture is heated at 80°C overnight. After cooling, the reaction mixture is diluted with water and extracted with ethyl acetate. The combined extracts are washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography on silica using hexane/ethyl acetate as an eluent to give tert-butyl 4-([1,1'-biphenyl]-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate as light yellow oil (0.900 g, 64%). A suspension of the resulting compound (0.900 g, 2.50 mmol) and 10% palladium on carbon (50% in water, 0.180 g) in ethyl acetate (30 ml) was pumped out several times in turn and purged with nitrogen while stirring. After the last pumping, the reaction mixture is again filled with hydrogen gas. The mixture is stirred overnight and then filtered through Celite, the filtrate is combined with ethyl acetate, washed with Celite and concentrated to give tert-butyl 4-([1,1'-biphenyl]-3-yl)piperidine-1-carboxylate as a yellow oil ( 0.898 g, 90%). To a solution of the resulting product (0.898 g, 2.66 mmol) in methylene chloride (10 ml) was added trifluoroacetic acid (2.5 ml) with stirring. The mixture is stirred overnight and then concentrated. The residue is dissolved in an aqueous sodium carbonate solution and extracted with methylene chloride. The combined extracts were dried (Na2SO4) and concentrated to give 4-([1,1'-biphenyl]-3-yl)piperidine as a light yellow oil (0.569 g, 90%). The resulting compound is reacted with intermediate 5 using General Procedure A to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) 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, 1H), 4.45 (s, 1H), 4.11-4.05 (m, 2H), 3.06-2.98 (m, 4H), 2.942, 88 (m, 4H), 2.76-1.75 (m, 1H), 2.45 (m, 1H), 1.96-1.87 (m, 5H), 1.78-1.55 ( m, 8H) ppm ¹³ C NMR (125 MHz, CDCl ₃ ) δ 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 LCMS purity >99% (214 and 254 nm); retention time 1.99 min; (M+H+) 418.4.

Example 53.

4-([1,G-Biphenyl]-4-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin-1-carboxamide.

Replacing 3-bromobiphenyl with 4-bromobiphenyl, the same reaction sequence as described in Example 52 was used to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 7.607.56 (m, 4H), 7.45 (t, J=7.5 Hz, 2H), 7.35 (t, J=7.5 Hz, 1H) , 7.30-7.289 (d, J=8.0 Hz, 2H), 4.43 (s, 1H), 4.104.05 (m, 2H), 3.08-2.85 (m, 8H), 2.76-2.71 (m, 1H), 2.44-2.42 (m, 1H), 1.97-1.53 (m, 13H) ppm. ¹³ C NMR (125 MHz, CDCl3) 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 . LCMS purity >99% (214 and 254 nm); retention time 1.99 min; (M+H+) 418.4.

Example 54.

1-(5-Fluoro-4-(4-fluorophenyl)pyrimidin-2-yl)-N-(3-methylquinuclidin-3-yl)piperidin-4-carboxamide.

Replacing 2,4-dichloropyrimidine with 2,4-dichloro-5-fluoropyrimidine and intermediate 5 with intermediate 1, use the same reaction sequence as described in

- 47 046304 at least 41 and obtain the compound named in the title. 1H NMR (500 MHz, CDC13) δ 8.25 (d, J=3.5 Hz, 1H), 8.14-8.11 (m, 2H), 7.20-7.16 (m, 2H) , 5.41 (br.s, 1H), 4.84-4.81 (m, 2H), 3.02-2.78 (m, 8H), 2.38-2.33 (m, 1H) , 2.18-2.16 (m, 1H), 1.95-1.92 (m, 2H), 1.80-1.70 (m, 4H), 1.56-1.46 (m, 5H) ppm ¹³ C NMR (125 MHz, CDCl ₃ ) 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. LCMS purity >99% (214 nm and 254 nm); retention time 1.50 min; (M+H+) 442.2.

Example 55.

1-(5-Fluoro-4-(4-fluorophenyl)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin4-carboxamide.

Replacing 2,4-dichloropyrimidine with 2,4-dichloro-5-fluoropyrimidine, the same reaction sequence as described in Example 41 was used to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 8.25 (d, J=3.0 Hz, 1H), 8.14-8.11 (m, 2H), 7.18 (t, J=8.5 Hz, 2H), 5.36 (s, 1H), 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. ¹³ C NMR (125 MHz, CDCl ₃ ) 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. LCMS purity >99% (214 nm and 254 nm); retention time 1.52 min; (M+H+) 456.2.

Example 56.

1-(5-Fluoro-4-(4-(2-methoxyethoxy)phenyl)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4yl)piperidine-4-carboxamide .

Replacing 2,4-dichloropyrimidine with 2,4-dichloro-5-fluoropyrimidine and 4-fluorophenylboronic acid with (4-(2-methoxyethoxy)phenyl)boronic acid, use the same reaction sequence as described in example 41 and obtain the product named in connection header. 1H NMR (500 MHz, CDCl ₃ ) δ 8.21 (d, J=4.0 Hz, 1H), 8.10 (d, J=8.5 Hz, 2H), 7.03 (dd, J= 7.0 Hz and 2.0 Hz, 2H), 5.37 (s, 1H), 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. ¹³ C NMR (125 MHz, CDCl ₃ ) 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. LCMS purity >99% (214 nm and 254 nm); retention time 1.33 min; (M+H+) 512.3.

Example 57.

1-(5-Fluoro-4-(4-(2-methoxyethoxy)phenyl)pyrimidin-2-yl)-N-(3-methylquinuclidin-3-yl)piperidin4-carboxamide.

Replacing 2,4-dichloropyrimidine with 2,4-dichloro-5-fluoropyrimidine, 4-fluorophenylboronic acid with (4-(2-methoxyethoxy)phenyl)boronic acid, and intermediate 5 with intermediate 1, use the same reaction sequence as described in Example 41 to obtain the title compound. 1H NMR (400 MHz, CDCl ₃ ) δ 8.09 (d, J=2.4 Hz, 1H), 7.53 (dd, J=8.8 Hz and 1.6 Hz, 2H), 7.02 (dd, J=7.2 Hz and 2.0 Hz, 2H), 6.68 (d, J=5.2 Hz, 1H), 5.61 (brs, 1H), 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, 11H) ppm ¹³ C 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 LCMS purity >99% (214 nm and 254 nm); retention time 1.27 min; (M+H+) 497.3.

Example 58.

1-(5-Fluoro-4-(4-((2-methoxyethoxy)methyl)phenyl)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl) piperidine-4-carboxamide.

Replacing 2,4-dichloropyrimidine with 2,4-dichloro-5-fluoropyrimidine and 4-fluorophenylboronic acid with 2-(4-((2-methoxyethoxy)methyl)phenyl)-4,4,5,5-tetramethyl-1, 3,2-dioxaborolane, the same reaction sequence as described in Example 41 was used to obtain the title compound. 1H NMR (400 MHz, CDCl ₃ ) δ 8.23 (d, J=3.6 Hz, 1H), 8.06 (d, J=8.3 Hz, 2H), 7.46 (d, J= 8.3 Hz, 2H), 5.49 (s, 1H), 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, 2H), 1.97- 1.45 (m, 13H) ppm UP-LCMS purity 99.1% (214 and 254 nm); retention time 0.89 min; (M+H+) 526.4.

Example 59.

1-(5-Fluoro-4-(4-((2-methoxyethoxy)methyl)phenyl)pyrimidin-2-yl)-N-(3-methylquinuclidin-3-yl)piperidin-4-carboxamide.

Replacing 2,4-dichloropyrimidine with 2,4-dichloro-5-fluoropyrimidine, 4-fluorophenylboronic acid with 2-(4-((2-methoxyethoxy)methyl)phenyl)-4,4,5,5-tetramethyl-1, 3,2-dioxaborolane and intermediate 5 to intermediate 1, use the same reaction sequence as described in Example 41 to obtain the title compound. 1H NMR (400 MHz, CDCl ₃ ) δ 8.23 (d, J=3.6 Hz, 1H), 8.06 (d, J=8.3 Hz, 2H), 7.46 (d, J= 8.3 Hz, 2H), 5.43 (s, 1H), 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, 1H), 2.16-2.11 (m, 1H), 1.96-1.86 (m, 2H), 1.82-1.66 (m, 2H ), 1.57-1.38 (m, 5H) ppm. Purity by UP-LCMS >99.9%

- 48 046304 (214 and 254 nm); retention time 0.87 min; (M+H+) 512.4.

Example 60.

1-(5-Fluoro-4-(4-(methoxymethyl)phenyl)pyrimidin-2-yl)-H-(4-methyl-1-azabicyclo[3.2.2]nonan-4yl)piperidin-4-carboxamide.

Replacing 2,4-dichloropyrimidine with 2,4-dichloro-5-fluoropyrimidine and 4-fluorophenylboronic acid with 2-(4-(methoxymethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane , use the same reaction sequence as described in example 41 to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 8.26 (d, J=3.5 Hz, 1H), 8.09 (d, J=7.5 Hz, 2H), 7.48 (d, J= 8.5 Hz, 2H), 5.44 (s, 1H), 4.864.83 (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. ¹³ C NMR (100 MHz, CDCl ₃ ) 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 LCMS purity >99% (214 nm and 254 nm); retention time 1.40 min; (M+H+) 482.2.

Example 61.

1-(5-Fluoro-4-(4-(methoxymethyl)phenyl)pyrimidin-2-yl)-N-(3-methylquinuclidin-3-yl)piperidin-4carboxamide.

Replacing 2,4-dichloropyrimidine with 2,4-dichloro-5-fluoropyrimidine, 4-fluorophenylboronic acid with 2-(4-(methoxymethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and intermediate 5 to intermediate 1, use the same reaction sequence as described in Example 41 to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 8.26 (d, J=3.5 Hz, 1H), 8.09 (d, J=8.0 Hz, 2H), 7.47 (d, J= 8.5 Hz, 2H), 5.58 (br.s, 1H), 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 ) m.d. ¹³ C NMR (100 MHz, CDCl ₃ ) 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 UP-LCMS purity >99.9% (214 nm and 254 nm); retention time 1.38 min; (M+H+) 468.3.

Example 62.

1-(5-Fluoro-4-(4-(3-methoxypropoxy)phenyl)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan4-yl)piperidin-4-carboxamide .

Replacing 2,4-dichloropyrimidine with 2,4-dichloro-5-fluoropyrimidine and 4-phenylboronic acid with 2(4-(3-methoxypropoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane, use the same reaction sequence as described in example 41 to obtain the title compound. 1H NMR (400 MHz, CDCl ₃ δ 8.17 (d, J=3.8 Hz, 1H), 8.06 (d, J=9.0 Hz, 2H), 6.97 (d, J=9 .0 Hz, 2H), 5.65 (s, 1H), 4.854.75 (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, 1H), 2.45-2.35 ( m, 1H), 2.12-2.01 (m, 2H), 2.01-1.53 (m, 10H), 1.47 (s, 3H) ppm UP-LCMS purity >99 .9% (214 and 254 nm); retention time 0.96 min; (M+H+) 526.3.

Example 63.

1-(5-Fluoro-4-(4-(3-methoxypropoxy)phenyl)pyrimidin-2-yl)-N-(3-methylquinuclidin-3-yl)piperidin-4-carboxamide.

Replacing 2,4-dichloropyrimidine with 2,4-dichloro-5-fluoropyrimidine, 4-fluorophenylboronic acid with 2-(4-(3-methoxypropoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2 -dioxaborolane and intermediate 5 to intermediate 1, use the same reaction sequence as described in Example 41 to obtain the title compound. 1H NMR (400 MHz, CDCl ₃ ) δ 8.19 (d, J=3.8 Hz, 1H), 8.07 (d, J=8.9 Hz, 2H), 6.98 (d, J= 8.9 Hz, 2H), 5.38 (s, 1H), 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), 3.00-2.88 (m, 4H), 2.88-2.71 (m, 4H), 2.37 -2.27 (m, 1H), 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 UP-LCMS purity >99.9% (214 and 254 nm); retention time 0.95 min; (M+H+) 512.3.

Example 64.

1-(4-(3,4-Difluorophenyl)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin-4carboxamide.

Replacing 4-fluorophenylboronic acid with 3,4-diphenylboronic acid, the same reaction sequence as described in Example 41 was used to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 8.39 (d, J=5.0 Hz, 1H), 7.94-7.93 (m, 1H), 7.78-7.77 (m, 1H ), 7.27-7.24 (m, 1H), 6.87 (d, J=5.0 Hz, 1H), 5.44 (lat, 1H), 4.96-4.93 (m , 2H), 3.06-2.87 (m, 8H), 2.41-2.39 (m, 2H), 1.97-1.52 (m, 13H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) δ 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 m.d. LCMS purity >99% (214 nm and 254 nm); retention time 1.23 min; (M+H+) 456.2.

Example 65.

1-(4-(3,5-Difluorophenyl)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin-4carboxamide.

Replacing 4-fluorophenylboronic acid with 3,5-diphenylboronic acid, the same reaction sequence as described in Example 41 was used to obtain the title compound.

- 49 046304 ¹ H NMR (500 MHz, CDCl3) δ 8.42 (d, J=5.5 Hz, 1H), 7.60-7.57 (m, 2H), 6.95-6.90 ( m, 1H), 6.87 (d, J=5.5 Hz, 1H), 5.49 (s, 1H), 4.96-4.93 (m, 2H), 3.06-2.87 (m, 8H), 2.44-2.37 (m, 2H), 1.99-1.93 (m, 3H), 1.94-1.52 (m, 10H) ppm. ¹³ C NMR (125 MHz, CDCl3) 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 LCMS purity >99% (214 nm and 254 nm); retention time 2.00 min; (M+H+) 456.3.

Example 66.

1-(4-(4-(2-Methoxyethoxy)phenyl)pyrimidin-2-yl)-H-(4-methyl-1-azabicyclo[3.2.2]nonan-4yl)piperidin-4-carboxamide.

Replacing 4-fluorophenylboronic acid with (4-(2-methoxyethoxy)phenylboronic acid, the same reaction sequence as described in Example 41 was used to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 8.33-8 .32 (d, J=5.0 Hz, 1H), 8.02 (d, J=9.0 Hz, 2H), 7.01 (d, J=8.5 Hz, 2H), 6.88 (d, J=5.0 Hz, 1H), 5.37 (s, 1H), 4.98-4.95 (m, 2H), 4.20 (t, J=5.0 Hz, 2H) , 3.79 (t, J=5.0 Hz, 2H), 3.48 (s, 3H), 3.01-2.83 (m, 8H), 2.38-2.36 (m, 2H ), 1.96-1.93 (m, 3H), 1.78-1.50 (m, 10H) ppm ¹³ C NMR (125 MHz, CDCl ₃ ) 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 by LCMS >99 % (214 nm and 254 nm); retention time 1.13 min; (M+H+) 494.3.

Example 67.

1-(4-(4-(3-Methoxypropoxy)phenyl)pyrimidin-2-yl)-H-(4-methyl-1-azabicyclo[3.2.2]nonan-4yl)piperidin-4-carboxamide.

Replacing 4-fluorophenylboronic acid with 2-(4-(3-methoxypropoxy)phenyl)-4,4,5,5-tetramethyl1,3,2-dioxaborolane, use the same reaction sequence as described in example 41 and obtain the product named in connection header. 1H NMR (500 MHz, CDCl ₃ ) δ 8.34 (d, J=5.0 Hz, 1H), 8.03 (d, J=9.0 Hz, 2H), 7.00 (d, J= 9.0 Hz, 2H), 6.89 (d, J=5.0 Hz, 1H), 5.38 (s, 1H), 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. ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity >99% (214 nm and 254 nm); retention time 1.28 min; (M+H+) 508.3.

Example 68.

1-(4'-(2-Methoxyethoxy)[1,G-biphenyl]-3-yl)-H-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidine4-carboxamide.

Replacing 4-fluorophenylboronic acid with (4-(2-methoxyethoxy)phenylboronic acid and intermediate 1 with intermediate 5, the same reaction sequence as described in Example 33 was used to obtain the title compound. ¹ H NMR (500 MHz, CDCl3) δ 7.52 (d, J=8.5 Hz, 2H), 7.31 (t, J=8.0 Hz, 1H), 7.12 (t, J=2.0 Hz, 1H) , 7.05 (d, J=7.5 Hz, 1H), 7.01 (d, J=8.5 Hz, 2H), 6.92 (dd, J=8.0 Hz and 2.0 Hz , 1H), 5.38 (s, 1H), 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, 1H), 2.25-2.20 (m, 1H), 1.97-1.53 (m, 13H) ppm ¹³ C NMR (125 MHz, CDCl ₃ ) 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 by LCMS >99% (214 nm and 254 nm); retention time 1.19 min (M+H); +) 492.3.

Example 69.

-(4'-((2-Methoxyethoxy)methyl)[1,1'-biphenyl]-3-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin- 4-carboxamide.

Replacing 4-fluorophenylboronic acid with 2-(4-(2-methoxypropoxy)phenyl)-4,4,5,5-tetramethyl1,3,2-dioxaborolane and intermediate 1 with intermediate 5, use the same reaction sequence as described in Example 33 to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 8.38 (d, J=5.5 Hz, 1H), 8.04 (d, J=8.0 Hz, 2H), 7.47 (d, J= 8.0 Hz, 2H), 6.95 (d, J=5.5 Hz, 1H), 5.46 (s, 1H), 4.99-4.96 (m, 2H), 4.66 ( s, 2H), 3.66-3.60 (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. ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity >98% (214 nm and 254 nm); retention time 1.29 min; (M+H+) 508.3. 1H NMR (400 MHz, CDCl ₃ ) 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, 1H), 7.10-7.08 (d, J=7.2 Hz, 1H), 6.96-6.94 (d, J= 8.0 Hz, 1H), 5.46 (s, 1H), 3.83-3.80 (m, 2H), 3.08-2.78 (m, 8H), 2.41 (m, 1H ), 2.24-2.21 (m, 1H), 2.01-1.52 (m, 13H) ppm. LCMS purity >95% (214 and 254 nm); retention time 1.38 min; (M+H+) 418.3.

Example 70.

1-(4-(4-(Methoxymethyl)phenyl)pyrimidin-2-yl)-H-(4-methyl-1-azabicyclo[3.2.2]nonan-4yl)piperidin-4-carboxamide.

Replacing 4-fluorophenylboronic acid with 2-(4-(methoxymethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane, the same reaction sequence as described in Example 41 was used to obtain the title compound . 1H NMR (500 MHz, CDCl ₃ ) δ 8.37 (d, J=5.0 Hz, 1H), 8.04 (d, J=8.0 Hz, 2H), 7.44 (d, J= 8.0 Hz, 2H), 6.94 (d, J=5.0 Hz, 1H), 5.39 (s, 1H), 4.99-4.96 (m, 2H), 4.54 ( s, 2H), 3.43 (s,

- 50 046304

3H), 3.02-2.85 (m, 8H), 2.39-2.37 (m, 2H), 1.96-1.51 (m, 13H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) δ 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 LCMS purity >99% (214 nm and 254 nm); retention time 1.82 min; (M+H+) 464.4.

Example 71.

1-(4-(4-(2-Fluoroethoxy)phenyl)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4yl)piperidin-4-carboxamide.

Replacing 4-fluorophenylboronic acid with 2-(4-(2-fluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane, use the same reaction sequence as described in example 41 and obtain the name in connection header. ¹ H NMR (500 MHz, CDCl3) δ 8.34 (d, J=5.0 Hz, 1H), 8.04 (d, J=9.0 Hz, 2H), 7.02 (d, J= 9.0 Hz, 2H), 6.89 (d, J=5.5 Hz, 1H), 5.36 (s, 1H), 4.98-4.95 (m, 2H), 4.86- 4.74 (dt, J=48 Hz and 4.0 Hz, 1H), 4.33-4.26 (dt, J=27 Hz and 4.0 Hz, 1H), 3.03-2.83 ( m, 8H), 2.39-2.36 (m, 2H), 1.97-1.51 (m, 13H) ppm. ¹³ C NMR (125 MHz, CDCl3) 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 LCMS purity >99% (214 nm and 254 nm); retention time 1.47 min; (M+H+) 482.2.

Example 72.

1-(4-(4-(3-Methoxypropoxy)phenyl)pyrimidin-2-yl)-N-(quinuclidin-3-yl)piperidin-4carboxamide

Replacing 4-fluorophenylboronic acid with 2-(4-(3-methoxypropoxy)phenyl)-4,4,5,5-tetramethyl1,3,2-dioxaborolane and intermediate 5 with quinuclidin-3-amine, the same reaction sequence is used as described in Example 41 to obtain the title compound. ¹ H NMR (500 MHz, CDCl3) δ 8.34 (d, J=5.0 Hz, 1H), 8.03 (d, J=9.0 Hz, 2H), 7.00 (d, J= 9.0 Hz, 2H), 6.89 (d, J=5.0 Hz, 1H), 6.14 (br.s, 1H), 4.99 (d, J=13.0 Hz, 2H) , 4.16 (t, J=6.5 Hz, 2H), 4.07 (m, 1H), 3.61 (t, J=6.0 Hz, 2H), 3.40-3.37 ( m, 4H), 3.08-2.71 (m, 7H), 2.50-2.46 (m, 1H), 2.11-1.56 (m, 11H) ppm. ¹³ C 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 LCMS purity >99% (214 nm and 254 nm); retention time 1.26 min; (M+H+) 480.3.

Example 73.

1-(4-(4-(Methoxymethyl)phenyl)pyrimidin-2-yl)-N-(3-methylquinuclidin-3-yl)piperidin-4carboxamide.

Replacing 4-fluorophenylboronic acid with 2-(4-(methoxymethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane and intermediate 5 with intermediate 1, use the same reaction sequence as described in Example 41 and obtain the title compound. 1H NMR (400 MHz, CDCl ₃ ) δ 8.36-8.34 (d, J=5.2 Hz, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.43 ( d, J=8.0 Hz, 2H), 6.92 (d, J=5.2 Hz, 1H), 5.45 (s, 1H), 4.95 (d, J=13.2 Hz, 2H), 4.52 (s, 2H), 3.41 (s, 3H), 3.00-2.76 (m, 8H), 2.40-2.35 (m, 1H), 2.15 -2.13 (m, 1H), 1.95-1.47 (m, 11H) ppm. ¹³ C NMR (100 MHz, CDCl ₃ ) 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 LCMS purity >96% (214 nm and 254 nm); retention time 1.25 min; (M+H+) 450.3.

Example 74.

1-(4-(4-((2-Methoxyethoxy)methyl)phenyl)pyrimidin-2-yl)-H-(4-methyl-1-azabicyclo[3.2.2]nonan-4yl)piperidine-4-carboxamide.

Replacing 4-fluorophenylboronic acid with 2-(4-((2-methoxyethoxy)methyl)phenyl)-4,4,5,5tetramethyl-1,3,2-dioxaborolane, use the same reaction sequence as described in example 41 and the compound named in the header is obtained. 1H NMR (500 MHz, CDCl ₃ ) δ 8.38 (d, J=5.5 Hz, 1H), 8.04 (d, J=8.0 Hz, 2H), 7.47 (d, J= 8.0 Hz, 2H), 6.95 (d, J=5.5 Hz, 1H), 5.46 (s, 1H), 4.99-4.96 (m, 2H), 4.66 ( s, 2H), 3.66-3.60 (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. ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity >98% (214 nm and 254 nm); retention time 1.29 min; (M+H+) 508.3.

Example 75.

4-Fluoro-1-(4-(4-(methoxymethyl)phenyl)pyrimidin-2-yl)-H-(4-methyl-1-azabicyclo[3.2.2]nonan-4yl)piperidin-4-carboxamide.

Replacing 4-fluorophenylboronic acid with 2-(4-(methoxymethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane and ethylpiperidine-4-carboxylate with ethyl 4-fluoropiperidine-4-carboxylate hydrochloride, using the same reaction sequence as described in Example 41 to obtain the title compound. 1H NMR (400 MHz, CDCl ₃ ) δ 8.36 (d, J=5.6 Hz, 1H), 8.01 (d, J=8.0 Hz, 2H), 7.42 (d, J= 8.0 Hz, 2H), 6.94 (d, J=5.6 Hz, 1H), 6.35 (m, 1H), 4.89-4.85 (m, 2H), 4.51 ( s, 2H), 3.40 (s, 3H), 3.31-3.25 (m, 2H), 3.04-2.83 (m, 6H), 2.34-2.21 (m, 4H), 1.95-1.61 (m, 10H) ppm. ¹³ C NMR (100 MHz, CDCl ₃ ) δ 171.1, 170.9, 164.1, 161.7, 158.3, 140.7, 140.0, 127.8, 127.1, 105.8 , 96.2 (d, J=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. LCMS purity >97% (214 nm and 254 nm); retention time 1.37 min; (M+H+) 482.2.

- 51 046304

Example 76.

4-Fluoro-1 -(4-(4-(3-methoxypropoxy)phenyl)pyrimidin-2-yl)-H-(3-methylquinuclidin-3 yl)piperidine-4-carboxamide.

Replacing 4-fluorophenylboronic acid with 2-(4-(3-methoxypropoxy)phenyl)-4,4,5,5-tetramethyl1,3,2-dioxaborolane, ethylpiperidine-4-carboxylate with ethyl 4-fluoropiperidine-4carboxylate hydrochloride and intermediate 5 to intermediate 1, use the same reaction sequence as described in Example 41 to obtain the title compound. 1H NMR (400 MHz, CDCI3) δ 8.33 (d, J=5.2 Hz, 1H), 8.01 (d, J=8.8 Hz, 2H), 6.98 (d, J=9 ,2 Hz, 2H), 6.91 (d, J=5.2 Hz, 1H), 6.39 (d, J=6.4 Hz, 1H), 4.89-4.85 (m, 2H ), 4.13 (t, J=6.4 Hz, 2H), 3.59 (t, J=6.4 Hz, 2H), 3.38 (s, 3H), 3.01-3.26 (m, 2H), 3.05-2.82 (m, 6H), 2.31-2.05 (m, 6H), 1.86-1.51 (m, 8H) ppm. ¹³ C NMR (100 MHz, CDCl ₃ ) 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. LCMS purity >96% (214 nm and 254 nm); retention time 1.54 min; (M+H+) 512.3.

Example 77.

4-Fluoro-1-(5-fluoro-4-(4-((2-methoxyethoxy)methyl)phenyl)pyrimidin-2-yl)-H-(4-methyl-1azabicyclo[3.2.2]nonane-4 - yl)piperidine-4-carboxamide.

Replacing 4-fluorophenylboronic acid with 2-(4-((2-methoxyethoxy)methyl)phenyl)-4,4,5,5tetramethyl-1,3,2-dioxaborolane, ethylpiperidine-4-carboxylate with ethyl-4-fluoropiperidine hydrochloride4 -carboxylate and 2,4-dichloropyrimidine to 2,4-dichloro-5-fluoropyrimidine, using the same reaction sequence as described in Example 41 to obtain the title compound. 1H NMR (400 MHz, CDCI3) δ 8.24 (d, J=3.6 Hz, 1H), 8.05 (d, J=8.2 Hz, 2H), 7.46 (d, J=8 ,2 Hz, 2H), 6.34 (d, J=7.2 Hz, 1H), 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), 2.352.17 (m, 3H ), 1.96-1.50 (m, 11H) ppm. ¹³ C 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 LCMS purity >99% (214 nm and 254 nm); retention time 1.57 min; (M+H+) 544.3.

Example 78.

4-Fluoro-1-(5-fluoro-4-(4-((2-methoxyethoxy)methyl)phenyl)pyrimidin-2-yl)-H-(4-methyl-1-azabicyclo[3.2.2]nonan- 4-yl)piperidine-4-carboxamide (single enantiomer A).

Replacing 4-fluorophenylboronic acid with 2-(4-((2-methoxyethoxy)methyl)phenyl)-4,4,5,5tetramethyl-1,3,2-dioxaborolane, ethylpiperidine-4-carboxylate with ethyl-4-fluoropiperidine hydrochloride4 -carboxylate, 2,4-dichloropyrimidine to 2,4-dichloro-5-fluoropyrimidine and intermediate 5 to intermediate 9, use the same reaction sequence as described in Example 41 to obtain the title compound. 1H NMR (400 MHz, CDCl ₃ ) δ 8.24 (d, J=3.5 Hz, 1H), 8.05 (d, J=8.4 Hz, 2H), 7.46 (d, J= 8.4 Hz, 2H), 6.34 (d, J=7.3 Hz, 1H), 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. UP-LCMS purity >99.9% (214 and 254 nm); retention time 0.92 min; (M+H+) 544.5.

Example 79.

4-Fluoro-1-(5-fluoro-4-(4-((2-methoxyethoxy)methyl)phenyl)pyrimidin-2-yl)-H-(4-methyl-1azabicyclo[3.2.2]nonane-4- yl)piperidine-4-carboxamide (single enantiomer B).

Replacing 4-fluorophenylboronic acid with 2-(4-((2-methoxyethoxy)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, ethylpiperidine-4-carboxylate with ethyl-4 hydrochloride -fluoropiperidine-4-carboxylate, 2,4-dichloropyrimidine to 2,4-dichloro-5-fluoropyrimidine and intermediate 5 to intermediate 10, use the same reaction sequence as described in Example 41 to obtain the title compound. 1H NMR (400 MHz, CDCl ₃ ) δ 8.24 (d, J=3.5 Hz, 1H), 8.05 (d, J=8.4 Hz, 2H), 7.46 (d, J= 8.4 Hz, 2H), 6.34 (d, J=7.3 Hz, 1H), 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. UP-LCMS purity >99.9% (214 and 254 nm); retention time 0.92 min; (M+H+) 544.5.

Example 80.

4-Fluoro-1 -(4-(4-(methoxymethyl)phenyl)pyrimidin-2-yl)-N-(3-methylquinuclidin-3-yl)piperidin-4carboxamide.

Replacing 4-fluorophenylboronic acid with 2-(4-(methoxymethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane, ethylpiperidine-4-carboxylate with ethyl 4-fluoropiperidine-4-carboxylate hydrochloride and intermediate 5 to intermediate 1, use the same reaction sequence as described in Example 41 to obtain the title compound. 1H NMR (500 MHz, CDCI3) δ 8.40 (d, J=5.5 Hz, 1H), 8.05 (d, J=8.0 Hz, 2H), 7.45 (d, J=8 .0 Hz, 2H), 6.98 (d, J=4.5 Hz, 1H), 6.44 (d, J=7.0 Hz, 1H), 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. ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity >97% (214 nm and 254 nm); retention time 1.50 min; (M+H+)

- 52 046304

468.3.

Example 81.

(b)-4-Fluoro-1-(4-(4-(methoxymethyl)phenyl)pyrimidin-2-yl)-H-(3-methylquinuclidin-3-yl)piperidin4-carboxamide.

Replacing 4-fluorophenylboronic acid with 2-(4-(methoxymethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane, ethylpiperidine-4-carboxylate with ethyl 4-fluoropiperidine-4-carboxylate hydrochloride and intermediate 5 to intermediate 11, use the same reaction sequence as described in Example 41 to obtain the title compound. ^1H NMR (500 MHz, CDCI3) δ 8.39 (d, J=5.5 Hz, 1H), 8.04 (d, J=8.5 Hz, 2H), 7.45 (d, J= 8.5 Hz, 2H), 6.97 (d, J=5.5 Hz, 1H), 6.40 (d, J=6.5 Hz, 1H), 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), 2.342.20 (m, 5H), 1.91-1.51 (m, 7H) ppm ¹³ C NMR (125 MHz, CDCl ₃ ) 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. LCMS purity >99% (214 nm and 254 nm); retention time 1.38 min; (M+H+) 468.2.

Example 82.

4-Fluoro-1-(4-(4-(3-methoxypropoxy)phenyl)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan4-yl)piperidin-4-carboxamide .

Replacing 4-fluorophenylboronic acid with 2-(4-(3-methoxypropoxy)phenyl)-4,4,5,5-tetramethyl1,3,2-dioxaborolane and ethylpiperidine-4-carboxylate with ethyl 4-(torpiperidine-4carboxylate) hydrochloride , use the same reaction sequence as described in example 41 to obtain the title compound. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33 (d, J=5.2 Hz, 1H), 8.01 ( d, J=8.8 Hz, 2H), 6.98 (d, J=8.4 Hz, 2H), 6.91 (d, J=5.2 Hz, 1H), 6.36 (d, J=7.6 Hz, 1H), 4.89-4.86 (m, 2H), 4.13 (t, J=6.4 Hz, 2H), 3.59 (t, J=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 ¹³ C NMR (100 MHz, CDC13) 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 UP-LCMS purity >96% (214 nm and 254 nm); retention time 1.57 min; (M+H+) 526.4.

Example 83.

4-Fluoro-1 -(4-(4-((2-methoxyethoxy)methyl)phenyl)pyrimidin-2-yl)-N-(3-methylquinuclidin-3 yl)piperidine-4-carboxamide.

Replacing 4-fluorophenylboronic acid with 2-(4-((2-methoxyethoxy)methyl)phenyl)-4,4,5,5tetramethyl-1,3,2-dioxaborolane, ethylpiperidine-4-carboxylate with ethyl-4-fluoropiperidine hydrochloride4 -carboxylate and intermediate 5 to intermediate 1, use the same reaction sequence as described in Example 41 to obtain the title compound. ¹ 11 NMR (500 MHz, CDC13) δ 8.39 (d, J=5.5 Hz, 1H), 8.04 (d, J=8.0 Hz, 2H), 7.47 (d, J= 8.0 Hz, 2H), 6.97 (d, J=5.0 Hz, 1H), 6.39 (d, J=7.5 Hz, 1H), 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, J=12.0 Hz, 2H), 2.97-2.83 (m, 6H), 2.35-2.19 (m, 3H), 1.91-1.51 (m, 9H) ppm. ¹³ C NMR (125 MHz, CDC13) δ 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 LCMS purity >99% (214 nm and 254 nm); retention time 1.34 min; (M+H+) 512.3.

Example 84.

^)-4-Fluoro-1-(4-(4-((2-methoxyethoxy)methyl)phenyl)pyrimidin-2-yl)-H-(3-methylquinuclidin-3yl)piperidine-4-carboxamide.

Replacing 4-fluorophenylboronic acid with 2-(4-((2-methoxyethoxy)methyl)phenyl)-4,4,5,5tetramethyl-1,3,2-dioxaborolane, ethylpiperidine-4-carboxylate with ethyl-4-fluoropiperidine hydrochloride4 -carboxylate and intermediate 5 to intermediate 11, use the same reaction sequence as described in Example 41 to obtain the title compound. ¹ 11 NMR (500 MHz, CDCl ₃ ) δ 8.38 (d, J=5.0 Hz, 1H), 8.03 (d, J=8.0 Hz, 2H), 7.46 (d, J =8.0 Hz, 2H), 6.96 (d, J=5.5 Hz, 1H), 6.41 (d, J=7.0 Hz, 1H), 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. ¹³ C NMR (100 MHz, CDC13) 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 LCMS purity >99% (214 nm and 254 nm); retention time 1.34 min; (M+H+) 512.3.

Example 85.

4-Fluoro-1-(4-(4-(2-methoxyethoxy)phenyl)pyrimidin-2-yl)-N-(3-methylquinuclidin-3-yl)piperidin4-carboxamide.

Replacing 4-fluorophenylboronic acid with (4-(2-methoxyethoxy))phenyl)boronic acid, ethylpiperidine-4-carboxylate with ethyl 4-fluoropiperidine-4-carboxylate hydrochloride, and intermediate 5 with intermediate 1, the same reaction sequence is used as described in Example 41 to obtain the title compound. ^1H NMR (500 MHz, CDCl3) δ 8.35 (d, J=5.0 Hz, 1H), 8.03 (d, J=9.0 Hz, 2H), 7.02 (d, J= 9.0 Hz, 2H), 6.92 (d, J=5.5 Hz, 1H), 6.58 (d, J=6.5 Hz, 1H), 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. ¹³ C NMR (125 MHz, CDCl3) δ 171.7, 171.5, 163.9, 161.7, 160.8,

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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 LCMS purity >99% (214 nm and 254 nm); retention time 1.32 min; (M+H+) 497.9.

Example 86.

(R)-4-Fluoro-1-(4-(4-(2-methoxyethoxy)phenyl)pyrimidin-2-yl)-H-(3-methylquinuclidin-3-yl)piperidin-4-carboxamide.

Replacing 4-fluorophenylboronic acid with (4-(2-methoxyethoxy))phenyl)boronic acid, ethylpiperidine-4-carboxylate with ethyl 4-fluoropiperidine-4-carboxylate hydrochloride, and intermediate 5 with intermediate 11, the same reaction sequence is used as described in Example 41 to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 8.34 (d, J=4.5 Hz, 1H), 8.02 (dd, J=11.0 Hz & 2.5 Hz, 2H), 7.02 (dd, J=11.0 Hz and 2.5 Hz, 2H), 6.91 (d, J=5.5 Hz, 1H), 6.38 (d, J=7.0 Hz, 1H), 4.89-4.86 (m, 2H), 4.20 (t, J=5.0 Hz, 2H), 3.80 (t, J=5.0 Hz, 2H), 3.48 (s , 3H), 3.32-3.26 (m, 2H), 2.95-2.74 (m, 6H), 2.33-2.18 (m, 3H), 1.92-1.75 (m, 4H), 1.58-1.43 (m, 5H) ppm ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity >99% (214 nm and 254 nm); retention time 1.35 min; (M+H+) 498.2.

Example 87.

4-Fluoro-1-(4-(4-(2-fluoroethoxy)phenyl)pyrimidin-2-yl)-N-(quinuclidin-3-yl)piperidin-4-carboxamide.

Replacing 4-fluorophenylboronic acid with 2-(4-(2-fluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane, ethylpiperidine-4-carboxylate with ethyl-4-(torpiperidine-4) hydrochloride -carboxylate and intermediate 5 on quinuclidine-3-amine, use the same reaction sequence as described in example 41 to obtain the title compound ¹ H NMR (500 MHz, CDCl3) δ 8.36 (d, J=4). .5 Hz, 1H), 8.05 (d, J=9.0 Hz, 2H), 7.03 (d, J=8.5 Hz, 2H), 6.93 (d, J=5.5 Hz, 1H), 6.85 (m, 1H), 4.91-4.76 (m, 4H), 4.32-4.06 (dt, J=19.5 Hz and 4.5 Hz, 2H ), 4.07-4.06 (m, 1H), 3.47-3.30 (m, 3H), 3.12-2.80 (m, 5H), 2.32-1.62 (m , 9H) ppm ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity >95% (214 nm and 254 nm); retention time 1.31 min (M+H); +) 472.0.

Example 88.

^)-4-Fluoro-1-(4-(4-(2-fluoroethoxy)phenyl)pyrimidin-2-yl)-N-(quinuclidin-3-yl)piperidin-4carboxamide.

Replacing 4-fluorophenylboronic acid with 2-(4-(2-fluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane, ethylpiperidine-4-carboxylate with ethyl-4-fluoropiperidine-4-hydrochloride carboxylate and intermediate 5 on (R)-quinuclidine-3-amine. using the same reaction sequence as described in Example 41 to obtain the title compound. ^1H NMR (500 MHz, CDC13) δ 8.36 (d, J=5.5 Hz, 1H), 8.04 (dd, J=7.0 Hz & 2.0 Hz, 2H), 7.03 (d, J=8.5 Hz, 2H), 6.93 (d, J=5.0 Hz, 1H), 6.65 (t, J=6.5 Hz, 1H), 4.91-4 .86 (m, 3H), 4.77 (t, J=4.0 Hz, 1H), 4.34-4.26 (m, 2H), 4.00 (m, 1H), 3.453.34 ( m, 1H), 3.35-3.30 (m, 2H), 2.89-2.83 (m, 4H), 2.61-2.58 (m, 1H), 2.35-2, 20 (m, 2H), 2.00-1.87 (m, 3H), 1.75-1.70 (m, 3H), 1.58-1.55 (m, 1H) ppm. ¹³ C NMR (100 MHz, CDCl ₃ ) δ 171.8, 171.6, 163.8, 161.6, 160.4, 158.2, 130.6, 128.6, 114.6, 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 LCMS purity >95% (214 nm and 254 nm); retention time 1.31 min; (M+H+) 472.2.

Example 89.

4-Fluoro-1 -(4-(4-((2-methoxyethoxy)methyl)phenyl)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl) piperidine-4-carboxamide.

Replacing 4-fluorophenylboronic acid with 2-(4-((2-methoxyethoxy)methyl)phenyl)-4,4,5,5tetramethyl-1,3,2-dioxaborolane and ethylpiperidine-4-carboxylate with ethyl-4-fluoropiperidine hydrochloride4 -carboxylate, use the same reaction sequence as described in Example 41 to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 8.39 (d, J=5.5 Hz, 1H), 8.04 (d, J=8.5 Hz, 2H), 7.47 (d, J= 8.0 Hz, 2H), 6.95 (d, J=5.0 Hz, 1H), 6.67 (d, J=7.5 Hz, 1H), 4.90-4.87 (m, 2H), 4.66 (s, 2H), 3.67-3.61 (m, 4H), 3.43 (s, 3H), 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. ¹³ C NMR (125 MHz, CDC13) δ 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. LCMS purity >99% (214 nm and 254 nm); retention time 1.36 min; (M+H+) 526.3.

Example 90.

4-Fluoro-1-(4-(4-(2-fluoroethoxy)phenyl)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4yl)piperidin-4-carboxamide .

Replacing 4-fluorophenylboronic acid with 2-(4-(2-fluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane and ethylpiperidine-4-carboxylate with ethyl 4-fluoropiperidine-4-hydrochloride carboxylate, use the same reaction sequence as described in Example 41 to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 8.36 (d, J=5.5 Hz, 1H), 8.04 (d, J=9.0 Hz, 2H), 7.03 (d,

- 54 046304

J=8.5 Hz, 2H), 6.93 (d, J=5.0 Hz, 1H), 6.38 (d, J=7.0 Hz, 1H), 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 ¹³ C NMR (125 MHz, CDCl ₃ ) δ 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. LCMS purity >96% (214 nm and 254 nm); retention time 1.33 min; (M+H+) 500.0.

Example 91.

4-Fluoro-1-(5-fluoro-4-(4-(2-methoxyethoxy)phenyl)pyrimidin-2-yl)-H-(4-methyl-1azabicyclo[3.2.2] nonan-4 -yl)piperidine -4-carboxamide.

By replacing 4-fluorophenylboronic acid with (4-(2-methoxyethoxy)phenyl)boronic acid, ethylpiperidine-4-carboxylate with ethyl 4-fluoropiperidine-4-carboxylate hydrochloride, and 2,4dichloropyrimidine with 2,4-dichloro-5-fluoropyrimidine, using the same reaction sequence as described in Example 41 to obtain the title compound. ^1H NMR (500 MHz, CDCl3) δ 8.22 (d, J=3.5 Hz, 1H), 8.10 (d, J=9.0 Hz, 2H), 7.03 (d, J= 8.0 Hz, 2H), 6.37 (d, J=7.5 Hz, 1H), 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 ¹³ C NMR (125 MHz, CDCl3) δ 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. LCMS purity >99% (214 nm and 254 nm); retention time 1.44 min; (M+H+) 530.2.

Example 92.

4-Fluoro-1 -(4-(4-(2-fluoroethoxy)phenyl)pyrimidin-2-yl)-N-(3-methylquinuclidin-3-yl)piperidin-4carboxamide.

Replacing 4-fluorophenylboronic acid with 2-(4-(2-fluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane, ethylpiperidine-4-carboxylate with ethyl-4-fluoropiperidine-4-hydrochloride carboxylate and intermediate 5 to intermediate 1, use the same reaction sequence as described in Example 41 to obtain the title compound. 1H NMR (400 MHz, CDCl ₃ ) δ 8.35 (d, J=5.2 Hz, 1H), 8.04 (d, J=8.8 Hz, 2H), 7.02 (d, J= 8.4 Hz, 2H), 6.92 (d, J=5.6 Hz, 1H), 6.41 (d, J=6.8 Hz, 1H), 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. ¹³ C NMR (100 MHz, CDCl ₃ ) 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 LCMS purity >99% (214 nm and 254 nm); retention time 1.32 min; (M+H+) 486.0.

Example 93.

4-Fluoro-1-(4-(4-(2-methoxyethoxy)phenyl)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4yl)piperidine-4-carboxamide .

Replacing 4-fluorophenylboronic acid with (4-(2-methoxyethoxy)phenyl)boronic acid and ethylpiperidine-4-carboxylate with ethyl 4-fluoropiperidine-4-carboxylate hydrochloride, use the same reaction sequence as described in example 41 and obtain the title in the connection header. 1H NMR (500 MHz, CDCl ₃ ) δ 8.35 (d, J=5.0 Hz, 1H), 8.03 (d, J=9.0 Hz, 2H), 7.02 (d, J= 9.0 Hz, 2H), 6.92 (d, J=5.5 Hz, 1H), 6.37 (d, J=7.0 Hz, 1H), 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. ¹³ C NMR (100 MHz, CDCl ₃ ) 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 LCMS purity >99% (214 nm and 254 nm); retention time 1.33 min; (M+H+) 512.0.

Example 94.

4-Fluoro-1-(4-(4-fluorophenyl)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin4-carboxamide.

Replacing ethylpiperidine-4-carboxylate with ethyl 4-fluoropiperidine-4-carboxylate hydrochloride, the same reaction sequence as described in Example 41 was used to obtain the title compound. 1H NMR (400 MHz, CDCl ₃ ) δ 8.36 (d, J=5.2 Hz, 1H), 8.07-7.96 (m, 2H), 7.14 (t, J=8.7 Hz, 2H), 6.89 (d, J=5.2 Hz, 1H), 6.35 (d, J=7.2 Hz, 1H), 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 ), 1.67-1.40 (m, 5H) ppm. UP-LCMS purity 99.7% (214 and 254 nm); retention time 0.87 min; (M+H+) 456.5.

Example 95.

4-Fluoro-1 -(4-(4-fluorophenyl)pyrimidin-2-yl)-N-(3-methylquinuclidin-3-yl)piperidin-4carboxamide.

Replacing ethylpiperidine-4-carboxylate with ethyl 4-fluoropiperidine-4-carboxylate hydrochloride and intermediate 5 with intermediate 1, the same reaction sequence as described in Example 41 was used to obtain the title compound. 1H NMR (400 MHz, CDCl ₃ ) δ 8.36 (d, J=5.1 Hz, 1H), 8.07-7.97 (m, 2H), 7.18-7.06 (m, 2H ), 6.89 (d, J=5.1 Hz, 1H), (d, J=6.9 Hz, 1H), 4.93-4.75 (m, 2H), 3.37-3, 18 (m, 2H), 2.99-2.67 (m, 6H), 2.37-2.09 (m, 3H), 1.95-1.67 (m, 4H), 1.601.34 ( m, 5H) ppm UP-LCMS purity 99.7% (214 and 254 nm); retention time 0.92 min; (M+H+)

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442.5.

Example 96.

1-(4-(4-(Methoxymethyl)phenyl)pyrimidin-2-yl)-4-methyl-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4yl)piperidin-4-carboxamide.

Replacing 4-fluorophenylboronic acid with 2-(4-(methoxymethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane and ethyl 4-piperidine-4-carboxylate with ethyl 4-fluoropiperidine-4carboxylate hydrochloride , use the same reaction sequence as described in example 41 to obtain the title compound. 1H NMR (400 MHz, CDCl ₃ ) δ 8.35 (d, J=5.1 Hz, 1H), 8.03 (d, J=8.2 Hz, 2H), 7.43 (d, J= 8.2 Hz, 2H), 6.92 (d, J=5.1 Hz, 1H), 5.48 (s, 1H), 4.52 (s, 2H), 4.27-4.16 ( m, 2H), 3.75-3.64 (m, 2H), 3.41 (s, 3H), 3.09-2.74 (m, 6H), 2.44-2.32 (m, 1H), 2.11-2.01 (m, 2H), 2.00-1.89 (m, 1H), 1.87-1.45 (m, 10H), 1.27 (s, 3H) m.d. UP-LCMS purity >99.9% (214 and 254 nm); retention time 0.83 min; (M+H+) 478.4.

Example 97.

1-(4-(4-((2-Methoxyethoxy)methyl)phenyl)pyrimidin-2-yl)-4-methyl-N-(4-methyl-1-azabicyclo[3.2.2] nonan-4-yl) piperidine-4-carboxamide.

Replacing 4-fluorophenylboronic acid with 2-(4-((2-methoxyethoxy)methyl)phenyl)-4,4,5,5tetramethyl-1,3,2-dioxaborolane and ethylpiperidine-4-carboxylate with ethyl-4-fluoropiperidine hydrochloride4 -carboxylate, use the same reaction sequence as described in Example 41 to obtain the title compound. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.36-8.35 (d, J=5.2 Hz, 1H), 8.03 (d, J=8.0 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 6.92 (d, J=4.8 Hz, 1H), 5.50 (s, 1H), 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 , 1H), 2.07-1.50 (m, 13H), 1.27 (s, 3H) ppm. ¹³ C NMR (100 MHz, CDCl3) δ 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 LCMS purity >95% (214 nm and 254 nm); retention time 1.35 min; (M+H+) 522.3.

Example 98.

1-(4-(4-((2-Methoxyethoxy)methyl)phenyl)pyrimidin-2-yl)-4-methyl-N-(3-methylquinuclidin-3yl)piperidine-4-carboxamide.

Replacing 4-fluorophenylboronic acid with 2-(4-((2-methoxyethoxy)methyl)phenyl)-4,4,5,5tetramethyl-1,3,2-dioxaborolane, ethylpiperidine-4-carboxylate with ethyl-4-fluoropiperidine hydrochloride4 -carboxylate and intermediate 5 to intermediate 1, use the same reaction sequence as described in Example 41 to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 8.37 (d, J=4.5 Hz, 1H), 8.04 (d, J=8.0 Hz, 2H), 7.46 (d, J= 8.5 Hz, 2H), 6.93 (d, J=5.5 Hz, 1H), 5.62 (s, 1H), 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, 1H), 2 .10-2.07 (m, 2H), 1.82-1.49 (m, 9H), 1.29 (s, 3H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) δ 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 LCMS purity >99% (214 nm and 254 nm); retention time 1.33 min; (M+H+) 508.3.

Example 99.

1-(4-(4-Fluorophenyl)pyrimidin-2-yl)-4-hydroxy-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin-4-carboxamide.

To a solution of 2,4-dichloropyrimidine (3.00 g, 20.1 mmol) in toluene (25 ml) add 4-fluorophenylboronic acid (2.82 g, 20.1 mmol), potassium carbonate (8.32 g) with stirring , 60.3 mmol), tetrakis(triphenylphosphine)palladium(0) (0.630 g, 0.545 mmol) and ethanol/water, 1:1 (v/v, 36 ml). The mixture is heated at 55°C for 12 hours and then concentrated. The residue is diluted with water and extracted with ethyl acetate. The combined extracts are washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by flash chromatography on silica using hexane/ethyl acetate to give 2-chloro-4-(4-fluorophenyl)pyrimidine as a yellow solid (2.50 g, 61%). To a solution of the resulting compound (1.04 g, 5.00 mmol) in N-dimethylformamide (15 ml), 4-hydroxypiperidine-4-carboxylic acid (0.910 g, 5.00 mmol) and cesium carbonate (3.43 g, 10.5 mmol). The mixture is heated overnight at 100°C and then concentrated. The residue was purified by flash chromatography on silica using hexane/ethyl acetate to give 1-(4-(4-fluorophenyl)pyrimidin-2-yl)-4-hydroxypiperidine-4-carboxylic acid as a yellow solid (1, 02 g, 64%). Using General Procedure D and Intermediate 5, the resulting carboxylic acid was amide coupled to give the title compound as a white solid (0.071 g, 39%). 1H NMR (500 MHz, CDCl ₃ ) δ 8.37 (d, J=5.0 Hz, 1H), 8.07-8.04 (m, 2H), 7.15 (t, J=8.5 Hz, 2H), 6.89 (d, J=5.0 Hz, 1H), 6.74 (s, 1H), 4.82 (d, J=12.5 Hz, 2H), 3.99 ( br.s, 1H), 3.34-3.30 (m, 2H), 3.01-2.84 (m, 6H), 2.39 (m, 1H), 2.17-2.14 ( m, 2H), 1.95-1.49 (m, 11H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity >98% (214 nm and 254 nm); retention time 1.52 min; (M+H+) 454.3.

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Example 100.

1-(4-(4-Fluorophenyl)pyrimidin-2-yl)-4-methoxy-H-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin-4-carboxamide.

To a solution of 2,4-dichloropyrimidine (3.00 g, 20.1 mmol) in toluene (25 ml) add 4-fluorophenylboronic acid (2.82 g, 20.1 mmol), potassium carbonate (8.32 g) with stirring , 60.3 mmol), tetrakis(triphenylphosphine)palladium(0) (0.630 g, 0.545 mmol) and ethanol/water, 1:1 (v/v, 36 ml). The mixture is heated at 55°C for 12 hours and then concentrated. The residue is diluted with water and extracted with ethyl acetate. The combined extracts are washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by flash chromatography on silica using hexane/ethyl acetate to give 2-chloro-4-(4-fluorophenyl)pyrimidine as a yellow solid (2.50 g, 61%). To a solution of the resulting compound (0.317 g, 1.00 mmol) in NN-dimethylformamide (15 ml) was added sodium hydride (60% dispersion in mineral oil, 0.120 g, 3.00 mmol) with stirring and cooling. After adding iodomethane (0.187 ml, 3.00 mmol), the mixture was stirred for 30 minutes and then the mixture was gradually warmed to room temperature and stirred overnight. The reaction mixture is concentrated and the residue is treated with water and ethyl acetate. The organic layer is combined with the other ethyl acetate extract, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography on silica using hexane/ethyl acetate to give methyl 1-(4-(4-fluorophenyl)pyrimidin-2-yl)-4-methoxypiperidin-4-carboxylate as a yellow oil (0.210 g, 61 %). To a solution of the resulting 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) with stirring. After stirring overnight, the solution is acidified with 2.0 M hydrochloric acid and extracted with ethyl acetate. The combined extracts were dried (Na ₂ SO ₄ ) and concentrated to give 1-(4-(4-fluorophenyl)pyrimidin-2-yl)-4methoxypiperidine-4-carboxylic acid as a white solid (0.157 g, 95%). Using General Procedure D and Intermediate 5, the resulting carboxylic acid was amide coupled to give the title compound as a white solid (0.061 g, 44%). 1H NMR (500 MHz, CDCl ₃ ) δ 8.37 (d, J=5.5 Hz, 1H), 8.07-8.05 (m, 2H), 7.16 (t, J=8.5 Hz, 2H), 6.90 (d, J=5.5 Hz, 1H), 6.46 (s, 1H), 4.70-4.67 (m, 2H), 3.36-3.29 (m, 5H), 3.08-2.87 (m, 6H), 2.39 (m, 1H), 2.131.51 (m, 13H) ppm. ¹³ C NMR (100 MHz, CDCI3) δ 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 LCMS purity >98% (214 nm and 254 nm); retention time 1.38 min; (M+H+) 468.3.

Example 101.

4-Methoxy-1-(4-(4-(3-methoxypropoxy)phenyl)pyrimidin-2-yl)-H-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin-4 -carboxamide.

Replacing 4-fluorophenylboronic acid with 2-(4-(3-methoxypropoxy)phenyl)-4,4,5,5-tetramethyl1,3,2-dioxaborolane, use the same reaction sequence as described in example 100 and obtain the name in connection header. 1H NMR (500 MHz, CDCl ₃ ) δ 8.34 (d, J=5.0 Hz, 1H), 8.02 (d, J=8.5 Hz, 2H), 6.99 (d, J= 9.0 Hz, 2H), 6.89 (d, J=5.0 Hz, 1H), 6.46 (s, 1H), 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, 1H), 2.12-1.52 (m, 15H) ppm ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity >96% (214 nm and 254 nm); retention time 1.36 min; (M+H+) 538.3.

Example 102.

1-(5-Fluoro-(4-(4-(2-fluoroethoxy)phenyl)pyrimidin-2-yl)-4-methoxy-H-(4-methyl-1-azabicyclo[3.2.2]nonane-4- yl)piperidine-4-carboxamide.

Replacing 4-fluorophenylboronic acid with 2-(4-(2-fluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane and 2,4-dichloropyrimidine with 2,4-dichloro-5-fluoropyrimidine , use the same reaction sequence as described in example 100 to obtain the title compound. ¹ H NMR (500 MHz, CDCI3) δ 8.22 (d, J=4.0 Hz, 1H), 8.11 (d, J=8.5 Hz, 2H), 7.03 (d, J= 8.5 Hz, 2H), 6.45 (s, 1H), 4.87-4.75 (dt, J=47.5 Hz and 4.0 Hz, 2H), 4.58-4.56 ( m, 2H), 4.33-4.27 (dt, J=27.5 Hz and 4.0 Hz, 2H), 3.34 (s, 3H), 3.31-3.27 (m, 2H ), 3.03-2.87 (m, 6H), 2.37 (m, 1H), 2.09-1.50 (m, 13H) ppm. ¹³ C NMR (125 MHz, CDCI3) 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, 39.0, 36.4, 31.3, 30.3, 25.0, 24.3, 24.1 ppm. LCMS purity >97% (214 nm and 254 nm); retention time 1.49 min; (M+H+) 530.3.

Example 103.

1-(4-(4-(2-Fluoroethoxy)phenyl)pyrimidin-2-yl)-4-methoxy-H-(4-methyl-1-azabicyclo[3.2.2]nonan-4yl)piperidine-4-carboxamide .

