WO2014124560A1

WO2014124560A1 - Mglur regulators

Info

Publication number: WO2014124560A1
Application number: PCT/CN2013/071644
Authority: WO
Inventors: Li Chen; John J. Baldwin; Chengde Wu; Chunli SHEN
Original assignee: Hua Medicine (Shanghai) Ltd.
Priority date: 2013-02-18
Filing date: 2013-02-18
Publication date: 2014-08-21
Also published as: CN105121424B; CN105121424A

Abstract

Provided herein are compounds of the formula I: (I), as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment or prevention of mGluR5 mediated disorders, such as acute and/or chronic neurological disorders, cognitive disorders and memory deficits, as well as acute and chronic pain.

Description

mGluR Regulators

Field of the Invention

[0001] The invention is directed to compounds of the formula I:

or a pharmaceutically acceptable salt thereof, and to pharmaceutical compositions comprising said compounds or a pharmaceutically acceptable salt thereof, wherein the definitions of Ri, R₂, R3, X, Y and a are as defined below. The compounds and compositions disclosed herein are mGluR5 receptor antagonists useful for the treatment or prevention of mGluR5 mediated disorders, such as acute and/or chronic neurological disorders, cognitive disorders and memory deficits, as well as acute and chronic pain.

[0002] All documents cited or relied upon below are expressly incorporated herein by reference.

Background of the Invention

[0003] Glutamate is the most prominent neurotransmitter in the body, being present in over 50% of nervous tissue. Glutamate mediates its effects through two major groups of receptors: ionotropic and metabotropic. Ionotropic glutamate receptors are ion channel receptors which are often responsible for fast excitatory transmission. They are generally divided into N-methyl-D-aspartate (NMD A), a-amino-3-hydroxy-5-methyl-4- isoxazole propionic acid (AMPA) and kainite receptors. By contrast, metabotropic glutamate receptors (mGluRs) belong to the class C G-protein-coupled receptor (GPCR) protein family and are mainly involved in the modulation of fast excitatory transmission. As such, they are attractive therapeutic targets for treatment of disorders involving malfunction of glutamate signaling. The mGluRs are further divided into three groups (Group I, II and III) based on amino acid sequence homology, signal transduction mechanism and pharmacological properties. Group I receptors include mGluRl and mGluR5, Group II includes mGluR2 and mGluR3 and Group III includes mGluR4, mGluR6, mGluR7 and mGluR8. The Group I mGluRl and mGluR5 receptors couple to G-proteins of the Gq family, Gq and Gi l, and their activation leads to activation of phospholipase C, resulting in the hydrolysis of membrane phosphatidylinositol (4,5)- bisphosphate to diacylglycerol, which subsequently activates protein kinase C, and inositol trisphosphate, which in turn activates the inositol trisphosphate receptor to promote the release of intracellular calcium.

[0004] Anatomical studies demonstrate a broad and selective distribution of mGluRs in the mammalian nervous system. For example, mGluR5 receptors are abundantly expressed in the striatum, cortex, hippocampus, caudate-putamen and nucleus accumbens; see for example: Shigemoto, R., Nomura, S., Hidemitsu, S., et al.

Neuroscience Lett 1993, 163, 53-57. As these brain areas have been shown to be involved in emotion, motivational processes, learning and memory, as well as motor control, mGluR5 modulators have long been regarded as possessing therapeutic potential for a wide range of indications.

[0005] mGluR5 receptor antagonists can be used for modulating the activity of the mGluR5 receptor and for use in the treatment or prevention of mGluR5 mediated disorders, such as acute and/or chronic neurological disorders, cognitive disorders and memory deficits, as well as acute and chronic pain. Other diseases contemplated include cerebral ischemia, chronic neurodegeneration including Huntington's chorea, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, psychiatric disorders, schizophrenia, mood disorders, emotion disorders, disorders of

extrapyramidal motor function, obesity, disorders of pulmonary system and respiration, motor control and function, attention deficit disorders, concentration disorders, mental retardation (including mental retardation related to Fragile X syndrome), pain disorders, neurodegenerative disorders, epilepsy, convulsive disorders, migraine, dyskinesia, eating disorders, vomiting, muscle spasms, urinary inconsistence, sleep disorders, sexual disorders, circadian disorders, drug withdrawal, drug addiction, compulsive disorders, anxiety, panic disorders, depressive disorders, skin disorders, retinal ischemia, retinal degeneration, glaucoma, disorders associated with organ transplantation, asthma, ischemia and astrocytomas, diseases of the cardiovascular system, diseases of the gastrointestinal system such as gastroesophageal reflux disease and irritable bowel syndrome, diseases of the endocrine system, diseases of the exocrine system, diseases of the skin, cancer and diseases of the ophthalmic system. The development and use of mGluR5 antagonists has been summarized in numerous review articles for example: Gasparini, F., Bilbe, G., Gomez-Mancilla, G., and Spooren, W., Current Opinion in Drug Discovery & Development 1 1(5): 655-665, 2008, Rocher, J. -P., Bonnet, B., Bolea, C, et al., Current Topics in Medicinal Chemistry 201 1 , 1 1 , 680-695, Dekundy, A., Gravius, A., Hechenberger, M, et al., J. Neural Transm 201 1 , 1 18, 1703-1716 and Niswender, C. M. and Conn, P. J., Annu Rev Pharmacol Toxicol 2010, 50, 295-322.

Summary of the Invention [0006] The present invention is directed to compounds of the formula I, or a

pharmaceutically acceptable salt thereof, pharmaceutical compositions containing them and to methods of treating diseases and disorders. The compounds and compositions disclosed herein are mGluR5 receptor antagonists useful for the treatment of mGluR5 mediated disorders, including acute and/or chronic neurological disorders, cognitive disorders and memory deficits, as well as acute and chronic pain.

Detailed Description of the Invention

[0007] In an embodiment of the present invention, provided are compounds of formula I:

or a pharmaceutically acceptable salt thereof,

wherein:

X is -F, -CI, -CN, -CF₃, -OH, or -0-CH₃;

Ri is a 5- to 10-membered mono- or bicyclic heteroaryl ring that contains 1-3

heteroatoms selected from the group consisting of N, O and S, wherein the 5- to 10-membered ring system is optionally substituted with 1-3 substituents independently selected from alkyl, -F, -CI, -Br, -OH, -CN, nitro, alkoxy, -CF₃, - 0-CF₃, -S(CH₃), -O-alkyl, -S-alkyl, -S(0)-alkyl, -S(0₂)-alkyl, -S(0₂)-aryl ,- CH₂-aryl, heteroaryl, alkanoyl, -O-aryl, -0-CH₂-aryl, -N(CH₃)₂, cycloalkyl, heterocycloalkyl, -C(0)cycloalkyl, -C(0)heterocycloalkyl, wherein the substituents may combine to form an optionally substituted 5-7 membered