Replacing 4-fluorophenylboronic acid with 2-(4-(2-fluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane, use the same reaction sequence as described in example 100 and obtain the name in connection header. 1H NMR (500 MHz, CDCl ₃ ) δ 8.33 (d, J=5.0 Hz, 1H), 8.03 (d, J=9.0 Hz, 2H), 7.01 (d, J= 9.0 Hz, 2H), 6.88 (d, J=4.5 Hz, 1H), 6.44 (s, 1H), 4.85-4.73 (dt, J=47.5 Hz and 4.0 Hz, 2H), 4.68-4.66 (m, 2H), 4.32-4.24 (dt, J=27.5 Hz and 4.0 Hz, 2H), 3.33- 3.27 (m, 5H), 3.07-2.84 (m, 6H), 2.37 (s, 1H),

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2.12-1.49 (m, 13H) ppm ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity >96% (214 nm and 254 nm); retention time 1.35 min; (M+H+) 512.3.

Example 104.

1-(4-(4-Fluorophenyl)-5-(2-methoxyethoxy)pyrimidin-2-yl)-H-(4-methyl-1-azabicyclo[3.2.2]nonan-4yl)piperidin-4-carboxamide.

Replacing 2,4-dichloropyrimidine with 2,4-dichloro-5-methoxypyrimidine, the first two steps of the reaction sequence described in Example 41 were used to prepare the intermediate 1(4-(4-fluorophenyl)-5-methoxypyrimidin-2-yl )piperidine-4-carboxylate. To a solution of the resulting compound (2.20 g, 6.13 mmol) in dichloromethane (30 ml) with stirring and cooling (-70°C) add a 4.0 M solution of boron tribromide in dichloromethane (6.13 ml, 24.5 mmol ). The reaction mixture is stirred at -70°C for 1 hour, warmed to 0°C and then stirred for a further 2 hours. After quenching by adding methanol, the reaction mixture is treated with water and dichloromethane. The aqueous phase is again extracted with dichloromethane and the combined organic layers are dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography on silica using dichloromethane/methanol as eluent to give ethyl 1-(4-(4-fluorophenyl)-5-hydroxypyrimidin-2-yl)piperidine-4-carboxylate as a brown oil (1. 50 g, 71%). To a solution of the resulting compound (0.900 g, 2.6 mmol) in N,Ndimethylformamide (10 ml), 1-bromo-2-methoxyethane (0.725 g, 5.22 mmol) and cesium carbonate (2.55 g, 7 .83 mmol). The reaction mixture was stirred at 60°C for 4 hours, then diluted with water and extracted with ethyl acetate. The combined organic layers are washed with water and aqueous sodium chloride, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography on silica using hexane/ethyl acetate to give ethyl 1-(4-(4-fluorophenyl)-5-(2-methoxyethoxy)pyrimidin-2-yl)piperidin-4-carboxylate as a brown oil. (0.550 g, 52%). To a solution of the resulting ester (0.550 g, 1.36 mmol) in a 1:1:1 tetrahydrofuran/water/methanol mixture (9 ml) was added sodium hydroxide (0.273 g, 6.82 mmol) with stirring. After 3 hours, the reaction mixture is concentrated and the residue is dissolved in water. The solution is acidified (pH~3) by adding 1.0N. hydrochloric acid and then extracted with ethyl acetate. The combined extracts were dried (Na ₂ SO ₄ ) and concentrated to give 1-(4-(4-fluorophenyl)-5-(2-methoxyethoxy)pyrimidin-2yl)piperidine-4-carboxylic acid as a light yellow solid (0.450 g, 88%). Using General Procedure D and Intermediate 5, the resulting carboxylic acid was amide coupled to give the title compound as a light yellow solid (0.090 g, 44%). ^1H NMR (500 MHz, CDCl3) δ 8.22-8.19 (m, 3H), 7.15-7.11 (m, 2H), 5.37 (s, 1H), 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. ¹³ C NMR (125 MHz, CDCl3) 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 LCMS purity >98% (214 nm and 254 nm); retention time 1.55 min; (M+H+) 512.3.

Example 105.

1-(4-(4-Fluorophenyl)-6-(2-methoxyethoxy)pyrimidin-2-yl)-H-(4-methyl-1-azabicyclo[3.2.2]nonan-4yl)piperidin-4-carboxamide.

Replacing 2,4-dichloropyrimidine with 2,4,6-trichloropyrimidine, the first step of the reaction sequence described in Example 41 was used to produce the 2,4-dichloro-6(4-fluorophenyl)pyrimidine intermediate. Cesium carbonate (3.23 g, 9.90 mmol) was added to a solution of the resulting compound (0.800 g, 3.30 mmol) in acetonitrile (20 ml) with stirring. The suspension is stirred at 0°C for 30 min and then 2-methoxyethanol (0.201 g, 2.64 mmol) is added dropwise over 2-3 min. The mixture is gradually warmed to room temperature, stirred for more than 2 hours and then concentrated. The residue was purified by flash chromatography on silica using hexane/ethyl acetate to give 2-chloro-(4-(4-fluorophenyl)-6-(2-methoxyethoxy)pyrimidine as a colorless oil (0.470 g, 51%). To a solution of the resulting compound (0.300 g, 1.06 mmol) in ethanol (5 ml), trifluoroacetic acid (0.081 ml, 1.06 mmol) and ethylpiperidine-4-carboxylate (0.200 g, 1.28 mmol) were added with stirring. the mixture is heated at 80°C overnight, cooled and concentrated. The residue is purified by flash chromatography on silica using hexane/ethyl acetate to give ethyl 1-(4-(4-fluorophenyl)-6-(2-methoxyethoxy). )pyrimidin-2yl)piperidine-4-carboxylate as a colorless oil (0.400 g, 94%). To a solution of the resulting intermediate (0.400 g, 0.990 mmol) in methanol (2 ml), tetrahydrofuran (1 ml) and water (1). ml) sodium hydroxide (0.199 g, 4.96 mmol) is added with stirring. After stirring overnight, the reaction mixture is concentrated in water and the solution is acidified (pH ~ 3) with 1.0 N hydrochloric acid. The resulting suspension is extracted with ethyl acetate. The combined extracts were dried (Na ₂ SO ₄ ) and concentrated to give 1-(4-(4-fluorophenyl)-6-(2-methoxyethoxy)pyrimidin-2yl)piperidine-4-carboxylic acid as a white solid (0.320 g, 86%). Using General Procedure D and Intermediate 5, the resulting carboxylic acid was amide coupled to give the title compound as a white solid.

- 58 046304 (0.100 g, 49%). 1H NMR (500 MHz, CDC13) δ 8.02-7.98 (m, 2H), 7.15-7.11 (m, 2H), 6.44 (s, 1H), 5.37 (s, 1H), 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), 2.882.84 (m, 2H), 2.40-2.33 (m, 2H), 1.95-1 .51 (m, 13H) ppm ¹³ C NMR (125 MHz, CDC13) δ 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 LCMS purity >97% (214 nm and 254 nm); retention time 1.40 min; (M+H+) 512.4.

Example 106.

1-(4-(4-Fluorophenyl)pyridin-2-yl)-H-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin-4-carboxamide.

To a solution of 4-bromo-2-fluoropyridine (1.76 g, 10.0 mmol) in acetonitrile (10 ml) add ethylpiperidine-4-carboxylate (2.36 g, 15.0 mmol) and potassium carbonate (2 .76 g, 20.0 mmol). The reaction mixture is heated at 60°C overnight and then concentrated. The residue was purified by flash chromatography on silica using hexane/ethyl acetate to give ethyl (4-bromopyridin-2-yl)piperidine-4-carboxylate as a colorless oil (2.40 g, 76%). To a solution of the resulting compound in a mixture of 1,4-dioxane/water, 10:1 (20 ml), 4-fluorophenylboronic acid (0.536 g, 3.83 mmol), potassium carbonate (1.10 g, 7.98 mmol) was added with stirring. and [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(P) (0.117 g, 0.160 mmol). The reaction mixture is heated overnight at 95°C. After dilution with water, the reaction mixture is extracted with ethyl acetate. The combined extracts are dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography on silica using hexane/ethyl acetate to give ethyl 1-(4-(4fluorophenyl)pyridin-2-yl)piperidine-4-carboxylate as a white solid (1.00 g, 95 %). Using the last two steps described in Example 41, the resulting intermediate was used to prepare the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 8.23 (d, J=5.0 Hz, 1H), 7.60-7.55 (m, 2H), 7.18-7.14 (m, 2H ), 6.80-6.78, (m, 2H), 5.37 (s, 1H), 4.45-4.42 (m, 2H), 3.072.80 (m, 8H), 2.39 -2.30 (m, 2H), 1.98-1.50 (m, 13H) ppm. ¹³ C NMR (125 MHz, CDC13) 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 LCMS purity >99% (214 nm and 254 nm); retention time 1.04 min; (M+H+) 437.2.

Example 107.

1-(5-(4-Fluorophenyl)pyridin-3-yl)-H-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin-4carboxamide.

A mixture of 3,5-dibromopyridine (0.500 g, 2.11 mmol), ethylpiperidine-4-carboxylate (1.60 g, 10.2 mmol) and cesium carbonate (0.729 g, 2.11 mmol) is heated in a microwave reactor with stirring at 150°C for 1 hour. The reaction mixture is cooled and concentrated. The residue was purified by flash chromatography on silica using hexane/ethyl acetate to give ethyl 1-(5-bromopyridin-3-yl) piperidine-4-carboxylate as a yellow oil (0.078 g, 12%). Using the last two steps described in Example 106, the resulting intermediate was used to prepare the title compound. ^1H NMR (500 MHz, CDCl ₃ ) δ 8.30 (d, J=2.0 Hz, 1H), 8.27 (s, 1H), 7.55-7.52 (m, 2H), 7 .30 (s, 1H), 7.16 (t, J=8.5 Hz, 2H), 5.43 (s, 1H), 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. ¹³ C NMR (125 MHz, CDC13) 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 LCMS purity >99% (214 nm and 254 nm); retention time 1.19 min; (M+H+) 437.3.

Example 108.

1-(2-(4-Fluorophenyl)pyridin-4-yl)-H-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin-4carboxamide.

To a solution of 2,4-dichloropyridine (4.00 g, 27.0 mmol) in a mixture of N.N-dimethylformamide (50 ml) and water (25 ml) add 4-fluorophenylboronic acid (3.78 g, 27.0 mmol) with stirring ), sodium bicarbonate (2.27 g, 27.03 mmol) and bis(triphenylphosphine) palladium(P) dichloride (0.948 g, 1.35 mmol).

The reaction mixture is heated overnight at 80°C and then concentrated. The residue is dissolved in ethyl acetate, washed with water and aqueous sodium chloride, dried (Na ₂ SO ₄ ) and concentrated.

The residue was purified by flash chromatography on silica using hexane/ethyl acetate to give 4-chloro-2-(4-fluorophenyl)pyridine as a colorless solid (2.21 g, 39%). The resulting intermediate (2.18 g, 10.5 mmol) was combined with ethylpiperidine-4carboxylate (3.30 g, 2.10 mmol), N,N-diisopropylethylamine (4.4 mL, 25 mmol) and acetonitrile (12 mL ) in a hermetically sealed microwave reactor. The mixture is heated with stirring in a microwave reactor for 5 hours at 180°C. The reaction mixture is then concentrated and the residue is dissolved in ethyl acetate and washed with aqueous sodium bicarbonate. The aqueous layer is again extracted with ethyl acetate and the combined organic layers are dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography on silica using hexane/ethyl acetate to give ethyl 1-(2-(4-fluorophenyl)pyridin-4-yl)piperidine-4-carboxylate as a pale amber oil.

- 59 046304 colors (2.88 g, 84%). Using the last two steps described in Example 41, the resulting intermediate was used to prepare the title compound. 1H NMR (400 MHz, CDC13) δ 8.22 (d, J=6.0 Hz, 1H), 8.15-8.09 (m, 2H), 7.42 (s, 1H), 7.33 -7.22 (m, 3H), 6.79 (dd, J=6.0, 2.5 Hz, 1H), 4.15-4.05 (m, 2H), 3.03-2.69 (m, 8H), 2.55-2.43 (m, 1H), 2.34-2.27 (m, 1H), 1.82-1.44 (m, 9H), 1.411.27 (m , 4H) ppm UP-LCMS purity 95% (214 and 254 nm); retention time 0.46 min; (M+H+) 437.4.

Example 109.

1-(4-(4-Fluorophenyl)pyrimidin-2-yl)-H-methyl-N-(quinuclidin-3-yl)piperidin-4-carboxamide.

Using general procedure D and reacting 1-(4-(4-fluorophenyl)pyrimidin-2-yl)piperidin-4-carboxylic acid (prepared as described in Example 41) and Nmethylquinuclidin-3-amine, the title connection header. 1H NMR (500 MHz, CDCl ₃ ) δ 8.39 (d, J=5.5 Hz, 1H), 8.08-8.05 (m, 2H), 7.17 (t, J=8.5 Hz, 2H), 6.90 (d, J = 5.0 Hz, 1H), 4.99-4.96 (m, 2H), 4.584.54 (m, 1H), 3.33-2.83 (m, 12H), 2.08-1.55 (m, 9H) ppm ¹³ C NMR (125 MHz, CDC13) 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. LCMS purity >96% (214 nm and 254 nm); retention time 1.24 min; (M+H+) 424.2.

Example 110.

1-Azabicyclo[3.2.2]nonan-4-yl-1-(4-(4-fluorophenyl)pyrimidin-2-yl)piperidin-4-carboxylate.

To a solution of ethyl 1-(4-(4-fluorophenyl)pyrimidin-2-yl)piperidin-4-carboxylate (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) add a 60% dispersion of sodium hydride in mineral oil (0.097 g, 2.43 mmol) and 4A molecular sieves with stirring. The mixture is refluxed for one and a half days, then the solids are filtered off and the mixture is concentrated. The residue was purified by preparative reverse phase HPLC to give the title compound as a yellow oil (0.066 g, 27%). 1H NMR (500 MHz, CDCl ₃ ) δ 8.38 (d, J=5.0 Hz, 1H), 8.09-8.05 (m, 2H), 7.17 (t, J=8.5 Hz, 2H), 6.90 (d, J=5.0 Hz, 1H), 5.05-5.00 (m, 1H), 4.83-4.80 (m, 2H), 3.22 -2.85 (m, 8H), 2.66-2.59 (m, 1H), 2.06-1.56 (m, 11H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity >98% (214 nm and 254 nm); retention time 1.47 min; (M+H+) 425.2.

Example 111.

1-(5-Fluoro-4-(4-(3-methoxypropoxy)phenyl)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan4-yl)piperidin-4-carboxamide .

Replacing 4-fluorophenylboronic acid with 2-(4-(3-methoxypropoxy)phenyl)-4,4,5,5-tetramethyl1,3,2-dioxaborolane, ethylpiperidine-4-carboxylate with methylazetidine-3-carboxylate hydrochloride and 2, 4-dichloropyrimidine to 2,4-dichloro-5-fluoropyrimidine, using the same reaction sequence as described in Example 41 to obtain the title compound. 1H NMR (500 MHz, CDC13) δ 8.23 (d, J=4.5 Hz, 1H), 8.10 (d, J=8.5 Hz, 2H), 7.00 (d, J=9 ,0 Hz, 2H), 5.55 (s, 1H), 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, 1H), 2.12-2.07 (m, 2H), 1.99-1.54 (m, 9H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) δ 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 LCMS purity >98% (214 nm and 254 nm); retention time 1.41 min; (M+H+) 498.3.

Example 112.

1-(5-Fluoro-4-(4-fluorophenyl)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)azetidine-3carboxamide.

Replacing ethylpiperidine-4-carboxylate with methylazetidine-3-carboxylate hydrochloride and 2,4-dichloropyrimidine with 2,4-dichloro-5-fluoropyrimidine, the same reaction sequence as described in Example 41 was used to obtain the title compound. 1H NMR (500 MHz, CDC13) δ 8.25 (d, J=3.0 Hz, 1H), 8.12-8.09 (m, 2H), 7.17-7.13 (m, 2H) , 5.42 (s, 1H), 4.32-4.27 (m, 4H), 3.36-3.33 (m, 1H), 3.01-2.80 (m, 6H), 2 .38 (m, 1H), 1.97-1.52 (m, 9H) ppm. ¹³ C NMR (125 MHz, CDC13) δ 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 LCMS purity >98% (214 nm and 254 nm); retention time 1.34 min; (M+H+) 428.2.

Example 113.

1-(4-(4-Fluorophenyl)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)azetidin-3-carboxamide.

Replacing ethylpiperidine-4-carboxylate with methylazetidine-3-carboxylate, the same reaction sequence as described in Example 41 was used to obtain the title compound. 1H NMR (500 MHz, CDC13) δ 8.36 (d, J=5.5 Hz, 1H), 8.06-8.03 (m, 2H), 7.14 (t, J=8.5 Hz , 2H), 6.96 (d, J=4.5 Hz, 1H), 5.44 (s, 1H), 4.35-4.33 (m, 4H), 3.38-3.35 ( m, 1H), 3.00-2.81 (m, 6H), 2.38 (m, 1H), 1.97-1.52 (m, 9H) ppm. ¹³ C NMR (125 MHz, CDC13) 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 . LCMS purity >99% (214 nm and 254 nm); retention time 1.26 min; (M+H+) 410.2.

- 60 046304

Example 114.

-(4'-Fluoro[1,1'-biphenyl]-3-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)azetidin-3-carboxamide.

Replacing ethylpiperidine-4-carboxylate with methylazetidine-3-carboxylate, the same reaction sequence as described in Example 33 was used to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 7.55-7.52 (m, 2H), 7.30 (t, J=8.0 Hz, 1H), 7.12 (t, J=8.5 Hz, 2H), 6.96 (d, J=7.5 Hz, 1H), 6.63 (s, 1H), 6.50 (d, J=8.0 Hz, 1H), 5.75 ( s, 1H), 4.12-4.02 (m, 4H), 3.39-3.35 (m, 1H), 3.03-2.84 (m, 6H), 2.40 (s, 1H), 1.98-1.55 (m, 9H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) δ 171.6, 163.4, 161.4, 151.9, 141.2, 137.7, 129.4, 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, 36.2, 24 .9, 24.2 ppm LCMS purity >98% (214 nm and 254 nm); retention time 1.42 min; (M+H+) 408.3.

Example 115.

1-(4-(4-Fluorophenoxy)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin-4carboxamide.

To a solution of 4-fluorophenol (0.448 g, 4.00 mmol) in tetrahydrofuran (35 ml) was added potassium tert-butoxide (0.493 g, 4.40 mmol) with stirring. After 30 minutes, 2,4-dichloropyrimidine (0.596 g, 4.00 mmol) was added and the reaction mixture continued to stir for an additional 6 hours. At this time, the reaction mixture was filtered to remove suspended solids, the filtrate was concentrated to yield crude 2-chloro- (4-fluorophenoxy)pyrimidine as a white solid (0.827 g, 92%). The resulting intermediate (0.548 g, 2.40 mmol), which is sufficiently pure to be used without purification, is combined with ethylpiperidine-4-carboxylate (0.452 g, 2.88 mmol) and triethylamine (1.0 ml, 7.2 mmol ) in ethanol (10 ml). The mixture is heated overnight at 80°C with stirring and then concentrated. The residue was purified by flash silica chromatography using hexane/ethyl acetate to give ethyl 1-(4-fluorophenoxy)pyrimidin-2-yl)piperidin-4-carboxylate as a light yellow oil (0.639 g, 76%). To a solution of the resulting intermediate (0.330 g, 0.960 mmol) in 1:1 methanol/water (v/v; 4 ml) was added solid sodium hydroxide (0.192 g, 4.80 mmol) with stirring. After stirring overnight, the reaction mixture is concentrated. The residue is dissolved in water and the solution is acidified (pH~3) by adding 1N hydrochloric acid and the mixture is extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give 1-(4-(4-fluorophenoxy)pyrimidin-2-yl)piperidin-4carboxylic acid as a white solid (0.288 g, 95%). Using General Procedure D and Intermediate 5, the resulting carboxylic acid was amide coupled to give the title compound as a white solid (0.019 g, 7%). 1H NMR (500 MHz, CDCl ₃ ) δ 8.16 (d, J=5.5 Hz, 1H), 7.12-7.05 (m, 4H), 5.99 (d, J=5.5 Hz, 1H), 5.28 (s, 1H), 4.624.60 (m, 2H), 3.01-2.80 (m, 8H), 2.34-2.26 (m, 2H), 1 .91-1.47 (m, 13H) ppm ¹³ C NMR (125 MHz, CDCl ₃ ) 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, 39.4, 36.1, 28.8, 28.5, 25.1, 24.4, 24 .2 ppm LCMS purity >99% (214 nm and 254 nm); retention time 1.32 min; (M+H+) 454.3.

Example 116.

4-Fluoro-1-(4-(4-fluorophenoxy)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin-4-carboxamide.

Replacing ethylpiperidine-4-carboxylate with ethyl 4-fluoropiperidine-4-carboxylate hydrochloride, the same reaction sequence as described in Example 115 was used to obtain the title compound. 1H NMR (400 MHz, CDCl ₃ ) δ 8.17 (d, J=5.5 Hz, 1H), 7.15-7.02 (m, 4H), 6.31 (d, J=7.3 Hz, 1H), 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, 1H), 2.26-2.02 (m, 2H), 2.00-1.89 (m, 1H), 1.87-1.67 (m, 5H), 1 .67-1.42 (m, 5H) ppm UP-LCMS purity >99.9% (214 and 254 nm); retention time 0.82 min; (M+H+) 472.4.

Example 117.

4-Fluoro-1-(4-(4-fluorophenoxy)-1,3,5-triazin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidine -4-carboxamide.

Replacing 2,4-dichloropyrimidine with 2,4-dichlorotriazine and ethylpiperidine-4-carboxylate with ethyl 4-fluoropiperidine-4-carboxylate hydrochloride, the same reaction sequence as described in Example 115 was used to obtain the title compound. 1H NMR (400 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 7.20-7.03 (m, 4H), 6.32 (d, J=7.1 Hz, 1H), 4, 85-4.72 (m, 1H), 4.60-4.47 (m, 1H), 3.34-3.11 (m, 2H), 3.102.74 (m, 6H), 2.37- 2.05 (m, 3H), 2.02-1.43 (m, 11H) ppm UP-LCMS purity >99.9% (214 and 254 nm); retention time 0.74 min; (M+H+) 473.5.

Example 118.

4-Fluoro-1-(5-fluoro-4-(4-(2-methoxyethoxy)phenoxy)pyrimidin-2-yl)-H-(3-methylquinuclidin-3yl)piperidine-4-carboxamide.

Replacing 4-fluorophenol with 4-(2-methoxyethoxy)phenol, ethylpiperidine-4-carboxylate with ethyl 4-fluoropiperidine-4-carboxylate hydrochloride, and intermediate 5 with intermediate 1, use the same reaction sequence as described in Example 115 and obtain the compound named in the header. 1H NMR (500 MHz, CDCl ₃ ) δ 8.08 (d, J=3.0 Hz, 1H), 7.11-7.08 (m, 2H), 6.96-6.93 (m,

- 61 046304

2H), 6.32 (d, J=7.0 Hz, 1H), 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), 3.092.75 (m, 8H), 2.18-2.02 (m, 3H), 1.87-1 .27 (m, 9H) ppm ¹³ C NMR (100 MHz, CDCl ₃ ) δ 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. LCMS purity >99% (214 nm and 254 nm); retention time 1.44 min; (M+H+) 532.2.

Example 119.

1-(4-(4-Cyanophenoxy)pyrimidin-2-yl)-4-fluoro-H-(3-methylquinuclidin-3-yl)piperidin-4-carboxamide.

Replacing 4-fluorophenol with 4-cyanophenol, ethylpiperidine-4-carboxylate with ethyl 4fluoropiperidine-4-carboxylate hydrochloride, and intermediate 5 with intermediate 1, the same reaction sequence as described in Example 115 was used to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 8.24 (d, J=6.5 Hz, 1H), 7.71 (d, J=8.5 Hz, 2H), 7.29 (d, J= 8.0 Hz, 2H), 6.35 (d, J=6.5 Hz, 1H), 6.17 (d, J=6.0 Hz, 1H), 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 ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity >99% (214 nm and 254 nm); retention time 1.39 min; (M+H+) 465.2.

Example 120.

1-(4-(4-Cyanophenoxy)pyrimidin-2-yl)-4-fluoro-H-(4-methyl-1-azabicyclo[3.2.2]nonan-4yl)piperidine-4-carboxamide.

Replacing 4-fluorophenol with 4-cyanophenol and ethylpiperidine 4-carboxylate with ethyl 4-fluoropiperidine 4-carboxylate, the same reaction sequence as described in Example 115 was used to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 8.24 (d, J=5.0 Hz, 1H), 7.70 (d, J=9.0 Hz, 2H), 7.29 (d, J= 8.5 Hz, 2H), 6.33 (d, J=7.5 Hz, 1H), 6.16 (d, J=5.5 Hz, 1H), 4.47 (m, 2H), 3 .15-2.82 (m, 8H), 2.34-2.31 (m, 1H), 2.17-1.49 (m, 13H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) δ 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 LCMS purity >99% (214 nm and 254 nm); retention time 1.43 min; (M+H+) 478.9.

Example 121.

1-(4-(4-Fluorophenoxy)pyrimidin-2-yl)-H-(3-methylquinuclidin-3-yl)piperidin-4-carboxamide.

Replacing 2,4-dichloropyrimidine with 2,4-dichloro-5-fluoropyrimidine and intermediate 5 with intermediate 1, the same reaction sequence as described in Example 115 was used to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 8.10 (d, J=2.5 Hz, 1H), 7.17-7.07 (m, 4H), 5.36 (s, 1H), 4, 41 (d, J=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. ¹³ C NMR (125 MHz, CDCl ₃ ) δ 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 LCMS purity >97% (214 nm and 254 nm); retention time 1.40 min; (M+H+) 458.0.

Example 122.

1-(5-Cyano-4-(4-fluorophenoxy)pyrimidin-2-yl)-4-fluoro-H-(3-methylquinuclidin-3-yl)piperidin-4carboxamide.

Replacing 2,4-dichloropyrimidine with 2,4-dichloro-5-fluoropyrimidine, ethylpiperidine-4-carboxylate with ethyl 4-fluoropiperidine-4-carboxylate, and intermediate 5 with intermediate 1, use the same reaction sequence as described in Example 115 and obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 8.45 (s, 1H), 7.15-7.08 (m, 4H), 6.34 (d, J=6.5 Hz, 1H), 4, 80 (d, J=12.5 Hz, 1H), 4.18 (d, J=12.0 Hz, 1H), 3.25 (t, J=12.5 Hz, 1H), 3.07 ( t, J=12.5 Hz, 1H), 2.94-2.79 (m, 6H), 2.18-1.72 (m, 7H), 1.58-1.49 (m, 5H) m.d. ¹³ C NMR (100 MHz, CDCl ₃ ) 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 LCMS purity >99% (214 nm and 254 nm); retention time 1.89 min; (M+H+) 483.1.

Example 123.

4-Fluoro-H-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)-1-(4-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-2-yl )piperidine-4-carboxamide.

To a solution of tetrahydro-2H-pyran-4-ol (1.12 g, 11.0 mmol) in NN-dimethylformamide (20 ml) add a 60% dispersion of sodium hydride in mineral oil (660 mg, 16.5 mmol). The mixture was stirred at 0°C for 20 minutes and then 2,4dichloropyrimidine (1.98 g, 13.2 mmol) was added. The reaction mixture is then allowed to gradually warm to room temperature and stirred overnight. After this, the reaction is quenched with water (~80 ml) and the mixture is extracted with ethyl acetate. The combined organic layers are washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography on silica using hexane/ethyl acetate to give 2-chloro-4-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidine as a light yellow oil (1.13 g, 53%). Replacing 2-chloro-4-(4-fluorophenyl)pyrimidine with the newly prepared intermediate, use the last three steps of Example 41 to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 8.08 (d, J=6.0 Hz, 1H), 6.35 (d,

- 62 046304

J=7.5 Hz, 1H), 6.00 (d, J=5.5 Hz, 1H), 5.25-5.20 (m, 1H), 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, 1H), 2.25-2.14 (m, 2H), 2.07-1.51 (m, 15H) ppm. ¹³ C NMR (100 MHz, CDCl3) 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, 23, 9, 23.6 ppm LCMS purity >99% (214 nm and 254 nm); retention time 1.13 min; (M+H+) 462.0.

Example 124.

4-Fluoro-1-(4-((4-fluorobenzyl)oxy)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin-4-carboxamide .

Replacing tetrahydro-4-pyranol with 4-fluorobenzyl alcohol, the same reaction sequence as described in Example 123 was used to obtain the title compound. 1H NMR (400 MHz, CDCl ₃ ) δ 8.07 (d, J=5.6 Hz, 1H), 7.42-7.34 (m, 2H), 7.09-7.01 (m, 2H ), 6.33 (d, J=7.4 Hz, 1H), 6.03 (d, J=5.6 Hz, 1H), 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, 1H), 2.302.08 (m , 2H), 2.01-1.90 (m, 1H), 1.89-1.69 (m, 5H), 1.67-1.45 (m, 5H) ppm. UP-LCMS purity >99.9% (214 and 254 nm); retention time 0.75 min; (M+H+) 486.3.

Example 125.

4-Fluoro-1-(4-((4-fluorobenzyl)oxy)pyrimidin-2-yl)-N-(3-methylquinuclidin-3-yl)piperidin-4-carboxamide.

Replacing tetrahydro-4-pyranol with 4-fluorobenzyl alcohol and intermediate 5 with intermediate 1, the same reaction sequence as described in Example 123 was used to obtain the title compound. 1H NMR (400 MHz, CDCl ₃ ) δ 8.07 (d, J=5.6 Hz, 1H), 7.42-7.35 (m, 2H), 7.09-7.01 (m, 2H ), 6.34 (d, J=6.8 Hz, 1H), 6.03 (d, J=5.6 Hz, 1H), 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), 1.89-1.68 (m, 4H), 1.59-1.40 (m, 5H) ppm. UP-LCMS purity >99.9% (214 and 254 nm); retention time 0.73 min; (M+H+) 472.3.

Example 126.

4-Fluoro-1-(6-(4-fluorophenoxy)pyrazin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin4-carboxamide.

To a solution of 2,6-dichloropyrazine (4.44 g, 29.8 mmol) and 4-fluorophenol (3.00 g, 26.8 mmol) in N,Ndimethylformamide (100 ml) with stirring, add in parts over ~5 min potassium tert-butoxide (6.01 g, 53.6 mmol). The reaction mixture is heated overnight at 90°C and then concentrated. The residue was purified by flash chromatography on silica using hexane/ethyl acetate to give 2-chloro-6-(4-fluorophenoxy)pyrazine as a white solid (5.70 g, 95%). To a solution of the resulting product (0.850 g, 3.78 mmol) in N-dimethylformamide (15 ml), 4-fluoropiperidine-4-carboxylate (0.960 g, 4.54 mmol) and cesium carbonate (2.46 g, 7 .55 mmol). The mixture is heated overnight at 60°C and then concentrated. The residue was purified by flash chromatography on silica using hexane/ethyl acetate to give 4fluoro-1-(6-(4-fluorophenoxy)pyrazin-2-yl)piperidine-4-carboxylate as a yellow solid (0.190 g, 14%) . To a solution of the resulting intermediate (0.300 g, 0.826 mmol) in methanol/tetrahydrofuran/water 2:1:1 (8 mL), add solid sodium hydroxide (0.165 g, 4.13 mmol). The mixture is stirred overnight and then concentrated. The residue is dissolved in water and acidified (pH~3) by adding 1N hydrochloric acid and the mixture is extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give 4-fluoro-1-(6-(4fluorophenoxy)pyrazin-2-yl)piperidine-4-carboxylic acid as a yellow solid (0.176 g, 64%). Replacing ethyl 1-(4-(4-fluorophenyl)pyrimidin-2-yl)piperidin-4-carboxylate with the newly prepared intermediate, the last two steps of Example 41 were used to obtain the title compound. 1H NMR (500 MHz, CDCU) δ 7.85 (s, 1H), 7.58 (s, 1H), 7.14-7.07 (m, 4H), 6.32 (d, J=7, 0 Hz, 1H), 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, 1H), 2.24-1.97 (m, 3H), 1.85-1.51 (m, 10H) ppm. ¹³ C NMR (125 MHz, CDCls) 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 LCMS purity >99% (214 nm and 254 nm); retention time 1.36 min; (M+H+) 472.0.

Example 127.

4-Fluoro-1-(5-(4-fluorophenoxy)pyridin-3-yl)-H-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin4-carboxamide.

To a suspension of a 60% dispersion of sodium hydride in mineral oil (1.30 g, 32.5 mmol) in N,Ndimethylformamide (20 ml) add 4-fluorophenol (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 is heated overnight at 90°C, then diluted with water and extracted with ethyl acetate. The combined extracts are dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography on silica using hexane/ethyl acetate to give 3-bromo-5-(4fluorophenoxy)pyridine as a light yellow oil (0.660 g, 13%). To a mixture of the resulting intermediate (600 mg, 2.24 mmol) and ethyl 4-fluoropiperidine-4-carboxylate hydrochloride (0.566 g, 2.68

- 63 046304 mmol) in toluene (15 ml) add tris(dibenzylideneacetone)dipalladium(0) (0.204 g, 0.223 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (0.278 g, 0.446 mmol) and potassium tert-butoxide (0.860 g, 4.48 mmol). The reaction mixture is heated overnight at 90°C, cooled and filtered through celite. The filtrate is concentrated to give a residue, which is diluted with 2.0N hydrochloric acid (40 ml) and extracted with ethyl acetate.

The combined organic layers are washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give 4-fluoro-1-(5-(4-fluorophenoxy)pyridin-3-yl)piperidine-4-carboxylic acid (the expected reaction product ester is hydrolyzed to during the catalytic amination reaction/process) as a white solid (420 mg, 57%). Using General Procedure D and Intermediate 5, the resulting carboxylic acid was amide coupled to give the title compound as a brown solid (0.031 g, 16%). 1H NMR (500 MHz, CDCl ₃ ) δ 8.10 (d, J=2.0 Hz, 1H), 7.81 (d, J=2.0 Hz, 1H), 7.10-7.02 ( m, 4H), 6.82-6.81 (m, 1H), 6.34 (d, J=7.5 Hz, 1H), 3.64-3.62 (m, 2H), 3.16 -2.82 (m, 8H), 2.40-2.32 (m, 3H), 1.99-1.52 (m, 11H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) δ 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. LCMS purity >99% (214 nm and 254 nm); retention time 1.22 min; (M+H+) 471.3.

Example 128.

4-Fluoro-1-(4-((4-fluorobenzyl)oxy)-1,3,5-triazin-2-yl)-N(4-methyl-1-azabicyclo[3.2.2]nonan-4yl)piperidine -4-carboxamide.

To a solution of 2,4-dichloro-1,3,5-triazine (1.00 g, 6.71 mmol) in 1,4-dioxane (10 ml) add NN-diisopropylethylamine (2.50 ml, 14. 4 mmol) and ethyl 4-fluoropiperidine 4-carboxylate hydrochloride (1.14 g, 5.37 mmol). The reaction mixture is stirred at 55°C for 1 hour and then concentrated. The residue was purified by flash chromatography on silica using hexane/ethyl acetate to give ethyl 1-(4-chloro-1,3,5-triazin-2-yl)-4-fluoropiperidin-4carboxylate as a colorless oil (1 .40 g, 72%). To a solution of (4-fluorophenyl)methanol (0.131 g, 1.04 mmol) in anhydrous tetrahydrofuran (1 ml) add a 60% dispersion of sodium hydride in mineral oil (0.046 g, 1.15 mmol) with stirring and cooling (0°C). ). After 1 hour at the indicated temperature, add the product from step 1 (0.030 g, 1.04 mmol) in one portion. The reaction mixture is then stirred at room temperature for 2 hours and then diluted with water and extracted with ethyl acetate. The combined organic layers are dried (Na ₂ SO ₄ ) and concentrated to yield the crude product, which is purified by flash reverse phase chromatography on C-18 silica using acetonitrile/water/trifluoroacetic acid as an eluent to yield ethyl-4-fluoro- 1-(4-((4-fluorobenzyl)oxy)-1,3,5-triazin-2-yl)piperidin-4-carboxylate (0.120 g, 30%) as a colorless oil. Replacing ethyl 1-(4-(4-fluorophenyl)pyrimidin-2-yl)piperidin-4-carboxylate with the newly prepared intermediate, the last two steps of Example 41 were used to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 8.38 (s, 1H), 7.45-7.42 (m, 2H), 7.07 (t, J=8.5 Hz, 2H), 6, 35 (d, J=6.5 Hz, 1H), 5.37 (s, 2H), 4.81-4.73 (m, 2H), 3.30-2.94 (m, 8H), 2 .47 (m, 1H), 2.24-2.03 (m, 6H), 1.87-1.53 (m, 7H) ppm. ¹³ C NMR (100 MHz, CDCl ₃ ) 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 LCMS purity >99% (214 nm and 254 nm); retention time 1.36 min; (M+H+) 487.2.

Example 129.

4-Fluoro-1-(5-(4-fluorophenoxy)pyrimidin-2-yl)-N(3-methylquinuclidin-3-yl)piperidin-4-carboxamide.

To a solution of 2-chloropyrimidin-5-ol (1.50 g, 11.6 mmol) in dichloromethane (20 ml) add 4-fluorophenylboronic acid (3.30 g, 23.2 mmol), copper(II) acetate with stirring. (2.49 g, 13.9 mmol) and triethylamine (8.0 ml, 57 mmol). The mixture is left exposed to air and stirred overnight. The suspension is then filtered through a pad of celite and concentrated. The residue was purified by flash chromatography on silica using hexane/ethyl acetate to give 2chloro-5-(4-fluorophenoxy)pyrimidine as a light yellow solid (0.400 g, 17%). Replacing 2chloro-4-(4-fluorophenyl)pyrimidine with the intermediate just prepared, ethylpiperidine 4-carboxylate with ethyl 4-fluoropiperidine-4-carboxylate hydrochloride, and intermediate 5 with intermediate 1, using the last three steps of Example 41 to obtain the title in the connection header. 1H NMR (400 MHz, CD3OD) δ 8.20 (s, 2H), 7.09-6.99 (m, 4H), 4.70-4.66 (m, 2H), 3.333.16 (m, 3H), 2.90-2.83 (m, 5H), 2.30-2.01 (m, 3H), 1.92-1.89 (m, 4H), 1.70-1.50 ( m, 5H) ppm ¹³ C 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 LCMS purity >99% (214 nm and 254 nm); retention time 1.39 min; (M+H+) 458.0.

Example 130.

1-(5-(4-Fluorophenoxy)pyrimidin-2-yl)-N(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin-4carboxamide.

Replacing 2-chloro-4-(4-fluorophenyl)pyrimidine with 2-chloro-5-(4-fluorophenoxy)pyrimidine (obtained

- 64 046304 as described in example 129), using the last three steps of example 41 to obtain the title compound. ^1H NMR (500 MHz, CDC13) δ 8.14 (s, 2H), 7.02-6.98 (m, 2H), 6.91-6.88 (m, 2H), 5.44 (s , 1H), 4.76-4.73 (m, 2H), 3.06-2.84 (m, 8H), 2.41-2.34 (m, 2H), 1.95-1.49 (m, 13H) ppm ¹³ C NMR (125 MHz, CDC13) 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 LCMS purity >99% (214 nm and 254 nm); retention time 1.38 min; (M+H+) 454.2.

Example 131.

4-Fluoro-1-(5-(4-(2-methoxyethoxy)phenoxy)pyrimidin-2-yl)-N(3-methylquinuclidin-3-yl)piperidin-4-carboxamide.

Replacing 4-fluorophenylboronic acid with (4-(2-methoxyethoxy)phenylboronic acid, use the first step of Example 129 to obtain 2-chloro-5-(4-(2-methoxyethoxy)phenoxy)pyrimidine. Replacing 2-chloro-4-( 4-fluorophenyl)pyrimidine to the resulting intermediate, ethylpiperidine-4-carboxylate to ethyl 4-fluoropiperidine-4-carboxylate hydrochloride and intermediate 5 to intermediate 1, use the last three steps of Example 41 to obtain the title compound ^1H . NMR (500 MHz, CDCl ₃ ) δ 8.16 (s, 2H), 6.91 (m, 4H), 6.38 (d, J=7.0 Hz, 1H), 4.67 (d, J =13.5 Hz, 1H), 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 ¹³ C NMR (100 MHz, CDC13) δ 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 by LCMS >99% (214 nm and 254 nm); retention time 1.39 min; (M+H+) 514.0.

Example 132.

4-Fluoro-1-(5-((4-fluorobenzyl)oxy)pyrimidin-2-yl)-N(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin-4-carboxamide.

To a solution of 5-bromo-2-chloropyrimidine (2.00 g, 10.3 mmol) in NN-dimethylformamide (30 ml) add ethyl 4-fluoropiperidine-4-carboxylate hydrochloride (2.63 g, 12.4 mmol) and cesium carbonate (3.37 g, 10.3 mmol). The suspension is heated overnight at 50°C and then concentrated. The residue is dissolved in ethyl acetate and washed with several portions of water. The organic layer is dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified by flash silica chromatography using hexane/ethyl acetate to give ethyl 1-(5-bromopyrimidin-2-yl)-4fluoropiperidin-4-carboxylate as a white solid (2.93 g, 85% ). To a solution of the resulting intermediate (2.89 g, 8.70 mmol) in N,N-dimethylformamide (32 ml), bis(pinacolato)diboron (2.65 g, 10.4 mmol), potassium acetate (4 .27 g, 43.5 mmol) and [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(P) (318 mg, 435 μmol). The mixture is heated overnight at 90°C and then cooled and concentrated. The residue is dissolved in water and ethyl acetate to obtain a non-separable emulsion. After vacuum filtration of the mixture through a layer of celite, the organic layer is separated and washed with additional portions of water. The solution is then dried (Na ₂ SO ₄ ) and concentrated to give ethyl 4-fluoro-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2 -yl)piperidine-4carboxylate as a dark brown solid (3.32 g, 101%). The crude reaction product is used in the next step without purification. To a solution of boronate (3.31 g, 8.73 mmol) in tetrahydrofuran/water 1:1 (80 ml), sodium perborate monohydrate (2.21 g, 21.0 mmol) was added with stirring. The reaction mixture is stirred overnight and then diluted with aqueous ammonium chloride (~100 ml). The mixture is extracted with ethyl acetate. The combined extracts are then washed with aqueous sodium chloride, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography on silica using ethyl acetate/chloroform as an eluent to give ethyl 4-fluoro-1-(5-hydroxypyrimidin-2-yl)piperidine-4-carboxylate as a gray-green solid (1.64 g , 70%). To a solution of the resulting intermediate (0.828 g, 3.07 mmol) in Ν,N-dimethylformamide (15 ml) add 1-(bromomethyl)-4-fluorobenzene (0.639 g, 3.38 mmol and cesium carbonate (2, 00 g, 6.15 mmol) The mixture is heated overnight at 40°C and then concentrated. The residue is dissolved in ethyl acetate and washed with several portions of water. The organic layer is then dried (Na ₂ SO ₄ ) and concentrated in flash. chromatography on silica using hexane/ethyl acetate as an eluent to obtain ethyl 4-fluoro-1-(5-((4fluorobenzyl)oxy)pyrimidin-2-yl)piperidin-4-carboxylate as a white solid (0.909 g, 78%). The reaction mixture is stirred overnight and then concentrated. The resulting suspension is treated with 1N hydrochloric acid (7.0 ml) and then extracted with chloroform. The combined extracts are dried (Na ₂ SO ₄ ) and concentrated to give 4-fluoro-1-(5-((4-fluorobenzyl)oxy)pyrimidin-2-yl)piperidine-4-carboxylic acid as a white solid (0.736 g , 90%). Using General Procedure E and Intermediate 5, the resulting carboxylic acid was amide coupled to give the title compound as a yellow solid (0.395 g, 81%). ^1H NMR (400 MHz, CDC13) δ 8.09 (s, 2H), 7.42-7.33 (m, 2H), 7.11-7.03 (m, 2H), 6.33

- 65 046304 (d, J=7.2 Hz, 1H), 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), 2.362.30 (m, 1H), 2.30-2.09 (m, 1H), 2 .00-1.89 (m, 1H), 1.88-1.68 (m, 5H), 1.67-1.44 (m, 5H) ppm. UPLCMS purity >99.9% (214 nm and 254 nm); retention time 0.73 min; (M+H+) 472.3.

Example 133.

4-Fluoro-1 -(5-(4-fluorophenoxy)pyrazin-2-yl)-N-(3-methylquinuclidin-3-yl)piperidin-4-carboxamide.

To a solution of 2,5-dibromopyrazine (0.500 g, 2.10 mmol) in NN-dimethylformamide (15 ml), ethyl 4-fluoropiperidine-4-carboxylate (0.444 g, 2.10 mmol) and cesium carbonate (1 .37 g, 4.20 mmol). The mixture is heated overnight at 60°C and then concentrated. The residue was purified by flash chromatography on silica using hexane/ethyl acetate to give ethyl 1-(5-bromopyrazin-2-yl)-4-fluoropiperidin-4-carboxylate as a yellow solid (0.330 g, 47%). The resulting intermediate (0.400 g, 1.20 mmol) was combined with 4-fluorophenol (0.175 g, 1.56 mmol), copper oxide (0.052 g, 0.363 mmol), imidazole-4-carboxylic acid (0.081 g, 0.723 mmol) , cesium carbonate (1.17 g, 3.59 mmol) and acetonitrile (12 ml) in a sealed microwave reactor. The mixture is heated with stirring in a microwave reactor at 120°C for 6 hours. The reaction mixture is then cooled and filtered to remove solids. The filtrate was concentrated and the residue was purified by flash chromatography on silica using hexane/ethyl acetate to give ethyl 4-fluoro-1-(5-(4-fluorophenoxy)pyrazin-2-yl)piperidine-4-carboxylate as yellow oils (0.120 g, 28%). To a solution of the resulting intermediate (0.120 g, 0.330 mmol) in 1:1 methanol/water (v/v; 4 ml) was added solid sodium hydroxide (0.066 g, 1.65 mmol) with stirring. After stirring overnight, the reaction mixture is concentrated. The residue is dissolved in water and acidified (pH~3) by adding 1N hydrochloric acid and the mixture is extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give 4-fluoro-1-(5-(4-fluorophenoxy)pyrazin-2-yl)piperidine-4-carboxylic acid as a white solid (0.900 g, 81%). Using General Procedure E and Intermediate 5, the resulting carboxylic acid was amide coupled to give the title compound as a yellow solid (0.019 g, 36%). 1H NMR (500 MHz, CDCl ₃ ) δ 7.99 (d, J=1.0 Hz, 1H), 7.76 (d, J=1.5 Hz, 1H), 7.07-7.06 ( m, 4H), 6.37 (d, J=6.5 Hz, 1H), 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. ¹³ C NMR (100 MHz, CDCl ₃ ) 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, 46.4, 41.2, 31.5, 31.4, 31.3, 31.2, 30 ,1, 24.2, 22.9, 22.3 ppm LCMS purity >98% (214 nm and 254 nm); retention time 1.41 min; (M+H+) 458.2.

Example 134.

4-Fluoro-1-(6-(4-fluorophenoxy)pyridazin-3-yl)-H-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidin-4-carboxamide.

To a solution of 3,6-dichloropyridazine (0.400 g, 2.68 mmol) in Ν,N-dimethylformamide (15 ml) add ethyl 4-fluoropiperidine-4-carboxylate (0.567 g, 8.04 mmol) and cesium carbonate with stirring (2.62 g, 8.04 mmol). The mixture is heated overnight at 60°C and then concentrated. The residue was purified by flash chromatography on silica using hexane/ethyl acetate to give ethyl 1-(6-chloropyridazin-3-yl)-4-fluoropiperidin-4-carboxylate as a white solid (0.400 g, 52%). The resulting 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), N,N-dimethylglycine (0.029 g, 0.281 mmol), potassium carbonate (0.576 g, 4.17 mmol) and 1-methyl-2-pyrrolidinone (8 ml) in a sealed microwave reactor. The mixture is heated with stirring in a microwave reactor at 160°C for 6 hours. The reaction mixture is then cooled and filtered to remove solids. The filtrate was concentrated and the residue was purified by flash chromatography on silica using hexane/ethyl acetate to give ethyl 4-fluoro-1-(6-(4-fluorophenoxy)pyridazin-3-yl)piperidine-4-carboxylate as white solid (0.120 g, 24%). Replacing ethyl 4-fluoro-1-(6-(4-fluorophenoxy)pyrazin-2-yl)piperidin-4-carboxylate with the newly prepared intermediate, the last two steps of Example 133 were used to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 7.17-7.05 (m, 6H), 6.36 (d, J=7.5 Hz, 1H), 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, 11H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) 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. LCMS purity >96% (214 nm and 254 nm); retention time 1.84 min; (M+H+) 472.2.

Example 135.

4-Fluoro-1 -(4-((4-fluorophenoxy)methyl)pyrimidin-2-yl)-N-(3-methylquinuclidin-3-yl)piperidin-4carboxamide.

To a solution of (2-chloropyrimidin-4-yl)methanol (0.600 g, 4.14 mmol) in dichloromethane (10 ml) was added thionyl chloride (0.488 g, 4.14 mmol) with stirring. The mixture was stirred at room temperature overnight and then concentrated to give 2-chloro-4-(chloromethyl)pyrimidine as a yellow oil (0.500 g, 74%). To a solution of the resulting intermediate (0.500 g, 3.07 mmol)

- 66 046304 and 4-fluorophenol (0.378 g, 3.37 mmol) in acetonitrile (10 ml) add potassium carbonate (0.847 g, 6.14 mmol) with stirring. The reaction mixture is refluxed for 1.5 hours and then concentrated. The residue was purified by flash chromatography on silica gel using hexane/ethyl acetate to give 2-chloro-4-((4-fluorophenoxy)methyl)pyrimidine as a white solid (0.300 g, 41%). To a solution of the resulting compound (0.400 g, 2.06 mmol) in acetonitrile (15 ml) add ethyl 4-fluoropiperidine-4-carboxylate hydrochloride (0.480 g, 2.26 mmol) and potassium carbonate (0.569 g, 4. 12 mmol). The reaction mixture is refluxed overnight, diluted with water (20 ml) and extracted with ethyl acetate. The combined organic layers are washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography on silica gel using hexane/ethyl acetate to give ethyl 4-fluoro-4-((4fluorophenoxy)methyl)pyrimidin-2-yl)piperidin-4-carboxylate as a white solid (0.400 g, 53%). Replacing ethyl 1-(4-(4-fluorophenyl)pyrimidin-2-yl)piperidin-4-carboxylate with the newly prepared intermediate, the last two steps of Example 41 were used to obtain the title compound. ¹ H NMR (400 MHz, CDCl3) δ 8.30 (d, J=4.8 Hz, 1H), 7.01-6.97 (m, 2H), 6.90-6.87 (m, 2H ), 6.69 (d, J=4.8 Hz, 1H), 6.38 (d, J=6.8 Hz, 1H), 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. ¹³ C NMR (100 MHz, CDCl3) 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 LCMS purity >95% (214 nm and 254 nm); retention time 1.42 min; (M+H+) 472.3.

Example 136.

4-Fluoro-1-(5-(4-fluorobenzyl)pyrimidin-2-yl)-H-(3-methylquinuclidin-3-yl)piperidin-4-carboxamide.

To a solution of 4-hydroxybenzaldehyde (6.00 g, 49.1 mmol) in acetonitrile (200 ml), add cesium carbonate (40.0 g, 123 mmol) and 1-chloro-2-methoxyethane (6.90 g, 73.7 mmol). The solution is refluxed overnight and diluted with water (100 ml). The mixture is extracted with ethyl acetate and the combined organic layers are washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography on silica using hexane/ethyl acetate to give 4-(2-methoxyethoxy)benzaldehyde as a light yellow oil (6.00 g, 67%). To a solution of the resulting compound (2.70 g, 15.0 mmol) in 1,4-dioxane (50 ml) was added 4-methylbenzenesulfonhydrazide (2.79 g, 15.0 mmol) with stirring. The solution was heated at 90°C for 1 hour, then concentrated to give crude N-(4-(2-methoxyethoxy)benzylidene)-4-methylbenzenesulfonhydrazide as a yellow solid (5.22 g, 99%). The resulting material is used in the next stage without purification. To a solution of hydrazone (5.22 g, 15.0 mmol) in 1,4-dioxane (50 ml) add potassium carbonate (6.20 g, 44.9 mmol) and 2-chloropyrimidin-5-ylboronic acid ( 2.37 g, 15.0 mmol). The mixture is heated at 90°C for 3 hours, diluted with water (100 ml) and extracted with ethyl acetate. The combined organic layers are washed with water and brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on silica using hexane/ethyl acetate to give 2-chloro-5-(4-(2-methoxyethoxy)benzyl)pyrimidine as a light yellow oil (0.700 g, 17%). To a solution of the resulting intermediate (0.700 g, 2.52 mmol) in acetonitrile (15 ml) add ethyl 4-fluoropiperidine-4carboxylate hydrochloride (0.453 g, 2.59 mmol) and cesium carbonate (2.46 g, 7) with stirring. .55 mmol). The mixture is heated at 80°C overnight, diluted with water (50 ml) and extracted with ethyl acetate. The combined organic layers are washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol as eluent to give ethyl 4-fluoro-1-5-(4-(2methoxyethoxy)benzyl)pyrimidin-2-yl)piperidin-4-carboxylate as light yellow solid (0.667 g, 74%). Replacing ethyl 1-(4-(4-fluorophenyl)pyrimidin-2-yl)piperidin-4-carboxylate with the newly prepared intermediate, the last two steps of Example 41 were used to obtain the title compound. 1H NMR (400 MHz, CDCl ₃ ) 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, 1H), 4.70-4.66 (m, 2H), 4.11 (t, J=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), 2.28-2. 15 (m, 3H), 1.87-1.77 (m, 4H), 1.58-1.50 (m, 5H) ppm. ¹³ C NMR (100 MHz, CDCl ₃ ) 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 LCMS purity >93% (214 nm and 254 nm); retention time 1.36 min; (M+H+) 512.3.

Example 137.

(3R)-3-Methyl-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)-4-(4-phenylpyrimidin-2-yl)piperazin-1 carboxamide (single enantiomer B) .

To a solution of 2,4-dichloropyrimidine (3.00 g, 20.1 mmol) in toluene (25 ml) add phenylboronic acid (2.47 g, 20.3 mmol), potassium carbonate (8.40 g, 60 .9 mmol), tetrakis(triphenylphosphine)palladium(0) (1.26 g, 1.02 mmol) and 1:1 (v/v) ethanol/water (36 mL). The mixture is heated overnight at 55°C and then concentrated. The residue is diluted with water and extracted with ethyl acetate. The combined extracts are washed with brine, dried (Na2SO4) and concentrated. Raw mate

- 67 046304 rial is purified by flash chromatography on silica using hexane/ethyl acetate to give 2-chloro-4-phenylpyrimidine as a yellow solid (3.20 g, 83%). To a solution of the resulting intermediate (1.10 g, 5.77 mmol) in butyronitrile (20 ml) was added N)-tert-butyl-3-methylpiperazine-1-carboxylate (2.31 g, 11.5 mmol) with stirring. and potassium carbonate (2.07 g, 15.0 mmol). The mixture is refluxed for 48 hours and then concentrated. The residue is dissolved in ethyl acetate and washed with water. The aqueous layer is again extracted with ethyl acetate and the combined organic layers are dried (Na ₂ SO ₄ ) and concentrated. The crude reaction product is purified by flash chromatography on silica using methanol/dichloromethane as an eluent to give N)-tert-butyl-3-methyl-4-(4-phenylpyrimidin-2-yl)piperazin-1-carboxylate as an amber solid. (1.72 g, 84%). Using General Procedure G, the tert-butoxycarbonyl protecting group is removed from the resulting compound to give (R)2-(2-methylpiperazin-1-yl)-4-phenylpyrimidine. This intermediate is in turn reacted with intermediate 10 using General Procedure A to produce the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (d, J=5.1 Hz, 1H), 8.18-8.10 (m, 2H), 7.57-7.48 ( m, 3H), 7.22 (d, J=5.1 Hz, 1H), 5.72 (s, 1H), 4.93-4.82 (m, 1H), 4.54-4.42 (m, 1H), 4.13-4.02 (m, 1H), 3.94-3.84 (m, 1H), 3.27-3.06 (m, 2H), 2.98-2 .64 (m, 7H), 2.43-2.33 (m, 1H), 1.83-1.63 (m, 4H), 1.57-1.24 (m, 5H), 1.16 (d, J=6.6 Hz, 3H) ppm UP-LCMS purity 99.7% (214 and 254 nm); retention time 0.82 min; (M+H+) 435.5.

Example 138.

(3R)-3-Methyl-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)-4-(4-phenylpyrimidin-2-yl)piperazin-1 carboxamide (single enantiomer A) .

Replacing intermediate 10 with intermediate 9, the same reaction sequence as described in Example 137 was used to obtain the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (d, J=5.2 Hz, 1H), 8.19-8.09 (m, 2H), 7.58-7.47 (m , 3H), 7.22 (d, J=5.2 Hz, 1H), 5.70 (s, 1H), 4.91-4.80 (m, 1H), 4.54-4.42 ( m, 1H), 4.07-3.88 (m, 2H), 3.27-3.14 (m, 1H), 3.14-3.04 (m, 1H), 3.00-2, 67 (m, 7H), 2.40-2.31 (m, 1H), 1.87-1.64 (m, 4H), 1.57-1.43 (m, 1H), 1.42- 1.26 (m, 4H), 1.15 (d, J=6.6 Hz, 3H) ppm UP-LCMS purity 99.4% (214 and 254 nm); retention time 0.83 min; (M+H+) 435.5.

Example 139.

(3S)-3-Methyl-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)-4-(4-phenylpyrimidin-2-yl)piperazin-1carboxamide (single enantiomer B).

Replacing ^)-tert-butyl-3-methylpiperazine-1-carboxylate with ^)-tert-butyl-3-methylpiperazine-1-carboxylate, the same reaction sequence as described in Example 137 was used to obtain the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (d, J=5.2 Hz, 1H), 8.18-8.09 (m, 2H), 7.57-7.47 (m , 3H), 7.22 (d, J=5.2 Hz, 1H), 5.70 (s, 1H), 4.91-4.80 (m, 1H), 4.53-4.42 ( m, 1H), 4.05-3.87 (m, 2H), 3.26-3.14 (m, 1H), 3.09 (dd, J=13.4, 3.8 Hz, 1H) , 2.99-2.67 (m, 7H), 2.40-2.31 (m, 1H), 1.87-1.63 (m, 4H), 1.56-1.43 (m, 1H), 1.42-1.26 (m, 4H), 1.15 (d, J=6.6 Hz, 3H) ppm. UP-LCMS purity >99.9% (214 and 254 nm); retention time 0.83 min; (M+H+) 435.5.

Example 140.

(3S)-3-Methyl-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)-4-(4-phenylpyrimidin-2-yl)piperazin-1carboxamide (single enantiomer A).

Replacing ^)-tert-butyl-3-methylpiperazine-1-carboxylate with ^)-tert-butyl-3-methylpiperazine-1-carboxylate and intermediate 10 with intermediate 9, use the same reaction sequence as described in Example 137 to obtain the connection named in the header. 1H NMR (400 MHz, DMSO46) δ 8.46 (d, J=5.2 Hz, 1H), 8.18-8.10 (m, 2H), 7.56-7.48 (m, 3H) , 7.22 (d, J=5.2 Hz, 1H), 5.73 (s, 1H), 4.93-4.81 (m, 1H), 4.54-4.43 (m, 1H ), 4.12-4.02 (m, 1H), 3.94-3.84 (m, 1H), 3.263.07 (m, 1H), 3.00-2.69 (m, 7H), 2.43-2.35 (m, 1H), 1.84-1.64 (m, 4H), 1.57-1.44 (m, 1H), 1.43-1.26 (m, 4H ), 1.16 (d, J=6.5 Hz, 3H) ppm. UP-LCMS purity 99.6% (214 and 254 nm); retention time 0.82 min; (M+H+) 435.5.

Example 141.

3-Methyl-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)-4-(4-phenylpyrimidin-2-yl)piperazine-1-carboxamide.

Replacing ^)-tert-butyl-3-methylpiperazine-1-carboxylate with racemic tert-butyl-3methylpiperazine-1-carboxylate and intermediate 10 with intermediate 5, use the same reaction sequence as described in example 137 to obtain the title in connection header. 1H NMR (500 MHz, CDCl ₃ ) δ 8.41 (d, J=5.5 Hz, 1H), 8.08-8.06 (m, 2H), 7.50-7.49 (m, 3H ), 7.00 (d, J=5.5 Hz, 1H), 5.06-4.98 (m, 1H), 4.66-4.58 (m, 1H), 4.37-4, 35 (m, 1H), 4.00-3.89 (m, 1H), 3.783.66 (m, 1H), 3.50-3.37 (m, 2H), 3.116-3.01 (m, 5H), 2.85-2.82 (m, 2H), 2.47-2.39 (m, 1H), 2.00-1.96 (m, 3H), 1.75-1.52 ( m, 6H), 1.31 (d, J=6.5 Hz, 3H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity >99% (214 and 254 nm);

- 68 046304 retention time 1.32 min; (M+H+) 435.3.

Example 142.

3-Ethyl-N(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)-4-(4-phenylpyrimidin-2-yl)piperazine-1-carboxamide.

Replacing ^)-tert-butyl-3-methylpiperazine-1-carboxylate with tert-butyl-3-ethylpiperazine-1-carboxylate and intermediate 10 with intermediate 5, use the same reaction sequence as described in Example 137 to obtain the title compound. ¹ H NMR (400 MHz, CDCl ₃ ) 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, 1H), 7.10-7.08 (d, J=7.2 Hz, 1H), 6.96-6.94 (d, J =8.0 Hz, 1H), 5.46 (s, 1H), 3.83-3.80 (m, 2H), 3.08-2.78 (m, 8H), 2.41 (m, 1H), 2.24-2.21 (m, 1H), 2.01-1.52 (m, 13H) ppm. UP-LCMS purity 97.7% (214 and 254 nm); retention time 0.89 min; (M+H+) 449.5.

Example 143.

3-Ethyl-N(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)-4-(4-phenylpyrimidin-2-yl)piperazine-1-carboxamide.

Replacing 2,4-dichloropyrimidine with 2,4-dichloro-5-fluoropyrimidine, ^)-tert-butyl-3-methylpiperazine 1-carboxylate with racemic tert-butyl-3-methylpiperazine-1-carboxylate, and intermediate 10 with intermediate 5 , use the same reaction sequence as described in example 137 to obtain the title compound. ^1H NMR (500 MHz, CDCl3) δ 8.29 (d, J=3.5 Hz, 1H), 8.12-8.09 (m, 2H), 7.53-7.50 (m, 3H ), 4.91-4.87 (m, 1H), 4.53-4.48 (m, 1H), 4.36-4.34 (m, 1H), 4.00-3.90 (m , 1H), 3.75-3.66 (m, 1H), 3.45-3.35 (m, 2H), 3.15-2.84 (m, 7H), 2.44-2.39 (m, 1H), 1.99-1.85 (m, 3H), 1.74-1.52 (m, 6H), 1.29 (dd, J=6.5 Hz and 2.0 Hz, 3H) ppm ¹³ C NMR (125 MHz, CDCl3) 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. LCMS purity >99% (214 nm and 254 nm); retention time 1.37 min; (M+H+) 453.3.

Example 144.

3-(Methoxymethyl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)-4-(4-phenylpyrimidin-2-yl)piperazin-1-carboxamide.

2-Chloro-4-phenylpyrimidine (prepared as described in Example 137; 0.332 g, 1.74 mmol), tert-butyl-3-(methoxymethyl)piperazine-1-carboxylate (0.400 g, 1.74 mmol), NN- Diisopropylethylamine (0.61 g, 3.49 mmol) and acetonitrile (8 ml) were charged into a sealed microwave reactor. The mixture is heated with stirring in a microwave reactor for 36 hours at 140°C. The reaction mixture is then concentrated and the residue is treated with water and ethyl acetate. The organic layer is combined with the second ethyl acetate extract, dried (Na ₂ SO ₄ ) and concentrated. The crude product is purified by flash chromatography on silica using dichloromethane/methanol as an eluent to give tert-butyl 3-(methoxymethyl)-4-(4-phenylpyrimidin-2-yl)piperazine-1-carboxylate as a pale glassy solid -amber color (0.397 g, 60%). Using General Procedure G, the tert-butoxycarbonyl protecting group was removed from the resulting compound to yield 2-(2-methoxymethyl)piperazin-1-yl)-4-phenylpyrimidine.

This intermediate is in turn reacted with intermediate 5 using the general procedure A to obtain the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.47 (d, J=5.1 Hz, 1H), 8.18-8.09 (m, 2H), 7.57-7.47 (m , 3H), 7.24 (d, J=5.1 Hz, 1H), 5.65 (s, 0.5H), 5.61 (s, 0.5H), 4.99-4.84 ( m, 1H), 4.58-4.42 (m, 1H), 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, 1H), 1.86-1.61 (m, 4H), 1.551.21 (m, 5H) ppm. UP-LCMS purity 99.4% (214 and 254 nm); retention time 0.83 min; (M+H+) 465.4.

Example 145.

4-(4-(4-Fluorophenyl)pyrimidin-2-yl)-3-methyl-N(4-methyl-1-azabicyclo[3.2.2]nonai-4-yl)piperazin-1-carboxamide.

Replacing 2-chloro-4-phenylpyrimidine with 2-chloro-4-(4-fluorophenyl)pyrimidine, (P)-tert-butyl-3methylpiperazine-1-carboxylate with racemic tert-butyl-3-methylpiperazine-1-carboxylate and intermediate compound 10 into intermediate 5, use the last three steps of Example 137 to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 8.38 (d, J=5.5 Hz, 1H), 8.06-8.03 (m, 2H), 7.15 (t, J=8.5 Hz, 2H), 6.92 (d, J=5.5 Hz, 1H), 4.99-4.96 (m, 1H), 4.60-4.56 (m, 1H), 4.34 (d, J=6.0 Hz, 1H), 3.98-3.88 (m, 1H), 3.73-3.64 (m, 1H), 3.45-3.34 (m, 2H ), 3.13-2.84 (m, 7H), 2.40-2.37 (m, 1H), 1.96-1.53 (m, 9H), 1.29 (dd, J=7 .0 Hz and 2.5 Hz, 3H) ppm ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity >97% (214 nm and 254 nm); retention time 1.37 min; (M+H+) 453.3.

Example 146.

4-(4-(4-Fluorophenyl)pyrimidin-2-yl)-3-methyl-N(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperazin-1-carboxamide.

- 69 046304

Replacing phenylboronic acid with (4-(2-methoxyethoxy)phenyl)boronic acid, 2,4dichloropyrimidine with 2,4-dichloro-5-fluoropyrimidine, (P)-tert-butyl-3-methylpiperazine-1-carboxylate with racemic tert- butyl 3-methylpiperazine-1-carboxylate and intermediate 10 to intermediate 5, use the same reaction sequence as described in Example 137 to obtain the title compound. 1H NMR (400 MHz, CDCl ₃ ) δ 8.21 (d, J=3.8 Hz, 1H), 8.09 (d, J=8.9 Hz, 2H), 7.02 (d, J= 8.9 Hz, 2H), 4.91-4.81 (m, 1H), 4.50-4.36 (m, 2H), 4.22-4.16 (m, 2H), 4.01 -3.87 (m, 1H), 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, 1H), 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. UP-LCMS purity 98.7% (214 and 254 nm); retention time 0.91 min; (M+H+) 527.5.

Example 147.

cis-3,6-Dimethyl-N(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)-4-(4-phenylpyrimidin-2-yl)piperazin-1-carboxamide.

Mixture of 2-chloro-4-pyrimidine (prepared as described in Example 137; 0.190 g, 0.999 mmol), 2,2,6,6-tetramethylpiperidine and tert-butyl-cis-3,5-dimethylpiperazine-1-carboxylate with stirring, heat at 140°C for 48 hours and then concentrate. The residue was purified by flash chromatography on silica using hexane/ethyl acetate to give tert-butyl-cis-3,5dimethyl-4-(4-phenylpyrimidin-2-yl)piperazine-1-carboxylate as a white solid (0.094 g, 26%). To a solution of the resulting intermediate (0.185 g, 0.500 mmol) in dichloromethane (1 ml) was added trifluoroacetic acid (4 ml) with stirring and cooling (0°C).

The reaction mixture is warmed to room temperature and stirred for an additional 2 hours. At this time, the mixture is diluted with saturated aqueous sodium carbonate (in an amount sufficient to make the solution alkaline) and extracted with dichloromethane. The combined extracts were dried (Na ₂ SO ₄ ) and concentrated to give 2-(cis-2,6-dimethylpiperazin-1-yl)-4-phenylpyrimidine as a yellow oil (0.136 g, 100%). Using General Procedure A and Intermediate 5, the resulting intermediate was used to prepare the title compound, which was obtained as a white solid (0.068 g, 31%). ^1H NMR (500 MHz, CDCl3) δ 8.43 (d, J=5.0 Hz, 1H), 8.09-8.06 (m, 2H), 7.51-7.49 (m, 3H ), 7.01 (d, J=5.5 Hz, 1H), 4.98-4.96 (m, 2H), 4.44 (s, 1H), 3.97 (d, J=12, 0 Hz, 1H), 3.78 (d, J=12.0 Hz, 1H), 3.28-2.90 (m, 8H), 2.48 (m, 1H), 1.98-1, 57 (m, 9H), 1.38 (t, J=7.5 Hz, 6H) ppm. ¹³ C NMR (125 MHz, CDCl3) 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 LCMS purity >95% (214 nm and 254 nm); retention time 1.99 min; (M+H+) 449.4.

Example 148.

4-(5-Fluoro-4-(4-(methoxymethyl)phenyl)pyrimidin-2-yl)-3-isopropyl-N(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperazin- 1-carboxamide.

Replacing 2,4-dichloropyrimidine with 2,4-dichloro-5-fluoropyrimidine and phenylboronic acid with 2-(4(methoxymethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, use the first step of Example 137 to obtain 2-chloro-5-fluoro-4-(4-(methoxymethyl)phenyl)pyrimidine. To a solution of the resulting intermediate (0.400 g, 1.58 mmol) in toluene (8 ml) add tert-butyl-3-isopropylpiperazine-1-carboxylate (0.434 g, 1.90 mmol), bis(tri-tert-butylphosphine) with stirring. palladium(0) (0.081 g, 0.158 mmol), trimethylhexadecylammonium chloride (0.101 g, 0.316 mmol) and 50% aqueous sodium hydroxide (0.25 ml, 4.73 mmol). The mixture is heated at 100°C overnight and concentrated. The residue is purified by flash chromatography on silica using hexane/ethyl acetate as an eluent to give partially purified tert-butyl-4-(5-fluoro-4-(4-(methoxymethyl)phenyl)pyrimidin-2-yl)-3-isopropylpiperazine -1-carboxylate as a light yellow oil (0.500 g). The resulting material is dissolved in dichloromethane (5 ml), stirred and treated with trifluoroacetic acid (3.0 ml). After 3 hours, the reaction mixture is concentrated and the residue is purified by reverse phase flash chromatography on C18 silica using acetonitrile/water/trifluoroacetic acid as an eluent. 5-Fluoro-2-(2-isopropylpiperazin-1-yl)-4-(4-(methoxymethyl)phenyl)pyrimidine was obtained as a light yellow oil (0.200 g, 36%, two steps). Using General Procedure A and Intermediate 5, the resulting intermediate was used to prepare the title compound, which was obtained as a white solid (0.105 g, 63%). Ή NMR (500 MHz, CDCl ₃ ) δ 8.24 (d, J=3.5 Hz, 1H), 8.08 (d, J=8.0 Hz, 2H), 7.48 (d, J= 8.5 Hz, 2H), 4.75-4.72 (m, 1H), 4.59-4.55 (m, 3H), 4.33-4.31 (m, 1H), 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, 1H), 2.26-2.19 (m, 1H), 1.94-1.50 (m, 9H), 1.13 (t, J=7.5 Hz, 3H), 0.87 (d, J=7.5 Hz, 3H) ppm ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity >99% (214 nm and 254 nm); retention time 1.54 min; (M+H+) 525.3.

Example 149.

4-(4-(4-(Methoxymethyl)phenyl)pyrimidin-2-yl)-N(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)-3(trifluoromethyl)piperazine-1-carboxamide .

- 70 046304

Replacing phenylboronic acid with 2-(4-(methoxymethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, use the first step of Example 137 to obtain 2-chloro-4-(4-( methoxymethyl)phenyl)pyrimidine. To a solution of the resulting intermediate (880 mg, 3.75 mmol) in toluene (30 ml) was added 1ret-butyl-3-(1fluoromethyl)piperazine-1-carboxylate (1.10 g, 4.33 mmol), carbonate, with stirring cesium (6.11 g, 18.75 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (700 mg, 1.12 mmol) and palladium(II) acetate (0.168 g, 0.748 mmol ). The mixture is refluxed overnight, cooled and diluted with water (~100 ml). The mixture is extracted with ethyl acetate and the combined organic layers are dried (Na ₂ SO ₄ ) and concentrated. The crude product is purified by flash chromatography on silica using hexane/ethyl acetate to give tert-butyl-4-(4-(4(methoxymethyl)phenyl)pyrimidin-2-yl)-3-(trifluoromethyl)piperazine-1- carboxylate as a colorless gum (0.179 g, 11%). Using General Procedure G, the tert-butoxycarbonyl protecting group was removed from the resulting compound to yield 4-(4-(methoxymethyl)phenyl)-2-(2-(trifluoromethyl)piperazin-1-yl)pyrimidine. This intermediate is in turn reacted with intermediate 5 using the general procedure A to obtain the title compound. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.42 (dd, J=5.2, 1.4 Hz, 1H), 8.02 (d, J=7.8 Hz, 2H), 7.45 (d, J=7.8 Hz, 2H), 7.27 (s, 1H), 7.09 (dd, J=5.2, 1.4 Hz, 1H), 5.72-5.58 ( m, 1H), 4.93-4.79 (m, 1H), 4.53 (s, 1H), 4.43-4.36 (m, 1H), 4.26-4.18 (m, 0.5H), 4.16-4.08 (m, 0.5H), 4.05-3.89 (m, 1H), 3.59-3.40 (m, 5H), 3.15- 2.75 (m, 7H), 2.44-2.35 (m, 1H), 1.98-1.41 (m, 9H) ppm. UP-LCMS purity >99.9% (214 and 254 nm); retention time 0.90 min; (M+H+) 533.3.

Example 150.

3-(Difluoromethyl)-4-(4-(4-(methoxymethyl)phenyl)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperazin-1 -carboxamide.

Replacing tert-butyl 3-isopropylpiperazine-1-carboxylate with tert-butyl 3-(difluoromethyl)piperazine-1-carboxylate, the last three steps of Example 148 were used to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 8.43 (d, J=5.5 Hz, 1H), 8.04 (d, J=8.0 Hz, 2H), 7.476 (d, J=8, 0 Hz, 2H), 7.09 (d, J=5.0 Hz, 1H), 6.17 (t, J=56 Hz, 1H), 5.14-5.10 (m, 1H), 4 .79 (m, 1H), 4.55 (s, 2H), 4.41-4.39 (m, 1H), 4.05-3.95 (m, 2H), 3.58-3.45 (m, 5H), 3.18-2.84 (m, 7H), 2.41-2.38 (m, 1H), 1.95-1.50 (m, 9H) ppm. ¹³ C NMR (100 MHz, CDCl ₃ ) δ 164.3, 161.5, 158.4, 156.4, 141.2, 136.4, 132.1, 131.9, 128.5, 128.4 , 114.7 (td, J=246 Hz and 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 LCMS purity >99% (214 nm and 254 nm); retention time 1.29 min; (M+H+) 515.3.

Example 151.

3-Isopropyl-4-(4-(4-(methoxymethyl)phenyl)-1,3,5-triazin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4- yl)piperazine-1-carboxamide.

To a suspension of 2,4-dichloro-1,3,5-triazine (0.800 g, 5.33 mmol) and potassium carbonate (1.47 g, 10.7 mmol) in tetrahydrofuran (20 ml) with stirring and cooling (0 °C) add a solution of tert-butyl 3-isopropylpiperazine-1-carboxylate (1.22 mg, 5.33 mmol) in tetrahydrofuran (10 ml) dropwise over 30 min. The mixture is stirred at 0°C for 2 hours and then at room temperature overnight. The reaction mixture was then concentrated and the residue was purified by neutral alumina column chromatography using hexane/ethyl acetate as an eluent to give tert-butyl-4-(4chloro-1,3,5-triazin-2-yl)-3-isopropylpiperazine-1- carboxylate as a white solid (1.10 g, 60%). To a solution of the resulting intermediate (0.450 g, 1.32 mmol) in 1,4-dioxane was added 2-(4-((2-methoxyethoxy)methyl)phenyl)-4,4,5,5-tetramethyl-1 with stirring ,3,2-dioxaborolane (0.391 g, 1.58 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.119 g, 0.130 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.124 g, 0.260 mmol) and cesium carbonate (1.08 g, 3.31 mmol). The mixture is heated overnight at 140°C for 16 hours, filtered through celite and concentrated. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol as eluent to give tert-butyl-3-isopropyl-4-(4-(4-(methoxymethyl)phenyl)-1,3,5-triazin-2-yl) piperazine-1-carboxylate as a white solid (200 mg, 35%). To a solution of the resulting intermediate (200 mg, 0.470 mmol) in dichloromethane (10 ml) was added trifluoroacetic acid (10 ml) with stirring and cooling (0°C). The reaction mixture is stirred for an additional 3 hours at 0°C and then diluted with 2.0 N aqueous potassium carbonate (enough to make the mixture alkaline) and extracted with dichloromethane. The combined organic phases are washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give 2-(2-isopropylpiperazin-1-yl)-4-(4(methoxymethyl)phenyl)-1,3,5-triazine as a white solid substances (150 mg, raw). Using General Procedure A and Intermediate 5, the resulting intermediate was used to prepare the title compound, which was obtained as a light yellow solid (0.040 g, 15%). 1H NMR (500 MHz, CDCl ₃ ) δ 8.65 (d, J=3.0 Hz, 1H), 8.41-8.37 (m, 2H), 7.47-7.45 (m, 2H ), 4.99 (m, 0.5H), 4.80 (m, 1H), 4.63 (m, 0.5H), 4.56 (s, 2H), 4.35 (d, J= 12.5 Hz, 1H), 4.08-3.89 (m, 2H), 3.44 (s, 3H), 3.19-2.84 (m, 9H), 2.42-2.40 (m, 1H), 2.24 (m, 1H), 1.98-1.56 (m, 9H), 1.19-1.13 (m, 3H), 0.89-0.85 (m , 3H) ppm ¹³ C NMR (125 MHz, CDCl ₃ ) δ 170.5, 170.2, 166.2, 166.0, 164.5, 156.8, 142.5, 135.6, 135.5, 128.6 ,

- 71 046304

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 LCMS purity >95% (214 nm and 254 nm); retention time 1.90 min; (M+H+) 508.3.

Example 152.

(3R)-4-(5-(4-Fluorophenoxy)pyrimidin-2-yl)-3-methyl-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4yl)piperazine-1-carboxamide.

Replacing 2-chloro-5-fluoro-4-(4-(methoxymethyl)phenyl)pyrimidine with 2-chloro-5-(4-fluorophenoxy)pyrimidine (prepared as described in Example 129) and tert-butyl-3- isopropylpiperazine-1-carboxylate to ^)-tert-butyl-3-methylpiperazine-1-carboxylate, use the last three steps of Example 148 to obtain the title compound. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.17 (s, 2H), 7.026.99 (m, 2H), 6.92-6.89 (m, 2H), 4.85-4.73 ( m, 1H), 4.45-4.32 (m, 2H), 3.97-3.88 (m, 1H), 3.73-3.62 (m, 1H), 3.37-3, 32 (m, 2H), 3.10-2.79 (m, 7H), 2.43-2.38 (m, 1H), 1.99-1.48 (m, 9H), 1.25- 1.23 (m, 3H) ppm ¹³ C NMR (100 MHz, CD3OD) 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 LCMS purity >96% (214 nm and 254 nm); retention time 1.37 min; (M+H+) 469.2.

Example 153.

3-Ethynyl-4-(4-(4-(Methoxymethyl)phenyl)pyrimidin-2-yl)-H-(4-methyl-1-azabicyclo[3.2.2]nonan-4yl)piperazine-1-carboxamide.

To a solution of 2-chloro-4-(4-(methoxymethyl)phenyl)pyrimidine (prepared as described in Example 149; 0.936 g, 4.00 mmol) in MH-dimethylformamide (10 ml) add tert-butyl- 3(hydroxymethyl)piperazine-1-carboxylate (1.73 g, 8.00 mmol). The reaction mixture is heated at 90°C for 5 days and then concentrated. The residue is purified by flash chromatography on silica gel using hexane/ethyl acetate as eluent to give tert-butyl 3-(hydroxymethyl)-4-(4-(4-(methoxymethyl)phenyl)pyrimidin-2-yl)piperazine-1-carboxylate as a white solid (1.066 g, 65%). To a solution of the resulting intermediate (0.543 g, 1.32 mmol) in ethyl acetate (10 ml) was added 2-iodoxybenzoic acid (1.10 g, 3.93 mmol) with stirring. The reaction mixture is heated at 80°C for 3 hours and then concentrated. The residue was purified by flash chromatography on silica gel using hexane/ethyl acetate as an eluent to give tert-butyl-3-ethynyl-4-(4-(4(methoxymethyl)phenyl)pyrimidin-2-yl)piperazine-1-carboxylate as yellow oil (0.480 g, 89%). Using General Procedure G, the tert-butoxycarbonyl protecting group was removed from the resulting compound to yield 2-(2-ethynylpiperazin-1-yl)-4-(4-(methoxymethyl)phenyl)pyrimidine. This intermediate is in turn reacted with intermediate 5 using the general procedure A to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 8.46 (d, J=5.5 Hz, 1H), 8.07 (d, J=8.0 Hz, 2H), 7.47 (d, J= 8.0 Hz, 2H), 7.10 (d, J=5.0 Hz, 1H), 5.78 (s, 1H), 4.67-4.50 (m, 4H), 4.29- 3.99 (m, 2H), 3.44 (s, 3H), 3.42-3.30 (m, 2H), 3.09-2.84 (m, 7H), 2.47-2, 41 (m, 1H), 2.23-2.22 (m, 1H), 1.99-1.55 (m, 9H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) 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, 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. LCMS purity >99% (214 nm and 254 nm); retention time 1.35 min; (M+H+) 489.3.

Example 154.

1-Azabicyclo[3.2.2]nonan-4-yl-3-methyl-4-(4-phenylpyrimidin-2-yl)piperazine-1-carboxylate.

By substituting racemic tert-butyl-3-methylpiperazine-1-carboxylate for ^)-tert-butyl-3-methylpiperazine-1-carboxylate, the first three steps of Example 137 are used to obtain 2-(2methylpiperazin-1-yl)-4-phenylpyrimidine. The intermediate is in turn reacted with Intermediate 3 using General Procedure C to produce the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 8.40 (d, J=5.5 Hz, 1H), 8.07-8.04 (m, 2H), 7.49-7.47 (m, 3H ), 6.99 (d, J=5.5 Hz, 1H), 5.08 (m, 1H), 4.98 (m, 1H), 4.67 (m, 1H), 4.25-4 .02 (m, 2H), 3.30-2.82 (m, 9H), 2.36-1.57 (m, 7H), 1.26 (d, J=7.0 Hz, 3H) m .d. ¹³ C NMR (125 MHz, CDCl ₃ ) δ 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. LCMS purity >99% (214 nm and 254 nm); retention time 1.48 min; (M+H+) 422.2.

Example 155.

Quinuclidin-3 -yl(2-(4'-(2-methoxyethoxy)[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate.

Using general procedure F and reacting ethyl 2-(4-bromophenyl)-2methylpropanoate with 4-(2-methoxyethoxy)phenylboronic acid, ethyl 2-(4'-(2-methoxyethoxy)[1,1'- biphenyl]-4-yl)-2-methylpropanoate as an off-white solid. Lithium hydroxide monohydrate (1, 47 g, 61.4 mmol). The mixture is refluxed overnight and then concentrated. The residue is dissolved in water, treated with 1N hydrochloric acid (65 ml) and extracted with ethyl acetate. combined organic layers

- 72 046304 washed with brine, dried (Na ₂ SO ₄ ) and concentrated to obtain 2-(4'-(2-methoxyethoxy)[1,1'-biphenyl]-4yl)-2-methylpropanoic acid as a white solid ( 2.75 g, 100%). The resulting intermediate and quinuclidin-3-ol were reacted according to General Procedure H to obtain the title compound as a colorless glassy solid (23%). 1H NMR (400 MHz, DMSO-de) δ 7.62-7.29 (m, 7H), 7.01 (d, J=8.9 Hz, 2H), 4.47-4.37 (m, 1H), 4.17-4.08 (m, 2H), 3.72-3.62 (m, 2H), 3.32 (s, 3H), 3.09-2.25 (m, 6H) , 2.05-1.18 (m, 11H) ppm ¹³ C NMR (100 MHz, DMSO46) 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, 54.2, 46.9, 45.9, 29.4, 25.3, 24.2, 19.2 ppm. UP-LCMS purity 100%, 99.1% (210 and 254 nm); retention time 0.87 min; (M+H+) 439.0.

Example 156.

(b)-Quinuclidin-3-yl(2-(4'-(2-methoxyethoxy)[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate.

Using general procedure H and reacting 2-(4'-(2-methoxyethoxy)[1,1'biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 1) and (S )quinuclidin-3-ol gives the title compound as a colorless glassy solid. NMR data corresponds to the data in example 1. Purity by UP-LCMS 100%, 100% (210 and 254 nm); retention time 0.87 min; (M+H+) 439.5.

Example 157.

(R)-1 -(2-(4'-(2-Methoxyethoxy)[1,1'-biphenyl]-4-yl)propan-2-yl)-3 -(3-methylquinuclidin-3-yl)urea .

Using General Procedure H and reacting 2-(4'-(2-methoxyethoxy)[1,1'biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 155) and intermediate 12 the title compound is obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) 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, 1H), 5.76 (s, 1H), 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 , 1H), 1.85-1.73 (m, 1H), 1.67-1.56 (m, 1H), 1.53 (d, J=11.9 Hz, 6H), 1.42- 1.31 (m, 1H), 1.29 (s, 2H), 1.29-1.20 (m, 1H) ppm. ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 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 by UPLCMS 100%, 99.9% (210 and 254 nm); retention time 0.97 min; (M+H+) 452.4.

Example 158.

^)-1-(2-(4'-(2-Methoxyethoxy)[1,1'-biphenyl]-4-yl)propan-2-yl)-3-(3-methylquinuclidin-3 yl)urea.

Using General Procedure H and reacting 2-(4'-(2-methoxyethoxy)[1,1'biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 155) and intermediate 11 the title compound is obtained as a white solid. NMR data consistent with Example 3. UP-LCMS purity 100%, 99.9% (210 and 254 nm); retention time 0.97 min; (M+H+) 452.4.

Example 159.

-(3-Ethylquinuclidin-3-yl)-3-(2-(4'-(2-methoxyethoxy)[1,1'-biphenyl]-4-yl)propan-2-yl)urea

Using General Procedure H and reacting 2-(4'-(2-methoxyethoxy)[1,1'biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 155) and intermediate 2 obtain the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) 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, J=8.8 Hz, 2H), 6.18 (s, 1H), 5.73 (s, 1H), 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) m. d. ¹³ C NMR (100 MHz, DMSO-d6) δ 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 UP-LCMS purity 100%, 99.9% (210 and 254 nm); retention time 1.00 min; (M+H+) 466.4.

Example 160.

1-(2-(4'-(2-Methoxyethoxy)[1,1'-biphenyl]-4-yl)propan-2-yl)-3-(4-methyl-1-azabicyclo[3.2.2]nonane -4yl)urea.

Using General Procedure H and reacting 2-(4'-(2-methoxyethoxy)[1,1'biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 155) and intermediate 5 the title compound is obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) 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, J=8.8 Hz, 2H), 6.22 (br.s, 1H), 5.72 (br.s, 1H), 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, 1H), 1.83-1.36 (m, 10H), 1.33-1.19 (m, 4H) ppm. ¹³ C NMR (100 MHz, DMSO-d 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 UP-LCMS purity 100%, 99.0% (210 and 254 nm); retention time 0.98 min; (M+H+) 466.4.

Example 161.

No.(2-(4'-(2-Methoxyethoxy)[1,G-biphenyl]-4-yl)propan-2-yl)-1,4-diazabicyclo[3.2.2]nonane-4-73 046304 carboxamide.

Using General Procedure H and reacting 2-(4'-(2-methoxyethoxy)[1,1'biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 155) and intermediate 6 the title compound is obtained as a white solid. 1H NMR (400 MHz, DMSO-de) 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, 1H), 4.19 (s, 1H), 4.12 (dd, J =5.4, 3.8 Hz, 2H), 3.75-3.62 (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. ¹³ C NMR (100 MHz, DMSO40 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 UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.85 min; (M+H+) 438.5.

Example 162.

1-(1 -(4'-(2-Methoxyethoxy)[1,1'-biphenyl]-4-yl)cyclopropyl)-3-(quinuclidin-3-yl)urea.

Replacing ethyl 2-(4-bromophenyl)-2-methylpropanoate with ethyl 1-(4-bromophenyl)cyclopropanecarboxylate, use the reaction sequence described in Example 155 to obtain 1-(4'-(2methoxyethoxy)[1,1 '-biphenyl]-4-yl)cyclopropanecarboxylic acid. The resulting intermediate and quinuclidine-3-amine are reacted according to General Procedure H to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d 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, 1H), 5.99 (br.s, 1H), 4, 15-4.09 (m, 2H), 3.75-3.63 (m, 2H), 3.61-3.50 (m, 1H), 3.32 (s, 3H), 3.06 ( dd, J=13.6, 9.5 Hz, 1H), 2.73-2.54 (m, 4H), 2.35-2.22 (m, 1H), 1.71-1.40 ( m, 4H), 1.36-1.24 (m, 1H), 1.21-1.08 (m, 4H) ppm. ¹³ C NMR (100 MHz, DMSO-d6) δ 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. UP-LCMS purity 100%, 99.9% (210 and 254 nm); retention time 0.82 min; (M+H+) 436.3.

Example 163.

1-(1 -(4'-(2-Methoxyethoxy)[1,1'-biphenyl]-4-yl)cyclopropyl)-3 -(3-methylquinuclidin-3-yl)urea.

Using general procedure H and reacting 1-(4'-(2-methoxyethoxy)[1,1'biphenyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 162) and intermediate 1, the title the title compound appears as a white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 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, 1H), 5.61 (s, 1H), 4.17-4, 06 (m, 2H), 3.80-3.61 (m, 2H), 3.32 (s, 3H), 2.82-2.52 (m, 6H), 1.99-1.82 ( m, 1H), 1.78-1.54 (m, 2H), 1.46-1.30 (m, 4H), 1.19 (m, 1H), 1.19-1.11 (m, 4H) ppm ¹³ C NMR (100 MHz, DMSO-d ₆ ) 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 m.d. UP-LCMS purity 100%, 99.9% (210 and 254 nm); retention time 0.85 min; (M+H+) 450.4.

Example 164.

-(3-Ethylquinuclidin-3-yl)-3 -(1 -(4'-(2-methoxyethoxy)[1,1'-biphenyl]-4-yl)cyclopropyl)urea.

Using general procedure H and reacting 1-(4'-(2-methoxyethoxy)[1,1'biphenyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 162) and intermediate 2, the title the title compound appears as a white solid. 1H NMR (400 MHz, DMSO-d6) 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, 1H), 5.57 (s, 1H), 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, 1H), 1.20 (m, 1H), 1.20-1.04 (m, 4H ), 0.73 (t, J=7.2 Hz, 3H) ppm. ¹³ C NMR (100 MHz, DMSO-d6) 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 UP-LCMS purity 99.9%, 99.5% (210 and 254 nm); retention time 0.89 min; (M+H+) 464.4.

Example 165.

1-(1 -(4'-(2-Methoxyethoxy)[1,1'-biphenyl]-4-yl)cyclopropyl)-3 -(4-methyl-1-azabicyclo[3.2.2]nonan4-yl)urea .

Using general procedure H and reacting 1-(4'-(2-methoxyethoxy)[1,1'biphenyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 162) and intermediate 5, the title the title compound appears as a white solid. 1H NMR (400 MHz, DMSO-d6) 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, 1H), 5.56 (s, 1H), 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 , 1H), 1.83-1.57 (m, 3H), 1.57-1.00 (m, 10H) ppm. ¹³ C NMR (100 MHz, DMSO46) 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 UP-LCMS purity 100%, 99.3% (210 and 254 nm); retention time 0.85 min; (M+H+) 464.4.

Example 166.

Quinuclidin-3 -yl(1 -(4'-(2-methoxyethoxy)[1,1'-biphenyl]-4-yl)cyclopropyl)carbamate.

Using General Procedure H and reacting 1-(4'-(2-methoxyethoxy)[1,1'biphenyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 162) and quinuclidin-3-ol obtain the title compound as a glassy violet solid

- 74 046304 substances. ^1H NMR (400 MHz, DMSO-d6) δ 8.02 (brs, 1H), 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, 1H), 4.17-4.07 (m, 2H), 3.72-3.61 (m , 2H), 3.32 (s, 3H), 3.13-2.89 (m, 1H), 2.832.24 (m, 5H), 1.84-1.01 (m, 9H) ppm . ¹³ C NMR (100 MHz, DMSO-d6) δ 157.9, 156.0, 142.4, 137.1, 132.4, 127.5, 125.8, 125.1, 114.8, 70.4, 70.4, bb, 9, 58.1, 55.5, 46.9, 46.0, 34.3, 25.3, 24.2, 19.2, 18.1 ppm. Purity by UPLCMS 100%, 99.9% (210 and 254 nm); retention time 0.83 min; (M+H+) 437.0.

Example 167.

Quinuclidin-3 -yl(2-(3'-(2-methoxyethoxy)[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate.

Replacing 4-(2-methoxyethoxy)phenylboronic acid with 3-(2-methoxyethoxy)phenylboronic acid, use the reaction sequence described in example 155 and obtain 2-(3'-(2methoxyethoxy)[1,1'-biphenyl]-4 -yl)-2-methylpropanoic acid. The resulting intermediate and quinuclidin-3-ol are reacted according to General Procedure H to obtain the title compound as a glassy, colorless solid. 1H NMR (400 MHz, DMSOd ₆ ) δ 7.63-7.31 (m, 6H), 7.24-7.10 (m, 2H), 6.92 (dd, J=8.2, 1, 9 Hz, 1H), 4.51-4.34 (m, 1H), 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. ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 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 UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.91 min; (M+H+) 439.4.

Example 168.

- Azabicyclo[3.2.2]nonan-4-yl(2-(3'-(2-methoxyethoxy)[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate.

Using General Procedure H and reacting 2-(3'-(2-methoxyethoxy)[1,1'biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 167) and intermediate 3 obtains the title compound as an amber glassy solid. 1H NMR (400 MHz, DMSO46) 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, 1H), 4.65-4.55 (m, 1H), 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. ¹³ C NMR (100 MHz, DMSO-d6) 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 UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.92 min; (M+H+) 453.4.

Example 169.

N(2-(3'-(2-Methoxyethoxy)[1,G-biphenyl]-4-yl)propan-2-yl)-1,4-diazabicyclo[3.2.2]nonane-4-carboxamide.

Using General Procedure H and reacting 2-(3'-(2-methoxyethoxy)[1,1'biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 167) and intermediate 6 obtains the title compound as an off-white solid. ^1H NMR (400 MHz, DMSO-d6) 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, 1H), 4.22-4.12 (m, 3H), 3.70-3.65 (m, 2H), 3.52-3.45 (m , 2H), 3.32 (s, 3H), 2.95-2.75 (m, 6H), 1.93-1.82 (m, 2H), 1.64-1.52 (m, 8H ) m.d. ¹³ C NMR (100 MHz, DMSO-d ₆ ) 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 by UPLCMS 100%, 100% (210 and 254 nm); retention time 0.86 min; (M+H+) 438.4.

Example 170.

Quinuclidin-3 -yl(2-(4'-(2-methoxyethoxy)[1,1'-biphenyl]-3-yl)propan-2-yl)carbamate.

Replacing ethyl 2-(4-bromophenyl)-2-methylpropanoate with ethyl 2-(3-bromophenyl)-2-methylpropanoate, using the reaction sequence described in example 155 to obtain 2-(4'-(2-methoxyethoxy) [1,1'-biphenyl]-4-yl)-2-methylpropanoic acid. The resulting intermediate and quinuclidin-3-ol are reacted according to General Procedure H to give the title compound as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) 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 ), 2.101.10 (m, 11H) ppm. ¹³ C NMR (100 MHz, DMSO-d6) 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 by UPLCMS 97.4%, 94.6% (210 and 254 nm); retention time 0.88 min; (M+H+) 439.3.

Example 171.

1-Azabicyclo[3.2.2]nonan-4-yl(2-(4'-(2-methoxyethoxy)[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate.

Using General Procedure H and reacting 2-(4'-(2-methoxyethoxy)[1,1'biphenyl]-3-yl)-2-methylpropanoic acid (prepared as described in Example 170) and the intermediate 3 affords the title compound as a brownish-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.60-7.19 (m, 7H), 7.03 (d, J=8.8 Hz, 2H), 4.66-4.55 (m, 1H), 4.174.09 (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 ¹³ C NMR (100 MHz, DMSO-d6) 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 UP-LCMS purity 97.0%, 93.9% (210 and 254 nm); retention time 0.89 min; (M+H+) 453.3.

Example 172.

Quinuclidin-3 -yl(2-(4'-(3-methoxypropoxy)[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate.

- 75 046304

To a solution of 4-iodophenol (10.05 g, 45.68 mmol) in acetonitrile (100 ml) add potassium carbonate (6.95 g, 50.2 mmol) and 1-chloro-3-methoxypropane (6.4 ml, 57.1 mmol). The mixture is refluxed overnight and then concentrated. The residue is dissolved in water and extracted with ethyl acetate. The combined extracts are washed with aqueous sodium bicarbonate, dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by flash silica chromatography using hexane/ethyl acetate to give 1-iodo-4-(3-methoxypropoxy)benzene as a colorless oil (4.39 g, 33%). The resulting intermediate and ethyl 2-methyl-2-(4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate are reacted according to General Procedure F to give 2- (4'-(3-methoxypropoxy)[1,1'-biphenyl]-4-yl)-2-methylpropanoate. Lithium hydroxide monohydrate (0.326 g, 7 .77 mmol). The mixture is refluxed overnight and then concentrated. The residue is dissolved in water, treated with 1N hydrochloric acid (10 ml) and extracted with ethyl acetate. The combined organic layers are washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give 2-(4'-(3-methoxypropoxy)[1,1'biphenyl]-4-yl)-2-methylpropanoic acid as a waxy white solid (0.630 g, 99%). The resulting intermediate and quinuclidin-3-ol were reacted according to General Procedure H to obtain the title compound as a glassy, colorless solid (62%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.61-7.29 (m, 7H), 7.00 (d, J=8.8 Hz, 2H), 4.47-4.36 ( m, 1H), 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. ¹³ C NMR (100 MHz, DMSO46) δ 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 . UP-LCMS purity 97.7%, 98.2% (210 and 254 nm); retention time 0.96 min; (M+H+) 453.5.

Example 173.

-(2-(4'-(3 -Methoxypropoxy)[1,1'-biphenyl]-4-yl)propan-2-yl)-3 -(3 -methylquinuclidin-3 -yl)urea.

Using General Procedure H and reacting 2-(4'-(3-methoxypropoxy)[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 172) and intermediate Compound 1 gives the title compound as a white solid. 1H NMR (400 MHz, DMSO46) 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, J=8.8 Hz, 2H), 6.17 (br.s, 1H), 5.79 (br.s, 1H), 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. ¹³ C NMR (100 MHz, DMSO-d6) 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 UP-LCMS purity 98.0%, 98.1% (210 and 254 nm); retention time 0.94 min; (M+H+) 466.5.

Example 174.

N(2-(4'-(3-Methoxypropoxy)[1,G-biphenyl]-4-yl)propan-2-yl)-1,4-diazabicyclo[3.2.2]nonane-4carboxamide.

Using General Procedure H and reacting 2-(4'-(3-methoxypropoxy)[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 172) and intermediate Compound 6 gives the title compound as a white solid. 1H NMR δ (400 MHz, DMSO-d ₆ ) 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, 1H), 4.22-4.16 (m, 1H), 4, 05 (t, J=6.4 Hz, 2H), 3.52-3.44 (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. ¹³ C NMR (100 MHz, DMSO-d ₆ ) 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. UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.88 min; (M+H+) 452.5.

Example 175.

Quinuclidin-3 -yl(2-(4'-(2-methoxyethoxy)[1,1'-biphenyl]-3-yl)propan-2-yl)carbamate.

Replacing ethyl 2-(4-bromophenyl)-2-methylpropanoate with ethyl 1-(4-bromophenyl)cyclopropanecarboxylate, using the reaction sequence described in example 18 to obtain 1-(4'-(3methoxypropoxy)[1,1' -biphenyl]-4-yl)cyclopropanecarboxylic acid. The resulting intermediate and quinuclidin-3-ol are reacted according to General Procedure H to obtain the title compound as a glassy, colorless solid. 1H NMR (7:3 mixture of rotomers) (400 MHz, DMSO-d6) δ 8.01 (br.s, 0.7H), 7.77 (br.s, 0.3H), 7.59-7, 47 (m, 4H), 7.287.16 (m, 2H), 6.99 (d, J=8.8 Hz, 2H), 4.57-4.47 (m, 1H), 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, 1H), 2 .81-2.25 (m, 6H), 2.00-1.03 (m, 7H) ppm. ¹³ C NMR (main rotomer) (100 MHz, DMSO-d6) 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 UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.91 min; (M+H+) 451.6.

Example 176.

1-(1 -(4'-(3-Methoxypropoxy)[1,1'-biphenyl]-4-yl)cyclopropyl)-3 -(3-methylquinuclidin-3-yl)urea.

- 76 046304

Using General Procedure H and reacting 1-(4'-(3-methoxypropoxy)[1,1'-biphenyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 175) and intermediate 1, the title compound as an off-white solid. ¹ H NMR (400 MHz, DMSO-de) 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, 1H), 5.62 (br.s, 1H), 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. ¹³ C NMR (100 MHz, DMSO46) 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 UP-LCMS purity 97.6%, 98.2% (210 and 254 nm); retention time 0.87 min; (M+H+) 464.6.

Example 177.

1-(1-(4'-(3-Methoxypropoxy)[1,1'-biphenyl]-4-yl)cyclopropyl)-3-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl )urea.

Using General Procedure H and reacting 1-(4'-(3-methoxypropoxy)[1,1'-biphenyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 175) and intermediate 5, the title compound as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.55 (d, J=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, 1H), 5.56 (br.s, 1H), 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, 1H), 2.0-1.91 (m, 2H), 1.80-1.60 (m, 3H), 1.55-1.88 (m , 10H) ppm ¹³ C NMR (100 MHz, DMSO-d6) 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, 45.0, 36.3, 33.9, 29.0, 26.1, 24.4, 23.9, 18.9, 18.7 ppm UP-LCMS purity 98.0%, 98.3% (210 and 254 nm); retention time 0.87 min; (M+H+) 478.6.

Example 178.

-Azabicyclo[3.2.2]nonan-4-yl(1 -(4'-(3-methoxypropoxy)[1,1'-biphenyl]-4-yl)cyclopropyl)carbamate.

Using General Procedure H and reacting 1-(4'-(3methoxypropoxy)[1,1'-biphenyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 175) and intermediate 3, the title The title compound appears as a glassy, colorless solid. ¹ H NMR (3:1 mixture of rotomers) (400 MHz, DMSO-d6) δ 7.96 (br.s, 0.75H), 7.71 (br.s, 0.25H), 7.27-7 .15 (m, 2H), 6.99 (d, J=8.4 Hz, 1H), 4.75-4.68 (m, 1H), 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. ¹³ C NMR (main rotomer) (100 MHz, DMSO-d6) 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, 24.6, 22.0, 18.0 ppm UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.92 min; (M+H+) 465.6.

Example 179.

Quinuclidin-3 -yl(2-(4'-(2-(1H-pyrazol-1-yl)[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate.

Using general procedure F and reacting ethyl 2-methyl-2-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate and 1-(2-(4- Bromophenoxy)ethyl)pyrazole gives ethyl 2-(4'-(2-(1H-pyrazol-1-yl)ethoxy)[1,1'-biphenyl]-4-yl)-2-methylpropanoate as a yellow oil. Lithium hydroxide monohydrate (1, 37 g, 57.1 mmol). The mixture is left for 6 days and then concentrated. The residue is dissolved in water and washed with diethyl ether. The aqueous layer was then treated with 1N hydrochloric acid (57 ml) and extracted with ethyl acetate. The combined organic layers are dried (Na ₂ SO ₄ ) and concentrated. The resulting solid is triturated in diethyl ether to give 2-(4'-(2-(1H-pyrazol-1-yl)ethoxy)[1,1'-biphenyl]-4-yl)-2methylpropanoic acid as a tan solids (1.18 g, 41%). The resulting intermediate and quinuclidin-3-ol are reacted according to General Procedure H to give the title compound as a white solid. ¹ H NMR (400 MHz, DMSOd6) δ 7.79 (d, J=2.1 Hz, 1H), 7.62-7.27 (m, 8H), 6.98 (d, J=8.7 Hz, 2H), 6.25 (t, J=2.1 Hz, 1H), 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 ¹³ C NMR (100 MHz, DMSO-d6) 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 UP-LCMS purity 100%, 99.5% (210 and 254 nm); retention time 1.00 min; (M+H+) 475.4.

Example 180.

-(2-(4'-(2-(1H-Pyrazol-1-yl)ethoxy)[1,1'-biphenyl]-4-yl)propan-2-yl)-3 -(3-methylquinuclidin-3 silt)urea.

Using general procedure H and reacting 2-(4'-(2-(1H-pyrazol-1yl)ethoxy)[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 179) and intermediate 1 give the title compound as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.79 (dd, J=2.2, 0.5 Hz, 1H), 7.55 (d, J=8.9 Hz, 2H), 7 .50 (d, J=8.6 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H), 6.98 (d, J=8.9 Hz, 2H), 6.25 (t, J=2.2 Hz, 1H), 6.15 (s, 1H), 5.76 (s, 1H), 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, 1H), 1.84-1.72 (m, 1H ), 1.65-1.45 (m,

- 77 046304

7H), 1.43-1.19 (m, 5H) ppm. ¹³ C NMR (100 MHz, DMSO-d 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 UP-LCMS purity 100%, 99.9% (210 and 254 nm); retention time 0.99 min; (M+H+) 488.4.

Example 181.

-(2-(4'-(2-(1H-pyrazol-1-yl)ethoxy)[1,1'-biphenyl]-4-yl)propan-2-yl)-3 -(4-methyl-1 -azabicyclo[3.2.2]-4-yl)urea.

Using general procedure H and reacting 2-(4'-(2-(1H-pyrazol-1yl)ethoxy)[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 179) and intermediate 5 give the title compound as a white solid. ^1H NMR (400 MHz, DMSO46) δ 7.79 (dd, J=2.2, 0.5 Hz, 1H), 7.58-7.33 (m, 6H), 6.98 (d, J =8.8 Hz, 2H), 6.25 (t, J=2.2 Hz, 1H), 6.21 (s, 1H), 5.72 (br.s, 1H), 4.51 (t , J=5.3 Hz, 2H), 4.37 (t, J=5.3 Hz, 2H), 2.912.58 (m, 6H), 2.11-2.01 (s, 1H), 1 .83-1.14 (m, 15H) ppm ¹³ C NMR (100 MHz, DMSO-d ₆ ) 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 UP-LCMS purity 100%, 98.8% (210 and 254 nm); retention time 0.99 min; (M+H+) 502.4.

Example 182.

Quinuclidin-3 -yl(2-(4'-(2-(1H-1,2,3-triazol-1 -yl)ethoxy)[1,1'-biphenyl]-4-yl)propan-2-yl )carbamate.

To a solution of 2-(4-bromophenoxy)ethanol (10.60 g, 48.8 mmol) and triethylamine (10.2 ml, 73.2 mmol) in methylene chloride (100 ml) with stirring and cooling (0°C) add dropwise methanesulfonyl chloride (5.7 ml, 73.2 mmol). The mixture is warmed to room temperature and then stirred overnight. The reaction solution is diluted with methylene chloride and washed with an aqueous sodium bicarbonate solution. The organic layer was dried (Na ₂ SO ₄ ) and concentrated to give crude 2-(4bromophenoxy)ethylmethanesulfonate as a yellow solid. Sodium azide (3.81 g, 58.6 mmol) was added to a solution of the resulting material in dimethyl sulfoxide (50 ml) with stirring. The mixture is left for 3 days and then diluted with water and extracted with ethyl acetate. The organic layer is washed with water and brine, dried (Na2SO4) and then concentrated. The crude material was purified by flash chromatography on silica using hexane/ethyl acetate to give 1(2-azidoethoxy)-4-benzene as a colorless oil (8.66 g, total 73%). The resulting 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), N,Ndimethylformamide (30 ml) and water (3 ml). The mixture is heated in a microwave reactor (110°C) with stirring for 90 minutes. The reaction mixture is filtered through a pad of celite, which is then washed with ethyl acetate. The combined filtrate is washed with water, aqueous sodium bicarbonate and brine and then dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by flash chromatography on silica using hexane/ethyl acetate as an eluent to give a mixture of 1-(2-(4bromophenoxy)ethyl 0-1H-1,2,3-triazole and 1-(2-(4-bromophenoxy) ethyl)-4-(trimethylsilyl)-1H-1,2,3-triazole (ratio ~70/30). The resulting material was dissolved in tetrahydrofuran (25 ml) and treated with a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (3.1 ml). The reaction mixture was stirred overnight, concentrated, and the residue was purified by flash chromatography on silica using hexane/ethyl acetate to give pure 1-(2-(4-bromophenoxy)ethyl)-1H1,2,3-triazole as white solid (1.81 g, 73% total) Resultant product and ethyl 2-methyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) propanoate is reacted according to general procedure F to obtain ethyl 2-(4'-(2-(1H-1,2,3-triazol-1-yl)ethoxy)[1,1'-biphenyl]-4-yl )-2methylpropanoate To a solution of the resulting compound (1.83 g, 4.83 mmol) in tetrahydrofuran/ethanol/water, 1:1:1 (v/v/v; 20 ml), lithium hydroxide (0.809 g, 33.8 mmol) was added with stirring. After refluxing overnight, the reaction mixture is diluted with water, washed with diethyl ether and treated with 1N hydrochloric acid (33 ml). The mixture was then extracted with chloroform/isopropanol 5:1 (v/v) and the combined organic layers were dried (Na2SO4) and concentrated.

The resulting solid is triturated in diethyl ether to obtain 2-(4'-(2-(1H-1,2,3triazol-1-yl)ethoxy)[1,1'-biphenyl]-4-yl)-2-methylpropane acid as an off-white solid (1.16 g, 69%). The resulting intermediate and quinuclidin-3-ol are reacted according to General Procedure H to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J=0.9 Hz, 1H), 7.75 (d, J=0.8 Hz, 1H), 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. ¹³ C NMR (100 MHz, DMSO46) 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, m. d. UP-LCMS purity 100%, 98.9% (210 and 254 nm); retention time 0.97 min; (M+H+) 476.4.

Example 183.

-(2-(4'-(2-(1H-1,2,3-Triazol-1-yl)ethoxy) [1,1'-biphenyl]-4-yl)propan-2-yl)-3 - (3-methylquinuclidin3-yl)urea.

- 78 046304

Using the general procedure H and introducing 2-(4'-(2-(1H-1,2,3-triazol-1yl)ethoxy)[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid into the reaction acid (prepared as described in Example 182) and intermediate 1 gave the title compound as a white solid. ¹ H NMR (400 MHz, DMSO40 δ 8.21 (d, J=0.9 Hz, 1H), 7.75 (d, J=0.8 Hz, 1H), 7.56 (d, J=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, 1H), 5.77 (br.s, 1H), 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), 1.431, 20 (m, 5H) ppm ¹³ C NMR (100 MHz, DMSO-d6) 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 by UPLCMS 100%, 99.9% (210 and 254 nm); retention time 0.95 min (M+H+) 489.4 .

Example 184.

-(2-(4'-(2-(1H-1,2,3-Triazol-1-yl)ethoxy) [1,1'-biphenyl]-4-yl)propan-2-yl)-3 - (3-ethylquinuclidin-3 yl)urea.

Using the general procedure H and introducing 2-(4'-(2-(1H-1,2,3-triazol-1yl)ethoxy)[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid into the reaction acid (prepared as described in Example 182) and intermediate 2 gave the title compound as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.21 (d, J=0.8 Hz, 1H), 7.75 (d, J=0.7 Hz, 1H), 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, 1H), 5.73 (br.s, 1H), 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. ¹³ C NMR (100 MHz, DMSO-d6) δ 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 by UPLCMS 100%, 99.9% (210 and 254 nm); retention time 0.99 min; (M+H+) 503.4.

Example 185.

-(2-(4'-(2-(1H-1,2,3-Triazol-1-yl)ethoxy) [1,1'-biphenyl]-4-yl)propan-2-yl)-3 - (4-methyl-1-azabicyclo[3.2.2] nonan-4-yl)urea.

Using the general procedure H and introducing 2-(4'-(2-(1H-1,2,3-triazol-1yl)ethoxy)[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid into the reaction acid (prepared as described in Example 182) and intermediate 5 gave the title compound as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J=0.9 Hz, 1H), 7.75 (d, J=0.9 Hz, 1H), 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, 1H), 5.74 (br.s, 1H), 4.80 (t, J=5.1 Hz, 2H), 4.45 ( t, J=5.2 Hz, 2H), 2.90-2.61 (m, 6H), 2.11-2.03 (s, 1H), 1.83-1.35 (m, 11H) , 1.331.16 (m, 4H) ppm ¹³ C NMR (100 MHz, DMSO-d6) 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 UP-LCMS purity 100%, 99.9% (210 and 254 nm); retention time 0.96 min; (M+H+) 503.4.

Example 186.

Quinuclidin-3 -yl(2-(4'-(2-methoxyethoxy)[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate.

Replacing 3-(4-bromophenoxy)propan-1-ol with 2-(4-bromophenoxy)ethanol, use the reaction sequence described in example 182 and obtain 2-(4'-(3-(1H-1,2,3 -triazol-1-yl)propoxy)[1,1'biphenyl]-4-yl)-2-methylpropanoic acid. The resulting intermediate and quinuclidin-3ol are reacted according to General Procedure H to obtain the title compound as a glassy, colorless solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.17 (s, 1H), 7.73 (s, 1H), 7.64-7.24 (m, 7H), 6.99 (d, J=8.7 Hz, 2H), 4.57 (t, J=7.0 Hz, 2H), 4.48-4.32 (m, 1H), 4.01 (t, J=6.0 Hz, 2H), 3.12-2.19 (m, 8H), 2.08-1.13 (m, 11H) ppm. ¹³ C NMR (100 MHz, DMSO46) 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 by UP-LCMS 96.5%, 100% (210 and 254 nm); retention time 0.81 min; (M+H+) 490.5.

Example 187.

1-Azabicyclo[3.2.2]nonan-4-yl(2-(4'-(3-(1H-1,2,3-triazol-1-yl)propoxy)[1,1'-biphenyl]-4 -yl)propan-2-yl)carbamate.

Using general procedure H and introducing 2-(4'-(3-(1H-1,2,3-triazol-1yl)propoxy)[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid into the reaction acid (prepared as described in Example 186) and intermediate 3 afforded the title compound as a pale yellow solid. ^1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.74 (s, 1H), 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 ¹³ C NMR (100 MHz, DMSO-d6) 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 UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.82 min; (M+H+) 504.5.

Example 188.

No.(2-(4'-(3-(1H-1,2,3-Triazol-1-yl)propoxy)[1,G-biphenyl]-4-yl)propan-2-yl)-1,4 -diazabicyclo[3.2.2] nonane-4-carboxamide.

Using the general procedure H and introducing 2-(4'-(3-(1H-1,2,3-triazol-1yl)propoxy)[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid into the reaction acid (prepared as described in Example 186) and intermediate 6 give the title compound as a white solid

- 79 046304 substances. ¹ H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J=0.9 Hz, 1H), 7.73 (d, J=0.9 Hz, 1H), 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, 1H), 4.57 (t, J=7.0 Hz, 2H), 4.22-4.16 (m, 1H), 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. ¹³ C NMR (100 MHz, DMSO-d6) 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. UP-LCMS purity 97.4%, 99.3% (210 and 254 nm); retention time 0.75 min; (M+H+) 489.5.

Example 189.

Quinuclidin-3 -yl(2-(4'-(3-cyanopropoxy)[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate.

To a solution of 4-bromophenol (17.1 g, 98.8 mmol) in acetonitrile (150 ml) add 1-bromobutylnitrile (12.3 ml, 124 mmol) and potassium carbonate (15.0 g, 109 mmol) with stirring. The mixture is refluxed overnight, cooled and concentrated. The residue is dissolved in water and extracted with ethyl acetate. The combined extracts were dried (Na ₂ SO ₄ ) and concentrated and the crude material was purified by flash silica chromatography using hexane/ethyl acetate to give 4-(4-bromophenoxy)butanenitrile as a white solid (20.8 g, 88 %). To a solution of the resulting product in NN-dimethylformide (100 ml), bis(pinacolato)diboron (4.60 g, 18.1 mmol), potassium acetate (7.41 g, 75.5 mmol) and complex [1, 1'bis(triphenylphosphino)ferrocene]dichloropalladium(P) with dichloromethane (0.616 g, 1.04 mmol). The mixture is refluxed overnight and then concentrated. The residue is dissolved in ethyl acetate and washed with water and brine. The organic layer was dried (Na ₂ SO ₄ ) and concentrated and the crude product was purified by flash chromatography on silica using hexane/ethyl acetate to give 4-(4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)phenoxy)butanenitrile as a white solid (3.43 g, 79%). The resulting product and quinuclidin-3-yl(2-(4-bromophenyl)propan-2-yl)carbamate (prepared by reacting quinuclidin-3-ol and 2-(4-bromophenyl)propan-2amine using general procedure H) are introduced into react according to General Procedure F to obtain the title compound as a white solid. ^1H NMR (400 MHz, DMSOd6) δ 7.67-7.26 (m, 7H), 7.02 (d, J=8.8 Hz, 2H), 4.50-4.33 (m, 1H ), 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, 11H) ppm ¹³ C NMR (100 MHz, DMSO-d6) δ 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 m .d. UP-LCMS purity 100%, 98.9% (210 and 254 nm); retention time 0.88 min; (M+H+) 448.6.

Example 190.

Quinuclidin-3 -yl(2-(4'-(cyanomethoxy)[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate.

Using general procedure F and reacting quinuclidin-3-yl(2-(4bromophenyl)propan-2-yl)carbamate (prepared by reacting quinuclidin-3-ol and 2-(4-bromophenyl)propan-2-amine using General procedure H) and 4-(cyanomethoxy)phenylboronic acid give the title compound as a pale amber solid. ¹ H NMR (400 MHz, DMSO-d6) δ 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, 1H), 3.18-2.19 (m, 6H), 2.05-1.18 ( m, 11H) ppm ¹³ C NMR (100 MHz, DMSOO 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 by UP-LCMS 100%, 100% (210 and 254 nm); retention time 0.85 min; (M+H+) 420.3.

Quinuclidin-3 -yl(2-(4'-((3-methyloxetan-3-yl)methoxy)[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate.

To a solution of 4-bromophenol (3.61 g, 20.8 mmol) in N,N-dimethylformamide (100 mL) was added sodium hydride (60% dispersion in mineral oil; 0.917 g, 22.9 mmol) with stirring. After 30 minutes, 3-(chloromethyl)-3-methyloxetane is added. The reaction mixture is heated at 80°C overnight and then concentrated. The residue is dissolved in ethyl acetate and washed with water and brine. The organic layer was dried (Na ₂ SO ₄ ) and concentrated, and the crude product was purified by flash chromatography on silica using hexane/ethyl acetate to give 3-((4-bromophenoxy)methyl)-3-methyloxetane as a colorless oil (4 .64 g, 87%). The resulting product and ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)phenyl)propanoate are reacted according to General Procedure F to obtain ethyl-2 -methyl-2-(4'-((3-methyloxetan-3-yl)methoxy)[1,1'-biphenyl]-4-yl)propanoate. To a solution of the resulting compound (1.37 g, 3.72 mmol) in a mixture of tetrahydrofuran/ethanol/water, 1:1:1 (v/v/v; 20 ml), add lithium hydroxide monohydrate (0.780 g) with stirring , 18.6 mmol). After refluxing overnight, the reaction mixture is diluted with water, washed with diethyl ether and treated with 1N hydrochloric acid (20 ml). The mixture was then extracted with ethyl acetate, the combined organic layers were dried (Na ₂ SO ₄ ) and concentrated to give 2-methyl-2-(4'-((3methyloxetan-3-yl)methoxy)[1,1'-biphenyl]-4- yl)propanoic acid as an off-white solid (1.20 g, 95%). The resulting intermediate and quinuclidin-3-ol are reacted according to General Procedure H to give the title compound as a white solid. ¹ H NMR (400 MHz, DMSO-d6) 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, 1H), 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. ¹³ C NMR (100 MHz, DMSO-d6) 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,

- 80 046304

46.9, 45.9, 39.0, 29.4, 25.3, 24.2, 21.0, 19.2 ppm. UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.93 min; (M+H+) 465.4.

Example 192.

-Azabicyclo[3.2.2]nonan-4-yl(2-(4'-((3-methyloxetan-3-yl)methoxy)[1,1'-biphenyl]-4-yl)propan-2yl)carbamate.

Using General Procedure H and reacting 2-methyl-2-(4'-((3methyloxetan-3-yl)methoxy)[1,1'-biphenyl]-4-yl)propanoic acid (prepared as described) Example 191) and intermediate 3 afford the title compound as a pale amber solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.58 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.5 Hz, 2H), 7.47 (br .s, 1H), 7.37 (d, J=8.1 Hz, 2H), 7.06 (d, J=8.8 Hz, 2H), 4.66-4.54 (m, 1H) , 4.51 (d, J=5.7 Hz, 2H), 4.32 (d, J=5.8 Hz, 2H), 4.09 (s, 2H), 3.09-2.55 ( m, 6H), 1.98-1.28 (m, 16H) ppm. ¹³ C NMR (100 MHz, DMSO-d6) 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 ppm UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.94 min; (M+H+) 479.4.

Example 193.

N-(2-(4'-((3-Methyloxetan-3-yl)methoxy)[1,1'-biphenyl]-4-yl)propan-2-yl)-1,4-diazabicyclo[3.2.2 ]nonane-4-carboxamide.

Using General Procedure H and reacting 2-methyl-2-(4'-((3methyloxetan-3-yl)methoxy)[1,1'-biphenyl]-4-yl)propanoic acid (prepared as described) Example 191) and intermediate 6 give the title compound as a pale amber solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 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, 1H), 4.51 (d, J=5.7 Hz, 2H) , 4.32 (d, J=5.8 Hz, 2H), 4.23-4.15 (m, 1H), 4.08 (s, 2H), 3.49 (t, J=5.5 Hz, 2H), 3.01-2.60 (m, 6H), 1.94-1.80 (m, 2H), 1.66-1.47 (m, 8H), 1.38 (s, 3H) ppm ¹³ C NMR (100 MHz, DMSO-d6) 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. UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.88 min; (M+H+) 464.4.

Example 194.

Quinuclidin-3 -yl(2-(4'-(2-(oxetan-3-yl)ethoxy)[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate.

To a solution of 2-(oxetan-3-yl)ethanol (4.07 g, 39.9 mmol) in methylene chloride (200 ml), triethylamine (5.8 ml, 41.6 mmol) and p-toluenesulfonyl chloride (8 .36 g, 43.8 mmol). The reaction mixture is stirred overnight and then washed with 0.2N hydrochloric acid and aqueous sodium bicarbonate. The organic layer was dried (Na ₂ SO ₄ ) and concentrated, and the resulting crude product was purified by flash chromatography on silica using hexane/ethyl acetate as an eluent to give 2-(oxetan-3-yl)ethyl-4-methylbenzenesulfonate as a colorless oil ( 6.65 g, total 65%). To a solution of the resulting product (3.00 g, 11.7 mmol) in acetone (45 ml) add 4-bromophenol (1.69 g, 9.77 mmol) and potassium carbonate (1.69 g, 12.2 mmol) with stirring. mmol). The reaction mixture is refluxed overnight, cooled and filtered. The filtrate was concentrated on silica and flash chromatographed on silica using hexane/ethyl acetate to give 3-(2-(4-bromophenoxy)ethyl)oxetane as a white solid (2.43 g, 97%). The resulting product and ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenyl)propanoate are reacted according to General Procedure F to obtain ethyl-2 -methyl-2-(4'-(2-oxetan-3-yl)ethoxy)[1,1'-biphenyl]-4-yl)propanoate. To a solution of the resulting compound (1.32 g, 3.58 mmol) in a mixture of tetrahydrofuran/ethanol/water, 1:1:1 (v/v/v; 25 ml), add lithium hydroxide monohydrate (0.752 g) with stirring , 17.9 mmol). After stirring at room temperature overnight, the reaction mixture is refluxed for 4 hours. At this time, the mixture is concentrated and the residue is dissolved in water. The solution is washed with diethyl ether and then treated with 1N hydrochloric acid (20 ml). The mixture was extracted with ethyl acetate, the combined organic layers were dried (Na ₂ SO ₄ ) and concentrated to give 2-methyl-2-(4'-(2-(oxetan-3yl)ethoxy)[1,1'-biphenyl]-4-yl )propanoic acid as an off-white solid (1.18 g, 97%). The resulting intermediate and quinuclidin-3-ol are reacted according to General Procedure H to obtain the title compound as a pale amber solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 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, 1H), 3.07-2.18 (m, 6H), 2.15-1.12 (m, 13H) ppm. ¹³ C NMR (100 MHz, DMSO-d ₆ ) 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 m.d. UP-LCMS purity 100%, 99.6% (210 and 254 nm); retention time 0.93 min; (M+H+) 465.

Example 195.

1-Azabicyclo[3.2.2]nonan-4-yl(2-(4'-(2-(oxetan-3-yl)ethoxy)[1,1'-biphenyl]-4-yl)propan-2-yl )carbamate.

Using General Procedure H and reacting 2-methyl-2-(4'-(2-(oxetan-3yl)ethoxy)[1,1'-biphenyl]-4-yl)propanoic acid (prepared as described in example 194) and about

- 81 046304 intermediate compound 3 gives the title compound in the form of a pale amber solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.61-7.26 (m, 7H), 6.97 (d, J=8.7 Hz, 2H), 4.67 (dd, J=7 ,9, 5.9 Hz, 2H), 4.64-4.56 (m, 1H), 4.37 (t, J=6.1 Hz, 2H), 3.98 (t, J=6, 2 Hz, 2H), 3.21-3.07 (m, 1H), 3.032.33 (m, 6H), 2.13-2.03 (m, 2H), 2.00-1.31 (m , 13H) ppm ¹³ C NMR (100 MHz, DMSO-d6) 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 UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.94 min; (M+H+) 479.

Example 196.

No.(2-(4'-(2-(Oxetan-3-yl)ethoxy)[1,1'-biphenyl]-4-yl)propan-2-yl)-1,4-diazabicyclo [3.2.2] nonane-4carboxamide.

Using General Procedure H and reacting 2-methyl-2-(4'-(2-(oxetan-3yl)ethoxy)[1,1'-biphenyl]-4-yl)propanoic acid (prepared as described) Example 194) and intermediate 6 give the title compound as a tan solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.55 (d, J=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, 1H), 4.67 (dd, J=7.8, 5.9 Hz, 2H), 4.36 (t, J=6.1 Hz, 2H), 4.244.14 (m, 1H), 3.97 (t, J=6.1 Hz, 2H), 3.56- 3.40 (m, 2H), 3.21-3.06 (m, 1H), 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 ¹³ C NMR (100 MHz, DMSO-d ₆ ) 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 by UPLCMS 100%, 100% (210 and 254 nm); retention time 0.87 min; (M+H+) 464.

Example 197.

Quinuclidin-3 -yl(2-(4'-((2-methoxyethoxy)methyl)[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate.

To a solution of 2-methoxyethanol (2.60 g, 32.9 mmol) in tetrahydrofuran (160 ml) was added sodium hydride (60% dispersion in mineral oil; 1.50 g, 36.2 mmol) with stirring. The mixture was stirred for 30 minutes and then 4-bromobenzyl bromide (8.64 g, 34.6 mmol) was added. After stirring overnight, the reaction mixture is concentrated. The residue is dissolved in ethyl acetate, washed with aqueous sodium bicarbonate and brine, dried (Na ₂ SO ₄ ) and concentrated. The resulting yellow oil was purified by flash chromatography on silica using hexane/ethyl acetate to give 1-bromo-4-((2-methoxyethoxy)methylbenzene as a colorless oil (6.43 g, 80%). Product and ethyl -2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate is reacted according to general procedure F to obtain ethyl-2-( 4'-((2methoxyethoxy)methyl)[1,1'-biphenyl]-4-yl)-2-methylpropanoate. To a solution of the resulting compound (0.759 g, 2.13 mmol) in tetrahydrofuran/ethanol/water, 1: 1:1 (v/v/v; 25 ml) lithium hydroxide (0.255 g, 10.6 mmol) is added with stirring. After refluxing overnight, the reaction mixture is concentrated and the residue is dissolved in water. diethyl ether and then treated with 1N hydrochloric acid (20 ml). The mixture was extracted with ethyl acetate, the combined organic layers were dried (Na ₂ SO ₄ ) and concentrated to give 2-(4'-((2-methoxyethoxy)methyl)[1,1'. biphenyl]-4-yl)-2-methylpropanoic acid as an off-white solid (0.657 g, 93%). The resulting intermediate and quinuclidin-3-ol are reacted according to General Procedure H to give the title compound as a soft beige solid. 1H NMR (400 MHz, DMSO- _d6 ) δ 7.68-7.52 (m, 5H), 7.48-7.34 (m, 4H), 4.52 (s, 1H), 4.46 -4.37 (m, 1H), 3.633.53 (m, 2H), 3.53-3.48 (m, 2H), 3.27 (s, 3H), 3.08-2.29 (m , 6H), 2.03-1.20 (m, 11H) ppm. ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 154.4, 147.4, 139.1, 137.5, 132.4, 128.1, 126.3, 126.2, 125.3, 71 .7, 71.3, 69.0, 58.1, 54.9, 54.2, 46.7, 45.7, 29.4, 25.0, 23.3, 18.7 ppm. UP-LCMS purity 100%, 99.6% (210 and 254 nm); retention time 0.91 min; (M+H+) 453.5.

Example 198.

-(2-(4'-((2-Methoxyethoxy)methyl) [1,1'-biphenyl]-4-yl)propan-2-yl)-3 -(3-methylquinuclidin-3 yl)urea.

Using General Procedure H and reacting 2-(4'-((2-methoxyethoxy)methyl)[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 197 ) and intermediate 1 afford the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J=8.2 Hz, 2H), 7.57 (d, J=8.5 Hz, 2H), 7.40 (dd, J =10.3, 8.4 Hz, 4H), 6.17 (s, 1H), 5.77 (s, 1H), 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, 1H) , 1.84-1.73 (m, 1H), 1.66-1.46 (m, 7H), 1.43-1.20 (m, 5H) ppm. ¹³ C NMR (100 MHz, DMSO-d 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, 29.9, 25.1, 23.0 , 22.3 ppm UP-LCMS purity 100%, 99.5% (210 and 254 nm); retention time 0.89 min; (M+H+) 466.6.

Example 199.

-(3-Ethylquinuclidin-3-yl)-3-(2-(4'-((2-methoxyethoxy)methyl)[1,1'-biphenyl]-4-yl)propan-2-yl)urea.

Using General Procedure H and reacting 2-(4'-((2-methoxyethoxy)methyl)[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 197 )

- 82 046304 and intermediate 2 give the title compound as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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, 1H), 5.73 (s, 1H), 4.52 (s , 2H), 3.64-3.55 (m, 2H), 3.55-3.45 (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 ¹³ C NMR (100 MHz, DMSO-d6) 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 UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.88 min; (M+H+) 480.6.

Example 200.

1-Azabicyclo[3.2.2]nonan-4-yl(2-(4'-((2-methoxyethoxy)methyl)[1,1'-biphenyl]-4-yl)propan-2yl)carbamate.

Using General Procedure H and reacting 2-(4'-((2-methoxyethoxy)methyl)[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 197 ) and intermediate 3 give the title compound as a soft, dense, amber-colored substance. 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.62 (d, J=8.0 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H), 7.49 (br. s, 1H), 7.45-7.35 (m, 4H), 4.65-4.56 (m, 1H), 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) m.d. ¹³ C NMR (100 MHz, DMSO-d 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 m.d. UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.87 min; (M+H+) 467.6.

Example 201.

-(2-(4'-((2-Methoxyethoxy)methyl)[1,1'-biphenyl]-4-yl)propan-2-yl)-3 -(4-methyl-1-azabicyclo[3.2.2 ] nonan-4-yl)urea.

Using General Procedure H and reacting 2-(4'-((2methoxyethoxy)methyl)[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 197) and intermediate 5 gives the title compound as a glassy, colorless solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.62 (d, J=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, 1H), 5.74 (br.s, 1H), 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, 1H), 1.84-1.35 (m, 11H), 1.35-1.17 (m, 4H) ppm. ¹³ C NMR (100 MHz, DMSO-d 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 UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.86 min; (M+H+) 480.6.

Example 202.

N(2-(4'-((2-Methoxyethoxy)methyl) [1,1'-biphenyl]-4-yl)propan-2-yl)-1,4-diazabicyclo[3.2.2]nonane4-carboxamide.

Using General Procedure H and reacting 2-(4'-((2-methoxyethoxy)methyl)[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 197 ) and intermediate 6 afford the title compound as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6) 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, 1H), 4.52 (s, 2H), 4.22-4.16 (m, 1H), 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. ¹³ C NMR (100 MHz, DMSO46) 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. UP-LCMS purity 90.8%, 91.5% (210 and 254 nm); retention time 0.80 min; (M+H+) 452.5.

Example 203.

Quinuclidin-3 -yl(2-(4'-((2-methoxyethoxy)methyl)[1,1'-biphenyl]-3-yl)propan-2-yl)carbamate.

Replacing ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate with ethyl 1-(4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxylate, use the reaction sequence described in example 197 to obtain 1-(4'-((2-methoxyethoxy)methyl)[1,1' biphenyl]-4-yl)cyclopropanecarboxylic acid. The resulting intermediate and quinuclidin-3-ol are reacted according to General Procedure H to obtain the title compound as a glassy, colorless solid. 1H NMR (7:3 mixture of rotomers) (400 MHz, DMSO-d6) δ 8.03 (br.s, 0.7H), 7.79 (br.s, 0.3H), 7.68-7, 49 (m, 4H), 7.39 (d, J=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, 1H), 2.83-2.24 (m, 6H), 1.95-1.00 (m, 9H) ppm. ¹³ C NMR main rotomer (100 MHz, DMSO-d6) 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 . UP-LCMS purity 100%, 99.0% (210 and 254 nm); retention time 0.83 min; (M+H+) 451.6.

Example 204.

-Azabicyclo[3.2.2]nonan-4-yl(1-(4'-((2-methoxyethoxy)methyl)[1,1'-biphenyl]-4-yl)cyclopropyl)carbamate.

Using General Procedure H and reacting 1-(4'-((2-methoxyethoxy)methyl)[1,1'-biphenyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 203) and the intermediate compounds 3 obtain the title compound in the form of a glassy

- 83 046304 colorless solid. 'H NMR (7:3 mixture of rotomers) (400 MHz, DMSO-d ₆ ) δ 7.97 (br.s, 0.7H), 7.72 (br.s, 0.3N), 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, 1H), 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), 1.991.37 (m, 7H), 1.25-1.09 (m, 4H) m. d. ¹³ C NMR (main rotomer) (100 MHz, DMSO-d ₆ ) 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 UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.84 min; (M+H+) 465.5.

Example 205.

1-(1 -(4'-((2-Methoxyethoxy)methyl) [1,1'-biphenyl]-4-yl)cyclopropyl)-3 -(3-methylquinuclidin-3 yl)urea.

Using General Procedure H and reacting 1-(4'-((2-methoxyethoxy)methyl)[1,1'-biphenyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 203) and the intermediate Compound 1 gives the title compound as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.62 (d, J=8.3 Hz, 2H), 7.56 (d, J=8.5 Hz, 2H), 7.38 (d, J=8.3 Hz, 2H), 7.21 (d, J=8.4 Hz, 2H), 6.64 (br.s, 1H), 5.63 (br.s, 1H), 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, 1H), 1.76-1.56 (m, 2H), 1.44-1.08 (m, 9H) ppm. ¹³ C NMR (100 MHz, DMSO-d ₆ ) 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 UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.80 min; (M+H+) 464.6.

Example 206.

-(3-Ethylquinuclidin-3-yl)-3 -(1 -(4'-((2-methoxyethoxy)methyl)[1,1'-biphenyl]-4-yl)cyclopropyl)urea.

Using General Procedure H and reacting 1-(4'-((2methoxyethoxy)methyl)[1,1'-biphenyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 203) and intermediate 2 obtain the title compound as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6) 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, 1H), 5.58 (br.s, 1H), 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 ¹³ C NMR (100 MHz, DMSO-d6) 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 UP-LCMS purity 100%, 99.6% (210 and 254 nm); retention time 0.83 min; (M+H+) 478.6.

Example 207.

1-(1 -(4'-((2-Methoxyethoxy)methyl) [1,1'-biphenyl]-4-yl)cyclopropyl)-3 -(4-methyl-1-azabicyclo[3.2.2] nonan- 4-yl)urea.

Using General Procedure H and reacting 1-(4'-((2methoxyethoxy)methyl)[1,1'-biphenyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 203) and intermediate 5 obtain the title compound in the form of a glassy, colorless solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.62 (d, J=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, 1H), 5.57 (br.s, 1H), 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, 1H), 1.81-1.60 (m, 3H), 1.55-1.38 (m, 2H), 1.38-1 .07 (m, 8H) ppm ¹³ C NMR (100 MHz, DMSOO δ 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 by UP-LCMS 100%, 100% (210 and 254 nm); retention time 0.79 min; (M+H+) 478.6.

Example 208.

-(3-Ethylquinuclidin-3-yl)-3 -(1 -(4'-((2-methoxyethoxy)methyl)[1,1'-biphenyl]-4-yl)cyclopropyl)urea (single enantiomer A).

Using General Procedure H and reacting 1-(4'-((2methoxyethoxy)methyl)[1,1'-biphenyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 203) and intermediate 13 obtain the title compound as an off-white solid. NMR data consistent with Example 52. Purity by UPLCMS 100%, 100% (210 and 254 nm); retention time 0.84 min; (M+H+) 478.4.

Example 209.

-(3-Ethylquinuclidin-3-yl)-3 -(1 -(4'-((2-methoxyethoxy)methyl)[1,1'-biphenyl]-4-yl)cyclopropyl)urea (single enantiomer B).

Using General Procedure H and reacting 1-(4'-((2methoxyethoxy)methyl)[1,1'-biphenyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 203) and intermediate 14 obtain the title compound as an off-white solid. NMR data consistent with Example 52. UPLCMS purity 100%, 99.7% (210 and 254 nm); retention time 0.84 min; (M+H+) 478.4.

Example 210.

- 84 046304 (S)-1-(1 -(4'-((2-Methoxyethoxy)methyl) [1,1'-biphenyl]-4-yl)cyclopropyl)-3 -(3-methylquinuclidin-3 yl) urea.

Using General Procedure H and reacting 1-(4'-((2methoxyethoxy)methyl)[1,1'-biphenyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 203) and intermediate 11 obtain the title compound as an off-white solid. NMR data consistent with Example 51. UPLCMS purity 100%, 99.4% (210 and 254 nm); retention time 0.79 min; (M+H+) 464.4.

Example 211.

(R)-1 -(1 -(4'-((2-Methoxyethoxy)methyl)[1,1'-biphenyl]-4-yl)cyclopropyl)-3 -(3-methylquinuclidin-3 yl)urea.

Using General Procedure H and reacting 1-(4'-((2methoxyethoxy)methyl)[1,1'-biphenyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 203) and intermediate 12 obtain the title compound as an off-white solid. NMR data consistent with Example 51. UPLCMS purity 100%, 100% (210 and 254 nm); retention time 0.79 min; (M+H+) 464.3.

Example 212.

-Azabicyclo[3.2.2]nonan-4-yl)(1 -(4'-(3-methoxypropyl)[1,1'-biphenyl]-4-yl)cyclopropyl)carbamate.

Using general procedure F and reacting ethyl 1-(4-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxylate and 1-bromo-4-(3- methoxypropyl)benzene gives ethyl 1-(4'-(3-methoxypropyl)[1,1'-biphenyl]-4-yl)cyclopropanecarboxylate as a yellow oil. Lithium hydroxide (0.704 g, 29.4 mmol). The mixture is refluxed overnight and then concentrated. The residue is dissolved in water and washed with diethyl ether. The aqueous layer was then treated with 1N hydrochloric acid (30 ml) and extracted with ethyl acetate. The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated to give 1-(4'(3-methoxypropyl)[1,1'-biphenyl]-4-yl)cyclopropanecarboxylic acid as a white solid (1.53 g, 84%). The resulting intermediate and Intermediate 3 were reacted according to General Procedure H to obtain the title compound as a white solid. ¹ H NMR (7:3 mixture of rotomers) (400 MHz, DMSO-d ₆ ) 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, 1H), 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. ¹³ C NMR (main rotomer) (100 MHz, DMSO46) δ 155.6, 143.0, 140.8, 137.4, 128.8, 126.3, 126.1, 125.2, 77.5, 71.1, 57.8, 51.4, 47.7, 44.5, 34.3, 33.5, 31.3, 30.7, 30.5, 24.6, 22.1, 18, 1 ppm UP-LCMS purity 97.5%, 98.0% (210 and 254 nm); retention time 0.95 min; (M+H+) 449.5.

Example 213.

1-(1-(4'-(3-Methoxypropyl)[1,1'-biphenyl]-4-yl)cyclopropyl)-3-(4-methyl-1-azabicyclo[3.2.2]nonan4-yl)urea .

Using General Procedure H and reacting 1-(4'-(3-methoxypropyl)[1,1'biphenyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 212) and intermediate 5, the title the title compound appears as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.54 (dd, J=8.2, 2.5 Hz, 4H), 7.26 (d, J=8.0 Hz, 2H), 7.22 (d, J=8.2 Hz, 2H), 6.71 (br.s, 1H), 5.57 (br.s, 1H), 3.33 (t, J=6.4 Hz, 3H) , 3.24 (s, 3H), 2.89-2.48 (m, 8H), 2.18-2.08 (m, 1H), 1.88-1.58 (m, 5H), 1 .56-1.04 (m, 10H) ppm ¹³ C NMR (100 MHz, DMSO-d6) δ 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 UP-LCMS purity 100%, 99.5% (210 and 254 nm); retention time 0.90 min; (M+H+) 462.6.

Example 214.

1-(1 -(4'-(3-Methoxypropyl)[1,1'-biphenyl]-4-yl)cyclopropyl)-3 -(3-methylquinuclidin-3-yl)urea.

Using general procedure H and reacting 1-(4'-(3-methoxypropyl)[1,1'biphenyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 212) and intermediate 1, the title the title compound appears as a white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 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, 1H), 5.63 (br.s, 1H), 3.34 (t, J=6.4 Hz, 3H ), 3.24 (s, 3H), 2.77-2.52 (m, 8H), 1.95-1.89 (m, 1H), 1.86-1.76 (m, 2H), 1.76-1.56 (m, 2H), 1.44-1.08 (m, 9H) ppm ¹³ C NMR (100 MHz, DMSO-d ₆ ) 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 UP-LCMS purity 100%, 99.6% (210 and 254 nm); retention time 0.91 min; (M+H+) 448.6.

Example 215.

-(3-Ethylquinuclidin-3-yl)-3 -(1 -(4'-(3-methoxypropyl)[1,1'-biphenyl]-4-yl)cyclopropyl)urea.

Using General Procedure H and reacting 1-(4'-(3-methoxypropyl)[1,1'biphenyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 212) and prom.

- 85 046304 of compound 2 the title compound is obtained in the form of a white solid. ^1H NMR (400 MHz, DMSO-d6) δ 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, 1H), 5.58 (br.s, 1H), 3.34 (t, J=6.4 Hz, 3H), 3.24 (s , 3H), 2.72-2.52 (m, 8H), 1.98-1.49 (m, 7H), 1.41-1.07 (m, 6H), 0.73 (t, J =7.2 Hz, 3H) ppm ¹³ C NMR (100 MHz, DMSO-d6) 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 UP-LCMS purity 100%, 99.9% (210 and 254 nm); retention time 0.95 min; (M+H+) 462.6.

Example 216.

Quinuclidin-3 -yl(1 -(4'-((pyridin-3-ylmethoxy)methyl)[1,1'-biphenyl]-4-yl)cyclopropyl)carbamate.

To a solution of 3-pyridinemethanol (2.00 g, 18.3 mmol) in tetrahydrofuran (80 ml) was added sodium hydride (60% dispersion in mineral oil; 0.806 g, 20.2 mmol) with stirring. After 2 hours, 4-bromobenzyl bromide (4.80 g, 19.2 mmol) was added and the mixture was stirred overnight. The reaction mixture is then concentrated and treated with water and ethyl acetate. The organic layer is combined with the second ethyl acetate extract, dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified by flash chromatography on silica using hexane/ethyl acetate to give 3(((4-bromobenzyl)oxy)methyl)pyridine as an amber oil (3.67 g, 72%). The resulting product and ethyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxylate are reacted according to General Procedure F to obtain ethyl 1-( 4'-((pyridin-3-ylmethoxy)methyl)[1,1'biphenyl]-4-yl)cyclopropanecarboxylate. To a solution of the resulting compound (1.81 g, 4.67 mmol) in a mixture of tetrahydrofuran/ethanol/water, 1:1:1 (v/v/v; 30 ml), add lithium hydroxide monohydrate (0.980 g) with stirring , 23.4 mmol). After stirring at room temperature overnight, the reaction mixture is concentrated and the residue is dissolved in water. The solution is washed with diethyl ether and then treated with 1N. hydrochloric acid (23.4 ml). The mixture was extracted with chloroform/isopropanol 4:1 (v/v), the combined organic layers were dried (Na ₂ SO ₄ ) and concentrated to give 1-(4'-((pyridin-3-ylmethoxy)methyl)[1 ,1'-biphenyl]-4-yl)cyclopropanecarboxylic acid as a beige solid (1.68 g, 100%). The resulting intermediate and quinuclidin3-ol are reacted according to General Procedure H to obtain the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.59 (brs, 1H), 8.548.49 (m, 1H), 8.05 (brs, 1H), 7.84-7.74 (m, 1H), 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, 1H), 2.82-2.24 (m, 5H), 1.94-1.67 (m, 2H), 1.65 -1.04 (m, 7H) ppm ¹³ C NMR (100 MHz, DMSO-d 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 UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.65 min; (M+H+) 484.

Example 217.

1-(3-Ethylquinuclidin-3-yl)-3-(1-(4'-((pyridin-3-ylmethoxy)methyl)[1,1'-biphenyl]-4-yl)cyclopropyl)urea.

Using General Procedure H and reacting 1-(4'-((pyridin-3-ylmethoxy)methyl)[1,1'-biphenyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 216) and intermediate 2 afford the title compound as a pale amber solid. 1H NMR (400 MHz, DMSO- _d6 ) δ 8.62-8.56 (m, 1H), 8.54-8.49 (m, 1H), 7.82-7.75 (m, 1H) , 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, 1H), 7.23 (d, J=8.4 Hz, 2H), 4.59 (br.s, 4H), 2.80- 2.50 (m, 6H), 1.98-1.84 (m, 2H), 1.79-1.48 (m, 3H), 1.41-1.07 (m, 6H), 0. 74 (t, J=7.0 Hz, 3H) ppm ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 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 UP-LCMS purity 100%, 99.6% (210 and 254 nm); retention time 0.66 min; (M+H+) 511.

Example 218.

1-(3-Propylquinuclidin-3-yl)-3-(1-(4'-((pyridin-3-ylmethoxy)methyl)[1,1'-biphenyl]-4-yl)cyclopropyl)urea.

Using General Procedure H and reacting 1-(4'-((pyridin-3-ylmethoxy)methyl)[1,1'-biphenyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 216) and intermediate 17 afford the title compound as a pale amber solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.59 (d, J=2.0 Hz, 1H), 8.52 (dd, J=4.8, 1.6 Hz, 1H), 7, 81-7.76 (m, 1H), 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, 1H), 7.22 (d, J=8.4 Hz, 2H), 6.67 (br.s, 1H), 5 .61 (br.s, 1H), 4.59 (s, 4H), 2.81-2.70 (m, 1H), 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) m .d. ¹³ C NMR (100 MHz, DMSO-d 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 UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.70 min; (M+H+) 525.

Example 219.

Quinuclidin-3 -yl(1 -(4'-((pyrimidin-5 -ylmethoxy)methyl)[1,1'-biphenyl]-4-yl)cyclopropyl)carbamate.

Replacing 3-pyridinemethanol with 5-pyrimidinemethanol, use the sequence of reactions described above:

- 86 046304 in example 216 and obtain 1-(4'-((pyrimidin-5-ylmethoxy)methyl)[1,1'-biphenyl]-4-yl)cyclopropanecarboxylic acid. The resulting intermediate and quinuclidin-3-ol are reacted according to General Procedure H to give the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.14 (s, 1H), 8.82 (s, 2H), 8.05 (br s, 1H), 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, 1H), 3.15-2.89 (m, 1H), 2.81- 2.25 (m, 5H), 1.95-1.02 (m, 9H) ppm. ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 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 UP-LCMS purity 100%, 99.3% (210 and 254 nm); retention time 0.78 min; (M+H+) 485.

Example 220.

-(3 -Ethylquinuclidin-3 -yl)-3 -(1 -(4'-((pyrimidin-5 -ylmethoxy)methyl) [1,1'-biphenyl]-4-yl)cyclopropyl)urea.

Using General Procedure H and reacting 1-(4'-((pyrimidin-5ylmethoxy)methyl)[1,1'-biphenyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 219) and the intermediate Compound 2 gives the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.14 (s, 1H), 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), b.68 (lat. s, 1H), 5.60 (br.s, 1H), 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 ) m.d. ¹³ C NMR (100 MHz, DMSO-d6) 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 UP-LCMS purity 100%, 98.7% (210 and 254 nm); retention time 0.78 min; (M+H+) 512.

Example 221.

1-Azabicyclo[3.2.2]nonan-4-yl(1-(4'-((pyrimidin-5-ylmethoxy)methyl)[1,1'-biphenyl]-4-yl)cyclopropyl)carbamate.

Using General Procedure H and reacting 1-(4'-((pyrimidin-3ylmethoxy)methyl)[1,1'-biphenyl]-4-yl)cyclopropanecarboxylic acid (prepared as described in Example 219) and the intermediate Compound 3 gives the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.14 (s, 1H), 8.82 (s, 2H), 7.99 (br s, 1H), 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, 1H), 4.63 (s, 2H), 4.62 (s, 2H), 3.00-2.55 (m, 6H), 2.00- 1.35 (m, 7H), 1.17 (brs, 4H) ppm. ¹³ C NMR (100 MHz, DMSOd6) 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 UP-LCMS purity 100%, 99.2% (210 and 254 nm); retention time 0.79 min; (M+H+) 499.

Example 222.

-(2-(4'-(3-Methoxypropyl)[1,1'-biphenyl]-4-yl)propan-2-yl)-3 -(3-methylquinuclidin-3-yl)urea.

Replacing ethyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxylate with ethyl 2-methyl-2-(4-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate, use the reaction sequence described in example 212 to obtain 2-(4'-(3-methoxypropyl)[1,1'- biphenyl]-4-yl)2-methylpropanoic acid. The resulting compound and Intermediate 1 were reacted according to General Procedure H to obtain the title compound as a white solid. 1H NMR (400 MHz, DMSO-d ₆ ) 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, 1H), 5.79 (br.s, 1H), 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 ¹³ C NMR (100 MHz, DMSO-d ₆ ) 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 UP-LCMS purity 99.9%, 98.1% (210 and 254 nm); retention time 0.97 min; (M+H+) 450.5.

Example 223.

Quinuclidin-3 -yl(2-(4'-(hydroxymethyl)[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate.

Using general procedure F and reacting 2-(4-bromophenyl)-2methylpropanoate and 4-formylphenylboronic acid, ethyl 2-(4'-formyl[1,1'-biphenyl]-4-yl)2-methylpropanoate is obtained in in the form of an amber solid. The resulting intermediate and quinuclidin-3-ol are reacted according to General Procedure H to give quinuclidin-3yl(2-(4'-formyl[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate in in the form of a hard yellow foam. To a solution of the resulting material (0.755 g, 1.92 mmol) in tetrahydrofuran/ethanol, 2:1 (v/v; 15 ml), sodium borohydride (0.073 g, 1.93 mmol) was added with stirring. After 45 minutes, the reaction mixture is diluted with water and extracted with chloroform. The combined extracts are dried (Na ₂ SO ₄ ) and concentrated on silica. Flash chromatography on silica using chloroform/methanol/ammonia as an eluent gave the title compound as a white solid (0.323 g, 43%). 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.66-7.29 (m, 9H), 5.18 (t, J=5.7 Hz, 1H), 4.53 (d, J=5 .7 Hz, 2H), 4.46-4.37 (m, 1H), 3.11-2.19 (m, 6H), 2.11-1.10 (m, 11H) ppm. ¹³ C NMR (100 MHz, DMSO-d 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. UP-LCMS purity 97.5%, 99.1% (210 and 254 nm); retention time 0.73 min; (M+H+) 395.

- 87 046304

Example 224.

-(2-(4'-(2-G hydroxyethyl)[1,1'-biphenyl]-4-yl)propan-2-yl)-3 -(3-propylquinuclidin-3-yl)urea.

Using general procedure F and reacting 1-(2-benzyloxy)-4bromobenzene and ethyl-2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)phenyl)propanoate gives ethyl 2-(4'-(benzyloxy)ethyl)[1,1'-biphenyl]-4-yl)-2-methylpropanoate as a colorless resin. To a solution of the resulting compound (1.34 g, 3.33 mmol) in a mixture of tetrahydrofuran/ethanol/water, 1:1:1 (v/v/v; 18 ml), add lithium hydroxide monohydrate (0.698 g) with stirring , 16.6 mmol). After refluxing overnight, the reaction mixture is concentrated and treated with water and diethyl ether. The resulting emulsion is re-extracted with 0.2N. aqueous sodium hydroxide solution (5x50 ml). The transparent part of the aqueous layer is removed each time. Then the combined aqueous layers are treated with 1.0N. hydrochloric acid (80 ml) and the resulting white solid suspension was extracted with ethyl acetate. The combined organic layers are dried (Na ₂ SO ₄ ) and concentrated to give 2-(4'-(2-(benzyloxy)ethyl)[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid as a white solid substances (1.20 g, 96%). The resulting compound and intermediate 17 are reacted according to General Procedure H to give 1-(2-(4'-(2-benzyloxy)ethyl)[1,1'biphenyl]-4-yl)propan-2-yl)- 3-(3-propylquinuclidin-3-yl)urea in the form of a solid white foam. To a solution of the resulting material (0.435 g, 0.806 mmol) in methanol, add 1.0 N hydrochloric acid (1 ml) and 10% palladium on carbon (50% in water; 0.87 g) with stirring. The mixture is cyclically evacuated and purged with nitrogen several times and after the last evacuation is filled with hydrogen. After 1.25 hours, the reaction mixture is filtered through celite and concentrated. The residue is dissolved in aqueous sodium carbonate and extracted with chloroform/isopropanol 4:1 (v/v). The combined extracts are dried (Na ₂ SO ₄ ) and concentrated on silica. Flash chromatography on silica using a chloroform/methanol/ammonia gradient gave the purified title compound as a foamy, colorless solid (0.296 g, 82%). ^1H NMR (400 MHz, DMSOd6) δ 7.56-7.47 (m, 4H), 7.44-7.37 (m, 2H), 7.33-7.26 (m, 2H), 6 .19 (s, 1H), 5.74 (s, 1H), 4.65 (br.s, 1H), 3.63 (t, J=7.0 Hz, 2H), 2.79-2, 46 (m, 8H), 1.89-1.82 (m, 1H), 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. ¹³ C NMR (100 MHz, DMSO-d6) 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 UP-LCMS purity 100%, 99.0% (210 and 254 nm); retention time 0.83 min; (M+H+) 450.

Example 225.

-(3-Ethylquinuclidin-3-yl)-3-(2-(4'-(2-hydroxyethyl)[1,1'-biphenyl]-4-yl)propan-2-yl)urea.

Replacing intermediate 17 with intermediate 2, the reaction sequence described in Example 224 was used to obtain the title compound as an off-white solid. 1H NMR (400 MHz, DMSO- _d6 ) δ 7.62-7.36 (m, 6H), 7.34-7.21 (m, 2H), 6.22 (brs, 1H), 5 .78 (br.s, 1H), 4.66 (br.s, 1H), 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. ¹³ C NMR (100 MHz, DMSO-d6) 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 by UPLCMS 100%, 98.0% (210 and 254 nm); retention time 0.79 min; (M+H+) 436.

Example 226.

Quinuclidin-3 -yl(2-(4'-(2-hydroxyethyl)[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate.

Replacing intermediate 17 with quinuclidin-3-ol, the reaction sequence described in Example 224 was used to obtain the title compound as a colorless solid. 1H NMR (400 MHz, DMSO- _d6 ) δ 7.85-7.63 (m, 1H), 7.63-7.19 (m, 8H), 4.78-4.62 (m, 2H) , 3.712.78 (m, 8H), 2.76 (t, J=6.8 Hz, 2H), 2.26-1.96 (m, 2H), 1.96-1.40 (m, 9H ) m.d. ¹³ C NMR (100 MHz, DMSO-d6) δ 153.8, 146.8, 138.7, 137.9, 137.6, 129.4, 126.3, 126.1, 125.3, 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. UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.75 min; (M+H+) 409.

Example 227.

Quinuclidin-3 -yl(2-(4'-(2-(1H-1,2,3-triazol-4-yl)ethyl)[1,1'-biphenyl]-4-yl)propan-2-yl )carbamate.

Benzyl azide is added to a solution of 1-bromo-4-(but-3-in-1-yl)benzene (1.73 g, 8.27 mmol) in a mixture of tert-butanol (76 ml) and water (24 ml) with stirring. (1.14 g, 9.13 mmol), sodium L-ascorbate (0.164 g, 0.828 mmol) and copper(II) sulfate pentahydrate (0.103 g, 0.413 mmol). After 2 days, more benzyl azide (0.25 ml, 2.00 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture is then concentrated and the residue is dissolved in aqueous sodium bicarbonate and extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and concentrated on silica. Flash chromatography on silica using hexane/ethyl acetate eluent gave 1-benzyl4-(4-bromophenethyl)-1H-1,2,3-triazole as a white solid (1.17 g, 41%). The resulting compound and ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate are reacted according to General Procedure F to obtain ethyl -2-(4'-(2-(1-benzyl-1H-1,2,3-triazol-4yl)ethyl)[1,1'-biphenyl]-4-yl)-1-methylpropanoate as a white solid substances. To a solution of the resulting compound (1.22 g, 2.69 mmol) in water/tetrahydrofuran/ethanol, 2:3:3 (v/v/v; 32 ml) at

- 88 046304 lithium hydroxide monohydrate (0.564 g, 13.4 mmol) is added while stirring. After refluxing overnight, the reaction mixture is concentrated and the residue is dissolved in water. The solution is washed with diethyl ether and then treated with 1N. hydrochloric acid (13.4 ml). The resulting milky suspension is extracted with ethyl acetate and the combined organic layers are dried (Na ₂ SO ₄ ) and concentrated to give 2-(4'-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)ethyl) [1,1'-biphenyl]4-yl)-2-methylpropanoic acid as a white solid (1.16 g, 100%). The resulting compound and quinuclidin-3-ol are reacted according to the general procedure H to obtain quinuclidin3-yl(2-(4'-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)ethyl )[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate in the form of a solid colorless foam. To a solution of the resulting intermediate (0.450 g, 0.819 mmol) in methanol (20 ml) add 1.0N hydrochloric acid (1 ml) and 10% palladium on carbon (50% in water; 0.225 g) with stirring. The mixture is cyclically evacuated and purged with nitrogen several times and after the last evacuation is filled with hydrogen. After 7 hours, the reaction mixture is filtered through celite and concentrated. The residue was purified by flash silica chromatography using a chloroform/methanol/ammonia gradient to give the title compound as a foamy, colorless solid (0.332 g, 88%). ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.63-7.25 (m, 10H), 4.484.35 (m, 1H), 3.09-2.19 (m, 10H), 2, 10-1.02 (m, 11H) ppm ¹³ C NMR (100 MHz, DMSO46) 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 . UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.83 min; (M+H+) 460.

Example 228.

1-Azabicyclo[3.2.2]nonan-4-yl(2-(4'-(2-(1H-1,2,3-triazol-4-yl)ethyl)[1,1'-biphenyl]-4 -yl)propan-2yl)carbamate.

Replacing quinuclidin-3-ol with intermediate 3, the reaction sequence described in Example 227 was used to obtain the title compound as a colorless solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 14.69 (br s, 1H), 7.59 (s, 1H), 7.55 (d, J=8.4 Hz, 4H), 7, 48 (br.s, 1H), 7.39 (d, J=8.1 Hz, 2H), 7.30 (d, J=8.3 Hz, 2H), 4.65-4.55 (m , 1H), 3.04-2.42 (m, 10H), 2.01-1.31 (m, 13H) ppm. ¹³ C NMR (100 MHz, DMSO-d ₆ ) 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 m.d. UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.83 min; (M+H+) 474.

Example 229.

Quinuclidin-3 -yl(2-(4'-(morpholinomethyl)[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate.

Using general procedure F and reacting ethyl 2-(4-bromophenyl)-2methylpropanoate and 4-(4-morpholinomethyl)boronic acid, ethyl 2-methyl-2-(4'-(morpholinomethyl)[1, 1'-biphenyl]-4-yl)propanoate in the form of an amber oil. To a solution of the resulting compound (2.86 g, 7.79 mmol) in a mixture of tetrahydrofuran/ethanol/water, 1:1:1 (v/v/v; 40 ml), add lithium hydroxide (1.31 g, 54.5 mmol). After refluxing overnight, the reaction mixture is diluted with water and washed with diethyl ether. The aqueous layer is treated with 1.0N. hydrochloric acid (56 ml) and extracted with a mixture of chloroform/isopropanol, 4:1 (v/v). The combined organic extracts are dried (Na ₂ SO ₄ ) and concentrated. The residue was triturated in diethyl ether to give 2-methyl-2-(4'-(morpholinomethyl)[1,1'-biphenyl]-4-yl)propanoic acid as a tan solid (2.50 g, 95% ). The resulting compound and quinuclidin-3-ol are reacted according to General Procedure H to obtain the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.67-7.26 (m, 9H), 4.50-4.34 (m, 1H), 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. ¹³ C NMR (100 MHz, DMSO-d6) 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 UP-LCMS purity 96.5%, 98.9% (210 and 254 nm); retention time 0.50 min; ((M+H+)/2) 232.9.

Example 230.

N(2-(4'-(Morpholinomethyl)[1,1'-biphenyl]-4-yl)propan-2-yl)-1,4-diazabicyclo[3.2.2]nonane-4-carboxamide.

Using General Procedure H and reacting 2-methyl-2-(4'-(morpholinomethyl)[1,1'-biphenyl]-4-yl)propanoic acid (prepared as described in Example 229) and the intermediate 6 obtain the title compound as a colorless solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.59 (d, J=8.1 Hz, 2H), 7.54 (d, J=8.3 Hz, 2H), 7.44-7, 32 (m, 4H), 6.16 (brs, 1H), 4.24-4.16 (m, 1H), 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 ¹³ C NMR (100 MHz, DMSO-d ₆ ) 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. UP-LCMS purity 97.2%, 99.9% (210 and 254 nm); retention time 0.44 min; ((M+H+)/2) 232.4.

Example 231.

Quinuclidin-3-yl(2-(4'-morpholino[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate.

Using general procedure F and reacting ethyl 2-(4-bromophenyl)-2methylpropanoate and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl )morpholine, ethyl is obtained

- 89 046304

2-methyl-2-(4'-morpholino[1,1'-biphenyl]-4-yl)propanoate as a white solid. To a solution of the resulting compound (3.32 g, 9.39 mmol) in a mixture of tetrahydrofuran/ethanol/water, 1:1:1 (v/v/v; 50 ml), add lithium hydroxide (1.57 g, 65.6 mmol). After refluxing for 3 hours, the reaction mixture is diluted with water and washed with diethyl ether. The aqueous layer is acidified to pH~5 with 1.0N hydrochloric acid and extracted with ethyl acetate. The combined extracts were filtered to remove solids and concentrated to give 2-methyl-2-(4'morpholino[1,1'-biphenyl]-4-yl)propanoic acid (2.62 g, 86%). The resulting compound and quinuclidin-3-ol are reacted according to General Procedure H to obtain the title compound as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.56-7.40 (m, 6H), 6.96 (d, J=8.8 Hz, 2H), 5.19 (br.s, 1H), 4.70-4.54 (m, 1H), 3.92-3.83 (m, 4H), 3.27-2.41 (m, 10H), 2.09-1.28 ( m, 11H) ppm ¹³ C NMR (100 MHz, DMSO4/I 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 UP-LCMS purity 100% , 100% (210 and 254 nm); retention time 1.02 min; (M+H+) 450.4.

Example 232.

-(3-Methylquinuclidin-3-yl)-3-(2-(4'-morpholino[1,1'-biphenyl]-4-yl)propan-2-yl)urea.

Using General Procedure H and reacting 2-methyl-2-(4'-morpholino[1,1'biphenyl]-4-yl)propanoic acid (prepared as described in Example 231) and Intermediate 1 afforded the title the title compound appears as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.57-7.40 (m, 6H), 6.96 (d, J=8.8 Hz, 2H), 5.19 (brs, 1H), 4 .71-4.53 (m, 1H), 3.93-3.82 (m, 4H), 3.27-2.11 (m, 10H), 2.09-1.25 (m, 11H) m.d. ¹³ C NMR (100 MHz, DMSO-d6) 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. UP-LCMS purity 100%, 99.9% (210 and 254 nm); retention time 0.82 min; (M+H+) 463.1.

Example 233.

1-(4-Methyl-1-azabicyclo[3.2.2]nonan-4-yl)-3 -(2-(4'-morpholino[1,1'-biphenyl]-4-yl)propan-2-yl )urea.

Using general procedure H and reacting 2-methyl-2-(4'-morpholino[1,1'biphenyl]-4-yl)propanoic acid (prepared as described in Example 231) and intermediate 5, the title the title compound appears as a white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.58-7.44 (m, 4H), 7.38 (d, J=8.4 Hz, 2H), 7.01 (d, J=8 .6 Hz, 2H), 6.21 (br.s, 1H), 5.72 (br.s, 1H), 3.85-3.63 (m, 4H), 3.23-3.02 ( m, 4H), 2.94-2.63 (m, 6H), 2.12-2.03 (m, 1H), 1.84-1.35 (m, 11H), 1.35-1, 17 (m, 4H) ppm ¹³ C NMR (100 MHz, DMSO-d 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 m.d. UP-LCMS purity 100%, 98.8% (210 and 254 nm); retention time 0.83 min; (M+H+) 477.1.

Example 234.

-(3-Ethylquinuclidin-3-yl)-3-(2-(4'-morpholino [1,1'-biphenyl]-4-yl)propan-2-yl)urea.

Using general procedure H and reacting 2-methyl-2-(4'-morpholino[1,1'biphenyl]-4-yl)propanoic acid (prepared as described in Example 231) and intermediate 2, the title the title compound appears as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.52 (d, J=8.9 Hz, 2H), 7.49 (d, J=8.5 Hz, 2H), 7.38 (d, J =8.5 Hz, 2H), 7.01 (d, J=8.9 Hz, 2H), 6.17 (br.s, 1H), 5.71 (br.s, 1H), 3.80 -3.69 (m, 4H), 3.20-3.08 (m, 4H), 2.84-2.53 (m, 6H), 1.92-1.41 (m, 11H), 1 .41-1.19 (m, 2H), 0.74 (t, J=7.3 Hz, 3H) ppm. ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 156.8, 150.2, 147.4, 137.4, 130.7, 126.9, 125.3, 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 m.d. UP-LCMS purity 100%, 99.9% (210 and 254 nm); retention time 1.03 min; (M+H+) 477.4.

Example 235.

Quinuclidin-3 -yl(2-(4'-(methylsulfonyl)[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate.

Using general procedure F and reacting ethyl 2-methyl-2-(4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate and 4-bromophenylmethylsulfone, ethyl2-methyl-2-(4'-(methylsulfonyl)[1,1'-biphenyl]-4-yl)propanoate as a white solid. To a solution of the resulting compound (1.03 g, 2.97 mmol) in a mixture of tetrahydrofuran/ethanol/water, 1:1:1 (v/v/v; 18 ml), add lithium hydroxide monohydrate (0.624 g) with stirring , 14.9 mmol). After stirring at room temperature overnight, the reaction mixture is refluxed for 3 hours, cooled and concentrated. The residue is dissolved in water and washed with diethyl ether. The aqueous layer is treated with 1.0N. hydrochloric acid (20 ml) and extracted with a mixture of chloroform/methanol, 4:1 (v/v). The combined extracts were dried (Na ₂ SO ₄ ) and concentrated to give 2-methyl-2-(4'-(methylsulfonyl)[1,1'-biphenyl]-4-yl)propanoic acid as an off-white solid (0.954 g, 100%). The resulting compound and quinuclidin-3-ol are reacted according to General Procedure H to obtain the title compound as an off-white solid. 1H NMR (400 MHz, DMSO- _d6 ) δ 8.02-7.96 (m, 2H), 7.96-7.87 (m, 2H), 7.73-7.42 (m, 5H) , 4.56-4.46 (m, 1H), 3.30-3.10 (m, 1H), 3.25 (s, 3H), 3.00-2.52 (m, 5H), 2 .03-1.80 (m, 2H), 1.76-1.33 (m, 9H) ppm. ¹³ C NMR (100 MHz, DMSO-d 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. UP-LCMS purity 100%, 100% (210 and 254 nm); holding time

- 90 046304 life 0.74 min; (M+H+) 443.

Example 236.

-(3-Ethylquinuclidin-3-yl)-3-(2-(4'-(methylsulfonyl)[1,1'-biphenyl]-4-yl)propan-2-yl)urea.

Using General Procedure H and reacting 2-methyl-2-(4'(methylsulfonyl)[1,1'-biphenyl]-4-yl)propanoic acid (prepared as described in Example 235) and intermediate 2 obtain the title compound as a white solid. 1H NMR (400 MHz, DMSO-de) 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, 1H), 5.86 (br.s, 1H), 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 ¹³ C NMR (100 MHz, DMSO-d6) δ 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 m .d. UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.76 min; (M+H+) 470.

Example 237.

-(2-(4'-(Methylsulfonyl)[1,1'-biphenyl]-4-yl)propan-2-yl)-3 -(3-propylquinuclidin-3-yl)urea.

Using General Procedure H and reacting 2-methyl-2-(4'(methylsulfonyl)[1,1'-biphenyl]-4-yl)propanoic acid (prepared as described in Example 235) and intermediate 17 obtain the title compound as a white solid. 1H NMR (400 MHz, DMSO- _d6 ) δ 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 (br.s, 1H), 5.76 (br.s, 1H), 3.25 (s, 3H), 2.73-2 .45 (m, 6H), 1.89-1.83 (m, 1H), 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 ¹³ C NMR (100 MHz, DMSO46) δ 156.8, 150.0, 145.0, 139.3, 135.7, 127.6, 127.3, 126.6, 125.6, 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 UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.81 min; (M+H+) 484.

Example 238.

Quinuclidin-3 -yl(2-(4'-((cyclopropylmethyl)sulfonyl)[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate.

Using general procedure F and reacting ethyl 2-methyl-2-(4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate and 1-bromo-4 -((cyclopropylmethyl)sulfonyl)benzene, ethyl 2-(4'-((cyclopropylmethylsulfonyl)[1,1'-biphenyl]-4-yl)-2-methylpropanoate is obtained in the form of an amber resin. To a solution of the resulting compound (1 .93 g, 4.99 mmol) in a mixture of tetrahydrofuran/ethanol/water, 1:1:1 (v/v/v; 36 ml) add lithium hydroxide monohydrate (1.05 g, 25.0 mmol). After stirring at room temperature overnight, the reaction mixture is refluxed for 2 hours, cooled and concentrated, the residue is dissolved in water and washed with diethyl ether. The aqueous layer is treated with 1.0 N hydrochloric acid (27 ml) and extracted with ethyl acetate. The combined extracts are dried (Na ₂ SO ₄ ) and concentrated to give 2-(4'-((cyclopropylmethyl)sulfonyl)[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid as an off-white solid. substances (1.81 g, 100%). The resulting compound and quinuclidin-3-ol are reacted according to General Procedure H to obtain the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.01-7.85 (m, 4H), 7.71 (d, J=8.1 Hz, 2H), 7.65-7.33 (m , 3H), 4.49-4.36 (m, 1H), 3.29 (d, J=7.1 Hz, 2H), 3.11-2.24 (m, 6H), 2.10- 1.15 (m, 11H), 0.97-0.78 (m, 1H), 0.53-0.41 (m, 2H), 0.20-0.08 (m, 2H) ppm . ¹³ C NMR (100 MHz, DMSO-d6) 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. UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.85 min; (M+H+) 483.

Example 239.

-(2-(4'-((Cyclopropylmethyl)sulfonyl)[1,1'-biphenyl]-4-yl)propan-2-yl)-3 -(3-ethylquinuclidin-3 yl)urea.

Using General Procedure H and reacting 2-(4'-((cyclopropylmethyl)sulfonyl)[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 238) and intermediate 2 gives the title compound as a white solid. 1H NMR (400 MHz, DMSO46) 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, 1H), 5.79 (s, 1H), 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, 1H), 0.76 (t, J=7.3 Hz, 3H), 0.51-0.42 (m, 2H), 0.18-0.10 (m, 2H) ppm. ¹³ C NMR (100 MHz, DMSO-d6) 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 UP-LCMS purity 100%, 98.8% (210 and 254 nm); retention time 0.87 min; (M+H+) 510.

Example 240.

-(2-(4'-((Cyclopropylmethyl)sulfonyl)[1,1'-biphenyl]-4-yl)propan-2-yl)-3 -(3-methylquinuclidin3-yl)urea.

Using General Procedure H and reacting 2-(4'-((cyclopropylmethyl)sulfonyl)[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 238) and intermediate 1 gives the title compound as a white solid. 1H NMR (400 MHz, DMSO-d ₆ ) 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 (s, 1H), 5.82 (s, 1H), 3.29 (d, J=7.1 Hz, 2H), 2.74-2.51 (m , 6H), 1.92-1.74 (m, 2H), 1.67-1.47 (m,

- 91 046304

7H), 1.44-1.20 (m, 5H), 0.93-0.82 (m, 1H), 0.51-0.42 (m, 2H), 0.18-0.10 ( m, 2H) ppm ¹³ C NMR (100 MHz, DMSO-d ₆ ) 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 UP-LCMS purity 100%, 98.7% (210 and 254 nm); retention time 0.84 min; (M+H+) 496.

Example 241.

-Azabicyclo[3.2.2]nonan-4-yl(2-(4'-((cyclopropylmethyl)sulfonyl)[1,1'-biphenyl]-4-yl)propan-2yl)carbamate.

Using General Procedure H and reacting 2-(4'-((cyclopropylmethyl)sulfonyl)[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 238) and intermediate 3 gives the title compound as a beige solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.00-7.87 (m, 4H), 7.70 (d, J=8.1 Hz, 2H), 7.53 (brs, 1H ), 7.46 (d, J=7.9 Hz, 2H), 4.65-4.56 (m, 1H), 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, 1H), 0.51-0.41 (m, 2H), 0 .17-0.10 (m, 2H) ppm ¹³ C NMR (100 MHz, DMSO-d6) δ 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 m .d. UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.86 min; (M+H+) 497.

Example 242.

Quinuclidin-3 -yl(2-(4'-((3-methoxypropyl)sulfonyl)[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate.

Using general procedure F and reacting ethyl 2-methyl-2-(4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate and 1-bromo-4 -((3-methoxypropyl)sulfonyl)benzene gives ethyl 2-(4'-((3-methoxypropyl)sulfonyl)[1,1'-biphenyl]-4-yl)-2-methylpropanoate as a yellow oil. Lithium hydroxide (0.302 g, 12.6 mmol). After stirring at 50°C overnight, the reaction mixture is cooled and concentrated. The residue is dissolved in water and washed with diethyl ether. The aqueous layer was treated with 1.0N hydrochloric acid (20 ml) and extracted with ethyl acetate. The combined extracts are dried (Na ₂ SO ₄ ) and concentrated to give 2-(4'-((3-methoxypropyl)sulfonyl)[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid as a white solid (1.12 g, 84%). The resulting compound and quinuclidin-3-ol are reacted according to General Procedure H to obtain the title compound as a white solid. 1H NMR (400 MHz, DMSO- _d6 ) δ 8.01-7.85 (m, 4H), 7.77 (m, 5H), 4.50-4.36 (m, 1H), 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 ¹³ C NMR (100 MHz, DMSO-d6) 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 m .d. UP-LCMS purity 99.9%, 99.9% (210 and 254 nm); retention time 0.81 min; (M+H+) 501.5.

Example 243.

-(3-Ethylquinuclidin-3-yl)-3-(2-(4'-((3-methoxypropyl)sulfonyl)[1,1'-biphenyl]-4-yl)propan-2yl)urea.

Using General Procedure H and reacting 2-methyl-2-(4'-((3-methoxypropyl)sulfonyl)[1,1'-biphenyl]-4-yl)propanoic acid (prepared as described in Example 242) and intermediate 2 give the title compound as a white solid. ¹ H NMR (400 MHz, DMSO-d6) 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, 1H), 5.81 (s, 1H), 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 ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 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 UP-LCMS purity 99.9%, 99.9% (210 and 254 nm); retention time 0.83 min; (M+H+) 528.6.

Example 244.

-(2-(4'-((3-Methoxypropyl)sulfonyl)[1,1'-biphenyl]-4-yl)propan-2-yl)-3 -(3-propylquinuclidin-3 yl)urea.

Using General Procedure H and reacting 2-methyl-2-(4'-((3methoxypropyl)sulfonyl)[1,1'-biphenyl]-4-yl)propanoic acid (prepared as described in Example 242) and intermediate 17 afford the title compound as a white solid. 1H NMR (400 MHz, DMSO46) 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, 1H), 6.33 (brs, 1H), 3.40-3.27 (m, 4H), 3.17 (s, 3H), 3, 10-2.66 (m, 6H), 2.03-1.90 (m, 2H), 1.90-1.36 (m, 13H), 1.32-1.13 (m, 2H), 0.87 (t, J=7.2 Hz, 3H) ppm ¹³ C NMR (100 MHz, DMSO-d6) 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 UP-LCMS purity 99.9%, 99.9% (210 and 254 nm); retention time 0.87 min; (M+H+) 542.6.

Example 245.

Quinuclidin-3 -yl(2-(4'-((3,3-dimethylbutyl)sulfonyl)[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate.

To a solution of 4-bromothiophenol (6.36 g, 33.6 mmol) in N.N-dimethylformamide (70 ml) was added sodium hydride (60% dispersion in mineral oil; 1.48 g, 37.0 mmol) with stirring. In 40 minutes

- 92 046304 1-chloro-3,3-dimethylbutane (5.6 ml, 40.3 mmol) was added and the mixture was continued to stir overnight. The reaction mixture is then concentrated and the residue is dissolved in ethyl acetate. The solution is washed with water, dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified by flash silica chromatography using a hexane/ethyl acetate gradient to give (4-bromophenyl)(3,3dimethylbutyl)sulfane as a colorless oil (8.71 g, 95%). To a solution of the resulting compound (8.69 g, 31.8 mmol) in methylene chloride (130 ml), 3-chloroperbenzoic acid (77%; 14.97 g, 66.80 mmol) was added portionwise over 20 minutes with stirring. The resulting suspension was stirred at room temperature overnight and then washed with aqueous 0.5N. sodium hydroxide solution. The organic layer was dried (Na ₂ SO ₄ ) and concentrated to give 1-bromo-4-((3,3-dimethylbutyl)sulfonyl)benzene as a white solid (9.82 g, 100%) which was used without purification. The resulting compound and ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate are reacted according to General Procedure F to obtain ethyl -2-(4'-((3,3-dimethylbutyl)sulfonyl)[1,1'-biphenyl]-4-yl)-2-methylpropanoate. To a solution of the resulting intermediate (2.17 g, 5.21 mmol) in tetrahydrofuran/ethanol/water, 1:1:1 (v/v/v; 36 ml), add lithium hydroxide monohydrate (1 .09 g, 26.0 mmol). After stirring at room temperature overnight, the reaction mixture is refluxed for 2.5 hours, cooled and concentrated. The residue is dissolved in water and washed with diethyl ether. The aqueous layer is treated with 1.0N. hydrochloric acid (30 ml) and extracted with ethyl acetate. The combined extracts are dried (Na ₂ SO ₄ ) and concentrated to give 2-(4'-((3,3-dimethylbutyl)sulfonyl)[1,1'-biphenyl]-4-yl)-2methylpropanoic acid as a white solid (1.94 g, 96%). The resulting compound and quinuclidin-3-ol are reacted according to General Procedure H to obtain the title compound as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.00 (m, 4H), 7.71 (d, J=8.3 Hz, 2H), 7.63-7.39 (m, 3H), 4.46-4.39 (m, 1H), 3.33-3.24 (m, 2H), 3.10-2.31 (m, 6H), 2.05-1.72 (m, 2H ), 1.671.24 (m, 11H), 0.84 (s, 9H) ppm. ¹³ C NMR (100 MHz, DMSO-d6) 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 m .d. UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 1.02 min; (M+H+) 513.

Example 246.

-(2-(4'-((3,3-Dimethylbutyl)sulfonyl)[1,1'-biphenyl]-4-yl)propan-2-yl)-3 -(3-methylquinuclidin-3 yl)urea.

Using general procedure H and reacting 2-(4'-((3,3-dimethylbutyl)sulfonyl)[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 245) and intermediate 1 give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 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, 1H), 5.81 (s, 1H), 3.32-3.24 (m, 2H), 2.72-2.52 (m, 6H), 1.91-1.74 (m, 2H), 1.43-1.44 (m, 9H), 1.431.22 (m, 5H), 0.84 (s, 9H) ppm. ¹³ C NMR (100 MHz, DMSO46) 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 UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 1.00 min; (M+H+) 526.

Example 247.

-(2-(4'-((3,3-Dimethylbutyl)sulfonyl)[1,1'-biphenyl]-4-yl)propan-2-yl)-3 -(3-ethylquinuclidin-3 yl)urea.

Using general procedure H and reacting 2-(4'-((3,3-dimethylbutyl)sulfonyl)[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 245) and intermediate 2 give the title compound as a white solid. 1H NMR (400 MHz, DMSO46) 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, 1H), 5.78 (s, 1H), 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 ¹³ C NMR (100 MHz, DMSO-d6) 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 UP-LCMS purity 100%, 98.6% (210 and 254 nm); retention time 1.03 min; (M+H+) 540.

Example 248.

-(2-(4'-((3,3-Dimethylbutyl)sulfonyl)[1,1'-biphenyl]-4-yl)propan-2-yl)-3 -(4-methyl-1 azabicyclo [3.2. 2] nonan-4-yl)urea.

Using general procedure H and reacting 2-(4'-((3,3-dimethylbutyl)sulfonyl)[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 245) and intermediate 5 give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d ₆ ) 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, 1H), 5.79 (s, 1H), 3.33-3.23 (m, 2H), 2.93-2.65 (m, 6H) , 2.12-2.05 (m, 1H), 1.85-1.35 (m, 13H), 1.34-1.19 (m, 4H), 0.85 (s, 9H) m. d. ¹³ C NMR (100 MHz, DMSO-d ₆ ) 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, 39.1, 36.2, 35.3, 30.4, 29.8, 29.7, 28.7 , 26.2, 24.3, 23.8 ppm UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 1.01 min; (M+H+) 540.

Example 249.

- 93 046304

Quinuclidin-3 -yl(2-(4'-((( 1 -(methoxymethyl)cyclopropyl)methyl)sulfonyl)[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate.

To a 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) with stirring and cooling (0°C) add methanesulfonyl chloride (2.7 ml, 34.7 mmol) dropwise. After 2 hours, the reaction solution was washed with an aqueous sodium bicarbonate solution. The organic layer is combined with the methylene chloride extracts of the aqueous layer, dried (Na ₂ SO ₄ ) and concentrated. Crude (1-(methoxymethyl)cyclopropyl)methylmethanesulfonate was obtained as an amber oil (6.15 g, 100%), which was used without purification. To a solution of 4-bromothiophenol (4.98 g, 26.3 mmol) in N,N-dimethylformamide (60 mL) was added sodium hydride (60% dispersion in mineral oil; 1.21 g, 31.6 mmol) with stirring. After 1 hour, a solution of the mesylate intermediate in N,N-dimethylformamide (20 ml) was added and the mixture was stirred for 3 hours at room temperature. The reaction mixture is then concentrated and the residue is dissolved in ethyl acetate, washed with water, dried (Na2SO4) and concentrated. The resulting pale amber oil was purified by flash silica chromatography using a hexane/ethyl acetate gradient to give (4-bromophenyl)(1-(methoxymethyl)cyclopropyl)methylsulfane as a colorless oil (6.98 g, 92%). To a solution of the resulting material (6.97 g, 24.3 mmol) in methylene chloride (100 ml), 3-chloroperbenzoic acid (77%; 11.42 g, 50.96 mmol) was added portionwise with stirring. The resulting suspension was stirred at room temperature overnight and then washed with 0.5 N aqueous sodium hydroxide solution. The organic layer was dried (Na ₂ SO ₄ ) and concentrated to give 1-bromo-4-(((1-methoxymethyl)cyclopropyl)methyl)sulfonyl)benzene as a white solid (9.82 g, 100%), which was used without cleaning. The resulting compound and ethyl 2-methyl-2-(4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate are reacted according to General Procedure F to obtain ethyl-2 -(4'-(((1-methoxymethyl)cyclopropyl)methyl)sulfonyl)[1,1'-biphenyl]-4-yl)2-methylpropanoate. To a solution of the resulting intermediate (3.54 g, 9.11 mmol) in tetrahydrofuran/ethanol/water, 1:1:1 (v/v/v; 60 ml), add lithium hydroxide monohydrate (1 .34 g, 31.9 mmol). After refluxing overnight, the reaction mixture is cooled and concentrated. The residue is dissolved in water and washed with diethyl ether. The aqueous layer was treated with 1.0N hydrochloric acid (40 ml) and extracted with ethyl acetate. The combined extracts are dried (Na ₂ SO ₄ ) and concentrated to give 2-(4'-(((1methoxymethyl)cyclopropyl)methyl)sulfonyl[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid as white solid (3.21 g, 88%). The resulting compound and quinuclidin-3-ol are reacted according to General Procedure H to obtain the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.02-7.85 (m, 4H), 7.71 (d, J=8.0 Hz, 2H), 7.657.38 (m, 3H), 4.50-4.36 (m, 1H), 3.40 (s, 2H), 3.18 (s, 2H), 3.13 (s, 3H), 3.13-2.24 (m, 6H), 2.09-1.20 (m, 11H), 0.53-0.37 (m, 4H) ppm. ¹³ C NMR (100 MHz, DMSO-d 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 UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.85 min; (M+H+) 527.

Example 250.

-(3-Ethylquinuclidin-3-yl)-3 -(2-(4'-((( 1 -methoxymethyl)cyclopropyl)methyl)sulfonyl) [1,1'-biphenyl]-4-yl)propan-2- silt)urea.

Using General Procedure H and reacting 2-(4'-(((1-methoxymethyl)cyclopropyl)methyl)sulfonyl[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 249) and intermediate 2 gave the title compound as a white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.98-7.90 (m, 4H), 7.68 (d, J=8.4 Hz, 2H), 7.48 (d, J=8 .4 Hz, 2H), 6.25 (s, 1H), 5.77 (s, 1H), 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. ¹³ C NMR (100 MHz, DMSO-d6) 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 UP-LCMS purity 97.6%, 100% (210 and 254 nm); retention time 0.86 min; (M+H+) 554.

Example 251.

-(2-(4'-((( 1 -Methoxymethyl)cyclopropyl)methyl)sulfonyl) [1,1'-biphenyl]-4-yl)propan-2-yl)-3 -(3 propylquinuclidin-3-yl )urea.

Using General Procedure H and reacting 2-(4'-(((1-methoxymethyl)cyclopropyl)methyl)sulfonyl[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 249) and intermediate 17 give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d 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, 1H), 5.76 (s, 1H), 3.39 (s, 2H), 3.17 (s, 2H), 3.13 (s, 3H ), 2.74-2.46 (m, 6H), 1.90-1.83 (m, 1H), 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), 0.520.38 (m, 4H) ppm. ¹³ C NMR (100 MHz, DMSO-d6) 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 UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.90 min; (M+H+) 568.

- 94 046304

Example 252.

Quinuclidin-3 -yl(2-(4'-(methylcarbamoyl)[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate.

To a solution of 4-bromobenzoic acid (6.00 g, 29.8 mmol) in methylene chloride (80 ml) add N(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (6.30 g, 32.9 mmol) with stirring. 4(dimethylamino)pyridine (7.70 g, 63.0 mmol) and methylamine hydrochloride (2.23 g, 33.0 mmol). The mixture is stirred overnight and then washed with 1.0N hydrochloric acid, dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by flash chromatography on silica using hexane/ethyl acetate to give 4-bromo-N-methylbenzamide as a white solid (5.80 g, 90%). To a solution of the resulting compound (4.00 g, 18.9 mmol) in 1,4-dioxane (10 ml), bis(pinacolato)diboron (11.9 g, 46.8 mmol), potassium acetate (5. 50 g, 56.1 mmol) and [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(P) (0.410 g, 0.560 mmol). The mixture is heated at 90°C overnight, filtered and concentrated. The residue was purified by flash chromatography on silica using hexane/ethyl acetate to give H-methyl-4-(4.4.5.5-tetramethyl-1.3.2dioxaborolan-2-yl)benzamide as a white solid (4.50 g, 91%). The resulting compound and ethyl 2-(4-bromophenyl)-2-methylpropanoate are reacted according to General Procedure F to produce ethyl 2-methyl-2-(4'-(methylcarbamoyl)[1,1'-biphenyl]-4 -yl)propanoate as an off-white solid. To a solution of the resulting intermediate (1.00 g, 3.07 mmol) in a mixture of tetrahydrofuran (8 ml) and water (3 ml) was added solid sodium hydroxide (0.640 g, 16.0 mmol) with stirring. After stirring at room temperature overnight, the reaction mixture is concentrated and the residue is dissolved in water. The solution is acidified (pH~6) with 1N hydrochloric acid and extracted with ethyl acetate. The combined extracts are washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give 2-methyl-2-(4'-(methylcarbamoyl)[1,1'-biphenyl]-4-yl)propanoic acid as a white solid ( 0.950 g, 100%). The resulting compound was used without purification and reacted with quinuclidin-3-ol according to General Procedure I to obtain the title compound as an off-white solid. 1H NMR (500 MHz, DMSO-d ₆ ) δ 8.47 (q.v., J=4.5 Hz, 1H), 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, 1H), 7.44 (d, J=6, 5 Hz, 2H), 4.43 (m, 1H), 3.76 (m, 1H), 2.81-2.63 (m, 7H), 2.47-2.36 (m, 1H), 1.85 (m, 2H), 1.56-1.34 (m, 9H) ppm ¹³ C NMR (125 MHz, CD3OD) δ 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. LCMS purity 100% (214 and 254 nm); retention time 1.72 min; (M+H+) 422.3.

Example 253.

NMethyl-(4'-(2-(3 -(3-methylquinuclidin-3-yl)ureido)propan-2-yl) [1,1'-biphenyl]-4-carboxamide.

Using General Procedure I and reacting 2-methyl-2-(4'-(methylcarbamoyl)[1,1'-biphenyl]-4-yl)propanoic acid (prepared as described in Example 252) and intermediate 1, the compound named in the title is obtained. 1H NMR (500 MHz, DMSO-d ₆ ) δ 8.47 (q.v., J=4.5 Hz, 1H), 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, 1H ), 5.79 (s, 1H), 2.80 (d, J=4.5 Hz, 3H), 2.67-2.52 (m, 6H), 1.88-1.78 (m, 2H), 1.61-1.25 (m, 12H) ppm. ¹³ C NMR (125 MHz, DMSO-d ₆ ) 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. LCMS purity >95% (214 and 254 nm); retention time 1.32 min; (M+H+) 435.3.

Example 254.

- Azabicyclo[3.2.2]nonan-4-yl(2-(4'-(methylcarbamoyl)[1,1'-biphenyl]-4-yl)propan-2-yl)carbamate.

Using General Procedure I and reacting 2-methyl-2-(4'(methylcarbamoyl)[1,1'-biphenyl]-4-yl)propanoic acid (prepared as described in Example 252) and intermediate 3 the compound named in the header is obtained. 1H NMR (500 MHz, CDCl ₃ ) δ 7.83-7.81 (d, J=8.5 Hz, 2H), 7.64-7.62 (d, J=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, 1H), 5.15 (s, 1H), 4.78-4.77 (m, 1H), 3.16-2.62 (m, 9H), 2.07-1.55 (m, 13H) ppm. ¹³ C NMR (125 MHz, CDC13) δ 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 . LCMS purity >97% (214 and 254 nm); retention time 1.70 min; (M+H+) 436.3.

Example 255.

No. Methyl-4'-(2-(3-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)ureido)propan-2-yl)biphenyl-4-carboxamide.

Using General Procedure I and reacting 2-methyl-2-(4'(methylcarbamoyl)[1,1'-biphenyl]-4-yl)propanoic acid (prepared as described in Example 252) and intermediate 5 the compound named in the header is obtained. ¹ H NMR (500 MHz, DMSOd6) δ 8.48-8.47 (sq., J=4.5 Hz, 1H), 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, J=8.5 Hz, 2H), 7.46-7.44 (d , J=9.0 Hz, 2H), 6.26 (s, 1H), 5.75 (s, 1H), 2.87-2.69 (m, 9H), 2.07 (m, 1H) , 1.79-1.25 (m, 15H) ppm ¹³ C NMR (125 MHz, CDCl3) δ 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 UP-LCMS purity 96.8%, 95.1% (214 nm and 254 nm); retention time 1.17 min; (M+H+) 449.3.

- 95 046304

Example 256.

H-(2-(4'-(Methylcarbamoyl)bi((enyl-4-yl)propan-2-yl)-1.4-diazabicyclo[3.2.2|nonane-4carboxamide.

Using General Procedure I and reacting 2-methyl-2-(4'-(methylcarbamoyl)[1,1'-biphenyl]-4-yl)propanoic acid (prepared as described in Example 252) and intermediate 6 the title compound is obtained. ^1H NMR (500 MHz, CDCl3) 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, J=8.5 Hz, 2H), 6.28-6.27 (sq., J=5 ,0 Hz, 1H), 4.78 (s, 1H), 4.02 (m, 1H), 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), 1.80-1.70 (m, 8H) ppm. ¹³ C NMR (125 MHz, CDCl3) 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. LCMS purity >99% (214 and 254 nm); retention time 1.13 min; (M+H+) 421.1.

Example 257.

Quinuclidin-3-yl-2-(4'-dimethylcarbamoyl)biphenyl-4-yl)propan-2-ylcarbamate.

Replacing methylamine hydrochloride with dimethylamine hydrochloride, the reaction sequence described in Example 252 is used to obtain 2-(4'-(dimethylcarbamoyl)[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid. The resulting intermediate and quinuclidin-3-ol are reacted according to General Procedure I to obtain the title compound. ¹ H NMR (500 MHz, DMSO-d6) δ 7.70 (d, J=7.0 Hz, 2H), 7.63 (d, J=8.0 Hz, 2H), 7.59 (s, 1H), 7.48 (d, J=8.0 Hz, 2H), 7.44 (d, J=7.0 Hz, 2H), 4.42 (m, 1H), 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 ¹³ C NMR (125 MHz, CDCl ₃ ) 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. LCMS purity >99% (214 and 254 nm); retention time 1.79 min; (M+H+) 436.3.

Example 258.

^NoDimethyl-4'-(2-(3-(3-methylquinuclidin-3-yl)ureido)propan-2-yl)biphenyl-4-carboxamide.

Using General Procedure I and reacting 2-(4'-(dimethylcarbamoyl)[1,1'bi(enyl|-4-yl)-2-methylpropanoic acid (prepared as described in Example 257) and intermediate 1 obtain the title compound. ¹ H NMR (500 MHz, CDCl3) δ 7.60-7.59 (m, 6H), 7.50-7.49 (d, J=8.5 Hz, 2H), 4.88 (brs, 1H), 4.33 (brs, 1H), 3.14 (s, 3H), 3.04 (s, 3H), 2.73-2.66 (m, 5H), 2.17 (m, 1H), 1.92-1.64 (m, 8H), 1.45-1.22 (m, 6H) ppm ¹³ C NMR (125 MHz, CDCl3) 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 by LCMS >98% (214 and 254 nm); retention time 1.38 min; (M+H+) 449.3.

Example 259.

1-Azabicyclo[3.2.2]nonan-4-yl-2-(4'-(dimethylcarbamoyl)biphenyl-4-yl)propan-2-ylcarbamate.

Using General Procedure I and reacting 2-(4'-(dimethylcarbamoyl)[1,1'bi(enyl|-4-yl)-2-methylpropanoic acid (prepared as described in Example 257) and intermediate 3 gives the title compound. ¹ H NMR (500 MHz, CDCl3) 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, 1H), 4.78-4.77 (m, 1H), 3.13-2.72 ( m, 12H), 2.28 (m, 1H), 2.05-1.18 (m, 12H) ppm ¹³ C NMR (125 MHz, CDCl3) 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 UP-LCMS purity 100% (214 and 254 nm time); retention 1.39 min; (M+H+) 450.3.

Example 260.

N(2-(4'-(Dimethylcarbamoyl)biphenyl-4-yl)propan-2-yl)-1,4-diazabicyclo[3.2.2]nonane-4-carboxamide.

Using General Procedure I and reacting 2-(4'-(dimethylcarbamoyl)[1,1'bi(enyl|-4-yl)-2-methylpropanoic acid (prepared as described in Example 257) and intermediate 6 gives the title compound. ¹ H NMR (500 MHz, CDCl3) 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, 1H), 4.04 (m, 1H), 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 ¹³ C NMR ( 125 MHz, CDCl3) δ 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 UP-LCMS purity 100% (214 and 254 nm time); retention 1.35 min; (M+H+) 435.4.

Example 261.

^NaDimethyl-4'-(2-(3-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)ureido)propan-2-yl)biphenyl-4-carboxamide.

Using General Procedure I and reacting 2-(4'-(dimethylcarbamoyl)[1,1'bi(enyl|-4-yl)-2-methylpropanoic acid (prepared as described in Example 257) and intermediate 5 gives the title compound. ¹ H NMR (400 MHz, CDCl3) δ 7.62-7.58 (m, 6H), 7.51-7.49 (d, J=8.4 Hz, 2H), 4.74 (s, 1H), 4.07 (s, 1H), 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, 1H), 1.84-1.50 (m, 10H), 1.47-1.15 (m, 5H) ppm ¹³ C NMR (100 MHz, CDCl3) δ 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 by LCMS >95% (214 and 254 nm); retention time 1.35 min (M+H+) 463.3.

- 96 046304

Example 262.

Quinuclidin-3-yl-2-(4'-(piperidin-1-carbonyl)biphenyl-4-yl)propan-2-yl-carbamate.

Replacing methylamine hydrochloride with piperidine, the reaction sequence described in Example 252 is used to obtain 2-methyl-2-(4'-(piperidin-1-carbonyl)[1,1'-biphenyl]-4-yl)propanoic acid. The resulting intermediate and quinuclidin-3-ol are reacted according to General Procedure I to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 7.52-7.51 (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, 1H), 4.55 (m, 1H), 3.65 (m, 2H), 3.33 (m, 2H), 3 .09-2.33 (m, 6H), 2.19-1.77 (m, 2H), 1.63-1.32 (m, 15H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) 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, 25.4, 24.6, 19 .5 ppm LCMS purity >99% (214 and 254 nm); retention time 1.11 min; (M+H+) 476.3.

Example 263.

1-Azabicyclo[3.2.2]nonan-4-yl-2-(4' -(piperidin-1-carbonyl)biphenyl-4-yl)propan-2-ylcarbamate.

Using General Procedure I and reacting 2-methyl-2-(4'-(piperidine-1carbonyl)[1,1'-biphenyl]-4-yl)propanoic acid (prepared as described in Example 262) and intermediate 3 gives the title compound. ¹ H NMR (500 MHz, CDCl3) δ 7.60-7.58 (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, 1H), 4.78 (m, 1H), 3.73 (m, 2H), 3.41 (m, 2H), 3 .10-2.49 (m, 7H), 2.05-1.36 (m, 18H) ppm. ¹³ C NMR (125 MHz, CDCl3) 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 LCMS purity >99% (214 and 254 nm); retention time 1.34 min; (M+H+) 490.2.

Example 264.

-(3-Ethylquinuclidin-3-yl)-3-(2-(4'-(piperidin-1-carbonyl)biphenyl-4-yl)propan-2-yl)urea.

Using General Procedure I and reacting 2-methyl-2-(4'-(piperidine-1carbonyl)[1,1'-biphenyl]-4-yl)propanoic acid (prepared as described in Example 262) and intermediate 2 gives the title compound. ¹ H NMR (500 MHz, CDCl3) δ 7.50-7.45 (m, 6H), 7.38-7.37 (d, J=7.5 Hz, 2H), 5.12 (s, 1H ), 4.26 (s, 1H), 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 ¹³ C NMR (125 MHz, CDCl ₃ ) 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 m. d. LCMS purity >99% (214 and 254 nm); retention time 1.13 min; (M+H+) 503.4.

Example 265.

Quinuclidin-3-yl-2-(4'-(morpholine-4-carbonyl)biphenyl-4-yl)propan-2-ylcarbamate.

Replacing methylamine hydrochloride with morpholine, use the reaction sequence described in example 252 to obtain 2-methyl-2-(4'-(morpholine-4-carbonyl)[1,1'-biphenyl]-4-yl)propanoic acid. The resulting intermediate and quinuclidin-3-ol are reacted according to General Procedure I to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 7.62-7.60 (d, J=7.5 Hz, 2H), 7.56-7.54 (d, J=8.5 Hz, 2H), 7.50-7.46 (m, 4H), 5.29 (s, 1H), 4.63 (m, 1H), 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. ¹³ C NMR (125 MHz, CDCl ₃ ) δ 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. LCMS purity >99% (214 and 254 nm); retention time 1.21 min; (M+H+) 478.3.

Example 266.

1-Azabicyclo[3.2.2]nonan-4-yl-2-(4'-(morpholine-4-carbonyl)biphenyl-4-yl)propan-2-ylcarbamate.

Using General Procedure I and reacting 2-methyl-2-(4'-(morpholine-4carbonyl)[1,1'-biphenyl]-4-yl)propanoic acid (prepared as described in Example 265) and intermediate 3 gives the title compound. ¹ H NMR (500 MHz, CDCl3) δ 7.62-7.61 (d, J=8.0 Hz, 2H), 7.55-7.54 (d, J=8.0 Hz, 2H), 7.49-7.47 (m, 4H), 5.20 (s, 1H), 4.78-4.77 (m, 1H), 3.76-3.54 (m, 8H), 3. 09-2.72 (m, 6H), 2.27-1.53 (m, 13H) ppm. ¹³ C NMR (125 MHz, CDCl3) 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 LCMS purity >99% (214 and 254 nm); retention time 1.22 min; (M+H+) 492.3.

Example 267.

1-(3-Methylquinuclidin-3-yl)-3-(2-(4'-(morpholine-4-carbonyl)biphenyl-4-yl)propan-2-yl)urea.

Using General Procedure I and reacting 2-methyl-2-(4'-(morpholine-4carbonyl)[1,1'-biphenyl]-4-yl)propanoic acid (prepared as described in Example 265) and intermediate 1 gives the title compound. ¹ H NMR (500 MHz, CDCl3) δ 7.61-7.53 (m, 6H), 7.48-7.47 (d, J=7.5 Hz, 2H), 5.14 (s, 1H ), 4.42 (s, 1H), 3.77-3.53 (m, 8H), 2.73-2.43 (m, 6H), 1.86 (m, 1H), 1.64- 1.63 (m, 7H), 1.38-1.18 (m, 6H) ppm ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity 100% (214 and 254 nm); retention time 1.32 min; (M+H+) 491.3.

Example 268.

1-(4-Methyl-1-azabicyclo[3.2.2]nonan-4-yl)-3 -(2-(4'-(morpholine-4-carbonyl)biphenyl-4-yl)propan-2yl)urea.

- 97 046304

Using General Procedure I and reacting 2-methyl-2-(4'-(morpholine-4carbonyl)[1,1'-biphenyl]-4-yl)propanoic acid (prepared as described in Example 265) and intermediate 5 gives the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 7.64-7.60 (m, 6H), 7.49-7.48 (d, J=8.5 Hz, 2H), 4.76 (s, 1H ), 4.07 (s, 1H), 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 ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity >99% (214 and 254 nm); retention time 1.34 min; (M+H+) 505.2.

Example 269.

N(2-(4'-(Morpholine-4-carbonyl)biphenyl-4-yl)propan-2-yl)-1,4-diazabicyclo[3.2.2]nonane-4-carboxamide.

Using General Procedure I and reacting 2-methyl-2-(4'-(morpholine-4carbonyl)[1,1'-biphenyl]-4-yl)propanoic acid (prepared as described in Example 265) and intermediate 5 gives the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 7.62-7.61 (d, J=8.0 Hz, 2H), 7.55-7.54 (d, J=8.5 Hz, 2H), 7.48-7.46 (m, 4H), 4.77 (s, 1H), 4.04 (m, 1H), 3.743.48 (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. ¹³ C NMR (125 MHz, CDCl ₃ ) 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. LCMS purity >96% (214 and 254 nm); retention time 1.34 min; (M+H+) 477.3.

Example 270.

Quinuclidin-3-yl-2-(4'-(4,4-difluoropiperidin-1-carbonyl)biphenyl-4-yl)propan-2-yl-carbamate.

Replacing methylamine hydrochloride with 4,4-difluoropiperidine, use the reaction sequence described in example 252 to obtain 2-(4'-(4,4-difluoropiperidin-1-carbonyl)[1,1'-biphenyl]-4-yl) 2-methylpropanoic acid. The resulting intermediate and quinuclidin-3-ol are reacted according to General Procedure I to obtain the title compound. ¹ H NMR (500 MHz, CDCl3) δ 7.63-7.61 (d, J=8.5 Hz, 2H), 7.57-7.55 (d, J=8.5 Hz, 2H), 7.51-7.47 (m, 4H), 5.21 (s, 1H), 4.63 (m, 1H), 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. ¹³ C NMR (125 MHz, CDCl3) 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 LCMS purity >99% (214 and 254 nm); retention time 1.47 min; (M+H+) 512.2.

Example 271.

1-Azabicyclo[3.2.2]nonan-4-yl-2-(4'-(4,4-difluoropiperidin-1-carbonyl)biphenyl-4-yl)propan-2ylcarbamate.

Using General Procedure I and reacting 2-(4'-(4,4-difluoropiperidin-1carbonyl)[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 270) and intermediate 3 give the title compound. ^1H NMR (500 MHz, CDCl3) δ 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, 1H), 4.79-4.77 (m, 1H), 3.84-3.66 (m, 4H), 3. 09-2.72 (m, 6H), 2.41-2.32 (m, 1H), 2.17-1.54 (m, 16H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) δ 170, 154.2, 146.9, 142.7, 138.3, 133.8, 127.5, 127.2, 127.1, 125.4, 121 .5 (t, J=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 LCMS purity >97% (214 and 254 nm); retention time 1.14 min; (M+H+) 526.3.

Example 272.

-(2-(4'-(4,4-Difluoropiperidin-1-carbonyl)biphenyl-4-yl)propan-2-yl)-3 -(3-ethylquinuclidin-3 yl)urea.

Using General Procedure I and reacting 2-(4'-(4,4-difluoropiperidin-1carbonyl)[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 270) and intermediate 2 give the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 7.62-7.57 (m, 6H), 7.49 (d, J=8.0 Hz, 2H), 5.06 (s, 1H), 4, 15 (s, 1H), 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 ¹³ C NMR (125 MHz, CDCl ₃ ) δ 170.5, 156.6, 146.3, 142.4, 139.1, 134.1, 127.6, 127.5, 127.2, 126.1 , 121.5 (t, J=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 LCMS purity >99% (214 and 254 nm); retention time 1.13 min; (M+H+) 539.3.

Example 273.

Quinuclidin-3-yl-2-(4'-(3,3-difluoroazetidin-1-carbonyl)biphenyl-4-yl)propan-2-yl)carbamate.

Replacing methylamine hydrochloride with 3,3-difluoroazetidine, use the reaction sequence described in example 252 to obtain 2-(4'-(3,3-difluoroazetidin-1-carbonyl)[1,1'-biphenyl]-4-yl) -2methylpropanoic acid. The resulting intermediate and quinuclidin-3-ol are reacted according to General Procedure I to obtain the title compound. ¹ H NMR (500 MHz, CDCl3) δ 7.72-7.71 (d, J=8.0 Hz, 2H), 7.66-7.64 (d, J=8.0 Hz, 2H), 7.59-7.51 (m, 4H), 5.21 (s, 1H), 4.644.56 (m, 5H), 3.19-2.27 (m, 6H), 2.12-1, 99 (m, 3H), 1.86-1.41 (m, 8H) ppm ¹³ C NMR (125 MHz, CDCl3) δ 170.6 (t, J=3.0 Hz), 154.5, 147.9, 147.2, 144.2, 138.1, 130.6, 128, 5, 127.2, 125.5, 115.4 (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 LCMS purity >98% (214 and 254 nm); retention time 1.29 min; (M+H+) 484.2.

- 98 046304

Example 274.

-Azabicyclo[3.2.2]nonan-4-yl-2-(4'-(3,3-difluoroazetidin-1-carbonyl)biphenyl-4-yl)propan-2-ylcarbamate.

Using General Procedure I and reacting 2-(4'-(3,3-difluoroazetidin-1carbonyl)[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 273) and intermediate 3 give the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 7.73-7.71 (d, J=8.5 Hz, 2H), 7.66-7.65 (d, J=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, 1H), 4 ,82-4.78 (m, 1H), 4.59 (t, J=12.0 Hz, 4H), 3.13-2.76 (m, 6H), 2.08-1.55 (m , 13H) ppm ¹³ C NMR (125 MHz, CDCl ₃ ) δ 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 m. d. LCMS purity >99% (214 and 254 nm); retention time 1.46 min; (M+H+) 498.3.

Example 275.

-(2-(4'-(3,3-Difluoroazetidin-1-carbonyl)biphenyl-4-yl)propan-2-yl)-3 -(3-ethylquinuclidin-3 yl)urea.

Using General Procedure I and reacting 2-(4'-(3,3-difluoroazetidin-1carbonyl)[1,1'-biphenyl]-4-yl)-2-methylpropanoic acid (prepared as described in Example 273) and intermediate 2 give the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 7.73-7.61 (m, 8H), 4.89 (s, 1H), 4.58 (t, J=12.0 Hz, 4H), 4, 04 (s, 1H), 2.71-2.18 (m, 6H), 1.97-1.20 (m, 13H), 0.66 (t, J=7.5 Hz, 3H) m. d. ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity >99% (214 and 254 nm); retention time 1.46 min; (M+H+) 511.3.

Example 276.

1-(4-Methyl-1-azabicyclo[3.2.2]nonan-4-yl)-3-(2-(3-(3-(morpholine-4-carbonyl)phenoxy)phenyl)propan-2-yl) urea.

To a solution of 3-hydroxybenzoic acid (8.28 g, 59.9 mmol) in MH-dimethylformamide (150 ml), add H-(3-dimethylaminopropyl)-H'-ethylcarbodiimide 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 is stirred overnight and then diluted with water and extracted with ethyl acetate. The combined extracts are washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by flash silica chromatography using hexane/ethyl acetate to give (3-hydroxyphenyl)(morpholino)methanone as a white solid (5.80 g, 47%). Ethyl 2-(3-bromophenyl)-2-methylpropanoate (8.00 g, 31.1 mmol) was added to a solution of the resulting compound (5.00 g, 24.1 mmol) in N,Ndimethylformamide (100 ml) with stirring. , cesium carbonate (15.7 g, 48.2 mmol), copper(1) iodide (1.40 g, 7.35 mmol) and 2-(dimethylamino)acetic acid hydrochloride (2.10 g, 14.5 mmol ). The mixture is heated at 120°C overnight. After cooling, the reaction mixture is diluted with water and extracted with ethyl acetate. The combined extracts are washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The crude material is purified by flash chromatography on silica using hexane/ethyl acetate to give ethyl 2-methyl-2-(3-(3-(morpholine-4-carbonyl)phenoxy)phenyl)propanoate as a viscous colorless oil (4. 40 g, 46%). To a solution of the resulting intermediate (4.40 g, 11.5 mmol) in methanol/water, 1:1 (v/v; 40 ml), add solid sodium hydroxide (2.30 g, 57.5 mmol) with stirring. mmol). After stirring for 6 hours, the reaction mixture is concentrated and the residue is dissolved in water. The solution is acidified (pH~6) with 1N hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give 2-methyl-2-(3-(3(morpholine-4-carbonyl)phenoxy)phenyl)propanoic acid as a white solid (3.60 g , 85%). The resulting compound was used without purification and reacted with intermediate 5 according to General Procedure I to obtain the title compound as an off-white solid. 1H NMR (500 MHz, CDCl ₃ ) δ 7.39-7.34 (m, 2H), 7.29-7.23 (m, 2H), 7.13-7.12 (d, J=7, 5 Hz, 1H), 7.06-7.022 (m, 2H), 6.92-6.90 (m, 1H), 4.78 (s, 1H), 4.17 (s, 1H), 3, 76-3.47 (m, 8H), 2.94-2.44 (m, 6H), 2.18 (m, 1H), 1.71-1.48 (m, 10H), 1.36- 1.21 (m, 5H) ppm ¹³ C NMR (125 MHz, CDCl ₃ ) δ 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 LCMS purity >97% (214 and 254 nm); retention time 1.78 min; (M+H+) 521.3.

Example 277.

1-(3-Methylquinuclidin-3-yl)-3-(2-(3-(3-(morpholine-4-carbonyl)phenoxy)phenyl)propan-2-yl)urea.

Using General Procedure I and reacting 2-methyl-2-(3-(3-(morpholine-4carbonyl)phenoxy)phenyl)propanoic acid (prepared as described in Example 276) and intermediate 1 afforded the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 7.39-7.34 (m, 2H), 7.28-7.27 (m, 2H), 7.13-7.12 (d, J=7, 5 Hz, 1H), 7.06-7.02 (m, 2H), 6.92-6.91 (m, 1H), 4.73 (s, 1H), 4.14 (s, 1H), 3.77-3.46 (m, 8H), 2.75-2.49 (m, 6H), 1.95-1.60 (m, 8H), 1.42-1.26 (m, 6H ) m.d. ¹³ C NMR (125 MHz,

- 99 046304

CDCl ₃ ) 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 LCMS purity >99% (214 and 254 nm); retention time 1.76 min; (M+H+) 507.3.

Example 278.

1-Azabicyclo[3.2.2]nonan-4-yl-2-(3-(3-(morpholine-4-carbonyl)phenoxy)phenyl)propan-2-ylcarbamate.

Using General Procedure I and reacting 2-methyl-2-(3-(3-(morpholine-4carbonyl)phenoxy)phenyl)propanoic acid (prepared as described in Example 276) and intermediate 3 afforded the title compound. ^1H NMR (500 MHz, CDCl3) δ 7.35-7.28 (m, 2H), 7.19-7.04 (m, 5H), 6.87-6.87 (m, 1H), 5 .10 (s, 1H), 4.77 (m, 1H), 3.76-3.45 (m, 8H), 3.09-2.46 (m, 6H), 2.18-1.31 (m, 13H) ppm ¹³ C NMR (125 MHz, CDCl3) δ 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. LCMS purity >99% (214 and 254 nm); retention time 1.40 min; (M+H+) 508.3.

Example 279.

Quinuclidin-3-yl-2-(3-(3-(morpholine-4-carbonyl)phenoxy)phenyl)propan-2-yl)carbamate.

Using general procedure I and reacting 2-methyl-2-(3-(3-(morpholine-4carbonyl)phenoxy)phenyl)propanoic acid (prepared as described in Example 276) and quinuclidin-3-ol, the title in the connection header. 1H NMR (500 MHz, CDCl ₃ ) δ 7.37-7.28 (m, 2H), 7.20-7.03 (m, 5H), 6.86-6.85 (d, J=8, 0 Hz, 1H), 5.19 (s, 1H), 4.61 (m, 1H), 3.75-3.16 (m, 8H), 2.83-2.37 (m, 6H), 1.95-1.12 (m, 11H) ppm ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity >97% (214 and 254 nm); retention time 1.39 min; (M+H+) 494.2.

Example 280.

1-(3-Methylquinuclidin-3-yl)-3-(2-(4-(4-(morpholine-4-carbonyl)phenoxy)phenyl)propan-2-yl)urea.

Replacing ethyl 2-(3-bromophenyl)-2-methylpropanoate with ethyl 2-(4-bromophenyl)-2-methylpropanoate and 3-hydroxybenzoic acid with 4-hydroxybenzoic acid, using the reaction sequence described in example 276 to obtain 2-methyl -2-(4-(4-(morpholine-4-carbonyl)phenoxy)phenyl)propanoic acid.

The resulting intermediate and quinuclidin-3-ol are reacted according to General Procedure I to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 7.51-7.49 (d, J=9.0 Hz, 2H), 7.42-7.40 (d, J=9.0 Hz, 2H), 7.05-7.00 (m, 4H), 4.82 (s, 1H), 4.21 (s, 1H), 3.72-3.48 (m, 8H), 2.78-2, 51 (m, 6H), 1.86-1.89 (m, 1H), 1.72-1.65 (m, 1H), 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, 1H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) 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. LCMS purity >100% (214 and 254 nm); retention time 1.73 min; (M+H+) 507.3.

Example 281.

1-(4-Methyl-1-azabicyclo[3.2.2]nonan-4-yl)-3-(2-(4-(4-(morpholine-4-carbonyl)phenoxy)phenyl)propan-2-yl) urea.

Using General Procedure I and reacting 2-methyl-2-(4-(4-(morpholine-4carbonyl)phenoxy)phenyl)propanoic acid (prepared as described in Example 280) and intermediate 5 afforded the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 7.52-7.51 (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, 1H), 4.29 (s, 1H), 3.72-3.57 (m, 8H), 2.97-2, 56 (m, 6H), 2.23 (m, 1H), 1.75-1.55 (m, 10H), 1.42-1.24 (m, 5H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) 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 m.d. LCMS purity >98% (214 and 254 nm); retention time 1.72 min; (M+H+) 521.3.

Example 282.

1-Azabicyclo[3.2.2]nonan-4-yl-2-(4-(4-(morpholine-4-carbonyl)phenoxy)phenyl)propan-2ylcarbamate.

Using General Procedure I and reacting 2-methyl-2-(4-(4-(morpholine-4carbonyl)phenoxy)phenyl)propanoic acid (prepared as described in Example 280) and intermediate 3 afforded the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 7.42-7.38 (m, 4H), 7.03-6.98 (m, 4H), 5.15 (s, 1H), 4.83 (m , 1H), 3.72-3.49 (m, 8H), 3.12-2.97 (m, 6H), 2.24-1.68 (m, 13H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) δ 170.3, 158.8, 154.9, 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. LCMS purity >98% (214 and 254 nm); retention time 1.72 min; (M+H+) 508.3.

Example 283.

Quinuclidin-3-yl-2-(4-(4-(dimethylcarbamoyl)phenoxy)phenyl)propan-2-ylcarbamate.

Replacing ethyl 2-(3-bromophenyl)-2-methylpropanoate with ethyl 2-(4-bromophenyl)-2-methylpropanoate, 3-hydroxybenzoic acid with 4-hydroxybenzoic acid, and morpholine with dimethyl hydrochloride

- 100 046304 use the sequence of reactions described in example 276 and obtain 2-(4-(4-(dimethylcarbamoyl)phenoxy)phenyl)-2-methylpropanoic acid. The resulting intermediate and quinuclidin-3-ol are reacted according to General Procedure I to obtain the title compound. ^1H NMR (500 MHz, CDCl3) δ 7.42-7.37 (m, 4H), 6.99-6.96 (m, 4H), 5.24 (s, 1H), 4.65-4 .62 (m, 1H), 3.17-3.02 (m, 7H), 2.88-2.61 (m, 5H), 1.99-1.39 (m, 11H) ppm. ¹³ C NMR (125 MHz, CDCl3) 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. LCMS purity >97% (214 and 254 nm); retention time 1.89 min; (M+H+) 452.3.

Example 284.

^NoDimethyl-4-(4-(2-(3-(3-methylquinuclidin-3-yl)ureido)propan-2-yl)phenoxy)benzamide.

Using General Procedure I and reacting 2-(4-(4-(dimethylcarbamoyl)phenoxy)phenyl)-2-methylpropanoic acid (prepared as described in Example 283) and Intermediate 1 afforded the title compound. 1H NMR (500 MHz, CDCl ₃ ) 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, 1H), 4.48 (s, 1H), 3.11-3.04 (m, 6H), 2.78-2.62 (m, 6H), 1 .72 (m, 1H), 1.72-1.68 (m, 1H), 1.62-1.60 (m, 6H), 1.49-1.46 (m, 2H), 1.38 (s, 3H), 1.32-1.25 (m, 1H) ppm ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity >98% (214 and 254 nm); retention time 1.22 min; (M+H+) 465.2.

Example 285.

^NaDimethyl-4-(4-(2-(3-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)ureido)propan-2-yl)phenoxy)benzamide.

Using General Procedure I and reacting 2-(4-(4-(dimethylcarbamoyl)phenoxy)phenyl)-2-methylpropanoic acid (prepared as described in Example 283) and intermediate 5 afforded the title compound. ¹ H NMR (500 MHz, CDCl3) 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, 1H), 4.79 (s, 1H), 3.07-2.68 (m, 12H), 2.21 (m, 1H), 1.68-1.28 (m, 15H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity >96% (214 and 254 nm); retention time 1.23 min; (M+H+) 479.3.

Example 286.

1-Azabicyclo[3.2.2]nonan-4-yl)-2-(4-(4-(dimethylcarbamoyl)phenoxy)phenyl)propan-2-ylcarbamate.

Using General Procedure I and reacting 2-(4-(4-(dimethylcarbamoyl)phenoxy)phenyl)-2-methylpropanoic acid (prepared as described in Example 283) and intermediate 3 afforded the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 7.437.38 (m, 4H), 7.02-6.98 (m, 4H), 5.08 (s, 1H), 4.82-4.78 (m , 1H), 3.11-2.75 (m, 12H), 2.09-1.55 (m, 13H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) 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 m. d. LCMS purity >98% (214 and 254 nm); retention time 1.73 min; (M+H+) 466.3.

Example 287.

Quinuclidin-3-yl-2-(4-(4-(dimethylcarbamoyl)phenoxy)phenyl)propan-2-ylcarbamate.

Replacing morpholine with dimethylamine hydrochloride, use the reaction sequence described in example 276 to obtain 2-(3-(3-(dimethylcarbamoyl)phenoxy)phenyl)-2-methylpropanoic acid. The resulting intermediate and quinuclidin-3-ol are reacted according to General Procedure I to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 7.34 (t, J=8.0 Hz, 1H), 7.21 (t, J=8.0 Hz, 1H), 7.18-7.17 ( d, J=8.5 Hz, 1H), 7.13-7.10 (m, 2H), 7.04-7.00 (m, 2H), b.86 (m, 1H), 5.20 (s, 1H), 4.62 (m, 1H), 3.16-2.33 (m, 12H), 1.96-1.36 (m, 11H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) δ 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 LCMS purity >99% (214 and 254 nm); retention time 1.82 min; (M+H+) 452.3.

Example 288.

1-Azabicyclo[3.2.2]nonan-4-yl-2-(3-(3-(dimethylcarbamoyl)phenoxy)phenyl)propan-2-ylcarbamate.

Using General Procedure I and reacting 2-(3-(3-(dimethylcarbamoyl)phenoxy)phenyl)-2-methylpropanoic acid (prepared as described in Example 287) and intermediate 3 afforded the title compound. ^1H NMR (500 MHz, CDCl3) δ 7.34-7.28 (m, 2H), 7.18-7.10 (m, 3H), 7.04-7.02 (m, 2H), 6 .87-6.85 (m, 1H), 5.11 (s, 1H), 4.78-4.75 (m, 1H), 3.09-2.63 (m, 12H), 2.03 -1.18 (m, 13H) ppm ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity >99% (214 and 254 nm); retention time 1.39 min; (M+H+) 466.3.

Example 289.

^NoDimethyl-3 -(3 -(2-(3 -(3 -methylquinuclidin-3 -yl)ureido)propan-2-yl)phenoxy)benzamide.

Using general procedure I and introducing 2-(3-(3-(dimethylcarbamo)

- 101 046304 yl)phenoxy)phenyl)-2-methylpropanoic acid (prepared as described in Example 287) and intermediate 1 give the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 7.387.33 (m, 2H), 7.28-7.21 (m, 2H), 7.15-7.13 (d, J=7.5 Hz, 1H ), 7.04-7.03 (m, 2H), 6.93-6.91 (m, 1H), 4.82 (br.s, 1H), 4.30 (br.s, 1H), 3.10 (s, 3H), 2.99 (s, 3H), 2.72-2.47 (m, 6H), 1.83-1.60 (m, 8H), 1.46-1, 23 (m, 6H) ppm ¹³ C NMR (125 MHz, CDCl ₃ ) δ 170.8, 157.2, 157.0, 156.8, 149.5, 138.0, 130.2, 130.0, 121.6, 120.6 , 119.6, 117.6, 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 LCMS purity >97% (214 and 254 nm); retention time 1.83 min; (M+H+) 465.4.

Example 290.

^NaDimethyl-4-(4-(2-(3-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)ureido)propan-2-yl)phenoxy)benzamide.

Using General Procedure I and reacting 2-(3-(3-(dimethylcarbamoyl)phenoxy)phenyl)-2-methylpropanoic acid (prepared as described in Example 283) and intermediate 5 afforded the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 7.37-7.31 (m, 2H), 7.28-7.25 (m, 1H), 7.21 (t, J=2.0 Hz, 1H ), 7.14-7.12 (d, J=7.5 Hz, 1H), 7.04-7.01 (m, 2H), 6.91-6.89 (m, 1H), 4, 91 (s, 1H), 4.32 (s, 1H), 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, 1H), 1.69-1.21 (m, 15H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) δ 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 LCMS purity >99% (214 and 254 nm); retention time 1.77 min; (M+H+) 479.4.

Example 291.

Quinuclidin-3-yl-2-(4-(4-(methylcarbamoyl)phenoxy)phenyl)propan-2-ylcarbamate.

Replacing ethyl 2-(3-bromophenyl)-2-methylpropanoate with ethyl 2-(4-bromophenyl)-2-methylpropanoate, 3-hydroxybenzoic acid with 4-hydroxybenzoic acid, and morpholine with methylamine hydrochloride, use the reaction sequence described in Example 276 and 2-methyl-2-(4-(4-(methylcarbamoyl)phenoxy)phenyl)propanoic acid is obtained. The resulting intermediate and quinuclidin3-ol are reacted according to General Procedure I to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) 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, 1H), 5.13 (s, 1H), 4.67-4.64 (m, 1H), 3.19-2.70 (m, 9H), 1 .97-1.38 (m, 11H) ppm ¹³ C NMR (125 MHz, CDCl ₃ ) 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. LCMS purity >99% (214 and 254 nm); retention time 1.75 min; (M+H+) 438.3.

Example 292.

1-Azabicyclo[3.2.2]nonan-4-yl-2-(4-(4-(methylcarbamoyl)phenoxy)phenyl)propan-2-ylcarbamate.

Using General Procedure I and reacting 2-methyl-2-(4-(4(methylcarbamoyl)phenoxy)phenyl)-2-methylpropanoic acid (prepared as described in Example 291) and intermediate 3 afforded the title compound. 1H NMR (500 MHz, CDCl ₃ ) 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 (br.s, 1H), 5.09 (s, 1H), 4.81-4.77 (m, 1H), 3.11- 2.73 (m, 9H), 2.10-1.521 (m, 13H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) 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. LCMS purity >99% (214 and 254 nm); retention time 1.19 min; (M+H+) 452.2.

Example 293.

No. Methyl-4-(4-(2-(3 -(3-methylquinuclidin-3-yl)ureido)propan-2-yl)phenoxy)benzamide.

Using General Procedure I and reacting 2-methyl-2-(4-(4(dimethylcarbamoyl)phenoxy)phenyl)propanoic acid (prepared as described in Example 291) and intermediate 1, the title compound was obtained. 1H NMR (500 MHz, CDCl ₃ ) δ 7.77-7.75 (d, J=8.5 Hz, 2H), 7.53-7.51 (d, J=8.5 Hz, 2H), 7.06-7.00 (m, 4H), 6.15 (br.s, 1H), 4.73 (b.s, 1H), 4.12 (br.s, 1H), 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 ¹³ C NMR (125 MHz, CDCl ₃ ) 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 m. d. LCMS purity >99% (214 and 254 nm); retention time 1.18 min; (M+H+) 451.2.

Example 294.

No. Methyl-4-(4-(2-(3-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)ureido)propan-2-yl)phenoxy)benzamide.

Using General Procedure I and reacting 2-methyl-2-(4-(4-(dimethylcarbamoyl)phenoxy)phenyl)propanoic acid (prepared as described in Example 291) and intermediate 5 afforded the title compound. 1H NMR (500 MHz, CDCl ₃ ) 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, 1H), 4 .67 (s, 1H), 4.03 (s, 1H), 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, 1H), 1.75-1.51 (m, 10H), 1.42-1.19 (m, 5H) ppm . ¹³ C NMR (125 MHz, CDCl ₃ ) δ 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 LCMS purity >96% (214 and 254 nm); retention time 1.19 min; (M+H+) 465.2.

Example 295.

(Quinuclidin-3-yl)-2-(3-(3-(methylcarbamoyl)phenoxy)phenyl)propan-2-ylcarbamate.

- 102 046304

Replacing morpholine with methylamine hydrochloride, use the reaction sequence described in example 276 to obtain 2-methyl-2-(3-(3-(methylcarbamoyl)phenoxy)phenyl)propanoic acid. The resulting intermediate and quinuclidin-3-ol are reacted according to General Procedure I to obtain the title compound. 1H NMR (500 MHz, DMSO-d ₆ ) δ 8.47 (s, 1H), 7.60-7.59 (d, J=7.5 Hz, 1H), 7.52 (s, 1H), 7.47-7.44 (m, 2H), 7.33 (t, J=7.5 Hz, 1H), 7.15-7.09 (m, 2H), 6.98-6.83 ( m, 2H), 4.40 (m, 1H), 2.98-2.37 (m, 9H), 1.76-1.24 (m, 11H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity >99% (214 and 254 nm); retention time 1.20 min; (M+H+) 438.3.

Example 296.

N-Methyl-3 -(3 -(2-(3 -(3 -methylquinuclidin-3 -yl)ureido)propan-2-yl)phenoxy)benzamide.

Using General Procedure I and reacting 2-methyl-2-(3-(3-(methylcarbamoyl)phenoxy)phenyl)propanoic acid (prepared as described in Example 295) and intermediate 1, the title compound was obtained. 1H NMR (500 MHz, CDCl ₃ ) δ 7.60-7.59 (d, J=8.0 Hz, 1H), 7.42 (t, J=8.0 Hz, 1H), 7.36 ( t, J=8.0 Hz, 1H), 7.26-7.13 (m, 5H), 6.90-6.88 (d, J=7.5 Hz, 1H), 4.78 (lat .s, 1H), 4.23 (br.s, 1H), 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, 1H) ppm ¹³ C NMR (125 MHz, CDCl ₃ ) δ 167.8, 157.2, 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 LCMS purity >99% (214 and 254 nm); retention time 1.79 min; (M+H+) 451.3.

Example 297.

No.Methyl-3-(3-(2-(3-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)ureido)propan-2-yl)phenoxy)benzamide.

Using General Procedure I and reacting 2-methyl-2-(3-(3(methylcarbamoyl)phenoxy)phenyl)propanoic acid (prepared as described in Example 295) and intermediate 5, the title compound was obtained. ¹ H NMR (500 MHz, CDCl3) δ 7.69-7.67 (m, 2H), 7.44 (t, J=8.0 Hz, 1H), 7.37-7.33 (m, 2H ), 7.24-7.21 (m, 3H), 6.90-6.88 (dd, J=8.0 and 2.0 Hz, 1H), 4.82 (s, 1H), 4, 31 (s, 1H), 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 ¹³ C NMR (125 MHz, CDCl ₃ ) 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. LCMS purity >98% (214 and 254 nm); retention time 1.74 min; (M+H+) 465.4.

Example 298.

1-Azabicyclo[3.2.2]nonan-4-yl)-2-(3-(3-(methylcarbamoyl)phenoxy)phenyl)propan-2-ylcarbamate.

Using General Procedure I and reacting 2-methyl-2-(3-(3(methylcarbamoyl)phenoxy)phenyl)propanoic acid (prepared as described in Example 295) and intermediate 3 afforded the title compound. ^1H NMR (500 MHz, CDCl3) δ 7.55-7.54 (m, 1H), 7.41-7.35 (m, 2H), 7.19-6.78 (m, 6H), 5 .10 (s, 1H), 4.65 (m, 1H), 3.04-2.70 (m, 9H), 1.96-1.43 (m, 13H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) δ 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 LCMS purity >97% (214 and 254 nm); retention time 1.77 min; (M+H+) 452.3.

Example 299.

1-Azabicyclo[3.2.2]nonan-4-yl)-2-(4-(4-(piperidin-1-carbonyl)phenoxy)phenyl)propan-2-ylcarbamate.

Replacing ethyl 2-(3-bromophenyl)-2-methylpropanoate with ethyl 2-(4-bromophenyl)-2-methylpropanoate, 3-hydroxybenzoic acid with 4-hydroxybenzoic acid, and morpholine with piperidine, use the reaction sequence described in Example 276 and 2-methyl-2-(4-(4-(piperidine-1carbonyl)phenoxy)phenyl)propanoic acid is obtained. The resulting intermediate and Intermediate 3 are reacted according to General Procedure I to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 7.39-7.37 (m, 4H), 7.00-6.97 (m, 4H), 5.11 (s, 1H), 4.80-4 .76 (m, 1H), 3.70-3.41 (m, 4H), 3.09-2.72 (m, 6H), 2.16 (m, 1H), 2.04-1.55 (m, 18H) ppm ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity >96% (214 and 254 nm); retention time 1.49 min; (M+H+) 506.3.

Example 300.

1-(4-Methyl-1-azabicyclo[3.2.2]nonan-4-yl)-3 -(2-(4-(4-(piperidin-1-carbonyl)phenoxy)phenyl)propan-2-yl) urea.

Using General Procedure I and reacting 2-methyl-2-(4-(4-(piperidine-1carbonyl)phenoxy)phenyl)propanoic acid (prepared as described in Example 299) and intermediate 5 afforded the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 7.48-7.47 (d, J=8.5 Hz, 2H), 7.39-7.37 (d, J=8.0 Hz, 2H) 7 .02-6.99 (m, 4H), 4.94 (s, 1H), 4.29 (s, 1H), 3.69-3.39 (m, 4H), 2.93-2.43 (m, 6H), 2.17 (m, 1H), 1.70-1.35 (m, 21H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) 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,

- 103 046304

26.2, 26.0, 24.5, 24.3, 23.8 ppm LCMS purity >97% (214 and 254 nm); retention time 1.34 min; (M+H+) 519.3.

Example 301.

1-Azabicyclo[3.2.2]nonan-4-yl)-2-(4-(4-(4,4-difluoropiperidin-1-carbonyl)phenoxy)phenyl)propan2-ylcarbamate.

Replacing ethyl 2-(3-bromophenyl)-2-methylpropanoate with ethyl 2-(4-bromophenyl)-2-methylpropanoate, 3-hydroxybenzoic acid with 4-hydroxybenzoic acid, and morpholine with 4,4-difluoropiperidine, use the reaction sequence described in Example 276 to obtain 2-(4-(4-(4,4difluoropiperidin-1-carbonyl)phenoxy)phenyl)-2-methylpropanoic acid. The resulting compound and intermediate 3 are reacted according to General Procedure I to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 7.40-7.38 (m, 4H), 7.02-6.91 (m, 4H), 5.19 (s, 1H), 4.80-4 .78 (m, 1H), 3.84-3.73 (m, 4H), 3.22-2.75 (m, 6H), 2.17-1.47 (m, 17H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity >98% (214 and 254 nm); retention time 1.92 min; (M+H+) 542.4.

Example 302.

1-(2-(4-(4-(4,4-Difluoropiperidin-1-carbonyl)phenoxy)phenyl)propan-2-yl)-3-(4-methyl-1-azabicyclo[3.2.2] nonan- 4-yl)urea.

Using general procedure I and reacting 2-(4-(4-(4,4-difluoropiperidine1-carbonyl)phenoxy)phenyl)-2-methylpropanoic acid (prepared as described in Example 301) and intermediate 5, the connection named in the header. 1H NMR (500 MHz, CDCl ₃ ) 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, 1H), 4.44 (s, 1H), 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. ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity >99% (214 and 254 nm); retention time 1.84 min; (M+H+) 555.4.

Example 303.

-(2-(4-(4-(3,3-Difluoroazetidin-1-carbonyl)phenoxy)phenyl)propan-2-yl)-3 -(4-methyl-1-azabicyclo[3.2.2]nonane-4 -yl)urea.

Replacing ethyl 2-(3-bromophenyl)-2-methylpropanoate with ethyl 2-(4-bromophenyl)-2-methylpropanoate, 3-hydroxybenzoic acid with 4-hydroxybenzoic acid, and morpholine with 3,3-difluoroazetidine hydrochloride, use the reaction sequence described in example 276 and obtain 2-(4(4-(3,3-difluoroazetidin-1-carbonyl)phenoxy)phenyl)-2-methylpropanoic acid. The resulting compound and intermediate 5 are reacted according to General Procedure I to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 7.66-7.63 (m, 2H), 7.55-7.53 (d, J=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, 1H), 1.79-1, 61 (m, 11H), 1.44-1.27 (m, 6H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) δ 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 m. d. LCMS purity >98% (214 and 254 nm); retention time 1.30 min; (M+H+) 527.3.

Example 304.

Quinuclidin-3-yl-2-(4-(4-phenylpiperazin-1-carbonyl)phenyl)propan-2-ylcarbamate.

To a solution of 2-(4-bromophenyl)propan-2-amine (1.00 g, 4.67 mmol) in methylene chloride (10 ml) add di-tert-butyl dicarbonate (6.10 g, 27.9 mmol) with stirring. and triethylamine (1.3 ml, 9.3 mmol). The mixture is stirred overnight and then concentrated. The residue was purified by flash chromatography on silica using a hexane/ethyl acetate gradient to give tert-butyl (2-(4-bromophenyl)propan-2-yl)carbamate as a light yellow solid (1.25 g, 85%). A 1.6 M solution of n-butyllithium in hexane (5.4 ml, 8.6 mmol). After stirring at -78°C for 1 hour, carbon dioxide gas was bubbled slowly through the reaction mixture for 1.5 hours. The mixture was then heated to -10°C, quenched by adding water and treated with ethyl acetate and water. The aqueous phase is acidified by adding 1N. hydrochloric acid and extracted with ethyl acetate. the combined extracts were dried (Na ₂ SO ₄ ) and concentrated to give 4-(2-((tert-butoxycarbonyl)amino)propan-2-yl)benzoic acid as a white solid (1.20 g, 75%). To a solution of the resulting intermediate (1.20 g, 4.30 mmol) in tetrahydrofuran (20 ml) was added carbonyldiimidazole (1.05 g, 6.44 mmol) and, 1 hour later, 1-phenylpiperazine (1.05 g, 6.44 mmol). The reaction mixture is stirred for a further 2 hours, then diluted with ethyl acetate and washed, in that order, with aqueous citric acid, water and aqueous sodium carbonate. The organic layer is dried (Na ₂ SO ₄ ) and concentrated. The crude material is purified by flash silica chromatography using a hexane/ethyl acetate gradient to give tert-butyl (2-(4-(4-phenylpiperazine-1-carbonyl)phenyl)propan-2-yl)carbamate as a white solid. (1.23 g, 68%). To a solution of the resulting compound (1.20 g, 2.84 mmol) in methylene chloride

- 104 046304 (8 ml) add trifluoroacetic acid (5 ml) while stirring. After 5 hours, the reaction mixture is concentrated and treated with 4N. aqueous sodium hydroxide and ethyl acetate. The organic layer is combined with the other ethyl acetate extracts, washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give (4-(2-aminopropan-2-yl)phenyl)(4-phenylpiperazin-1-yl)methanone as a white solid substances (0.850 g, 93%). To a suspension of the resulting intermediate (0.200 g, 0.618 mmol) in water (3 ml) and concentrated hydrochloric acid (0.3 ml) was added toluene (3 ml) with stirring. The mixture is cooled (0°C) and treated simultaneously for 1 hour with a solution of triphosgene (0.275 g, 0.928 mmol) in toluene (3 ml) and saturated aqueous sodium bicarbonate (5 ml). After addition is complete, the reaction mixture is stirred for an additional 30 minutes and then the upper toluene layer is removed and dried (Na ₂ SO ₄ ). At the same time, a solution of quinuclidin-3-ol (0.200 g, 0.573 mmol) in tetrahydrofuran (2 ml) was treated with sodium hydride (60% dispersion in mineral oil; 0.046 g, 1.15 mmol) with stirring. The resulting mixture was stirred for 1 hour and then added to a solution of crude isocyanate in toluene. The reaction mixture was stirred overnight, the reaction was quenched by adding aqueous ammonium chloride (10 ml) and the mixture was extracted with chloroform/isopropanol, 4:1 (v/v). The combined extracts are dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash reverse phase chromatography on silica to give the title compound as a white solid (0.110 g, 37%). ^1H 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, 1H), 4.65-4.63 (m, 1H), 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 ¹³ C NMR (125 MHz, CDCl3) 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. LCMS purity >99% (214 and 254 nm); retention time 1.25 min; (M+H+) 477.2.

Example 305.

N(2-(4-(4-(Methylcarbamoyl)phenoxy)phenyl)propan-2-yl)-1,4-diazabicyclo[3.2.2]nonane-4-carboxamide.

Replacing quinuclidin-3-ol with intermediate 3, the reaction sequence described in Example 304 was used to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) 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, 1H), 4.80-4.77 (m, 1H), 3. 94-3.65 (m, 4H), 3.25-2.76 (m, 10H), 2.07-1.55 (m, 13H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity >98% (214 and 254 nm); retention time 1.25 min; (M+H+) 491.2.

Example 306.

-(3-Ethylquinuclidin-3-yl)-3-(2-(4-(4-phenylpiperazine-1-carbonyl)phenyl)propan-2-yl)urea.

Replacing quinuclidin-3-ol with intermediate 2, the reaction sequence described in Example 304 was used to obtain the title compound. 1H NMR (500 MHz, CDCl ₃ ) δ 7.52-7.50 (d, J=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, 1H), 4.54 (brs, 1H), 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. ¹³ C NMR (125 MHz, CDCl ₃ ) 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 m. d. LCMS purity >99% (214 and 254 nm); retention time 1.16 min; (M+H+) 504.3.

Example 307.

Quinuclidin-3-yl-2-(4-(6-(2-methoxyethoxy)pyridin-3-yl)phenyl)propan-2-ylcarbamate.

To a solution of 5-bromopyridin-2-ol (3.00 g, 17.2 mmol) in N-dimethylformamide (30 ml) add 1-chloro-2-methoxyethane (2.45 g, 26.0 mmol) with stirring and potassium carbonate (4.80 g, 34.7 mmol). The reaction mixture is heated at night at 90°C for 8 hours, cooled to room temperature and diluted with water. The mixture is extracted with ethyl acetate and the combined extracts are dried (Na2SO4) and concentrated. The residue was purified by flash silica chromatography using a hexane/ethyl acetate gradient to give 5-bromo-2-(2-methoxyethoxy)pyridine as a light yellow solid (1.70 g, 43%). The resulting compound and ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenyl)propanoate are reacted according to General Procedure F to obtain ethyl-2 -(4-(6-(2-methoxyethoxy)pyridin-3-yl)phenyl)-2-methylpropanoate. To a solution of the resulting intermediate (0.800 g, 2.43 mmol) in water/methanol 1:1 (v/v; 10 ml) was added solid sodium hydroxide (0.300 g, 7.50 mmol) with stirring. After heating at 88°C for 2 hours, the reaction mixture is concentrated and dissolved in water. The solution is acidified (pH~6) with 1N hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4) and concentrated to give 2-(4-(6-(2-methoxyethoxy)pyridin-3-yl)phenyl)-2-methylpropanoic acid as a yellow solid (0.600 g, 78% ). The resulting compound was used without purification and reacted with quinuclidin-3-ol according to General Procedure I to obtain the title compound as a yellow solid. 1H NMR (500 MHz, CDCl ₃ ) δ 7.63-7.61 (dd, J=9.0 Hz and 2.0 Hz, 1H), 7.57-7.57 (d, J=2.5 Hz, 1H), 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, 1H), 5.20 (s, 1H), 4.64-4.63 (m, 1H), 4.19 (t, J=5.0 Hz, 1H), 3.71 (t, J=5.0 Hz, 1H), 3.34 (s, 1H),

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3.17-2.62 (m, 6H), 2.18-1.40 (m, NN) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) 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 LCMS purity >96% (214 and 254 nm); retention time 1.66 min; (M+H+) 440.3.

Example 308.

Quinuclidin-3-yl-2-(4-(5-(2-methoxyethoxy)pyridin-2-yl)phenyl)propan-2-ylcarbamate.

To a solution of 6-chloropyridin-3-ol (3.00 g, 23.0 mmol) in NN-dimethylformamide (30 ml) add 1-chloro-2-methoxyethane (3.30 g, 34.5 mmol) with stirring. potassium carbonate (6.40 g, 46.0 mmol) and potassium iodide (0.200 g, 1.20 mmol). The reaction mixture is heated overnight at 100°C, cooled to room temperature and diluted with water. The mixture is extracted with ethyl acetate and the combined extracts are washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash silica chromatography using a hexane/ethyl acetate gradient to give 2-chloro-5-(2methoxyethoxy)pyridine as a yellow oil (3.80 g, 88%). The resulting compound (0.570 g, 3.00 mmol), ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate ( 1.10 g, 3.60 mmol), potassium carbonate (1.20 g, 8.68 mmol), [1,G-bis(diphenylphosphino)ferrocene]dichloropalladium(P) (0.110 g, 0.150 mmol) and mixture 1 ,4-dioxane/water, 5:1 (v/v; 3 ml) was charged into a microwave reactor. The reaction mixture is stirred and heated (130°C) under microwave irradiation for 2 hours. After cooling, the reaction mixture is diluted with water and extracted with ethyl acetate. The combined extracts are washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography on silica using hexane/ethyl acetate to give ethyl 2-(4-(5-(2methoxyethoxy)pyridin-2-yl)phenyl)-2-methylpropanoate as a yellow solid (0.520 g , 52%). To a solution of the resulting 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) with stirring. After stirring overnight, the reaction mixture is concentrated and dissolved in water. The solution is acidified (pH~6) with 1N hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4) and concentrated to give 2-(4-(5-(2-methoxyethoxy)pyridin-2-yl)phenyl)-2-methylpropanoic acid as a white solid (0.500 g, 100% ). The resulting compound was used without purification and reacted with quinuclidin-3-ol according to General Procedure I to obtain the title compound as a yellow solid. 1H NMR (500 MHz, CDC13) δ 8.33-8.32 (d, J=2.5 Hz, 1H), 7.82-7.80 (d, J=8.5 Hz, 2H), 7 .57-7.55 (d, J=9.0 Hz, 1H), 7.41-7.40 (d, J=8.0 Hz, 2H), 7.22-7.20 (m, 1H ), 5.24 (s, 1H), 4.55 (m, 1H), 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. ¹³ C NMR (125 MHz, CDCl ₃ ) 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, 19.5 m. d. LCMS purity >96% (214 and 254 nm); retention time 1.09 min; (M+H+) 440.2.

Example 309.

Quinuclidin-3-yl-2-(3-(5-(2-methoxyethoxy)pyridin-2-yl)phenyl)propan-2-ylcarbamate.

Replacing ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate with ethyl 2-methyl-2-(3-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate, use the reaction sequence described in Example 304 to obtain 2-(3-(5-(2-methoxyethoxy)pyridinium- 2yl)phenyl)-2-methylpropanoic acid. The resulting compound is reacted with quinuclidin-3-ol according to General Procedure I to obtain the title compound. ¹ H NMR (500 MHz, CDCl3) δ 8.41-8.41 (d, J=3.0 Hz, 1H), 8.01 (s, 1H), 7.75-7.74 (d, J =11.5 Hz, 1H), 7.65-7.63 (d, J=9.0 Hz, 1H), 7.43-7.39 (m, 2H), 7.31-7.29 ( dd, J=9.0 Hz and 3.0 Hz, 1H), 5.20 (s, 1H), 4.62 (s, 1H), 4.21 (t, J=4.5 Hz, 2H) , 3.79 (t, J=4.5 Hz, 2H), 3.48 (s, 3H), 3.17-2.45 (m, 6H), 2.03-0.99 (m, 11H ) m.d. ¹³ C NMR (125 MHz, CDCl3) δ 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 LCMS purity >99% (214 and 254 nm); retention time 1.89 min; (M+H+) 440.3.

Example 310.

1-Azabicyclo[3.2.2]nonan-4-yl-2-(4-(5-(2-methoxyethoxy)pyridin-2-yl)phenyl)propan-2-ylcarbamate.

Using general procedure I and reacting 2-(4-(5-(2-methoxyethoxy)pyridin-2-yl)phenyl)-2-methylpropanoic acid (prepared as described in Example 308) and intermediate 3, the connection named in the header. 1H NMR (500 MHz, CDCl ₃ ) δ 8.40-8.40 (d, J=2.8 Hz, 1H), 7.89-7.87 (d, J=8.4 Hz, 2H), 7.64-7.62 (d, J=8.8 Hz, 1H), 7.48-7.46 (d, J=8.0 Hz, 2H), 7.30-7.27 (m, 1H), 5.20 (s, 1H), 4.79-4.76 (m, 1H), 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, 1H), 2.03-1.52 (m, 12H) m.d. ¹³ C NMR (125 MHz, CDCl ₃ ) 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, 30.6, 29.4, 24.8, 22.2 m. d. LCMS purity >99% (214 and 254 nm); retention time 1.10 min; (M+H+) 454.2.

Example 311.

1-Azabicyclo[3.2.2]nonan-4-yl-2-(3-(5-(2-methoxyethoxy)pyridin-2-yl)phenyl)propan-2-ylcarbamate.

Using general procedure I and reacting 2-(3-(5-(2-methoxyethoxy)pyridin-2-yl)phenyl)-2-methylpropanoic acid (prepared as described in Example 309) and intermediate 3, the connection named in the header. ¹ H NMR (500 MHz, CDCl3) δ

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8.41-8.41 (d, J=3.0 Hz, 1H), 8.00 (s, 1H), 7.75-7.74 (m, 1H), 7.65-7.63 ( d, J=8.5 Hz, 1H), 7.41-7.40 (m, 2H), 7.31-7.29 (m, 1H), 5.16 (s, 1H), 4.77 (m, 1H), 4.22 (t, J=4.5 Hz, 2H), 3.80 (t, J=4.5 Hz, 2H), 3.48 (s, 3H), 3.102.62 (m, 6H), 2.16-1.53 (m, 13H) ppm. ¹³ C NMR (125 MHz, CDCl ₃ ) δ 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, 48.1, 45.1, 33.5, 30.4, 29.4, 24.6, 22.0 ppm LCMS purity >96% (214 and 254 nm); retention time 0.94 min; (M+H+) 454.3.

Example 312.

Quinuclidin-3 -yl(2-(3 -(6-(3-methoxypropoxy)pyridazin-3-yl)phenyl)propan-2-yl)carbamate.

To a solution of 3-methoxy-1-propanol (5.00 mL, 52 mmol) in NN-dimethylformamide (300 mL) was added sodium hydride (60% dispersion in mineral oil; 3.14 g, 78.4 mmol) with stirring. After 2 hours, 3,6-dichloropyridazine (7.79 g, 52.3 mmol) was added. The reaction mixture is stirred at room temperature overnight, concentrated and treated with chloroform and water. The organic layer is washed with aqueous sodium bicarbonate, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash silica chromatography using a hexane/ethyl acetate gradient to give 3-chloro-6-(3-methoxypropoxy)pyridazine as a pale yellow oil (8.05 g, 76%). A suspension of the resulting compound (1.77 g, 5.88 mmol), ethyl 2-methyl-2-(3-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)phenyl)propanoate (1.77 g, 5.58 mmol) and potassium carbonate (4.90 g, 35.5 mmol) in a mixture of N,N-dimethylformamide/water, 4:1 (v/v; 75 ml) are deoxygenated, bubbling nitrogen through the mixture for several minutes. Bis(triphenylphosphine)palladium(II) dichloride (0.089 g, 0.127 mmol) was added and the reaction mixture was heated at 100°C for 6 hours. The reaction mixture was then concentrated and treated with water and ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate and brine, dried (Na2SO4) and concentrated. The crude material was purified by silica flash chromatography using a hexane/ethyl acetate gradient to give ethyl 2-(3-(6-(3-methoxypropoxy)pyridazin-3-yl)phenyl)-2-methylpropanoate as a colorless oil (1. 58 g, 87%). To a solution of the resulting compound (1.58 g, 4.41 mmol) in a mixture of tetrahydrofuran/ethanol/water, 1:1:1 (v/v/v; 30 ml), add lithium hydroxide monohydrate (0.925 g) with stirring , 22.0 mmol). After refluxing overnight, the reaction mixture is cooled and concentrated. The residue is dissolved in water and washed with diethyl ether. The aqueous layer was treated with 1.0N hydrochloric acid (22 ml) and extracted with ethyl acetate. The combined extracts were dried (Na ₂ SO ₄ ) and concentrated to give 2-(3-(6-(3-methoxypropoxy)pyridazin-3-yl)phenyl)-2methylpropanoic acid as a colorless solid (1.41 g, 97% ). The resulting compound is reacted with quinuclidin-3-ol according to General Procedure H to obtain the title compound as a tan solid. 1H NMR (400 MHz, DMSO- _d6 ) δ 8.20-7.99 (m, 2H), 7.91-7.76 (m, 1H), 7.67-7.34 (m, 3H) , 7.30 (d, J=9.2 Hz, 1H), 4.53 (t, J=6.4 Hz, 2H), 4.474.34 (m, 1H), 3.51 (t, J= 6.2 Hz, 2H), 3.27 (s, 3H), 3.11-2.15 (m, 6H), 2.13-1.10 (m, 13H) ppm. ¹³ C NMR (100 MHz, DMSO-d6) 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 UP-LCMS purity 97.8%, 98.7% (210 and 254 nm); retention time 0.76 min; (M+H+) 455.3.

Example 313.

1-Azabicyclo[3.2.2]nonan-4-yl(2-(3-(6-(3-methoxypropoxy)pyridazin-3-yl)phenyl)propan-2yl)carbamate.

Using general procedure H and reacting 2-(3-(6-(3-methoxypropoxy)pyridazin-3-yl)phenyl)-2-methylpropanoic acid (prepared as described in Example 312) and intermediate 3, the connection named in the header. 1H NMR (400 MHz, DMSOd6) δ 8.10 (d, J=9.3 Hz, 1H), 8.06 (brs, 1H), 7.98-7.74 (m, 1H), 7 .53 (br.s, 1H), 7.46-7.35 (m, 2H), 7.30 (d, J=9.3 Hz, 1H), 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. ¹³ C NMR (100 MHz, DMSO-d6) δ 163.9, 154.8, 154.3, 149.0, 135.6, 128.5, 127.7, 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 UP-LCMS purity >99.9%, 99.5% (210 and 254 nm); retention time 0.76 min; (M+H+) 469.4.

Example 314.

H-(2-(3-(6-(3-Methoxypropoxy)pyridazin-3-yl)phenyl)propan-2-yl)-1,4-diazabicyclo[3.2.2]nonane4-carboxamide.

Using general procedure H and reacting 2-(3-(6-(3-methoxypropoxy)pyridazin-3-yl)phenyl)-2-methylpropanoic acid (prepared as described in Example 312) and intermediate 6, the connection named in the header. 1H NMR (400 MHz, DMSOd ₆ ) δ 8.09 (d, J=9.3 Hz, 1H), 8.07-8.03 (m, 1H), 7.82-7.71 (m, 1H ), 7.48-7.34 (m, 2H), 7.29 (d, J=9.3 Hz, 1H), 6.21 (brs, 1H), 4.53 (t, J= 6.5 Hz, 2H), 4.22-4.14 (m, 1H), 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) m. d. ¹³ C NMR (100 MHz, DMSO-d6) 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 m .d. UP-LCMS purity >99.9%, 99.1% (210 and 254 nm); retention time 0.70 min; (M+H+) 454.4.

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Example 315.

Quinuclidin-3-yl(2-(3-(5-(3-methoxypropoxy)pyrazin-2-yl)phenyl)propan-2-yl)carbamate.

To a solution of 3-methoxy-1-propanol (3.2 ml, 34 mmol) in N,N-dimethylformamide (200 ml) add sodium hydride (60% dispersion in mineral oil; 2.02 g, 50.6 mmol) with stirring ). After 30 minutes, 2,5-dichloropyrazine (5.03 g, 33.7 mmol) was added. The reaction mixture is stirred at room temperature overnight, concentrated and treated with ethyl acetate and water. The organic layer was washed with aqueous sodium bicarbonate and brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash silica chromatography using a hexane/ethyl acetate gradient to give 2-chloro-5-(3-methoxypropoxy)pyrazine as a colorless oil (4.47 g, 65%). A suspension of the resulting compound (1.00 g, 4.94 mmol), ethyl 2-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenyl)propanoate (1.73 g, 5.43 mmol) and potassium carbonate (4.78 g, 34.6 mmol) in KH-dimethylformamide/water. 4:1 (v/v; 75 ml) deoxygenate by bubbling nitrogen through the mixture for several minutes. Bis(triphenylphosphine)palladium(II) dichloride (0.087 g, 0.124 mmol) was added and the reaction mixture was heated at 100°C for 6 hours. The reaction mixture was then concentrated and treated with ethyl acetate and water. The organic layer was washed with aqueous sodium bicarbonate and brine, dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by flash silica chromatography using a hexane/ethyl acetate gradient to give ethyl 2-(3-(5-(3methoxypropoxy)pyrazin-2-yl)phenyl)-2-methylpropanoate as a colorless oil (1. 37 g, 77%). To a solution of the resulting compound (1.37 g, 3.81 mmol) in a mixture of tetrahydrofuran/ethanol/water, 1:1:1 (v/v/v; 25 ml), add lithium hydroxide monohydrate (0.800 g) with stirring , 19.1 mmol). After refluxing overnight, the reaction mixture is cooled and concentrated. The residue is dissolved in water and washed with diethyl ether. The aqueous layer was treated with 1.0N hydrochloric acid (19 ml) and extracted with ethyl acetate. The combined extracts were dried (Na ₂ SO ₄ ) and concentrated to give 2-(3-(5-(3-methoxypropoxy)pyrazin-2-yl)phenyl)-2-methylpropanoic acid as a colorless solid (1.20 g, 95%). The resulting compound and quinuclidin-3-ol are reacted according to General Procedure H to obtain the title compound as a pale amber solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.74 (d, J=1.3 Hz, 1H), 8.36 (brs, 1H), 8.03 (brs, 1H), 7.86-7.77 (m, 1H), 7.57 (br.s, 1H), 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., J=6.4 Hz, 2H), 1.95-1.19 (m, 10H) ppm. ¹³ C NMR (100 MHz, DMSO-d6) δ 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 UP-LCMS purity >99.9%, 98.7% (210 and 254 nm); retention time 0.84 min; (M+H+) 455.4.

Example 316.

1-Azabicyclo[3.2.2]nonan-4-yl(2-(3-(5-(3-methoxypropoxy)pyrazin-2-yl)phenyl)propan-2-yl)carbamate.

Using general procedure H and reacting 2-(3-(5-(3-methoxypropoxy)pyrazin-2-yl)phenyl)-2-methylpropanoic acid (prepared as described in Example 315) and intermediate 3, the connection named in the header. ¹ H NMR (400 MHz, DMSOd6) δ 8.73 (d, J=1.3 Hz, 1H), 8.40-8.33 (m, 1H), 8.00 (brs, 1H), 7.85-7.76 (m, 1H), 7.52 (br.s, 1H), 7.467.33 (m, 2H), 4.64-4.53 (s, 1H), 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. ¹³ C NMR (100 MHz, DMSO-d6) δ 158.8, 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 UP-LCMS purity >99.9%, >99.9% (210 and 254 nm); retention time 0.85 min; (M+H+) 469.4.

Example 317.

H-(2-(3-(5-(3-Methoxypropoxy)pyrazin-2-yl)phenyl)propan-2-yl)-1,4-diazabicyclo[3.2.2]nonane-4carboxamide.

Using General Procedure H and reacting 2-(3-(5-(3methoxypropoxy)pyrazin-2-yl)phenyl)-2-methylpropanoic acid (prepared as described in Example 315) and intermediate 6, the title connection header. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.72 (d, J=1.4 Hz, 1H), 8.35 (d, J=1.4 Hz, 1H), 7.98 (s, 1H), 7.80-7.74 (m, 1H), 7.37 (d, J=4.8 Hz, 2H), 6.19 (brs, 1H), 4.39 (t, J =6.5 Hz, 2H), 4.18 (s, 1H), 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) m. d. ¹³ C NMR (100 MHz, DMSO-d ₆ ) 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 m.d. UP-LCMS purity 95.4%, 97.7% (210 and 254 nm); retention time 0.78 min; (M+H+) 454.4.

Example 318.

Quinuclidin-3 -yl(2-(3 -(6-ethoxypyridazin-3 -yl)phenyl)propan-2-yl)carbamate.

Replacing 3-methoxy-1-propanol with ethanol, the reaction sequence described in Example 312 was used to obtain the title compound. 1H NMR (400 MHz, DMSO- _d6 ) δ 8.17-8.02 (m, 2H), 7.87-7.80 (m, 1H), 7.65-7.34 (m, 3H) , 7.28 (d, J=9.3 Hz, 1H), 4.54 (sq., J=7.0 Hz, 2H), 4.45-4.33 (m, 1H),

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3.12-2.18 (m, 6H), 2.05-1.10 (m, 14H) ppm. ¹³ C NMR (100 MHz, DMSO-d ₆ ) 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 m.d. UP-LCMS purity >99.9%, 99.5% (210 and 254 nm); retention time 0.78 min; (M+H+) 411.3.

Example 319.

1-Azabicyclo[3.2.2]nonan-4-yl(2-(3-(6-ethoxypyridazin-3-yl)phenyl)propan-2-yl)carbamate.

Replacing 3-methoxy-1-propanol with ethanol and quinuclidin-3-ol with intermediate 3, the reaction sequence described in Example 312 was used to obtain the title compound. ¹ H NMR (400 MHz, DMSO-d6) δ 8.10 (d, J=9.3 Hz, 1H), 8.07 (brs, 1H), 7.86-7.79 (m, 1H ), 7.607.37 (m, 3H), 7.28 (d, J=9.3 Hz, 1H), 4.64-4.55 (m, 1H), 4.54 (sq., J=7 .0 Hz, 2H), 3.01-2.34 (m, 6H), 1.98-1.21 (m, 3H) ppm. ¹³ C NMR (100 MHz, DMSO46) 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 UP-LCMS purity >99.9%, 99.4% (210 and 254 nm); retention time 0.79 min; (M+H+) 425.3.

Example 320.

Quinuclidin-3-yl(2-(4-(5-(3-methoxypropoxy)pyrazin-2-yl)phenyl)propan-2-yl)carbamate

Replacing ethyl 2-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate with ethyl 2-methyl-2-(4-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate, use the reaction sequence described in Example 315 to obtain the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.74 (d, J=1.2 Hz, 1H), 8.35 (d, J=1.3 Hz, 1H), 7.93 (d, J=7.9 Hz, 2H), 7.56 (br.s, 1H), 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, 11H) ppm. ¹³ C NMR (100 MHz, DMSO-d ₆ ) 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 m.d. UP-LCMS purity >99.9%, >99.9% (210 and 254 nm); retention time 0.86 min; (M+H+) 455.4.

Example 321.

1-Azabicyclo[3.2.2]nonan-4-yl(2-(4-(5-(3-methoxypropoxy)pyrazin-2-yl)phenyl)propan-2-yl)carbamate.

Replacing ethyl 2-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate with ethyl 2-methyl-2-(4-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate and quinuclidin-3-ol on intermediate 3, using the reaction sequence described in Example 315 to obtain the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.74 (d, J=1.2 Hz, 1H), 8.35 (d, J=1.3 Hz, 1H), 7.92 (d, J=8.4 Hz, 2H), 7.51 (br.s, 1H), 7.43 (d, J=8.2 Hz, 2H), 4.65-4.55 (m, 1H), 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. ¹³ C NMR (100 MHz, DMSO-d ₆ ) 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 UP-LCMS purity 98.8%, >99.9% (210 and 254 nm); retention time 0.87 min; (M+H+) 469.4.

Example 322.

H-(2-(4-(5-(3-Methoxypropoxy)pyrazin-2-yl)phenyl)propan-2-yl)-1,4-diazabicyclo[3.2.2]nonane-4carboxamide.

Replacing ethyl 2-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate with ethyl 2-methyl-2-(4-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate and quinuclidin-3-ol to intermediate 6, using the reaction sequence described in Example 315 to obtain the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.73 (d, J=1.4 Hz, 1H), 8.35 (d, J=1.4 Hz, 1H), 7.89 (d, J=8.5 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H), 6.17 (s, 1H), 4.39 (t, J=6.5 Hz, 2H) , 4.22-4.16 (m, 1H), 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), 1.651.49 (m, 8H) ppm. ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 158.7, 155.4, 150.3, 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. UP-LCMS purity >99.9%, >99.9% (210 and 254 nm); retention time 0.80 min; (M+H+) 454.4.

Example 323.

Quinuclidin-3-yl(2-(3-(5-(3-methoxypropoxy)pyrimidin-2-yl)phenyl)propan-2-yl)carbamate.

To a solution of 2-chloropyrimidin-5-ol (5.04 g, 38.6 mmol) in KH-dimethylformamide (25 ml) add 1-bromo-3-methoxypropane (10.8 ml, 96.5 mmol) and potassium carbonate with stirring (12.26 g, 88.74 mmol). The mixture is heated at 60°C overnight, concentrated and treated with ethyl acetate and aqueous sodium bicarbonate. The organic layer is washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash silica chromatography using a hexane/ethyl acetate gradient to give 2-chloro-5-(3-methoxypropoxy)pyrimidine as a white solid (4.90 g, 63%). The resulting compound and ethyl 2-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)propanoate are reacted according to General Procedure F to obtain ethyl-2 -(3-(5-(3methoxypropoxy)pyrimidin-2-yl)phenyl)-2-methylpropanoate. To a solution of the resulting intermediate (1.93 g, 5.38 mmol) in tetrahydrofuran/ethanol/water, 1:1:1 (v/v/v; 36 ml), add lithium hydroxide monohydrate (1 .13 g, 16.9 mmol). After refluxing overnight, the reaction mixture is cooled and concentrated. The residue is dissolved in water and washed with diethyl ether. The aqueous layer is treated with 1.0 N hydrochloric acid (27 ml) and

- 109 046304 extracted with ethyl acetate. The combined extracts were dried (Na ₂ SO ₄ ) and concentrated to give 2(3-(5-(3-methoxypropoxy)pyrimidin-2-yl)phenyl)-2-methylpropanoic acid as a colorless solid (1.49 g, 84 %). The resulting compound and quinuclidin-3-ol are reacted according to General Procedure H to obtain the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.63 (brs, 2H), 8.36 (brs, 1H), 8.15-8.09 (m, 1H), 7.61 (br.s, 1H), 7.50-7.37 (m, 2H), 4.44-4.35 (m, 1H), 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. ¹³ C NMR (100 MHz, DMSO-d6) δ 156.4, 154.6, 151.4, 148.7, 144.0, 136.7, 128.3, 126.3, 124.7, 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 m .d. UP-LCMS purity 96.8%, 97.9% (210 and 254 nm); retention time 0.79 min; (M+H+) 455.4.

Example 324.

1-Azabicyclo[3.2.2]nonan-4-yl(2-(3-(5-(3-methoxypropoxy)pyrimidin-2-yl)phenyl)propan-2yl)carbamate.

Using general procedure H and reacting 2-(3-(5-(3-methoxypropoxy)pyrimidin-2-yl)phenyl)-2-methylpropanoic acid (prepared as described in Example 323) and intermediate 3, the connection named in the header. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.63 (s, 2H), 8.34 (br s, 1H), 8.15-8.09 (m, 1H), 7.50 (br .s, 1H), 7.46-7.36 (m, 2H), 4.63-4.53 (m, 1H), 4.24 (t, J=6.4 Hz, 2H), 3, 50 (t, J=6.3 Hz, 2H), 3.26 (s, 3H), 2.99-2.32 (m, 6H), 2.01 (quin., J=6.6 Hz, 2H), 1.96-1.29 (m, 11H) ppm. ¹³ C NMR (100 MHz, DMSO46) 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 UP-LCMS purity 96.8%, 98.2% (210 and 254 nm); retention time 0.80 min; (M+H+) 469.4.

Example 325.

1-(3-Ethylquinuclidin-3-yl)-3-(4-(4-(2-methoxyethyl)phenyl)-2-methylbut-3-yn-2-yl)urea.

To a solution of 1-bromo-4-(2-methoxyethyl)benzene (2.09 g, 9.73 mmol) in diisopropylamine (10 ml), copper iodide (0.185 g, 0.973 mmol) and tert-butyl -methylbut-3-yn-2yl)carbamate (2.14 g, 11.7 mmol). Nitrogen was bubbled through the mixture for several minutes and then bis(triphenylphosphine)palladium(II) dichloride (0.342 g, 0.487 mmol) was added.

The reaction mixture is refluxed overnight, diluted with ethyl acetate and water and filtered through a pad of celite. The organic layer of the filtrate was washed with aqueous sodium bicarbonate and brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on silica using a hexane/ethyl acetate gradient to give tert-butyl (4-(4-(2-methoxyethyl)phenyl)-2-methylbut-3-yn-2-yl)carbamate as an orange oil ( 2.22 g, 72%). To a solution of the resulting compound (2.22 g, 6.99 mmol) in 1,4-dioxane (20 ml) was added a 4M solution of hydrogen chloride in 1,4-dioxane (20 ml) with stirring. After stirring overnight, the reaction mixture is concentrated and treated with 1N hydrochloric acid and diethyl ether. The aqueous layer is made alkaline (pH~10) by adding concentrated ammonium hydroxide and extracted with ethyl acetate. The combined extracts were dried (Na ₂ SO ₄ ) and concentrated to give 4-(4-(2methoxyethyl)phenyl)-2-methylbut-3-yn-2-amine as a yellow oil (1.07 g, 70%). The resulting compound and intermediate 2 were reacted according to General Procedure J to obtain the title compound as a white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.287.16 (m, 4H), 5.99 (br s, 1H), 5.75 (br s, 1H), 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 ¹³ C NMR (100 MHz, DMSO-d ₆ ) 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 m.d. UP-LCMS purity >99.9%, >99.9% (210 and 254 nm); retention time 0.86 min; (M+H+) 398.5.

Example 326.

-(4-(4-(2-Methoxyethyl)phenyl)-2-methylbut-3-in-2-yl)-3-(3-propylquinuclidin-3-yl)urea.

Using General Procedure J and reacting 4-(4-(2-methoxyethyl)phenyl)2-methylbut-3-yne-2-amine (prepared as described in Example 325) and intermediate 17 afforded the title compound. 1H NMR (400 MHz, DMSO- _d6 ) δ 7.27-7.16 (m, 4H), 5.95 (brs, 1H), 5.73 (brs, 1H), 3.51 (t, J=6.8 Hz, 2H), 3.22 (s, 3H), 2.79 (t, J=6.8 Hz, 2H), 2.76-2.50 (m, 6H) , 1.96-1.91 (m, 1H), 1.91-1.66 (m, 2H), 1.66-1.46 (m, 7H), 1.43-1.09 (m, 2H), 0.83 (t, J=7.3 Hz, 3H) ppm. ¹³ C NMR (100 MHz, DMSO-d6) 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 UP-LCMS purity >99.9%, >99.9% (210 and 254 nm); retention time 0.91 min; (M+H+) 412.6.

Example 327.

-(3-Ethylquinuclidin-3-yl)-3-(4-(4-(methoxymethyl)phenyl)-2-methylbut-3-in-2-yl)urea.

Replacing 1-bromo-4-(2-methoxyethyl)benzene with 1-bromo-4-(methoxymethyl)benzene, the reaction sequence described in Example 325 was used to obtain the title compound. 1H NMR (400 MHz, DMSO- _d6 ) δ 7.49-7.15 (m, 4H), 5.99 (brs, 1H), 5.74 (brs, 1H), 4.40 (s, 2H), 3.28 (s, 3H), 2.842.55 (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)

- 110 046304

m.d. ¹³ C NMR (100 MHz, DMSO-d 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. UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.82 min; (M+H+) 384.5.

Example 328.

1-(4-(4-(Methoxymethyl)phenyl)-2-methylbut-3-yn-2-yl)-3-(3-propylquinuclidin-3-yl)urea.

Replacing 1-bromo-4-(2-methoxyethyl)benzene with 1-bromo-4-(methoxymethyl)benzene and intermediate 2 with intermediate 17, the reaction sequence described in Example 325 was used to obtain the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.40-7.19 (m, 4H), 5.96 (brs, 1H), 5.72 (brs, 1H), 4.40 (s, 2H), 3.28 (s, 3H), 2.80-2.52 (m, 6H), 1.97-1.92 (m, 1H), 1.921.79 (m, 1H), 1.79-1.64 (m, 2H), 1.64-1.44 (m, 7H), 1.42-1.31 (m, 1H), 1.31-1.09 (m, 3H ), 0.82 (t, J=7.3 Hz, 3H) ppm. ¹³ C NMR (100 MHz, DMSO-d6) 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 m .d. UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.88 min; (M+H+) 398.5.

Example 329.

Quinuclidin-3-yl(4-(4-(2-methoxyethoxy)phenyl)-2-methylbut-3-yn-2-yl)carbamate.

Replacing 1-bromo-4-(2-methoxyethyl)benzene with 1-bromo-4-(2-methoxyethoxy)benzene and intermediate 2 with quinuclidin-3-ol, use the reaction sequence described in Example 325 to obtain the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.35 (brs, 1H), 7.26 (d, J=8.8 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 4.63-4.51 (s, 1H), 4.13-4.05 (m, 2H), 3.68-3.60 (m, 2H), 3.30 (s, 3H), 3.13-3.03 (m, 1H), 2.77-2.41 (m, 5H), 1.92-1.71 (m, 2H), 1.64-1.40 ( m, 8H), 1.36-1.24 (m, 1H) ppm. ¹³ C NMR (100 MHz, DMSO-d6) 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 UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.76 min; (M+H+) 387.5.

Example 330.

-(4-(4-(2-Methoxyethoxy)phenyl)-2-methylbut-3-in-2-yl)-3-(3-propylquinuclidin-3-yl)urea.

Replacing 1-bromo-4-(2-methoxyethyl)benzene with 1-bromo-4-(2-methoxyethoxy)benzene and intermediate 2 with intermediate 17, the reaction sequence described in Example 325 was used to obtain the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.24 (d, J=8.6 Hz, 2H), 6.91 (d, J=8.6 Hz, 2H), 5.93 (br. s, 1H), 5.71 (brs, 1H), 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, 11H), 1.45-1.07 (m, 4H), 0.83 (t, J=7, 2 Hz, 3H) ppm ¹³ C NMR (100 MHz, DMSO-d6) δ 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, 29.9, 29.8, 28.2, 22.6, 22.2, 16.7, 14.6 m .d. UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.79 min; (M+H+) 478.6.

Example 331.

Quinuclidin-3-yl(4-(4-(3-methoxypropoxy)phenyl)-2-methylbut-3-yn-2-yl)carbamate.

Replacing 1-bromo-4-(2-methoxyethyl)benzene with 1-bromo-4-(3-methoxypropoxy)benzene and intermediate 2 with quinuclidin-3-ol, use the reaction sequence described in Example 325 to obtain the title compound. 1H NMR (400 MHz, DMSO- _d6 ) δ 7.35 (s, 1H), 7.29-7.18 (m, 2H), 6.95-6.76 (m, 2H), 4.57 (s, 1H), 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, 1H), 2.76-2.43 (m, 5H), 1.97-1.72 (m, 4H), 1.63-1.40 (m, 8H), 1 .35-1.25 (m, 1H) ppm ¹³ C NMR (100 MHz, DMSO-d6) δ 158.3, 158.3, 132.7, 132.6, 114.6, 114.6, 92.7, 79.4, 68.4, 64, 7, 57.9, 55.5, 46.8, 45.9, 29.5, 28.8, 25.3, 24.2, 19.3 ppm. UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.85 min; (M+H+) 401.5.

Example 332.

-(3-Ethylquinuclidin-3-yl)-3-(2-methyl-4-(4-((pyridin-3-ylmethoxy)methyl)phenyl)but-3-in-2-yl)urea.

Replacing 1-bromo-4-(2-methoxyethyl)benzene with 3-(((4-bromobenzyl)oxy)methyl)pyridine (prepared as described in Example 215), using the reaction sequence described in Example 325 to obtain the title in the connection header. 1H NMR (400 MHz, DMSO- _d6 ) δ 8.72-8.36 (m, 2H), 7.89-7.65 (m, 1H), 7.59-7.07 (m, 5H) , 6.08 (b/s, 1H), 5.89 (b/s, 1H), 4.56 (b/s, 4H), 2.94-2.37 (m, 6H), 2.15 -1.12 (m, 13H), 0.74 (brs, 3H) ppm ¹³ C NMR (100 MHz, DMSO-d ₆ ) 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 UP-LCMS purity 99.90%, 99.6% (210 and 254 nm); retention time 0.61 min; ((M+H+)/2) 231.4.

Example 333.

1-(2-Methyl-4-(4-((pyridin-3-ylmethoxy)methyl)phenyl)but-3-yn-2-yl)-3-(3-propylquinuclidin-3yl)urea.

Replacing 1-bromo-4-(2-methoxyethyl)benzene with 3-(((4-bromobenzyl)oxy)methyl)pyridine (prepared as described in Example 215) and intermediate 2 with intermediate 17, the following reaction sequence is used: , described in example 325 and obtain the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.79-8.38 (m, 2H), 7.77 (d, J=7.6 Hz, 1H), 7.53-7.10 (m , 5H), 6.04

- 111 046304 (broad s, 1H), 5.84 (broad s, 1H), 4.56 (broad s, 4H), 2.94-2.47 (m, 6H), 2.06- 1.00 (m, 15H), 0.83 (t, J=7.1 Hz, 3H) ppm ¹³ C NMR (100 MHz, DMSO-d ₆ ) 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 by UPLCMS 99.9%, 99.9% (210 and 254 nm); retention time 0.67 min; (M+H+) 475.5.

Example 334.

Quinuclidin-3 -yl(4-(4-((3,3-dimethylbutyl)sulfonyl)phenyl)-2-methylbut-3-in-2-yl)carbamate.

Replacing 1-bromo-4-(2-methoxyethyl)benzene with 1-bromo-4-((3,3-dimethylbutyl)sulfonyl)benzene (prepared as described in Example 245) and intermediate 2 with quinuclidine-3- ol, use the sequence of reactions described in example 325 and obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J=8.5 Hz, 2H), 7.60 (d, J=8.5 Hz, 2H), 7.51 (br.s , 1H), 4.64-4.57 (m, 1H), 3.30-3.21 (m, 2H), 2.80-2.50 (m, 5H), 1.95-1.87 (m, 1H), 1.86-1.74 (m, 1H), 1.65-1.43 (m, 8H), 1.43-1.27 (m, 3H), 0.81 (s , 9H) ppm ¹³ C NMR (100 MHz, DMSO-d 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. UP-LCMS purity 90.0%, 99.6% (210 and 254 nm); retention time 0.95 min; (M+H+) 461.

Example 335.

1-Azabicyclo[3.2.2]nonan-4-yl(4-(4-((3,3-dimethylbutyl)sulfonyl)phenyl)-2-methylbut-3-yn-2yl)carbamate.

Replacing 1-bromo-4-(2-methoxyethyl)benzene with 1-bromo-4-((3,3-dimethylbutyl)sulfonyl)benzene (prepared as described in Example 245) and intermediate 2 with intermediate 3, use the reaction sequence described in Example 325 to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J=8.5 Hz, 2H), 7.60 (d, J=8.5 Hz, 2H), 7.44 (br.s , 1H), 4.80-4.72 (m, 1H), 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 ¹³ C NMR (100 MHz, DMSO-d6) 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. UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.96 min;

(M+H+) 475.

Example 336.

-(4-(4-((3,3-Dimethylbutyl)sulfonyl)phenyl)-2-methylbut-3-in-2-yl)-3 -(4-methyl-1-azabicyclo[3.2.2]nonan- 4-yl)urea.

Replacing 1-bromo-4-(2-methoxyethyl)benzene with 1-bromo-4-((3,3-dimethylbutyl)sulfonyl)benzene (prepared as described in Example 245) and intermediate 2 with intermediate 5, use the reaction sequence described in Example 325 to obtain the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.88 (d, J=8.5 Hz, 2H), 7.57 (d, J=8.5 Hz, 2H), 6.15 (s, 1H), 5.79 (s, 1H), 3.30-3.20 (m, 2H), 2.90-2.70 (m, 6H), 2.23-2.17 (m, 1H) , 1.88-1.64 (m, 3H), 1.62-1.42 (m, 8H), 1.42-1.25 (m, 6H), 0.81 (s, 9H) m. d. ¹³ C NMR (100 MHz, DMSO46) δ 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 UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.94 min; (M+H+) 488.

Example 337.

-(4-(4-((3,3-Dimethylbutyl)sulfonyl)phenyl)-2-methylbut-3-in-2-yl)-3 -(3-methylquinuclidin-3 yl)urea.

Replacing 1-bromo-4-(2-methoxyethyl)benzene with 1-bromo-4-((3,3-dimethylbutyl)sulfonyl)benzene (prepared as described in Example 245) and intermediate 2 with intermediate 1, use the reaction sequence described in Example 325 to obtain the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.88 (d, J=8.5 Hz, 2H), 7.58 (d, J=8.5 Hz, 2H), 6.04 (s, 1H), 5.77 (s, 1H), 3.29-3.21 (m, 2H), 2.75-2.56 (m, 6H), 1.96-1.91 (m, 1H) , 1.81-1.51 (m, 8H), 1.45-1.33 (m, 7H), 0.81 (s, 9H) ppm. ¹³ C NMR (100 MHz, DMSO-d ₆ ) 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, 46.0, 35.4, 30.4, 29.6, 29.5, 28.6, 25.0, 22.9, 22.2 ppm. UP-LCMS purity 97.8%, 99.2% (210 and 254 nm); retention time 0.93 min; (M+H+) 474.

Example 338.

-(4-(4-((3,3-Dimethylbutyl)sulfonyl)phenyl)-2-methylbut-3-in-2-yl)-3 -(3-ethylquinuclidin-3 yl)urea.

Replacing 1-bromo-4-(2-methoxyethyl)benzene with 1-bromo-4-((3,3-dimethylbutyl)sulfonyl)benzene (prepared as described in Example 245), use the reaction sequence described in Example 325 and obtain the compound named in the header. 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.88 (d, J=8.5 Hz, 2H), 7.57 (d, J=8.5 Hz, 2H), 6.04 (s, 1H), 5.74 (s, 1H), 3.29-3.21 (m, 2H), 2.76-2.53 (m, 6H), 1.98-1.87 (m, 2H) , 1.801.67 (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 ¹³ C NMR (100 MHz, DMSO-d6) 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 UP-LCMS purity 97.5%, 98.3% (210 and 254 nm); retention time 0.96 min; (M+H+) 488.

Example 339.

-(4-(4-(1-Methoxy-2-methylpropan-2-yl)phenyl)-2-methylbut-3-in-2-yl)-3 -(3-methylquinuclidine-3

- 112 046304 il)urea.

A solution of 2-(4-bromophenyl)-2methylpropanoate (11, 25 g, 41.47 mmol) in tetrahydrofuran (40 ml). The reaction mixture is stirred with cooling for 1 hour and then the reaction is quenched by gradually adding ethyl acetate (~15 ml). After another 20 minutes, the reaction mixture is diluted with 1N hydrochloric acid and extracted with ethyl acetate. The combined extracts are washed with 1N. hydrochloric acid and brine, dried (Na ₂ SO ₄ ) and concentrated to give 2-(4-bromophenyl)-2-methylpropan-1-ol as a white solid (9.50 g, 100%). To a solution of crude alcohol (1.92 g, 8.38 mmol) in NN-dimethylformamide (17 ml) was added sodium hydride (60% dispersion in mineral oil; 0.402 g, 10.1 mmol) with stirring. After 20 minutes, iodomethane (0.70 ml, 10.9 mmol) is added dropwise through a syringe. The reaction mixture is stirred overnight, concentrated and treated with ethyl acetate and water. The organic layer was washed with aqueous sodium bicarbonate and brine, dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica flash chromatography using a hexane/ethyl acetate gradient to give 1-bromo-4-(1-methoxy-2-methylpropan-2-yl)benzene as a colorless oil (1.26 g, 62%). Replacing 1-bromo4-(2-methoxyethyl)benzene with the newly prepared intermediate and intermediate 2 with intermediate 1, the reaction sequence described in Example 325 was used to obtain the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.34 (d, J=8.5 Hz, 2H), 7.25 (d, J=8.5 Hz, 2H), 5.99 (s, 1H), 5.80 (s, 1H), 3.34 (s, 2H), 3.19 (s, 3H), 2.82-2.57 (m, 6H), 1.96-1.90 (m, 1H), 1.83-1.73 (m, 1H), 1.71-1.60 (m, 1H), 1.55 (d, J=5.0 Hz, 1H), 1, 47-1.18 (m, 11H) ppm ¹³ C NMR (100 MHz, DMSO-d6) 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 m .d. UP-LCMS purity 100%, 99.5% (210 and 254 nm); retention time 0.94 min; (M+H+) 412.5.

Example 340.

Quinuclidin-3-yl(2-(2-(4-(3-methoxypropoxy)phenyl)thiazol-4-yl)propan-2-yl)carbamate.

To a suspension of 4-methoxythiobenzamide (9.99 g, 59.7 mmol) in ethanol (75 ml) was added 4-chloroacetoacetate (8.1 ml, 60 mmol) with stirring. The mixture is refluxed for 4 hours, then more 4-chloroacetoacetate (0.81 mL, 6.0 mmol) is added and refluxed again. After heating for a further 4 hours, the reaction mixture is concentrated and treated with ethyl acetate and aqueous sodium bicarbonate. The organic layer is combined with the other ethyl acetate extracts, dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified by flash silica chromatography using a hexane/ethyl acetate gradient to give ethyl 2-(2-(4methoxyphenyl)thiazol-4-yl)acetate as a pale amber oil (14.5 g, 87% ). To a solution of the resulting compound (14.48 g, 52.2 mmol) in N,N-dimethylformamide (125 ml), sodium hydride (60% dispersion in mineral oil; 6.27 g, 157 mmol). The resulting red suspension is cooled (0°C) and treated dropwise with iodomethane (9.80 mL, 157 mmol) over 10 min. The cooling bath is removed and the reaction mixture is stirred for 4 hours, then concentrated and treated with ethyl acetate and water. The organic layer is washed twice more with water, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash silica chromatography using a hexane/ethyl acetate gradient to give ethyl 2-(2-(4methoxyphenyl)thiazol-4-yl)-2-methylpropanoate as a pale amber oil (14.12 g, 89%). To a solution of the resulting intermediate (14.12 g, 46.24 mmol) in methylene chloride (250 ml) boron tribromide (11.0 ml, 116 mmol) was added dropwise with stirring over 5 min. After stirring overnight, the reaction is quenched by gradually adding methanol (~20 ml) and then the mixture is concentrated. The residue is dissolved in methanol (250 ml) and concentrated sulfuric acid (7.0 ml). The solution is refluxed with stirring for 2 hours, concentrated and treated with ethyl acetate and an aqueous solution of sodium bicarbonate. Combine the organic layer with the other ethyl acetate extract, dry (Na2SO4) and concentrate to give methyl 2-(2-(4hydroxyphenyl)thiazol-4-yl)-2-methylpropanoate as a white solid (12.56 g, 98%) . To a solution of 1-bromo-3-methoxypropane (1.66 g, 10.8 mmol) in acetone (30 ml) add intermediate phenol (2.00 g, 7.21 mmol) and potassium carbonate (1.25 g) with stirring , 9.04 mmol). The mixture is refluxed overnight, filtered and concentrated. The residue was purified by flash chromatography on silica using a hexane/ethyl acetate gradient to give methyl 2-(2-(4-(3-methoxypropoxy)phenyl)thiazol-4-yl)-2-methylpropanoate as a pale amber resin (2. 47 g, 98%). Lithium hydroxide monohydrate (1, 47 g, 35.0 mmol). After stirring overnight, the reaction mixture is concentrated and treated with water and diethyl ether. The aqueous layer was treated with 1.0N hydrochloric acid (40 ml) and extracted with ethyl acetate. The combined extracts were dried (Na2SO4) and concentrated to give 2(2-(4-(3-methoxypropoxy)phenyl)thiazol-4-yl)-2-methylpropanoic acid as a white solid (2.19 g, 93%). The resulting compound and quinuclidin-3-ol are interacted according to the general

- 113 046304 procedure H and obtain the title compound in the form of a soft, dense substance of pale amber color. 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.82 (d, J=8.9 Hz, 2H), 7.36 (brs, 1H), 7.24 (brs, 1H), 7.03 (d, J=8.9 Hz, 2H), 4.49-4.41 (m, 1H), 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 ¹³ C NMR (100 MHz, DMSO-d ₆ ) 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. UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.87 min; (M+H+) 460.

Example 341.

1-Azabicyclo[3.2.2]nonan-4-yl(2-(2-(4-(3-methoxypropoxy)phenyl)thiazol-4-yl)propan-2-yl)carbamate.

Using general procedure H and reacting 2-(2-(4-(3methoxypropoxy)phenyl)thiazol-4-yl)-2-methylpropanoic acid (prepared as described in Example 340) and intermediate 3, the title connection header. ¹ H NMR (400 MHz, DMSO-d6) δ 7.81 (d, J=8.8 Hz, 2H), 7.29 (br s, 1H), 7.21 (s, 1H), 7, 03 (d, J=8.8 Hz, 2H), 4.68-4.60 (m, 1H), 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. ¹³ C NMR (100 MHz, DMSO-d6) 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 m .d. UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.88 min; (M+H+) 474.

Example 342.

N(2-(2-(4-(3-Methoxypropoxy)phenyl)thiazol-4-yl)propan-2-yl)-1,4-diazabicyclo[3.2.2]nonane-4carboxamide.

Using general procedure H and reacting 2-(2-(4-(3-methoxypropoxy)phenyl)thiazol-4-yl)-2-methylpropanoic acid (prepared as described in Example 340) and intermediate 6, the connection named in the header. ¹ H NMR (400 MHz, DMSOd6) δ 7.81 (d, J=8.8 Hz, 2H), 7.19 (s, 1H), 7.03 (d, J=8.8 Hz, 2H) , 6.08 (s, 1H), 4.16-4.11 (m, 1H), 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) m .d. ¹³ C NMR (100 MHz, DMSO-d6) 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. UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.82 min; (M+H+) 459.

Example 343.

Quinuclidin-3-yl(2-(2-(4-(2-methoxyethoxy)phenyl)thiazol-4-yl)propan-2-yl)carbamate.

To a solution of 2-bromoethyl methyl ether (1.88 g, 13.5 mmol) in acetone, add methyl 2-(2-(4-hydroxyphenyl)thiazol-4-yl)-2-methylpropanoate (prepared as described) with stirring in example 185; 2.00 g, 7.21 mmol) and potassium carbonate (1.56 g, 11.3 mmol). After refluxing overnight, the mixture was worked up by adding more 2-bromoethyl methyl ether (1.88 g, 13.5 mmol) and potassium carbonate (1.56 g, 11.3 mmol). The reaction mixture is refluxed overnight, filtered and concentrated. The residue was purified by flash silica chromatography using a hexane/ethyl acetate gradient to give methyl 2-(2-(4-(2methoxyethoxy)phenyl)thiazol-4-yl)-2-methylpropanoate as a white solid (2. 71 g, 90%). Lithium hydroxide monohydrate (1, 70 g, 40.5 mmol). After stirring overnight, the reaction mixture is concentrated and treated with water and diethyl ether. The aqueous layer was treated with 1.0N hydrochloric acid (41 ml) and extracted with ethyl acetate. The combined extracts were dried (Na ₂ SO ₄ ) and concentrated to give 2-(2-(4-(2methoxyethoxy)phenyl)thiazol-4-yl)-2-methylpropanoic acid as a white solid (2.57 g, 99% ). The resulting compound and quinuclidin-3-ol are reacted according to General Procedure H to obtain the title compound as a pale amber solid. 1H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J=8.8 Hz, 2H), 7.36 (brs, 1H), 7.24 (brs, 1H), 7 .04 (d, J=8.8 Hz, 2H), 4.49-4.41 (m, 1H), 4.19-4.12 (m, 2H), 3.71-3.65 (m , 2H), 3.32 (s, 3H), 3.11-2.87 (m, 1H), 2.86-2.19 (m, 5H), 1.92-1.16 (m, 11H ) m.d. ¹³ C NMR (100 MHz, DMSO-d6) 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. UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.85 min; (M+H+) 446.

Example 344.

1-Azabicyclo[3.2.2]nonan-4-yl(2-(2-(4-(2-methoxyethoxy)phenyl)thiazol-4-yl)propan-2-yl)carbamate.

Using general procedure H and reacting 2-(2-(4-(2-methoxyethoxy)phenyl)thiazol-4-yl)-2-methylpropanoic acid (prepared as described in Example 343) and intermediate 3, the connection named in the header. ¹ H NMR (400 MHz, DMSOd ₆ ) δ 7.81 (d, J=8.8 Hz, 2H), 7.29 (brs, 1H), 7.21 (brs, 1H), 7 .04 (d, J=8.8 Hz, 2H), 4.67-4.60 (m, 1H), 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. ¹³ C NMR (100 MHz, DMSO-d6) 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. UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.86 min; (M+H+) 460.

- 114 046304

Example 345.

H-(2-(2-(4-(2-Methoxyethoxy)phenyl)thiazol-4-yl)propan-2-yl)-1.4-diazabicyclo[3.2.2|nonane-4carboxamide.

Using general procedure H and reacting 2-(2-(4-(2-methoxyethoxy)phenyl)thiazol-4-yl)-2-methylpropanoic acid (prepared as described in Example 343) and intermediate 6, the connection named in the header. 1H NMR (400 MHz, DMSOd6) δ 7.82 (d, J=8.8 Hz, 2H), 7.20 (s, 1H), 7.05 (d, J=8.8 Hz, 2H), 6.09 (s, 1H), 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. ¹³ C NMR (100 MHz, DMSO-d6) 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 UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.79 min; (M+H+) 445.

Example 346.

Quinuclidin-3-yl-2-(5-(4-(2-methoxyethoxy)phenyl)pyridin-2-yl)propan-2-yl)carbamate.

Using general procedure F and reacting 5-bromopicolinonitrile with 2(4-(2-methoxyethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 5-(4-(2 -methoxyethoxy)phenyl)picolinonitrile. Cerium trichloride (8.05 g, 21.6 mmol) was charged to the flask and dried by heating (170°C) in vacuo for 3 hours. The solid was dissolved in tetrahydrofuran (20 ml) and stirred vigorously for 30 minutes. The suspension is cooled to -78°C and treated by dropwise addition of a 3.0 M solution of methyllithium in diethyl ether (7.2 ml, 21.6 mmol). After addition was complete, the reaction mixture was stirred at -78°C for 1 hour and then a solution of the arylborate obtained above (1.83 g, 7.20 mmol) in tetrahydrofuran (20 ml) was added. The mixture is kept at -78°C for 2 hours and then warmed to room temperature. At this time, the reaction is quenched by adding aqueous ammonium hydroxide (10 ml) and the mixture is filtered through a pad of celite. The filtrate is extracted with ethyl acetate and the combined extracts are washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash chromatography on silica using ethyl acetate as eluent to give 2-(5-(4-(2methoxyethoxy)phenyl)pyridin-2-yl)propan-2-amine as a yellow solid (0.800 g, 39%). To a suspension of the resulting intermediate (0.500 g, 1.75 mmol) in water (10 ml) and concentrated hydrochloric acid (0.44 ml) was added toluene (10 ml) with stirring. The mixture is cooled (0°C) and treated simultaneously for 1 hour with a solution of triphosgene (0.776 g, 2.62 mmol) in toluene (10 ml) and a solution of sodium bicarbonate (2.2 g, 26 mmol) in water (20 ml). After addition is complete, the reaction mixture is stirred for another 30 minutes and then the upper toluene layer is removed and dried (Na ₂ SO ₄ ). At the same time, a solution of quinuclidin-3-ol (0.445 g, 3.64 mmol) in tetrahydrofuran (10 ml) was treated with sodium hydride (60% dispersion in mineral oil; 0.154 g, 3.85 mmol) with stirring. The resulting mixture was stirred for 5 minutes, quenched by adding brine (5 ml) and extracted with ethyl acetate. The combined extracts are dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by flash reverse phase chromatography on silica to give the title compound as a light yellow solid. ^1H NMR (500 MHz, CDCl3) δ 8.70-8.70 (d, J=2.0 Hz, 1H), 7.83-7.81 (m, 1H), 7.49-7.47 (d, J=9.0 Hz, 2H), 7.45-7.43 (d, J=8.0 Hz, 1H), 7.03-7.01 (d, J=8.5 Hz, 2H), 6.63 (br.s, 1H), 4.68-4.66 (m, 1H), 4.16 (t, J=5.0 Hz, 2H), 3.77 (t, J =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. ¹³ C NMR (125 MHz, CDCl3) 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 LCMS purity >99% (214 and 254 nm); retention time 1.32 min; (M+H+) 440.2.

Example 347.

1-Azabicyclo[3.2.2]nonan-4-yl-2-(5-(4-(2-methoxyethoxy)phenyl)pyridin-2-yl)propan-2-ylcarbamate.

Replacing quinuclidin-3-ol with intermediate 3, the reaction sequence described in Example 346 was used to obtain the title compound. ^1H NMR (500 MHz, CDCl3) δ 8.71 (s, 1H), 7.85-7.83 (m, 1H), 7.50 (d, J=8.5 Hz, 2H), 7, 45 (d, J=8.5 Hz, 1H), 7.04 (d, J=8.5 Hz, 2H), 6.54 (s, 1H), 4.85-4.82 (m, 1H ), 4.18 (t, J=4.5 Hz, 2H), 3.79 (t, J=4.5 Hz, 2H), 3.46 (s, 3H), 3.12-2.76 (m, 6H), 2.35-1.43 (m, 13H) ppm. ¹³ C NMR (125 MHz, CDCl3) 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 LCMS purity >97% (214 and 254 nm); retention time 1.02 min; (M+H+) 454.2.

Example 348.

1-Azabicyclo[3.2.2]nonan-4-yl-2-(5-(4-(2-methoxyethoxy)phenyl)pyridin-2-yl)propan-2-ylcarbamate (single enantiomer A).

Using general procedure F and reacting methyl 2-(5-bromopyridin-2yl)-2-methylpropanoate (Org. Lett., 2005, 7(21), 4585-4588) and 4-(2-methoxyethoxy)phenyl )boronic acid, methyl 2-(5-(4-(2-methoxyethoxy)phenyl)pyridin-2-yl)-2-methylpropanoate is obtained. Lithium hydroxide monohydrate (2, 68 g, 63.9 mmol). After stirring overnight, the reaction mixture is concentrated and treated with water and diethyl ether. The aqueous layer is treated with 1.0N. hydrochloric acid (61.4 ml) and extracted with ethyl acetate. United

- 115 046304 the extracts are dried (Na ₂ SO ₄ ) and concentrated to obtain 2-(5-(4-(2-methoxyethoxy)phenyl)pyridin-2-yl)2-methylpropanoic acid as an off-white solid (5, 90 g, 88%). The resulting compound and intermediate 15 are reacted according to General Procedure H to obtain the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-de) δ 8.74 (d, J=2.1 Hz, 1H), 7.96 (dd, J=8.3, 2.4 Hz, 1H), 7.63 (d, J=8.3 Hz, 2H), 7.51 (br.s, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.06 (d, J=8, 8 Hz, 2H), 4.69-4.57 (m, 1H), 4.17-4.11 (m, 2H), 3.71-3.65 (m, 2H), 3.32 (s , 3H), 3.00-2.42 (m, 6H), 1.98-1.33 (m, 13H) ppm. ¹³ C NMR (100 MHz, DMSO-d6) 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 UP-LCMS purity 100%, 100% (210 and 254 nm); retention time 0.65 min; (M+H+) 454.4.

Example 349.

1-Azabicyclo[3.2.2]nonan-4-yl-2-(5-(4-(2-methoxyethoxy)phenyl)pyridin-2-yl)propan-2-yl)carbamate (single enantiomer B).

Replacing intermediate 15 with intermediate 16, the reaction sequence described in Example 348 was used to obtain the title compound. NMR data consistent with Example 348. UP-LCMS purity 100%, 99.4% (210 and 254 nm); retention time 0.65 min; (M+H+) 454.4.

Example 350.

Inhibition of glucosylceramide synthase activity by certain compounds of the invention is measured by 1) a microsomal assay, in which HPLC directly measures the conversion of ceramide to glucosylceramide, and 2) another cellular phenotypic assay, which monitors cell surface expression of the downregulated lipid GM3 using antibody-mediated immunofluorescence. Cellular analysis is performed on two different cell types, B16 and C32. Another cellular assay also evaluates cell viability.

The results of such analyzes are presented below in table. 1. The connection number in the table corresponds to the connection disclosed in the example with the same number. Microsomal assay results are expressed as GCS IC50, which indicates the concentration of compound that causes 50% inhibition of glucosylceramide synthase activity. The results of cell-based assays (performed in two different cell systems, i.e., mouse B16 melanoma and 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 of compound causing 50% inhibition of cell surface GM3 expression. Viability assay results are expressed as Viability, B16 IC50 or Viability, C32 IC50, respectively. These values represent the concentration of a compound that causes 50% cell death. Values greater than 10 represent no cell death.

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Connection number Connection name Number pr-ra GC8 IC50 (µM) GM3 B16 (µM) GM3 C32 (µM) Vitality IC50 B16 (µM) Viability IC32 IC50 (µM) 1 4-([1,1 '-Biphenyl]-4-yl)-N-(3 methylquinuclidin-3 yl)piperazine-1-carboxamide 1 0.719 1.26 0.109 7.16 10. 2 4 -([ 1,1 ’ -Biphenyl] -4 -yl) -N (quinuclidin-3 -yl) piperazin- 1-carboxamide 2 6.93 1.6 0.667 5.28 7.58 3 4-([ 1,1 ’ -Biphenyl]-4-yl)-N-( 1 azabicyclo[3.2.2]nonan-4yl)piperazin-1-carboxamide 3 10.9 6.84 1.0 4.18 2.51 4 4 -([ 1,1 ’ -Biphenyl] -4 -yl) -N-(4 methyl-1- azabicyclo[3.2.2]nonane-4- yl)piperazine-1-carboxamide 4 1.0 1.38 0.0625 6.16 6.31 5 4-([ 1,1 ’ -Biphenyl] -4l)piperazin-1 -yl) (1,4diazabicyclo[3.2.2]nonan-4yl)methanone 5 thirty, 2.0 2.0 2.0 2.0 6 Quinuclidin-3-yl-4-([1,1’biphenyl]-4-yl)piperazine-1 carboxylate 6 5.6 3.52 1.0 5.21 4.12 7 4-Phenyl-N-(quinuclidine-3 - yl)piperazine-1-carboxamide 7 12.2 >10 7.08 10. 10. 8 N-(1-Azabicyclo[3,2.2]nonan4-yl)-4-phenylpiperazine-1 carboxamide 8 3.31 >10 0.518 10. 10. 9 N-(3-Methylquinuclidin-3-yl)4-phenylpiperazine-1 carboxamide 9 12.2 >10 7.59 10. 10. 10 M-(4-Methyl-1azabicyclo[3.2.2]nonan-4-yl)4-phenylpiperazine-1 carboxamide 10 14.7 >10 4.24 10. 10. eleven 1.4- eleven 20.8 >10 >10 10. 10.

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Diazabicyclo[3,2.2]nonan-4yl(4-phenylpiperazin-1yl)methanone 12 Quinuclidin-3-yl-4phenylpiperazine-1 carboxylate 12 12.2 >10 >10 10. 10. 13 4-([ 1, G-Biphenyl]-3-yl)-N(quinuclidin-3-yl)piperazine1-carboxamide 13 2.47 6.8 0.697 8.59 10. 14 4-([ 1, G -Biphenyl] -3 -yl)-N-( 1 azabicyclo[3.2.2]nonan-4yl)piperazin-1-carboxamide 14 0.705 3.39 0.108 6.79 10. 15 4-([ 1, G -Biphenyl]-3 -yl)-N-(3 methylquinuclidin-3 yl)piperazine-1-carboxamide 15 0.839 0.368 0.172 10. 10. 16 4-([1, G-Biphenyl]-3-yl)-N-(4methyl-1- azabicyclo[3.2.2]nonan-4yl)piperazine-1-carboxamide 16 0.0495 0.181 0.0124 6.76 1.0 17 4-([1, G-Biphenyl]-3 and l)piperazin-1-yl) (1,4diazabicyclo[3.2.2] nonan-4 yl)methanone 17 12.2 6.31 6.36 10. 10. 18 Quinuclidin-3 -yl-4-([1,1’biphenyl]-3 -yl)piperazine-1 carboxylate 18 0.551 2.04 0.563 8.36 10. 19 1-Azabicyclo[3.2.2]nonan-4yl-4-([1,G-biphenyl]-3yl)piperazine-1-carboxylate 19 2.67 1.48 0.456 7.09 9.09 20 1 - Azabicyclo[3.2.2]nonan-3 yl-4-([1, G-biphenyl]-3 yl)piperazine-1-carboxylate 20 16.6 4.47 10.7 7.71 15.1 21 4-([1, G-Biphenyl]-3-yl)-N-(3 ethylquinuclidin-3 yl)piperazine-1-carboxamide 21 0.288 0.168 0.0252 7.23 3.16 22 4-(4' -Fluoro-[1, G-biphenyl]-3 and l)-N-(4 -methyl-1 azabicyclo[3.2.2]nonan-4yl)piperazine-1-carboxamide 22 0.613 0.629 0.0411 7.06 1.0 23 N-(3 -Ethylquin clidin-3 -yl)4-(4 '-fluoro-[1, G-biphenyl] -3 - 23 1.58 0.351 0.0909 7.07 3.16

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yl)piperazine-1-carboxamide 24 1 -Azabicyclo [3.2.2] nonan-4yl-4-(4 '-fluoro-[1, G-biphenyl] - 3-yl)piperazine-1 carboxylate 24 9.52 1.68 1.08 3.61 3.98 25 1 -Azabicyclo [3.2.2] nonan-3 yl-4-(4 '-fluoro- [1, G-biphenyl] - 3-yl)piperazine-1 carboxylate 25 3.48 4.86 9.38 5.39 5.41 26 M-(4-Methyl-1azabicyclo [3.2.2] but nan-4 -yl) 4-(3 -(pyrimidin-2yl)phenyl)piperazine-1 carboxamide 26 6.9 >10 0.36 10. 10. 27 M-(4-Methyl-1- azabicyclo [3.2.2] but nan-4 -yl) 4-(3-(pyrimidin-5yl)phenyl)piperazine-1 carboxamide 27 16.5 >10 0.798 10. 10. 28 4-(3-Isopropylphenyl)-N-(4methyl-1- azabicyclo [3.2.2] but nan-4 yl)piperazine-1-carboxamide 28 1.59 1.44 0.0866 10. 3.16 29 4-(3-Cyclohexylphenyl)-Н(4-methyl-1- azabicyclo [3.2.2] but nan-4 yl)piperazine-1-carboxamide 29 0.309 2.66 0.0382 7.81 1.0 thirty 4-([ 1, G -Biphenyl]-3 -yl)-2methyl-N-(4-methyl-1 azabicyclo[3.2.2] but nan-4 yl)piperazin-1-carboxamide thirty 0.376 0.864 0.0639 7.64 1.0 31 4-([ 1, G -Biphenyl] -3 -yl)-3 methyl-N-(4-methyl-1 azabicyclo[3.2.2] but nan-4 yl)piperazin-1-carboxamide 31 0.00406 0.0707 0.0015 1 7.62 1.0 32 4-([ 1,1 ’ -Biphenyl] -3 -yl)-3 methyl-N-(4-methyl-1 azabicyclo[3.2.2] but nan-4 yl)piperazin-1-carboxamide 32 0.544 0.462 0.0465 7.29 3.16 33 1 -(4 '-Fluoro-[1,1'-biphenyl]-3 yl)-N-(3-methylquinuclidine-3 - 33 0.0221 0.237 0.0050 2 6.91 1.0

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yl)piperidine-4-carboxamide 34 1 -(4 ’ -Fluoro- [ 1, G -biphenyl] -3 and l) -N-(4 -methyl-1 azabicyclo [3.2.2] but nan-4 yl)piperidine-4-carboxamide 34 0.00478 0.079 0.0008 72 4.72 0.316 35 1 -([ 1, G -Biphenyl] -3 -yl)-N-(3 methylquinuclidin-3 yl)piperidine-4-carboxamide 35 0.0496 0.149 0.0071 1 7.31 1.0 36 1 -([ 1, G -Biphenyl] -3 -yl)-N-(4methyl-1- azabicyclo [3.2.2] but nan-4 yl)piperidine-4-carboxamide 36 0.0103 0.136 0.0025 7.57 1.0 37 1 -([ 1, G-Biphenyl]-4-yl)-N-(3 methylquinuclidin-3 yl)piperidine-4-carboxamide 37 1.55 1.8 0.131 7.05 6.9 38 1 -([ 1, G-Biphenyl]-4-yl)-N-(4methyl-1- azabicyclo [3.2.2] but nan-4 yl)piperidine-4-carboxamide 38 1.05 2.6 0.0894 6.62 6.74 39 M-(4-Methyl-1azabicyclo [3.2.2] but nan-4 -yl) 1 -(3 -(pyrimidin-2yl)phenyl)piperidine-4carboxamide 39 1.8 7.24 0.126 10. 3.16 40 M-(4-Methyl-1azabicyclo [3.2.2] but nan-4 -yl) 1 -(3 -(pyrimidin-5yl)phenyl)piperidine-4carboxamide 40 0.291 5.5 0.0152 0.0713 1.0 41 1-(4-(4- Fluorophenyl)pyrimidin-2-yl)- M-(4-methyl-1azabicyclo [3.2.2] but nan-4 yl)piperidine-4-carboxamide 41 0.00114 0.0097 0.0001 24 6.44 0.020 42 1-(4-(4- Fluorophenyl)pyrimidin-2-yl)- M-(4-methyl-1azabicyclo [3.2.2] but nan-4 yl)piperidine-4-carboxamide (single enantiomer A) 42 0.0941 0.918 0.0098 2 7.66 4.64 43 1-(4-(4- 43 0.00125 0.00654 0.0000 7.14 8.92

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Fluorophenyl)pyrimidin-2-yl)- M-(4-methyl-1- azabicyclo[3.2.2]nonan-4yl)piperidine-4-carboxamide (single enantiomer B) 65 5 44 1-(4-(4- Fluorophenyl)pyrimidin-2-yl)- N-(3-methylquinuclidin-3 yl)piperidine-4-carboxamide 44 0.00124 0.0499 0.0002 05 9.27 0.316 45 1-(4-(4- Fluorophenyl)pyrimidin-2-yl)- N-Skhine clidin-3 - yl)piperidine-4-carboxamide 45 0.00267 0.125 0.0004 57 10. 1.0 46 1 -(6-(4-Fluorophenyl)pyrazin-2l)-N-(4-methyl-1 azabicyclo[3.2.2]nonan-4yl)piperidine-4-carboxamide 46 0.00279 0.0766 0.0004 25 7.31 0.316 47 1 -(6-(4-Fluorophenyl)pyrazin-2l)-N-(4-methyl-1 azabicyclo[3.2.2]nonan-4yl)piperidine-4-carboxamide (single enantiomer A) 47 0.258 2.19 0.050 7.83 3.16 48 1 -(6-(4-Fluorophenyl)pyrazin-2l)-N-(4-methyl-1 azabicyclo[3.2.2] nonan-4yl)piperidine-4-carboxamide (single enantiomer B) 48 0.00161 0.0477 0.0000 96 7.76 0.0051 7 49 1 -(6-(4-Fluorophenyl)pyrazin-2yl)-N-(3-methylquinuclidin-3yl)piperidine-4-carboxamide 49 0.0041 0.145 0.0008 22 8.16 1.0 50 1-(4-(4-Fluorophenyl)-1,3,5triazin-2-yl)-N-(4-methyl-1 azabicyclo[3.2.2]nonan-4yl)piperidin-4-carboxamide 50 0.0325 0.162 0.0007 08 10. 3.16 51 1-(2-(4- Fluorophenyl)pyrimidin-4-yl)- M-(4-methyl-1azabicyclo[3.2.2]nonan-4yl)piperidine-4-carboxamide 51 0.0466 0.335 0.0038 8 8.26 3.16 52 4-([ 1,1 ’ -Biphenyl]-3 -yl)-M-(4methyl-1- 52 0.503 1.06 0.337 7.36 8.64

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azabicyclo[3.2.2]nonane-4- yl)piperidine-1-carboxamide 53 4-([ 1, G-Biphenyl]-4-yl)-N-(4methyl-1- azabicyclo[3.2.2]nonan-4yl)piperidine-1-carboxamide 53 2.21 1.24 0.175 6.74 6.29 54 1-(5-Fgor-4-(4- fluorophenyl)pyrimidin-2-yl)- N-(3-methylquinuclidin-3 yl)piperidine-4-carboxamide 54 0.00073 4 0.106 0.0000 90 2 5.13 8.04 55 1-(5-Fgor-4-(4- fluorophenyl)pyrimidin-2-yl)- M-(4-methyl-1azabicyclo[3.2.2]nonan-4yl)piperidine-4-carboxamide 55 0.00073 6 0.0475 0.0000 47 9 3.74 0.10 56 1-(5-Fgor-4-(4-(2- methoxyethoxy)phenyl)pyrimidin-2-yl)-N-(4-methyl-1 azabicyclo[3.2.2]nonan-4yl)piperidin-4-carboxamide 56 0.00463 0.0209 0.0001 73 6.76 7.42 57 1-(5-Fgor-4-(4-(2- methoxyethoxy)phenyl)pyrimidin-2-yl)-N-(3- methylquinuclidine-3 - yl)piperidine-4-carboxamide 57 0.00241 0.0693 0.0001 69 10. 1.0 58 1-(5-Fgor-4-(4-((2- methoxyethoxy)methyl)phenyl)p-irimidin-2-yl)-N-(4-methyl l1-azabicyclo[3.2.2]nonan-4yl)piperidin-4-carboxamide 58 0.00339 0.0405 0.0001 7 10. 1.0 59 1-(5-Fgor-4-(4-((2- methoxyethoxy)methyl)phenyl)p irimidin-2-yl)-N-(3 methylquinuclidine-3 - yl)piperidine-4-carboxamide 59 0.00918 0.152 0.0003 39 10. 0.464 60 1-(5-Fgor-4-(4- (methoxymethyl)phenyl)pyrimidin-2-yl)-N-(4-methyl-1 azabicyclo[3.2.2]nonan-4yl)piperidin-4-carboxamide 60 0.00168 0.0155 0.0001 3.5 0.0464 61 1-(5-Fgor-4-(4- 61 0.00141 0.0524 0.0001 8.54 0.0464

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(methoxymethyl)phenyl)pyrimidin-2-yl)-I-(3methylquinuclidin-3yl)piperidine-4-carboxamide 3 62 1-(5-Fgor-4-(4-(3- methoxypropoxy)phenyl)pyrimidin-2-yl)-M-(4-methyl-1 azabicyclo [3.2.2] but nan-4 yl)piperidin-4-carboxamide 62 0.00093 1 0.0105 0.0001 09 2.39 0.10 63 1-(5-Fgor-4-(4-(3- methoxypropoxy)phenyl)pyri midin-2-yl)-M-(3methylquinuclidin-3 yl)piperidine-4-carboxamide 63 0.00058 6 0.0408 0.0000 98 8 3.52 0.10 64 1-(4-(3,4- Difluorophenyl)pyrimidin-2l) -N-(4 -methyl-1 azabicyclo [3.2.2] but nan-4 yl)piperidine-4-carboxamide 64 0.0017 0.0329 0.0000 62 3.42 5.53 65 1-(4-(3.5- Difluorophenyl)pyrimidin-2l)-N-(4-methyl-1 azabicyclo [3.2.2] but nan-4 yl)piperidine-4-carboxamide 65 0.00131 0.0561 0.0000 93 4 4.14 0.215 66 1-(4-(4-(2- Methoxyethoxy)phenyl)pyrim idin-2-yl)-N-(4-methyl-1 azabicyclo [3.2.2] but nan-4 yl)piperidin-4-carboxamide 66 0.00317 0.0693 0.0003 29 8.2 0.215 67 1-(4-(4-(3- Methoxypropoxy)phenyl)pyrimidin-2-yl)-N-(4-methyl-1 azabicyclo [3.2.2] but nan-4 yl)piperidin-4-carboxamide 67 0.00188 0.00724 0.0001 14 4.95 1.0 68 1 -(4 ’ -(2-Methoxyethoxy)[1, G biphenyl]-3 -yl)-I-(4-methyl-1azabicyclo[3.2.2] but nan-4 yl)piperidin-4-carboxamide 68 0.0213 0.132 0.0035 3 7.12 3.16 69 1-(4’-((2- Methoxyethoxy)methyl) [1, G biphenyl]-3-yl)-I-(4-methyl-1- 69 0.0362 0.303 0.0046 4 4.64 1.0

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azabicyclo [3.2.2] but nan-4 - yl)piperidine-4-carboxamide 70 1-(4-(4- (Methoxymethyl)phenyl)pyrimidin-2-yl)-N-(4-methyl-1 azabicyclo [3.2.2] but nan-4 yl)piperidin-4-carboxamide 70 0.00396 0.0156 0.0000 90 5 1.0 1.0 71 1-(4-(4-(2- Fluoroethoxy)phenyl)pyrimidin-2-yl)-N-(4-methyl-1azabicyclo [3.2.2] but nan-4 yl)piperidin-4-carboxamide 71 0.00248 0.00429 0.0001 26 2.15 0.010 72 1-(4-(4-(3- Methoxypropoxy)phenyl)pyrimidin-2-yl)-N-(quinuclidin3-yl)piperidin-4carboxamide 72 0.00116 0.0795 0.0002 6 8.63 0.464 73 1-(4-(4- (Methoxymethyl)phenyl)pyrim idin-2-yl)-N-(3methylquinuclidin-3 yl)piperidine-4-carboxamide 73 0.00346 0.0474 0.0002 5 4.64 0.631 74 1-(4-(4-((2- Methoxyethoxy)methyl)phenyl)pyrimidin-2-yl)-N-(4-methyl1-azabicyclo[3.2.2]nonan-4yl)piperidin-4-carboxamide 74 0.0128 0.0325 0.0007 1 10. 0.215 75 4-Fluoro-1-(4-(4(methoxymethyl)phenyl)pyrimidin-2-yl)-N-(4-methyl-1 azabicyclo [3.2.2] but nan-4 yl)piperidin-4-carboxamide 75 0.00283 0.0489 0.0003 83 5.27 0.316 76 4-Fluoro-1-(4-(4-(3- methoxypropoxy)phenyl)pyrimidin-2-yl)-N-(3methylquinuclidine-3 - yl)piperidine-4-carboxamide 76 0.00134 0.0587 0.0001 41 3.87 1.0 77 4-Fluoro-1-(5-fluoro-4-(4-((2methoxyethoxy)methyl)phenyl)p irimidin-2-yl) -N-(4-methyl l1 -azabicyclo[3.2.2]nonan-4- 77 0.00167 0.0863 0.0003 16 3.76 0.316

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yl)piperidine-4-carboxamide 78 4-Fluoro-1-(5-fluoro-4-(4-((2methoxyethoxy)methyl)phenyl)p-irimidin-2-yl)-N-(4-methyl l1-azabicyclo[3.2.2]nonan-4yl) piperidine-4-carboxamide (single enantiomer A) 78 0.0647 3.12 0.0048 7 3.54 1.0 79 4-Fluoro-1-(5-fluoro-4-(4-((2methoxyethoxy)methyl)phenyl)p-irimidin-2-yl)-N-(4-methyl l1-azabicyclo[3.2.2]nonan-4yl) piperidine-4-carboxamide (single enantiomer B) 79 0.0018 0.109 0.0001 91 4.28 0.215 80 4-Fluoro-1-(4-(4- (methoxymethyl)phenyl)pyrimidin-2-yl)-N-(3- methylquinuclidine-3 - yl)piperidine-4-carboxamide 80 0.0040 0.0685 0.0005 25 10. 0.215 81 (8)-4-Fluoro-1-(4-(4- (methoxymethyl)phenyl)pyrimidin-2-yl)-N-(3- methylquinuclidine-3 - yl)piperidine-4-carboxamide 81 0.0023 0.0481 0.0002 22 10. 0.316 82 4-Fgor-1-(4-(4-(3- methoxypropoxy)phenyl)pyrimidin-2-yl)-M-(4-methyl-1 azabicyclo[3.2.2] nonan-4yl)piperidin-4-carboxamide 82 0.00126 0.0421 0.0001 28 2.79 1.0 83 4-Fluorine-1-(4-(4-((2- methoxyethoxy)methyl)phenyl)p irimidin-2-yl)-N-(3 methylquinuclidine-3 - yl)piperidine-4-carboxamide 83 0.0134 0.119 0.0011 3 10. 1.0 84 (8)-4-Fluorine-1-(4-(4-((2- methoxyethoxy)methyl)phenyl)p irimidin-2-yl)-M-(3 methylquinuclidine-3 - yl)piperidine-4-carboxamide 84 0.00535 0.0903 0.0006 21 10. 1.0 85 4-Fluoro-1-(4-(4-(2- methoxyethoxy)phenyl)pyrimidin-2-yl)-N-(3- 85 0.0105 0.0799 0.0003 89 10. 0.316

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methylquinuclidine-3 - yl)piperidine-4-carboxamide 86 (8)-4-Fluoro-1-(4-(4-(2- methoxyethoxy)phenyl)pyrimidin-2-yl)-N-(3- methylquinuclidine-3 - yl)piperidine-4-carboxamide 86 0.00346 0.048 0.0002 41 10. 1.0 87 4-Fluoro-1-(4-(4-(2- fluoroethoxy)phenyl)pyrimidium and-2-yl)-N-(quinu clidin-3 yl)piperidine-4-carboxamide 87 0.00191 0.0643 0.0001 77 8.91 0.215 88 (8)-4-Fluoro-1-(4-(4-(2fluoroethoxy)phenyl)pyrimidium and-2-yl)-N-(quinu clidin-3 yl)piperidine-4-carboxamide 88 0.00168 0.0568 0.0002 52 10. 1.0 89 4-Fluoro-1-(4-(4-((2methoxyethoxy)methyl)phenyl)p-irimidin-2-yl)-N-(4-methyl l1-azabicyclo[3.2.2]nonan-4yl)piperidin-4- carboxamide 89 0.00823 0.109 0.0011 7 9.47 0.316 90 4-Fluoro-1-(4-(4-(2fluoroethoxy)phenyl)pyrimidi n-2-yl)-N-(4-methyl-1azabicyclo[3.2.2] nonan-4yl)piperidine-4-carboxamide 90 0.00226 0.0134 0.0000 95 3 3.06 0.215 91 4-Fluoro-1-(5-fluoro-4-(4-(2methoxyethoxy)phenyl)pyrimidin-2-yl)-N-(4-methyl-1 azabicyclo[3.2.2] nonan-4yl)piperidin-4 -carboxamide 91 0.00204 0.0714 0.0001 17 2.66 0.10 92 4-Fluoro-1-(4-(4-(2- fluoroethoxy)phenyl)pyrimidin n-2-yl)-N-(3- methylquinuclidine-3 - yl)piperidine-4-carboxamide 92 0.00146 0.029 0.0001 06 6.83 0.10 93 4-Fluoro-1-(4-(4-(2methoxyethoxy)phenyl)pyrimidin-2-yl)-N-(4-methyl-1 azabicyclo[3.2.2]nonan-4yl)piperidine-4-carboxamide 93 0.00396 0.0439 0.0002 61 3.96 0.316 94 4-Fluoro-1-(4-(4- 94 0.00073 0.0144 0.0000 2.1 0.0464

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fluorophenyl)pyrimidin-2-yl)- M-(4-methyl-1azabicyclo [3.2.2] but nan-4 yl)piperidine-4-carboxamide 6 96 4 95 4-Fluoro-1-(4-(4- fluorophenyl)pyrimidin-2-yl)- N-(3-methylquinuclidin-3 yl)piperidine-4-carboxamide 95 0.00058 5 0.020 0.0000 83 6 4.69 0.0316 96 1-(4-(4- (Methoxymethyl)phenyl)pyrim idin-2-yl)-4-methyl-N-(4 methyl-1- azabicyclo [3.2.2] but nan-4 yl)piperidine-4-carboxamide 96 0.0070 0.145 0.0008 04 3.39 1.0 97 1-(4-(4-((2- Methoxyethoxy)methyl)phenyl)pyrimidin-2-yl)-4-methyl-N(4-methyl-1azabicyclo [3.2.2] but nan-4 yl)piperidin-4-carboxamide 97 0.0134 0.285 0.0013 6 10. 1.0 98 1-(4-(4-((2- Methoxyethoxy)methyl)phenyl)pyrimidin-2-yl)-4-methyl-N(3-methylquinuclidin-3 yl)piperidin-4-carboxamide 98 0.0769 1.91 0.0081 3 8.19 1.0 99 1-(4-(4- Fluorophenyl)pyrimidin-2-yl)4-hydroxy-M-(4-methyl-1 azabicyclo [3.2.2] but nan-4 yl)piperidin-4-carboxamide 99 0.00223 0.012 0.0000 55 2 3.78 0.0464 100 1-(4-(4- Fluorophenyl)pyrimidin-2-yl)4-methoxy-M-(4-methyl-1azabicyclo[3.2.2]nan-4yl)piperidin-4-carboxamide 100 0.00368 0.0265 0.0001 09 1.9 1.0 101 4-Metho xy-1 -(4-(4-(3 methoxypropoxy)phenyl)pyrimidin-2-yl)-M-(4-methyl-1 azabicyclo [3.2.2] but nan-4 yl)piperidin-4 -carboxamide 101 0.00338 0.0785 0.0004 36 2.03 1.0 102 1-(5-Fgor-(4-(4-(2- 102 0.00103 0.0929 0.0002 2.85 0.10

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fluoroethoxy)phenyl)pyrimidin n-2-yl)-4-methoxy-N-(4methyl-1- azabicyclo[3.2.2]nonan-4yl)piperidine-4-carboxamide 58 103 1-(4-(4-(2- Fluoroethoxy)phenyl)pyrimidin n-2-yl)-4-methoxy-N-(4methyl-1- azabicyclo[3.2.2]nonan-4yl)piperidine-4-carboxamide 103 0.00365 0.0738 0.0002 9 3.11 0.316 104 1-(4-(4-Fluorophenyl)-5-(2methoxyethoxy)pyrimidine-2l)-N-(4-methyl-1 azabicyclo[3.2.2]nonan-4yl)piperidine-4-carboxamide 104 0.0251 0.0513 0.0030 10. 1.0 105 1-(4-(4-Fluorophenyl)-6-(2methoxyethoxy)pyrimidine-2l)-N-(4-methyl-1 azabicyclo[3.2.2]nonan-4yl)piperidine-4-carboxamide 105 0.0105 0.272 0.0020 3.66 1.0 106 1 -(4-(4-Fluorophenyl)pyridin- 2 -yl)-N-(4 -methyl-1 azabicyclo[3.2.2]nonan-4yl)piperidine-4-carboxamide 106 0.00085 8 0.0153 0.0000 95 6.97 9.02 107 1 -(5 -(4-Fluorophenyl)pyridin- 3-yl)-N-(4-methyl-1 azabicyclo[3.2.2]nonan-4yl)piperidine-4-carboxamide 107 0.00476 0.299 0.0009 35 10. 0.0785 108 1 -(2-(4-Fluorophenyl)pyridin- 4 -yl)-N-(4 -methyl-1 azabicyclo[3.2.2]nonan-4yl)piperidine-4-carboxamide 108 0.0808 1.08 0.0541 5.65 3.16 109 1-(4-(4- Fluorophenyl)pyrimidin-2-yl)- M-methyl-M-(quinuclidin-3 yl)piperidine-4-carboxamide 109 0.0401 2.23 0.0089 9 9.53 3.16 BY 1-Azabicyclo[3.2.2]nonan-4yl-1-(4-(4fluorophenyl)pyrimidin-2yl)piperidine-4-carboxylate BY 0.00122 0.528 0.0023 9 3.81 1.0

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111 1-(5-Fgor-4-(4-(3- methoxypropoxy)phenyl)pyrimidin-2-yl)-N-(4-methyl-1 azabicyclo [3.2.2] but nan-4 yl)azetidine-4-carboxamide 111 0.0020 0.119 0.0001 9 3.65 1.0 112 1-(5-Fgor-4-(4- fluorophenyl)pyrimidin-2-yl)- M-(4-methyl-1azabicyclo [3.2.2] but nan-4 yl)azetidine-3-carboxamide 112 0.00737 0.122 0.0002 38 7.24 0.316 113 1-(4-(4- Fluorophenyl)pyrimidin-2-yl)- M-(4-methyl-1azabicyclo [3.2.2] but nan-4 yl)azetidine-3-carboxamide 113 0.00831 0.546 0.0008 84 10. 0.316 114 1 -(4 '-Fluoro [1, G-biphenyl]-3 and l) -N-(4 -methyl-1 azabicyclo [3.2.2] but nan-4 yl)azetidine-3-carboxamide 114 0.051 0.272 0.0111 3.46 1.0 115 1-(4-(4- Fluorophenoxy)pyrimidin-2l)-N-(4-methyl-1 azabicyclo [3.2.2] but nan-4 yl)piperidine-4-carboxamide 115 0.00245 0.00894 0.0001 4 9.3 0.0464 116 4-Fluoro-1-(4-(4fluorophenoxy)pyrimidine-2- and k) -N-(4-methyl-1 azabicyclo [3.2.2] but nan-4 yl)piperidine-4-carboxamide 116 0.00143 0.0159 0.0001 55 5.72 0.10 117 4-Fluoro-1-(4-(4-fluorophenoxy)- 1,3,5-triazin-2-yl)-N-(4 methyl-1- azabicyclo [3.2.2] but nan-4 yl)piperidine-4-carboxamide 117 0.168 0.0884 0.0090 5 10. 1.0 118 4-Fluoro-1-(4-(4-fluorophenoxy)- 1,3,5-triazin-2-yl)-N-(4 methyl-1- azabicyclo [3.2.2] but nan-4 yl)piperidine-4-carboxamide 118 0.00254 0.0634 0.0011 6 4.64 1.0 119 1-(4-(4- Cyanophenoxy)pyrimidine-2- 119 0.00671 0.0544 0.0004 76 10. 0.316

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yl)-4-fluoro-N-(3methylquinuclidin-3 yl)piperidine-4-carboxamide 120 1-(4-(4- Cyanophenoxy)pyrimidin-2yl)-4-fluoro-N-(4-methyl-1azabicyclo[3.2.2]nan-4yl)piperidine-4-carboxamide 120 0.00412 0.0188 0.0003 32 10. 0.316 121 1-(4-(4- Fluorophenoxy)pyrimidin-2yl)-N-(3-methylquinuclidin-3yl)piperidine-4-carboxamide 121 0.00133 0.0263 0.0000 93 7.65 0.10 122 1-(5-Cyano-4-(4- fluorophenoxy)pyrimidin-2yl)-4-fluoro-N-(3methylquinuclidin-3 yl)piperidine-4-carboxamide 122 0.00441 0.112 0.0006 39 10. 0.316 123 4-Fluoro-N-(4-methyl-1 azabicyclo [3.2.2] but nan-4 -yl) 1 -(4-((tetrahydro-2H-pyran-4yl)oxy)pyrimidin-2yl)piperidin-4- carboxamide 123 0.0423 0.226 0.0022 6 10. 1.0 124 4-Fluoro-1-(4-((4fluorobenzyl)oxy)pyrimidine- 2 -yl)-N-(4 -methyl-1 azabicyclo [3.2.2] but nan-4 yl)piperidine-4-carboxamide 124 0.000553 0.0178 0.0000 849 3.42 0.10 125 4-Fluoro-1-(4-((4- fluorobenzyl)oxy)pyrimidin2-yl)-M-(3-methylquinuclidin3-yl)piperidin-4carboxamide 125 0.000643 0.0177 0.0000 509 4.29 0.158 126 4-Fluoro-1-(6-(4fluorophenoxy)pyrazin-2-yl)- M-(4-methyl-1azabicyclo [3.2.2] but nan-4 yl)piperidine-4-carboxamide 126 0.00157 0.036 0.0007 26 6.26 1.0 127 4-Fluoro-1-(5-(4- fluorophenoxy)pyridin-3-yl)- M-(4-methyl-1- azabicyclo [3.2.2] but nan-4 - 127 0.00227 0.106 0.0005 69 6.98 0.316

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yl)piperidine-4-carboxamide 128 4-Fluoro-1-(4-((4fluorobenzyl)oxy)-1,3,5triazin-2-yl)-N-(4-methyl-1 azabicyclo[3.2.2]nonan-4yl)piperidine-4-carboxamide 128 0.0198 0.654 0.0034 10. 1.0 129 4-Fluoro-1-(5-(4- fluorophenoxy)pyrimidine-2- yl)-N-(3-methylquinuclidin-3 yl)piperidine-4-carboxamide 129 0.00427 0.0978 0.0003 8 8.26 0.316 130 1-(5-(4- Fluorophenoxy)pyrimidin-2l)-N-(4 -methyl-1 azabicyclo[3.2.2]nonan-4yl)piperidine-4-carboxamide 130 0.00088 9 0.0169 0.0001 56 5.67 0.316 131 4-Fluoro-1-(5-(4-(2- methoxyethoxy)phenoxy)pyrimidin-2-yl)-N-(3methylquinuclidine-3 - yl)piperidine-4-carboxamide 131 0.00681 0.0527 0.0008 58 10. 1.0 132 4-Fluoro-1-(5-((4fluorobenzyl)oxy)pyrimidine- 2 -yl)-N-(4 -methyl-1 azabicyclo[3.2.2]nonan-4yl)piperidine-4-carboxamide 132 0.0107 0.115 0.0026 5 4.59 1.0 133 4-Fluoro-1-(5-(4- fluorophenoxy)pyrazin-2-yl)- N-(3-methylquinuclidin-3 yl)piperidine-4-carboxamide 133 0.0459 0.467 0.0048 3 10. 1.0 134 4-Fluoro-1-(6-(4fluorophenoxy)pyridazin-3 and l)-N-(4 -methyl-1 azabicyclo[3.2.2]nonan-4yl)piperidine-4-carboxamide 134 0.0145 0.343 0.0028 3 10. 1.0 135 4-Fluoro-1-(4-((4- fluorophenoxy)methyl)pyrimide in-2-yl)-N-(3- methylquinuclidine-3 - yl)piperidine-4-carboxamide 135 0.00138 0.0317 0.0001 32 8.25 0.0464 136 4-Fluoro-1-(5-(4- fluorobenzyl)pyrimidin-2-yl)- 136 0.0079 0.0249 0.0007 16 10. 1.0

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N-(3-methylquin clidin-3 yl)piperidine-4-carboxamide 137 (3K)-3-Methyl-N-(4-methyl-1azabicyclo[3.2.2]nonan-4-yl) 4-(4-phenylpyrimidin-2yl)piperazine-1-carboxamide (single enantiomer B) 137 0.0032 0.0501 0.0001 98 5.72 1.0 138 (ZV.)-3-Methyl-N-(4-methyl-1azabicyclo[3.2.2]nonan-4-yl) 4-(4-phenylpyrimidin-2yl)piperazine-1-carboxamide (single enantiomer A) 138 0.902 >10 0.0636 9.31 3.16 139 (3 S)-3-Methyl-N-(4-methyl-1 azabicyclo[3.2.2]nonan-4-yl) 4-(4-phenylpyrimidin-2yl)piperazine-1-carboxamide (single enantiomer B) 139 0.0173 0.067 0.0013 7 5.25 3.16 140 (3 S)-3-Methyl-N-(4-methyl-1 azabicyclo[3.2.2]nonan-4-yl) 4-(4-phenylpyrimidin-2yl)piperazine-1-carboxamide (single enantiomer A) 140 0.0469 9.08 0.574 6.49 3.16 141 3-Methyl-N-(4-methyl-1 azabicyclo[3.2.2]nonan-4-yl) 4-(4-phenylpyrimidin-2yl)piperazine-1-carboxamide 141 0.00596 0.209 0.0008 88 4.67 0.316 142 3-Ethyl-N-(4-methyl-1 azabicyclo[3.2.2]nonan-4-yl) 4-(4-phenylpyrimidin-2yl)piperazine-1-carboxamide 142 0.00769 0.10 0.0008 61 5.34 9.21 143 3-Ethyl-N-(4-methyl-1 azabicyclo[3.2.2]nonan-4-yl) 4-(4-phenylpyrimidin-2yl)piperazine-1-carboxamide 143 0.00179 0.0523 0.0003 04 3.11 3.16 144 3-(Methoxymethyl)-M-(4methyl-1- azabicyclo[3.2.2]nonan-4-yl) 4-(4-phenylpyrimidin-2yl)piperazine-1-carboxamide 144 0.0673 0.529 0.0063 3 10. 1.0 145 4-(4-(4- Fluorophenyl)pyrimidin-2-yl)- 145 0.00801 0.0763 0.0005 07 6.98 0.316

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3-venstil-N-(4-vengerstyl-1azabicyclo [3.2.2] but nan-4 yl)piperazine-1-carboxamide 146 4-(4-(4- Fluorophenyl)pyrimidin-2-yl)3-methyl-M-(4-methyl-1azabicyclo[3.2.2]nan-4yl)piperazin-1-carboxamide 146 0.0166 0.11 0.0005 59 6.37 1.0 147 cis-3,5 - Dimethyl-N - (4 -methyl1-azabicyclo[3.2.2]nonan-4l) -4 -(4-phenylpyrimidin-2yl)piperazine-1-carboxamide 147 0.00545 0.096 0.0010 3.51 1.0 148 4-(5-Fluoro-4-(4- (methoxymethyl)phenyl)pyrimidin-2-yl)-3-isopropyl-M-(4 methyl-1- azabicyclo [3.2.2] but nan-4 yl)piperazine-1-carboxamide 148 0.0174 0.39 0.0085 9 3.46 1.0 149 4-(4-(4(Methoxymethyl)phenyl)pyrim idin-2 -yl)-N-(4 -methyl-1 azabicyclo [3.2.2] but nan-4 -yl) 3 -(trifluoromethyl)piperazine1-carboxamide 149 0.0109 0.279 0.0015 4.31 1.0 150 3 -(Difluoromethyl)-4-(4-(4(methoxymethyl)phenyl)pyrimidin-2-yl) -N-(4-methyl-1 azabicyclo [3.2.2] but nan-4 yl)piperazine-1 - carboxamide 150 0.023 0.195 0.0010 6 5.44 1.0 151 3-Isopropyl-4-(4-(4(methoxymethyl)phenyl)-1,3,5triazin-2-yl)-M-(4-methyl-1 azabicyclo [3.2.2] but nan-4 yl)piperazin- 1-carboxamide 151 0.324 1.82 0.0956 9.84 1.0 152 (3R)-4-(5-(4- Fluorophenoxy)pyrimidin-2yl)-3-methyl-M-(4-methyl-1 azabicyclo [3.2.2] but nan-4 yl)piperazine-1-carboxamide 152 0.00288 0.0763 0.0004 39 6.77 0.316 153 3-Ethynyl-4-(4-(4- (Methoxymethyl)phenyl)pyrim 153 0.0534 2.64 0.0117 10. 1.0

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idin-2-yl)-N-(4-methyl-1 azabicyclo[3.2.2]nonan-4yl)piperazin-1-carboxamide 154 1-Azabicyclo[3.2.2]nonan-4yl-3-methyl-4-(4phenylpyrimidin-2yl)piperazine-1-carboxylate 154 0.057 1.93 0.0165 2.84 1.0 155 Quinuclidin-3 -yl(2-(4 ’ -(2methoxyethoxy) [1, G biphenyl]-4-yl)propan-2yl)carbamate 155 0.00348 0.0386 0.0006 57 1.0 0.215 156 (8)-Quinuclidin-3-yl(2-(4’-(2methoxyethoxy) [1, G biphenyl]-4-yl)propan-2yl)carbamate 156 0.00414 0.0437 0.0013 1 4.74 0.763 157 (R)-1-(2-(4’-(2- Methoxyethoxy) [1, G biphenyl]-4-yl)propan-2-yl)3 -(3-methylquin clidin-3 yl)urea 157 0.228 0.538 0.042 3.16 3.16 158 (S)-1-(2-(4’-(2Methoxyethoxy) [1, G biphenyl]-4-yl)propan-2-yl)3 -(3-methylquin clidin-3 yl)urea 158 0.00285 0.00762 0.0005 29 0.631 0.631 159 1 -(3 -Egilquin clidin-3-yl)-3 (2-(4 ’ -(2-methoxyethoxy) [1, G biphenyl]-4-yl)propan-2yl)urea 159 0.0056 0.00446 0.0006 36 1.0 1.0 160 1-(2-(4’-(2- Methoxyethoxy) [1, G biphenyl]-4-yl)propan-2-yl)3-(4-methyl-1- azabicyclo[3.2.2] nonan-4yl)urea 160 0.00391 0.0019 0.0005 44 1.0 1.0 161 N-(2-(4’-(2- Methoxyethoxy)[1, G biphenyl]-4-yl)propan-2-yl)1,4-diazabicyclo[3.2.2]nonane4-carboxamide 161 0.25 0.311 0.0327 3.16 3.16 162 1-(1-(4’-(2- 162 0.0281 0.0727 0.0022 3.54 1.0

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Methoxyethoxy) [1, G biphenyl]-4-yl)cyclopropyl)3 -(quinuclidin-3-yl)urea 1 163 1-(1-(4’-(2- Methoxyethoxy) [1, G biphenyl]-4-yl)cyclopropyl)3 -(3-methylquinuclidin-3 yl)urea 163 0.00849 0.00657 0.0005 39 1.0 0.173 164 1 -(3 -Ethylquinuclidin-3 -yl)-3 (1 -(4 ’ -(2-methoxyethoxy) [1, G biphenyl]-4yl)cyclopropyl)urea 164 0.00616 0.00251 0.0002 05 1.0 0.173 165 1-(1-(4’-(2- Methoxyethoxy) [1, G biphenyl]-4-yl)cyclopropyl)3-(4-methyl-1- azabicyclo[3.2.2] nonan-4yl)urea 165 0.00415 0.00051 6 0.0002 4 0.316 0.0316 166 Quinuclidin-3 -yl(1 -(4' -(2methoxyethoxy)[1,1'biphenyl]-4yl)cyclopropyl)carbamate 166 0.00569 0.0219 0.0018 1 0.316 0.215 167 Quinuclidin-3 -yl(2-(3' -(2methoxyethoxy)[1,1'biphenyl]-4-yl)propan-2yl)carbamate 167 0.0104 0.109 0.0053 1 10. 1.0 168 1-Azabicyclo[3.2.2]nonan-4yl(2-(3’-(2- methoxyethoxy)[1,1’biphenyl]-4-yl)propan-2yl)carbamate 168 0.00556 0.0793 0.0033 4 10. 1.0 169 N-(2-(3’-(2- Methoxyethoxy)[1, G biphenyl]-4-yl)propan-2-yl)1,4-diazabicyclo[3.2.2]nonane4-carboxamide 169 0.257 0.283 0.018 10. 1.0 170 Quinuclidin-3 -yl(2-(4' -(2methoxyethoxy) [1,1'biphenyl] -3 -yl)propan-2yl)carbamate 170 0.0267 0.0295 0.0049 4 10. 10. 171 1-Azabicyclo[3.2.2]nonane-4- 171 0.0325 0.0119 0.0014 0.0746 3.98

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il(2-(4’-(2- methoxyethoxy)[1,1’biphenyl]-3-yl)propan-2yl)carbamate 5 172 Quinuclidin-3 -yl(2-(4' -(3 methoxypropoxy) [1,1'biphenyl] -4-yl)propan-2yl)carbamate 172 0.00241 0.0666 0.0015 6 8.29 10. 173 1-(2-(4’-(3- Methoxypropoxy) [1, G biphenyl]-4-yl)propan-2-yl)3 -(3-methylquin clidin-3 yl)urea 173 0.00198 0.0203 0.0007 66 10. 10. 174 N-(2-(4’-(3- Methoxypropoxy)[1, G biphenyl]-4-yl)propan-2-yl)1,4-diazabicyclo[3.2.2]nonane4-carboxamide 174 0.134 0.386 0.0225 10. 1.0 175 Quinuclidin-3 -yl(2-(4' -(2methoxyethoxy) [1,1'biphenyl] -3 -yl)propan-2yl)carbamate 175 0.0025 0.0713 0.0018 7 10. 9.0 176 1-(1-(4’-(3- Methoxypropoxy) [1, G biphenyl]-4-yl)cyclopropyl)3 -(3-methylquin clidin-3 yl)urea 176 0.0041 0.022 0.0014 7 10. 10. 177 1-(1-(4’-(3- Methoxypropoxy) [1, G biphenyl]-4-yl)cyclopropyl)3-(4-methyl-1- azabicyclo[3.2.2] nonan-4yl)urea 177 0.00159 0.00175 0.0004 97 10. 10. 178 1-Azabicyclo[3.2.2]nonan-4yl(1-(4’-(3methoxypropoxy) [1,1biphenyl]-4yl)cyclopropyl)carbamate 178 0.00354 0.0679 0.0026 1 10. 7.1 179 Quinuclidin-3 -yl(2-(4 ’ -(2(1H-pyrazol-1- yl)ethoxy) [1, G-biphenyl] -4- 179 0.00673 0.0952 0.0049 9 8.73 3.16

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yl)propan-2-yl)carbamate 180 1-(2-(4’-(2-(1H-Pyrazole-1- yl)ethoxy) [1, G-biphenyl]-4yl)propan-2-yl)-3 -(3 methylquinuclidin-3 yl)urea 180 0.0053 0.0463 0.0018 1 3.16 3.16 181 1-(2-(4’-(2-(1H-Pyrazole-1- yl)ethoxy) [1, G-biphenyl]-4yl)propan-2-yl)-3 -(4-methyl-1 azabicyclo[3.2.2]nonan-4yl)urea 181 0.00233 0.00515 0.0005 87 1.0 1.0 182 Quinuclidin-3 -yl(2-(4 ’ -(2(1H-1,2,3-triazol-1yl)ethoxy) [1, G-biphenyl]-4yl)propan-2-yl)carbamate 182 0.0431 0.388 0.0131 3.16 1.0 183 1-(2-(4’-(2-(1H-1,2,3-Triazol- 1 -yl)ethoxy) [1,1’-biphenyl] -4yl)propan-2-yl)-3 -(3 methylquinuclidin-3 yl)urea 183 0.0316 0.969 0.0102 5.62 2.51 184 1-(2-(4’-(2-(1H-1,2,3-Triazol- 1 -yl)ethoxy) [1,1’-biphenyl] -4yl)propan-2-yl)-3 -(3 ethylquinuclidine-3 - silt)urea 184 0.0211 0.188 0.0034 6 3.16 1.0 185 1-(2-(4'-(2-(1H-1,2,3-Triazol1 -yl)ethoxy) [1,1'-biphenyl]-4yl)propan-2-yl)-3 -(4- methyl-1 azabicyclo[3.2.2] nonan-4yl)urea 185 0.0129 0.0999 0.0038 7 3.16 1.0 186 Quinuclidin-3 -yl(2-(4' -(2methoxyethoxy) [1,1'biphenyl] -3 -yl)propan-2yl)carbamate 186 0.045 0.157 0.0107 10. 1.0 187 1-Azabicyclo[3.2.2]nonan-4yl(2-(4'-(3-(1H-1,2,3-triazol1 -yl)propoxy) [1, G biphenyl]-4-yl)propan-2yl )carbamate 187 0.0202 0.106 0.0077 4 10. 1.0 188 N-(2-(4 '-(3 -(1H-1,2,3 -Triazol1 -yl)propoxy) [1, G - 188 0.597 0.365 0.0774 10. 1.0

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biphenyl]-4-yl)propan-2-yl)- 1,4-diazabicyclo[3.2.2]nonane4-carboxamide 189 Quinu clidin-3 -yl(2-(4 ’ -(3 cyanopropoxy) [1, G biphenyl]-4-yl)propan-2yl)carbamate 189 0.00957 0.0865 0.0032 2 10. 8.47 190 Quinuclidin-3 -yl(2-(4' (cyanomethoxy) [1, G biphenyl]-4-yl)propan-2yl)carbamate 190 0.00259 0.0477 0.0007 75 10. 1.0 191 Quinuclidin-3 -yl(2-(4 ’ -((3 methyloxetan-3 yl)methoxy) [1, G-biphenyl]-4yl)propan-2-yl)carbamate 191 0.0072 0.0718 0.0032 4 5.25 1.0 192 1 -Azabicyclo[3.2.2]nonan-4yl(2-(4 ’ -((3-methyloxetan-3yl)methoxy) [1, G-biphenyl]-4yl)propan-2-yl)carbamate 192 0.00569 0.0816 0.0018 6 5.84 1.0 193 1 -Azabicyclo[3.2.2]nonan-4yl(2-(4 ’ -((3-methyloxetan-3yl)methoxy) [1, G-biphenyl]-4yl)propan-2-yl)carbamate 193 0.297 0.318 0.0447 10. 10. 194 Quinuclidin-3 -yl(2-(4 ’ -(2(oxetan-3 -yl)ethoxy) [1, G biphenyl]-4-yl)propan-2yl)carbamate 194 0.0105 0.115 0.0040 6 9.93 1.0 195 1 -Azabicyclo [3.2.2] nonan-4yl(2-(4 ’ -(2-(oxetan-3 yl)ethoxy) [ 1, G -biphenyl] -4yl)propan-2-yl)carbamate 195 0.00567 0.0948 0.0010 1 8.03 0.10 196 X-(2-(4'-(2-(Oxetan-3yl)ethoxy) [1, G-biphenyl]-4yl)propan-2-yl)-1,4diazabicyclo[3.2.2]nonane-4 carboxamide 196 0.538 0.274 0.0283 10. 1.0 197 Quinuclidin-3 -yl(2-(4 ’ -((2methoxyethoxy)methyl) [1, G biphenyl]-4-yl)propan-2yl)carbamate 197 0.0322 0.309 0.0096 7 10. 10. 198 1-(2-(4’-((2- 198 0.0252 0.118 0.0032 10. 10.

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Methoxyethoxy)methyl) [1,1biphenyl]-4-yl)propan-2-yl)3 -(3-methylquinuclidin-3 yl)urea 4 199 1 -(3 -Ethylquinuclidin-3 -yl)-3 (2-(4’-((2- methoxyethoxy)methyl)[1,1biphenyl]-4-yl)propan-2yl)urea 199 0.0147 0.0317 0.0018 1.0 1.0 200 1-Azabicyclo[3.2.2]nonan-4yl(2-(4’-((2methoxyethoxy)methyl) [1,1biphenyl]-4-yl)propan-2yl)carbamate 200 0.024 0.22 0.0061 6 10. 1.0 201 1-(2-(4’-((2- Methoxyethoxy)methyl)[1,1biphenyl]-4-yl)propan-2-yl)3-(4-methyl-1- azabicyclo[3.2.2] nonan-4yl)urea 201 0.0139 0.023 0.0007 6 10. 0.316 202 N-(2-(4’-((2- Methoxyethoxy)methyl)[1,1biphenyl]-4-yl)propan-2-yl)1,4-diazabicyclo[3.2.2]nonane4-carboxamide 202 2.35 0.933 0.154 10. 10. 203 Quinuclidin-3 -yl(2-(4 ’ -((2methoxyethoxy)methyl) [1,1biphenyl]-3 -yl)propan-2yl)carbamate 203 0.0296 0.0963 0.0065 3 10. 1.78 204 1-Azabicyclo[3.2.2]nonan-4yl(1-(4’-((2methoxyethoxy)methyl) [1,1biphenyl]-4yl)cyclopropyl)carbamate 204 0.0433 0.0993 0.0082 6 10. 1.47 205 1-(1-(4’-((2- Methoxyethoxy)methyl)[1,1biphenyl]-4-yl)cyclopropyl)3 -(3-methylquinuclidin-3yl)urea 205 0.0515 0.156 0.0053 1 10. 1.78 206 1 -(3 -Egilquinu clidin-3 -yl)-3 (1-(4’-((2- 206 0.0278 0.0596 0.0026 6 10. 1.78

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methoxyethoxy)methyl) [1,1biphenyl]-4- yl)cyclopropyl)urea 207 1-(1-(4’-((2- Methoxyethoxy)methyl)[1,1biphenyl]-4-yl)cyclopropyl)3-(4-methyl-1- azabicyclo [3.2.2] but nan-4 yl)urea 207 0.0123 0.0313 0.0013 9 10. 1.78 208 1 -(3 -Egilquinuclidin-3 -yl)-3 (1-(4’-((2- methoxyethoxy)methyl) [1,1- biphenyl]-4- yl)cyclopropyl)urea (single enantiomer A) 208 2.71 0.988 0.0739 10. 10. 209 1 -(3 -Egilquin clidin-3 -yl)-3 (1-(4'-((2methoxyethoxy)methyl) [1,1biphenyl]-4yl)cyclopropyl)urea (single enantiomer B) 209 0.0174 0.0392 0.0010 5 10. 1.78 210 (S)-l-(l-(4’-((2- Methoxyethoxy)methyl)[1,1biphenyl]-4-yl)cyclopropyl)3 -(3-methylquinuclidin-3yl)urea 210 0.0502 0.087 0.0033 4 10. 10. 211 (R)-1-(1-(4’-((2- Methoxyethoxy)methyl)[1,1biphenyl]-4-yl)cyclopropyl)3 -(3-methylquinuclidin-3yl)urea 211 0.938 0.683 0.072 10. 3.16 212 1-Azabicyclo[3.2.2] nonan-4yl)(1-(4’-(3methoxypropyl) [1,1biphenyl]-4yl)cyclopropyl)carbamate 212 0.00385 0.0479 0.0025 3 6.36 10. 213 1-(1-(4’-(3- Methoxypropyl)[1,1’biphenyl]-4-yl)cyclopropyl)3-(4-methyl-1- azabicyclo [3.2.2] but nan-4 - 213 0.00112 0.0059 0.0003 5 9.22 10.

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silt)urea 214 1-(1-(4’-(3- Methoxypropyl) [1, G biphenyl]-4-yl)cyclopropyl)3 -(3-methylquinuclidin-3yl)urea 214 0.00329 0.0329 0.0012 6 10. 10. 215 1 -(3 -Ethylquinuclidin-3 -yl)-3 (1 -(4 ’ -(3 -methoxypropyl) [1, G biphenyl]-4yl)cyclopropyl)urea 215 0.00248 0.0162 0.0005 42 7.55 10. 216 Quinu clidin-3 -yl (1 -(4 '((pyridin-3ylmethoxy)methyl) [1, G biphenyl]-4yl)cyclopropyl)carbamate 216 0.00933 0.201 0.0111 7.94 10. 217 1 -(3 -Ethylquin clidin-3 -yl)-3 (1 -(4 ’ -((pyridin-3 ylmethoxy)methyl) [ 1, G biphenyl]-4yl)cyclopropyl)urea 217 0.0133 0.168 0.0040 2 10. 10. 218 1 -(3 -Propylquin clidin-3 yl)-3 -(1 -(4 ’ -((pyridin-3 ylmethoxy)methyl) [ 1, G biphenyl]-4yl)cyclopropyl)urea 218 0.011 0.0809 0.0029 7 7.95 10. 219 Quinu clidin-3 -yl( 1 -(4 ’ ((pyrimidin-5 ylmethoxy)methyl) [ 1, G biphenyl]-4yl)cyclopropyl)carbamate 219 0.0466 0.118 0.0209 10. 10. 220 1 -(3 -Ethylquin clidin-3 -yl)-3 (1 -(4 ’ -((pyrimidin-5 ylmethoxy)methyl) [ 1, G biphenyl]-4yl)cyclopropyl)urea 220 0.0516 0.114 0.0060 6 10. 3.16 221 1-Azabicyclo[3.2.2]nonan-4yl( 1 -(4 ’ -((pyrimidin-5 ylmethoxy)methyl) [ 1, G biphenyl]-4yl)cyclopropyl)carbamate 221 0.0521 0.0992 0.0211 10. 10. 222 1-(2-(4’-(3- 222 0.0017 0.0307 0.0007 10. 10.

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Methoxypropyl) [1,1’biphenyl]-4-yl)propan-2-yl)3 -(3-methylquinuclidin-3 yl)urea 58 223 Quinuclidin-3 -yl(2-(4’ (hydroxymethyl) [1,1’biphenyl]-4-yl)propan-2yl)carbamate 223 0.454 0.881 0.0216 10. 10. 224 1-(2-(4’-(2- Hydroxyethyl) [1, G-biphenyl] 4-yl)propan-2-yl)-3-(3propylquinuclidin-3 yl)urea 224 0.0202 0.0643 0.0016 10. 10. 225 1 -(3-Ethylquinuclidin-3-yl)-3 (2-(4’-(2-hydroxyethyl)[1,1’biphenyl]-4-yl)propan-2yl)urea 225 0.0294 0.229 0.0019 2 10. 10. 226 Quinuclidin-3 -yl(2-(4' -(2hydroxyethyl) [1, G-biphenyl]4-yl)propan-2-yl)carbamate 226 0.148 0.656 0.0223 10. 10. 227 Quinuclidin-3 -yl(2-(4 ’ -(2(1H-1,2,3-triazol-4yl)ethyl) [1,1’ -biphenyl] -4yl)propan-2-yl)carbamate 227 0.027 0.122 0.0104 10. 1.0 228 1-Azabicyclo[3.2.2]nonan-4yl(2-(4'-(2-(1H-1,2,3-triazol4-yl)ethyl) [1, G-biphenyl]-4yl)propan-2- yl)carbamate 228 0.0182 0.0808 0.0060 8 7.65 3.16 229 Quinuclidin-3 -yl(2-(4’ (morpholinomethyl) [1,1’biphenyl]-4-yl)propan-2yl)carbamate 229 0.158 0.524 0.0532 10. 10. 230 N-(2-(4’- (Morpholinomethyl)[1,1’biphenyl]-4-yl)propan-2-yl)- 1,4-diazabicyclo[3.2.2]nonane4-carboxamide 230 2.28 1.79 0.417 10. 10. 231 Quinuclidin-3 -yl(2-(4' morpholino [1, G-biphenyl]-4yl)propan-2-yl)carbamate 231 0.071 0.23 0.015 2.0 2.0 232 1 -(3 -Methylquinuclidin-3 -yl)- 232 0.0309 0.0642 0.0071 1.0 1.0

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3 -(2-(4'-morpholino[1,1'biphenyl]-4-yl)propan-2yl)urea 7 233 1-(4-Methyl-1- azabicyclo [3.2.2] but nan-4 -yl) 3 -(2-(4’ -morpholino [1,1’biphenyl]-4-yl)propan-2yl)urea 233 0.00568 0.00551 0.0007 26 1.0 1.0 234 1 -(3-Egilquinuclidin-3-yl)-3 (2-(4’ -morpholino[1,1’biphenyl]-4-yl)propan-2yl)urea 234 0.0146 0.0326 0.0018 1 1.0 1.0 235 Quinuclidin-3 -yl(2-(4’ (methylsulfonyl) [1,1’biphenyl]-4-yl)propan-2yl)carbamate 235 0.111 0.118 0.0199 10. 10. 236 1 -(3 -Egilquin clidin-3 -yl)-3 (2-(4 ’ -(methylsulfonyl) [1,1’biphenyl] -4-yl)propan-2yl)urea 236 0.0538 0.0744 0.0094 6 10. 10. 237 1-(2-(4’- (Methylsu fonil) [1,1’biphenyl]-4-yl)propan-2-yl)3 -(3-propylquin clidin-3 yl)urea 237 0.0354 0.0329 0.0067 1 10. 10. 238 Quinuclidin-3 -yl(2-(4' ((cyclopropylmethyl)sulfonyl) [1, G-biphenyl]-4yl)propan-2-yl)carbamate 238 0.0154 0.0501 0.0044 5 10. 1.0 239 1-(2-(4- ((Cyclopropylmethyl)sulfonyl) [1, G-biphenyl]-4yl)propan-2-yl)-3 -(3 ethylquinuclidin-3 yl)urea 239 0.00987 0.0285 0.0032 1 10. 1.0 240 1-(2-(4’- ((Cyclopropylmethyl)sulfonyl) [1, G-biphenyl]-4yl)propan-2-yl)-3 -(3 methylquinuclidin-3 yl)urea 240 0.0133 0.0865 0.0059 7 10. 1.0

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241 1-Azabicyclo[3.2.2]nonan-4yl(2-(4’- ((cyclopropylmethyl)sulfonyl) [1, G-biphenyl]-4yl)propan-2-yl)carbamate 241 0.00423 0.0122 0.0014 4 10. 3.16 242 Quinuclidin-3 -yl(2-(4 ’ -((3 methoxypropyl)su fonyl) [ 1, 1 ’ -biphenyl] -4-yl)propan-2yl)carbamate 242 0.0325 0.0825 0.0102 10. 3.16 243 1 -(3 -Ethylquin clidin-3 -yl)-3 (2-(4’-((3- methoxypropyl)su fonyl) [1, 1 '-biphenyl]-4-yl)propan-2yl)urea 243 0.0328 0.0573 0.0074 9 10. 3.16 244 1-(2-(4’-((3- Methoxypropyl)su fonyl) [1, 1 '-biphenyl]-4-yl)propan-2yl)-3 -(3-propylquinuclidin3-yl)urea 244 0.0371 0.0341 0.0069 9 10. 3.16 245 Quinuclidin-3 -yl(2-(4 '-((3,3dimethylbutyl)su fonyl) [1,1 '-biphenyl]-4-yl)propan-2yl)carbamate 245 0.00185 0.0663 0.0007 16 6.74 0.316 246 1-(2-(4'-((3,3Dimethylbutyl)su fonyl) [1, 1'-biphenyl]-4-yl)propan-2yl)-3 -(3-methylquinu clidin-3 yl)urea 246 0.0017 0.0114 0.0006 24 10. 1.0 247 1-(2-(4’-((3,3- Dimethylbutyl)su fonyl) [1, 1 '-biphenyl]-4-yl)propan-2yl)-3 -(3-ethylquin clidin-3 yl)urea 247 0.00166 0.00428 0.0003 96 6.64 1.0 248 1-(2-(4’-((3,3- Dimethylbutyl)suphonyl) [1, 1 '-biphenyl]-4-yl)propan-2yl)-3 -(4-methyl-1 azabicyclo[3.2.2] nonan-4yl)urea 248 0.00080 4 0.00684 0.0003 15 7.73 1.0 249 Quinuclidin-3 -yl(2-(4 ’ -(((1 (methoxymethyl)cyclopropyl) 249 0.0535 0.247 0.0058 2 10. 2.15

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methyl)su fonyl)[1,1’biphenyl]-4-yl)propan-2yl)carbamate 250 1 -(3 -Ethylquinuclidin-3 -yl)-3 (2-(4’-(((1- methoxymethyl)cyclopropyl)m ethyl)su fonyl)[1,1’biphenyl]-4-yl)propan-2yl)urea 250 0.0201 0.0845 0.0044 1 10. 1.0 251 1-(2-(4’-(((1- Methoxymethyl)cyclopropyl)methyl)sulfonyl)[1,1’biphenyl]-4-yl)propan-2-yl)3 -(3-propylquinuclidin-3 yl)urea 251 0.021 0.0475 0.0050 1 10. 1.0 252 Quinuclidin-3 -yl(2-(4’ (methylcarbamoyl) [1,1’biphenyl]-4-yl)propan-2yl)carbamate 252 1.84 1.5 0.22 10. 10. 253 N-Methyl-(4’ -(2-(3-(3methylquinuclidin-3yl)ureido)propan-2-yl) [1,1’biphenyl]-4-carboxamide 253 0.751 2.0 0.201 2.0 2.0 254 1-Azabicyclo[3.2.2]nonan-4yl(2-(4’- (methylcarbamoyl)[1,1’biphenyl]-4-yl)propan-2yl)carbamate 254 0.60 0.65 0.0638 10. 10. 255 X-Methyl-4 ’ -(2-(3 -(4-methyl-1 azabicyclo[3.2.2] nonan-4yl)ureido)propan-2yl)biphenyl-4-carboxamide 255 0.0469 3.42 0.0201 6.79 1.0 256 N-(2-(4’- (Methylcarbamoyl)biphenyl-4yl)propan-2-yl)-1,4diazabicyclo[3.2.2]nonane-4 carboxamide 256 12.3 4.44 0.729 10. 10. 257 Quinuclidin-3 -yl-2-(4 'dimethylcarbamoyl)biphenyl4-yl)propan-2-ylcarbamate 257 0.365 0.786 0.0772 10. 10. 258 Ν,N-Dimethyl-4 ’ -(2-(3-(3 - 258 0.281 2.34 0.049 10. 10.

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methylquinuclidin-3yl)ureido)propan-2yl)biphenyl-4-carboxamide 259 1-Azabicyclo[3.2.2]nonan-4yl-2-(4’- (dimethylcarbamoyl)biphenyl4-yl)propan-2-ylcarbamate 259 0.134 0.179 0.0205 10. 10. 260 N-(2-(4’- (Dimethylcarbamoyl)biphenyl4-yl)propan-2-yl)-1,4diazabicyclo[3.2.2]nonane-4 carboxamide 260 8.55 1.64 0.302 10. 10. 261 X,X-Dimethyl-4’-(2-(3-(4methyl-1- azabicyclo [3.2.2] nonan-4yl)ureido)propan-2yl)biphenyl-4-carboxamide 261 0.0608 0.354 0.0141 10. 3.16 262 Quinuclidin-3 -yl-2-(4 '(piperidin-1 carbonyl)biphenyl-4yl)propan-2-yl)carbamate 262 0.0196 0.112 0.0035 10. 1.0 263 1-Azabicyclo[3.2.2]nonan-4yl-2-(4 ’ -(piperidin-1 carbonyl)biphenyl-4yl)propan-2-ylcarbamate 263 0.0145 0.075 0.0030 1 10. 1.0 264 1 -(3 -Egilquinuclidin-3-yl)-3 (2-(4 ’ -(piperidin-1 carbonyl)biphenyl-4yl)propan-2-yl)urea 264 0.0137 0.0674 0.0021 3 10. 1.0 265 Quinuclidin-3 -yl-2-(4 '(morpholine-4carbonyl)biphenyl-4yl)propan-2-ylcarbamate 265 0.48 0.454 0.0399 10. 2.15 266 1-Azabicyclo[3.2.2]nonan-4yl-2-(4 ’ -(morpholine-4carbonyl)biphenyl-4yl)propan-2-ylcarbamate 266 0.399 0.284 0.0227 10. 1.0 267 1 -(3 -Methylquinuclidin-3 -yl)3 -(2-(4 ’ -(morpholine-4carbonyl)biphenyl-4yl)propan-2-yl)urea 267 0.363 2.77 0.119 0.565 10.

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268 1-(4-Methyl-1- azabicyclo [3.2.2] nonan-4 -yl) 3 -(2-(4 ’ -(morpholine-4carbonyl)biphenyl-4yl)propan-2-yl)urea 268 0.166 0.648 0.0315 10. 1.0 269 X-(2-(4'-(Morpholine-4carbonyl)biphenyl-4yl)propan-2-yl)-1,4diazabicyclo[3.2.2] nonane-4 carboxamide 269 23, 2.16 0.518 10. 10. 270 Quinuclidin-3 -yl-2-(4 ’ -(4,4difluoropiperidin-1 carbonyl)biphenyl-4yl)propan-2-yl)carbamate 270 0.025 0.067 0.0035 6 10. 1.0 271 1-Azabicyclo[3.2.2]nonan-4yl-2-(4’-(4,4difluoropiperidin-1 carbonyl)biphenyl-4yl)propan-2-ylcarbamate 271 0.00942 0.0607 0.0026 4 10. 0.316 272 1-(2-(4’-(4,4- Difluoropiperidin-1 carbonyl)biphenyl-4yl)propan-2-yl)-3 -(3 ethylquinuclidin-3 yl)urea 272 0.0164 0.0249 0.0021 5 10. 1.0 273 Quinuclidin-3 -yl-2-(4 '-(3,3difluoroazetidin-1 carbonyl)biphenyl-4yl)propan-2-yl)carbamate 273 0.108 0.074 0.0106 10. 3.16 274 1-Azabicyclo[3.2.2]nonan-4yl-2-(4’-(3,3-difluoroazetidin1-carbonyl)biphenyl-4yl)propan-2-ylcarbamate 274 0.0304 0.0673 0.0047 8 10. 1.0 275 1 -(2-(4 ’ -(3,3 - Difluoroazetidin1 -carbonyl)biphenyl-4yl)propan-2-yl)-3 -(3 ethylquinuclidin-3 yl)urea 275 0.0756 0.0554 0.0029 2 10. 1.0 276 1-(4-Methyl-1- azabicyclo[3.2.2]nonan-4-yl) - 3 -(2-(3 -(3 -(morpholine-4- 276 0.020 1.53 0.0296 10. 3.16

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carbonyl)phenoxy)phenyl)pro pan-2-yl)urea 277 1 -(3 -Methylquinuclidin-3 -yl)3 -(2-(3 -(3 -(morpholine-4carbonyl)phenoxy)phenyl)pro pan-2-yl)urea 277 0.0917 2.03 0.0801 10. 10. 278 1 -Azabicyclo[3.2.2]nonan-4yl-2-(3 -(3 -(morpholine-4carbonyl)phenoxy)phenyl)pro pan-2-ylcarbamate 278 0.593 1.44 0.053 10. 10. 279 Quinu clidin-3 -yl-2-(3 -(3 (morpholine-4carbonyl)phenoxy)phenyl)pro pan-2-yl)carbamate 279 4.33 3.92 0.217 10. 3.16 280 1 -(3-Methylquinuclidin-3-yl)3 -(2-(4-(4-(morpholine-4carbonyl)phenoxy)phenyl)pro pan-2-yl)urea 280 0.164 1.94 0.0491 10. 1.0 281 1-(4-Methyl-1- azabicyclo [3.2.2] but nan-4 -yl) 3 -(2-(4-(4-(morpholine-4carbonyl)phenoxy)phenyl)pro pan-2-yl)urea 281 0.0316 0.44 0.0077 9 10. 1.0 282 1-Azabicyclo[3.2.2]nonan-4yl-2-(4-(4-(morpholine-4carbonyl)phenoxy)phenyl)pro pan-2-ylcarbamate 282 0.479 0.66 0.0404 10. 3.16 283 Quinu clidin-3 -yl-2-(4-(4(dimethylcarbamoyl)phenoxy)phenyl)propan-2-ylcarbamate 283 0.606 1.03 0.114 10. 10. 284 Ν,Ν-Dimethyl-4-(4-(2-(3 -(3 methylquinuclidin-3yl)ureido)propan-2yl)phenoxy)benzamide 284 0.201 3.78 0.0607 10. 10. 285 Ν,N-Dimethyl-4-(4-(2-(3 -(4methyl-1- azabicyclo [3.2.2] but nan-4 yl)ureido)propan-2yl)phenoxy)benzamide 285 0.0163 0.725 0.0064 8 10. 1.0 286 1 -Azabicyclo[3.2.2]nonan-4yl)-2-(4-(4- 286 0.437 0.793 0.0316 10. 10.

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(dimethylcarbamoyl)phenoxy)phenyl)propan-2-ylcarbamate 287 Quinuclidin-3 -yl-2-(4-(4(dimethylcarbamoyl)phenoxy)phenyl)propan-2-ylcarbamate 287 1.33 2.2 0.229 10. 3.16 288 1-Azabicyclo[3.2.2]nonan-4yl-2-(3-(3- (dimethylcarbamoyl)phenoxy)phenyl)propan-2-ylcarbamate 288 0.203 1.18 0.0502 10. 10. 289 Ν,Ν-Dimethyl-3 -(3-(2-(3-(3methylquinuclidin-3yl)ureido)propan-2yl)phenoxy)benzamide 289 0.104 1.41 0.0917 9.26 10. 290 Ν,N-Dimethyl-4-(4-(2-(3 -(4methyl-1- azabicyclo [3.2.2] nonan-4yl)ureido)propan-2yl)phenoxy)benzamide 290 0.0191 2.58 0.0268 10. 3.16 291 Quinuclidin-3-yl-2-(4-(4(methyl carbamoyl)phenoxy)phenyl)propan-2-ylcarbamate 291 1.91 2.31 0.0902 10. 3.16 292 1-Azabicyclo[3.2.2]nonane-4- IL-2-(4-(4- (methyl lcarbamoyl)phenoxy)phen nyl)propan-2-ylcarbamate 292 0.207 1.22 0.0412 10. 10. 293 X-Methyl-4-(4-(2-(3-(3methylquinuclidin-3yl)ureido)propan-2yl)phenoxy)benzamide 293 0.186 5.37 0.046 10. 1.0 294 X-Methyl-4-(4-(2-(3 -(4-methyl1-azabicyclo[3.2.2]nonan-4yl)ureido)propan-2yl)phenoxy)benzamide 294 0.0124 0.843 0.0070 6 10. 1.0 295 (Quinuclidin-3 -yl)-2-(3 -(3 (methyl carbamoyl)phenoxy)phenyl)propan-2-ylcarbamate 295 1.02 1.75 0.147 10. 10. 296 X-Methyl-3-(3-(2-(3-(3methylquinuclidin-3yl)ureido)propan-2yl)phenoxy)benzamide 296 0.20 5.47 0.155 10. 10. 297 N-Methyl-3 -(3-(2-(3 -(4-methyl- 297 0.0102 1.37 0.0132 10. 1.0

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1-azabicyclo[3.2.2]nonan-4yl)ureido)propan-2yl)phenoxy)benzamide 298 1 -Azabicyclo[3.2.2]nonan-4yl)-2-(3-(3- (methyl lcarbamoyl)phenoxy)phenyl)propan-2-ylcarbamate 298 0.138 1D 0.0308 10. 3.16 299 1 -Azabicyclo[3.2.2] nonan-4yl)-2-(4-(4-(piperidin-1 carbonyl)phenoxy)phenyl)pro pan-2 -ylcarbamate 299 0.0154 0.192 0.0036 7 10. 1.0 300 1-(4-Methyl-1- azabicyclo [3.2.2] but nan-4 -yl) 3 -(2-(4-(4-(piperidin-1 carbonyl)phenoxy)phenyl)pro pan-2-yl)urea 300 0.00685 0.0876 0.0015 4 10. 0.316 301 1 -Azabicyclo[3.2.2]nonan-4yl)-2-(4-(4-(4,4difluoropiperidin-1 - carbonyl)phenoxy)phenyl)pro pan-2-ylcarbamate 301 0.0172 0.0494 0.0033 9 10. 1.0 302 1-(2-(4-(4-(4,4Difluoropiperidin-1 carbonyl)phenoxy)phenyl)pro pan-2-yl)-3 -(4-methyl-1 azabicyclo [3.2.2] but nan-4 yl )urea 302 0.00422 0.0317 0.0014 7 10. 1.0 303 1-(2-(4-(4-(3,3- Difluoroazetidin-1 carbonyl)phenoxy)phenyl)pro pan-2-yl)-3 -(4-methyl-1 azabicyclo [3.2.2] but nan-4 yl)urea 303 0.00763 0.0389 0.0012 4 10. 0.316 304 Quinuclidin-3-yl-2-(4-(4phenylpiperazine-1 carbonyl)phenyl)propan-2ylcarbamate 304 1.73 0.355 0.0959 10. 10. 305 N-(2-(4-(4- (Methylcarbamoyl)phenoxy)phenyl)propan-2-yl)-1,4diazabicyclo[3.2.2]nonane-4- 305 0.399 0.299 0.0195 10. 1.0

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carboxamide 306 1-(3-Egilquinuclidin-3-yl)-3 (2-(4-(4-phenylpiperazine-1carbonyl)phenyl)propan-2yl)urea 306 0.0951 0.257 0.032 10. 3.16 307 Quinuclidin-3 -yl-2-(4-(6-(2methoxyethoxy)pyridin-3 yl)phenyl)propan-2ylcarbamate 307 0.735 4.34 0.0972 10. 10. 309 Quinuclidin-3 -yl-2-(4-(6-(2methoxyethoxy)pyridin-2yl)phenyl)propan-2ylcarbamate 309 0.106 0.188 0.014 10. 3.16 308 Quinuclidin-3 -yl-2-(3 -(5-(2methoxyethoxy)pyridin-2yl)phenyl)propan-2ylcarbamate 308 0.254 0.314 0.0358 7.77 1.0 312 Quinuclidin-3 -yl-2-(3 -(6-(2methoxypropoxy)pyridazin3 -yl)phenyl)propan-2ylcarbamate 312 1.66 1.34 0.103 10. 1.0 313 1-Azabicyclo[3.2.2]nonan-4yl-2-(3-(6-(2methoxypropoxy)pyridazin2-yl)phenyl)propan-2ylcarbamate 313 0.0889 0.47 0.0107 10. 10. 314 N-(2-(3 -(6-(3methoxypropoxy)pyridazin3 -yl)phenyl)propan-2-yl-)-1,4diazobicyclo [3.2.2] nonane-4carboxamate 314 2.63 4.91 0.118 10. 10. 315 Quinuclidin-3 -yl(2-(3 -(5-(3 methoxypropoxy)pyrazin-2yl)phenyl)propan-2yl)carbamate 315 0.197 0.435 0.0259 10. 1.0 316 1-Azabicyclo[3.2.2]nonan-4yl(2-(3-(5-(3- methoxypropoxy)pyrazin-2yl)phenyl)propan-2yl)carbamate 316 0.028 0.152 0.0043 9 10. 10. 317 N-(2-(3-(5-(3- 317 0.295 0.656 0.0291 10. 1.0

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Methoxypropoxy)pyrazin-2and l)phenyl)propan-2-yl)-1,4diazabicyclo[3.2.2]nonane-4 carboxamide 318 Quinu clidin-3 -yl (2-(3 -(6ethoxypyridazin -3yl)phenyl)propan-2yl)carbamate 318 1.46 0.635 0.0699 #NUM! 1.0 319 1-Azabicyclo[3.2.2]nonan-4yl(2-(3-(6-(3ethoxypyridazin-3yl)phenyl)propan-2yl)carbamate 319 0.075 0.121 0.0080 4 10. 10. 310 1-Azabicyclo[3.2.2]nonan-4yl-2-(4-(5-(2- methoxyethoxy)pyridin-2yl)phenyl)propan-2ylcarbamate 310 0.123 0.145 0.0121 10. 3.16 320 Quinu clidin-3 -yl(2-(4-(5-(3 methoxypropoxy)pyrazin-2yl)phenyl)propan-2yl)carbamate 320 0.131 0.201 0.0112 10. 1.0 321 1-Azabicyclo[3.2.2]nonan-4yl(2-(4-(5-(3- methoxypropoxy)pyrazin-2yl)phenyl)propane-2- yl)carbamate 321 0.0461 0.108 0.0063 9 10. 1.0 322 N-(2-(4-(5-(3- Methoxypropoxy)pyrazin-2yl)phenyl)propan-2-yl)-1,4diazabicyclo[3.2.2]nonane-4 carboxamide 322 1.07 1.44 0.0999 10. 1.0 311 1-Azabicyclo[3.2.2]nonan-4yl-2-(4-(5-(2- methoxyethoxy)pyridin-2yl)phenyl)propan-2ylcarbamate 311 0.076 0.103 0.0085 10. 3.16 323 Quinu clidin-3 -yl(2-(3 -(5-(3 methoxypropoxy)pyrimidin2-yl)phenyl)propan-2yl)carbamate 323 1.16 0.508 0.0488 10. 1.0

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324 1-Azabicyclo[3.2.2]nonan-4yl(2-(3-(5-(3methoxypropoxy)pyrimidin2-yl)phenyl)propan-2yl)carbamate 324 0.0969 0.157 0.0084 9 10. 1.0 325 1 -(3-Egilquin clidin-3-yl)-3 (4-(4-(2-methoxyethyl)phenyl)2-methylbut-3-in-2yl)urea 325 0.092 0.399 0.0079 4 10. 10. 326 1-(4-(4-(2- Methoxyethyl)phenyl)-2methylbut-3-in-2-yl)-3 -(3 propylquinuclidin-3 yl)urea 326 0.0266 0.123 0.0042 9 3.16 3.16 327 1 -(3-Egilquin clidin-3-yl)-3 (4-(4-(methoxymethyl)phenyl)2-methylbut-3-in-2yl)urea 327 0.0962 0.343 0.0147 10. 10. 328 1-(4-(4- (Methoxymethyl)phenyl)-2 methylbut-3-in-2-yl)-3 -(3 propylquinuclidin-3 yl)urea 328 0.0251 0.115 0.0033 2 3.16 3.16 329 Quinuclidin-3-yl(4-(4-(2methoxyethoxy)phenyl)-2methylbut-3-in-2-yl)carbamate 329 3.14 2.7 0.284 10. 10. 330 1-(4-(4-(2- Methoxyethoxy)phenyl)-2methylbut-3-in-2-yl)-3 -(3 propylquinuclidin-3 yl)urea 330 0.104 0.203 0.0064 1 10. 3.16 331 Quinuclidin-3-yl(4-(4-(3methoxypropoxy)phenyl)-2methylbut-3-yn-2-yl)carbamate 331 1.33 1.76 0.118 10. 10. 332 1 -(3-Egilquin clidin-3-yl)-3 (2-methyl-4-(4-((pyridin-3 ylmethoxy)methyl)phenyl)but- 3-in-2-yl)urea 332 0.0494 0.945 0.0155 10. 10. 333 1 -(2-Methyl-4-(4-((pyridin-3 ylmethoxy)methyl)phenyl)but3-in-2-yl)-3-(3- 333 0.0161 0.413 0.0061 8 10. 3.16

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propylquinuclidin-3 yl)urea 334 Quinuclidin-3 -yl(4-(4-((3,3 dimethylbutyl)sulfonyl)phenyl)-2-methylbut-3-in-2yl)carbamate 334 0.0802 0.317 0.0118 3.28 10. 335 1-Azabicyclo[3.2.2]nonan-4yl(4-(4-((3,3- dimethylbutyl)sulfonyl)phenyl)-2-methylbut-3-in-2yl)carbamate 335 0.0146 0.193 0.0043 2 2.15 1.0 336 1-(4-(4-((3,3- Dimethylbutyl)sulfonyl)phenyl)-2-methylbut-3-in-2-yl)-3 (4-methyl-1- azabicyclo[3.2.2] nonan-4yl)urea 336 0.0012 0.0388 0.0009 02 10. 10. 337 1-(4-(4-((3,3- Dimethylbutyl)sulfonyl)phenyl)-2-methylbut-3-in-2-yl)-3 (3-methylquin clidin-3 yl)urea 337 0.0145 0.0941 0.0025 4 2.15 1.0 338 1-(4-(4-((3,3- Dimethylbutyl)sulfonyl)phenyl)-2-methylbut-3-in-2-yl)-3 (3-ethylquin clidin-3 yl)urea 338 0.00445 0.0721 0.0009 84 2.15 1.0 339 1 -(4-(4-( 1 -Metho xy-2 methyl lpropan-2 -yl)phenyl)-2methylbut-3-in-2-yl)-3 -(3 methylquinuclidin-3 yl)urea 339 0.136 0.72 0.0257 10. 10. 340 Quinuclidin-3-yl(2-(2-(4-(3 methoxypropoxy)phenyl)thiaz ol-4-yl)propan-2-yl)carbamate 340 0.17 0.197 0.0426 10. 10. 341 1-Azabicyclo[3.2.2]nonan-4yl(2-(2-(4-(3- methoxypropoxy)phenyl)thiaz ol-4-yl)propan-2-yl)carbamate 341 0.0193 0.0904 0.0071 9 10. 10. 342 N-(2-(2-(4-(3- Methoxypropoxy)phenyl)thiase 342 0.666 0.393 0.0851 10. 10.

- 154 046304

ol-4-yl)propan-2-yl)-1,4diazabicyclo[3.2.2] nonan-4 carboxamide 343 Quinuclidin-3 -yl(2-(2-(4-(2methoxyethoxy)phenyl)thiazol4-yl)propan-2-yl)carbamate 343 0.36 0.106 0.0198 10. 1.0 344 1 -Azabicyclo[3.2.2]nonan-4yl(2-(2-(4-(2- methoxyethoxy)phenyl)thiazol4-yl)propan-2-yl)carbamate 344 0.0658 0.0564 0.0087 6 10. 1.0 345 N-(2-(2-(4-(2- Methoxyethoxy)phenyl)thiazol4-yl)propan-2-yl)-1,4diazabicyclo[3.2.2]nonane-4 carboxamide 345 2.54 0.369 0.091 10. 3.16 346 Quinuclidin-3-yl-2-(5-(4-(2methoxyethoxy)phenyl)pyridin-2-yl)propan-2-yl)carbamate 346 0.0507 0.266 0.0111 10. 3.16 347 1 -Azabicyclo[3.2.2]nonan-4yl-2-(5-(4-(2- methoxyethoxy)phenyl)pyridinium n-2-yl)propan-2-ylcarbamate 347 0.0368 0.15 0.0058 2 10. 1.41 348 1 -Azabicyclo[3.2.2]nonan-4yl-2-(5-(4-(2- methoxyethoxy)phenyl)pyridinium n-2-yl)propan-2-ylcarbamate (single enantiomer A) 348 0.0278 0.0872 0.0035 2 10. 1.0 349 1 -Azabicyclo[3.2.2]nonan-4yl-2-(5-(4-(2- methoxyethoxy)phenyl)pyridinium n-2-yl)propan-2-yl)carbamate (single enantiomer B) 349 0.25 0.233 0.0144 10. 1.0

Example 351.

Inhibition of glucosylceramide synthase in a model of polycystic kidney disease.

Mice homozygous for the Nek8jck mutation cause polycystic kidney disease (jck mice). Histology shows that the kidneys of some 3-day-old mice from heterozygous parents have small individual cysts outlined by cuboidal epithelial cells and 15-day-old mice have cysts outlined by flattened epithelium. The disease is progressive but not obvious by palpation of the kidneys until at least 4 to 5 weeks of age. Homozygotes usually remain active almost until death and usually die between 20 and 25 weeks of age. Homozygous females are fertile but subsequently do not care for their litter; homozygous males are fertile, but fertility has been reported to decline beyond 15 weeks of age. No histological abnormalities were found in the liver, spleen or pancreas (Atala et al., 1993).

To evaluate the effect of a GCS inhibitor on polycystic kidney disease, compound 156 (S)quinuclidin-3-yl(2-(4'-(2-methoxyethoxy)[1,1'-biphenyl]-4-yl)propan-2- yl)carbamate is added to the diet of jck mice at doses of 15, 30 and 50 mg/kg. The second compound quinuclidin-3-yl(2-(4'-fluoro[1,1'-biphenyl]-3-yl)propan2-yl)carbamate (hereinafter referred to as GZ 161) is administered to the diet of jck mice at a dose of 60 mg /kg.

Compound administration begins at 3 to 4 weeks of age and continues until mice are sacrificed at 9 weeks of age. The effect of compounds on disease phenotype is assessed by measuring body weight, blood urea nitrogen (BUN) and serum GL1. Additional effects on kidney weight/body weight (K/BW) ratio, cyst volume, BUN, renal GL1 and serum GL1 are also measured at the end of life at the end of the study.

As shown in FIG. 3, compound 156 causes dose-dependent inhibition of GL1, which is associated with reduced cyst growth and preservation of renal function. Dose-dependent reduction in pre

- 155 -

Claims (20)

expressed graphically as well as numerically, with the percentages expressed representing the percentage reduction in GL1 levels compared to vehicle controls. Fig. 3 shows body weight measurements for the vehicle control group, the three-dose Compound 156 test groups, and the GZ 161 group, with the 30 mg/kg and 50 mg/kg Compound 156 doses showing statistical differences from the vehicle control group. Fig. 3 also shows kidney weight to body weight ratio measurements between the vehicle control group, the three dose Compound 156 test groups, and the GZ 161 group, with all Compound 156 and GZ 161 groups being statistically different from the vehicle control group. Fig. 3 also shows measurements of cyst volume and BUN in the vehicle control group, the three-dose Compound 156 test groups, and the GZ 161 group, with all GZ 161 and Compound 156 groups statistically different from the vehicle control group. CLAIM 1. A method of treating a lysosomal storage disease in a subject, wherein the lysosomal storage disease is selected from the group consisting of Gaucher disease, Fabry disease, G _M1 gangliosidosis, GM2 activator deficiency, Tay-Sachs disease or Sandhoff disease, comprising administering to the subject an effective amount of a compound represented by the following structural formula: or a pharmaceutically acceptable salt thereof, where n is 1, 2; m is 0 or 1; p equals 1; t is 0 or 1; y is 1; z is 0 or 1; E represents O; X ¹ represents CR ¹ when m is 1, or N when m is 0; X ² represents O or -NH; X ³ represents a direct bond or -NH; X ⁴ represents direct link or CR4R ⁵ ; X ⁵ represents a direct connection or O; R ¹ represents H or (C ₁ -C ₆ )αalkyl; R ⁴ and R ⁵ are selected independently from (C ₁ -C ₆ )alkyl or, taken together with the carbon atom to which they are attached, form a spiro(C ₃ -C ₁₀ )cycloalkyl ring; R ⁶ represents -H or (C ₁ -C ₆ )alkyl, optionally substituted with one to four halogen atoms; A ¹ is (C6-C12)aryl, (C2-C9)heteroaryl or (C2-C9)heterocycloalkyl, wherein A ¹ is optionally substituted with one or more substituents selected from the group consisting of halogen, (C1-C6)alkyl, optionally substituted with one to three halogen atoms; (C1- _C6 )alkoxy, -OH; A ² is (C6-C12)aryl or (C2-C9)heteroaryl, wherein A ² is substituted with one or more substituents selected from the group consisting of halogen, (C2- _C9 )heterocycloalkyl; R ⁸ R ⁹ N-CO-, wherein each of R ⁸ and R ⁹ is selected independently from the group consisting of hydrogen and (C1-C6)alkyl, or R ⁸ and R ⁹ can be taken together with the nitrogen atom to which they attached to form a (C2- _C9 )heterocycloalkyl group, optionally substituted with one to three halogen groups; (C1- _C6 )alkylsulfonyl, optionally substituted with one or two groups selected from (C1- _C6 )alkoxy and ( _C3 - _C10 )cycloalkyl; (C1- _C6 )alkyl substituted with one to four substituents selected from the group consisting of halogen, hydroxy, cyano, (C1- _C6 )alkoxy, (C1- _C6 )alkoxy, (C1- _C6 )alkoxy, ( C ₂ -C ₉ )heterocycloalkyl, (C ₂ -C ₉ )heteroaryl, optionally substituted (C1 -C ₆ )alkoxy; or (C ₃ -C ₁₀ )cycloalkoxy, optionally substituted (C1 -C ₆ )alkoxy; and (C1- _C6 )alkyloxy substituted with one to four substituents selected from the group consisting of halogen, hydroxy, cyano, (C1- _C6 )alkoxy, (C1- _C6 )alkoxy(C1- _C6 )alkoxy, (C ₂ -C ₉ )heterocycloalkyl, (C ₂ -C ₉ )heteroaryl, optionally substituted (C1 -C ₆ )alkoxy; or (C ₃ -C ₁₀ )cycloalkoxy, optionally substituted (C1 -C ₆ )alkoxy; with the proviso that when X ³ is -NH and X ⁴ is CR4R ⁵ then A ² must be substituted with one or more substituents selected from the group consisting of - 156 046304 (C ₂ -C ₉ )heterocycloalkyl, R8R9N-CO-, where each of R ⁸ and R ⁹ is selected independently from the group consisting of hydrogen and (C1-C6)alkyl, or R ⁸ and R ⁹ can be taken together with the nitrogen atom to which they are attached to form a (C2- _C9 )heterocycloalkyl or ( _C2 - _C9 )heterocycloalkyl group, optionally substituted by one to three halogen groups; (C ₁ -C ₆ )alkylsulfonyl, optionally substituted with one or two groups selected from (C 1 -C ₆ )alkoxy and (C ₃ -C ₁₀ )cycloalkyl; (C ₁ -C ₆ )alkyl substituted with one to four substituents selected from the group consisting of hydroxy, cyano, (C1-C ₆ )alkoxy, (^-Qwokc^Ci-Qwokcu, (C2-C ₉ )heterocycloalkyl, (C ₂ -C ₉ )hetero-aryl, optionally substituted (C1-C ₆ )alkoxy; or (C ₃ -C ₁₀ )cycloalkoxy, optionally substituted (C1-C ₆ )alkoxy; or (C1- _C6 )alkyloxy substituted with one to four substituents selected from the group consisting of hydroxy, cyano, (C1- _C6 )alkoxy, (C1- _C6 )alkoxy(C1- _C6 )alkoxy, (C2 -C ₉ )heterocycloalkyl, (C2-C ₉ )heteroaryl, optionally substituted (C1-C ₆ )alkoxy; or (C ₃ -C ₁₀ )cycloalkoxy, optionally substituted (C 1 -C ₆ )alkoxy, provided that the compound is not 1-{2-[4'-(2-methoxyethoxy)biphenyl-4yl]propan-2- yl } -3 -(3 -methyl-1 -azabicyclo[2.2.2]oct-3 -yl)urea, where in each case (C ₂ -C ₉ )heterocycloalkyl contains from 3 to 10 ring atoms, where from 2 to 9 of the ring atoms are carbon atoms and the remaining ring atoms are selected from the group consisting of nitrogen, sulfur and oxygen; and wherein in each case (C ₂ -C ₉ )heteroaryl contains 5-10 ring atoms, where 2-9 ring atoms are carbon atoms, and the remaining ring atoms are selected from the group consisting of nitrogen, sulfur and oxygen. 2. Method according to claim 1, where n is 1; t is 0; y is 1; and z is equal to 1. 3. Method according to claim 1 or 2, where m is equal to 1; E represents O; X ² represents O; and X ³ represents NH. 4. The method according to any one of claims 1 to 3, wherein X ⁴ represents CR4R ⁵ , where each of R ⁴ and R ⁵ independently represents methyl. 5. Method according to any one of claims 1-4, where R ⁶ represents H. 6. Method according to any one of claims 1 to 5, where R ¹ represents hydrogen or methyl. 7. Method according to any one of claims 1 to 6, where X ⁴ represents a direct connection. 8. Method according to any one of claims 1-7, where A ¹ represents (C ₂ -C ₉ )heteroaryl selected from isothiazole, furan, oxazole, isoxazole, pyrrole, imidazole, pyrazole, triazole, pyridine, pyrimidine, pyridazine, indole, benzothiazole, benzoisoxazole, benzopyrazole, benzoimidazole, benzofuran and benzoxazole. 9. Method according to any one of claims 1 to 8, where X ⁵ represents a direct connection. 10. Method according to any one of claims 1 to 9, wherein the lysosomal storage disease is Fabry disease. 11. The method according to any one of claims 1 to 9, wherein the lysosomal storage disease is Gaucher disease type 2 or Gaucher disease type 3. 12. Use of a compound represented by formula (I), which is defined in any one of claims 1 to 9, for the preparation of a medicament intended for the treatment of a lysosomal storage disease in a subject, wherein the lysosomal storage disease is selected from the group consisting of Gaucher's disease, Fabry, G _M1 gangliosidosis, G _M2 activator deficiency, Tay-Sachs or Sandhoff disease. 13. Use according to claim 12, wherein the lysosomal storage disease is Gaucher disease or Fabry disease. 14. Use of a compound represented by formula (I), as defined in any one of claims 1 to 9, for the treatment of a lysosomal storage disease in a subject, wherein the lysosomal storage disease is selected from the group consisting of Gaucher disease, Fabry disease, G _M1 gangliosidosis, G _M2 -activator deficiency, Tay-Sachs disease or Sandhoff disease. 15. Use according to claim 14, wherein the lysosomal storage disease is Gaucher disease or Fabry disease. 16. A compound represented by the following structural formula: or a pharmaceutically acceptable salt thereof, where n is 1, 2; — 157 — m is equal to 1; p equals 1; t is 0 or 1; y is 1; z is 0 or 1; E represents O; X ¹ represents CR ¹ ; X ² represents O or -NH; X ³ represents -NH; X ⁴ represents a direct link or CR ⁴ R ⁵ ; X ⁵ represents a direct connection or O; R ¹ represents H or (C1-C ₆ )alkyl; R ⁴ and R ⁵ are selected independently from (C 1 -C ₆ )alkyl or, taken together with the carbon atom to which they are attached, form a spiro(C ₃ -C ₁₀ )cycloalkyl ring; R ⁶ represents -H or (C ₁ -C ₆ )alkyl; And ¹ is (C6-C12)aryl or (C2-C9)heteroaryl selected from isothiazole, furan, oxazole, isoxazole, pyrrole, imidazole, pyrazole, triazole, pyridine, pyrimidine, pyridazine, indole, benzothiazole, benzisoxazole, benzopyrazole, benzoimidazole, benzofuran and benzooxazole, wherein A ¹ is optionally substituted with one or more substituents selected from the group consisting of halogen, (C1-C6)alkyl, optionally substituted with one to three halogen atoms; (C1- _C6 )alkoxy, -OH; A ² is (C6-C12)aryl or (C2-C9)heteroaryl, wherein A ² is substituted with one or more substituents selected from the group consisting of halogen, (C3- _C6 )cycloalkyl and ( _C2 - _C9 ) heterocycloalkyl; R ⁸ R ⁹ N-CO-, wherein each of R ⁸ and R ⁹ is selected independently from the group consisting of hydrogen and (C1-C6)alkyl, or R ⁸ and R ⁹ can be taken together with the nitrogen atom to which they attached to form a (C2- _C9 )heterocycloalkyl group, optionally substituted with one to three halogen groups; (C1- _C6 )alkylsulfonyl, optionally substituted with one or two groups selected from (C1- _C6 )alkoxy and ( _C3 - _C10 )cycloalkyl; (C1 -C ₆ )alkyl substituted with one to four substituents selected from the group consisting of hydroxy, (C1 -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy, (C ₂ -C ₉ )heterocycloalkyl and (C ₂ -C ₉ )heteroaryl; and (C1- _C6 )alkyloxy substituted with one to four substituents selected from the group consisting of cyano, (C1- _C6 )alkoxy, ( _C2 - _C9 )heterocycloalkyl and ( _C2 - _C9 )heteroaryl; with the proviso that when X ⁴ is CR4R ⁵ then A ² must be substituted with one or more substituents selected from the group consisting of (C ₂ -C ₉ )heterocycloalkyl; R8R9N-CO-, wherein each of ^R8 and ^R9 is independently selected from the group consisting of hydrogen and (C1-C6)alkyl, or ^R8 and ^R9 may be taken together with the nitrogen atom to which they are attached to form (C2- _C9 )heterocycloalkyl group, optionally substituted with one to three halogen groups; a (C1- _C6 )alkylsulfonyl group optionally substituted with one or two groups selected from (C1- _C6 )alkoxy and ( _C3 - _C10 )cycloalkyl; (C1- _C6 )alkyl substituted with one to four substituents selected from the group consisting of hydroxy, (C1- _C6 )alkoxy, (C1- _C6 )alkoxy, (C1- _C6 )alkoxy, ( _C2 -C ₉ ) heterocycloalkyl and (C ₂ -C ₉ ) heteroaryl; and (C1- _C6 )alkyloxy substituted with one to four substituents selected from the group consisting of cyano, (C1- _C6 )alkoxy, ( _C2 - _C9 )heterocycloalkyl and ( _C2 - _C9 )heteroaryl; and provided that the compound is not 1-{2-[4'-(2-methoxyethoxy)biphenyl-4yl]propan-2-yl}-3-(3-methyl-1-azabicyclo [2.2.2] oct-3-yl)urea, wherein in each case the (C ₂ -C ₉ )heterocycloalkyl contains from 3 to 10 ring atoms, where from 2 to 9 ring atoms are carbon atoms and the remaining ring atoms are selected from the group consisting of nitrogen, sulfur and oxygen; and wherein in each case (C ₂ -C ₉ )heteroaryl contains 5-10 ring atoms, where 2-9 ring atoms are carbon atoms and the remaining ring atoms are selected from the group consisting of nitrogen, sulfur and oxygen. 17. The connection according to claim 16, where n is 1; t is 0; y is 1; and z is equal to 1. 18. Connection according to claim 16 or 17, where m is equal to 1; E represents O; X ² represents O; and X ³ represents NH. 19. A compound according to any one of claims 16 to 18, wherein X ⁴ is CR4R ⁵ , wherein each of R ⁴ and R ⁵ independently represents methyl. 20. A compound according to any one of claims 16-19, where R ⁶ represents H. - 158 -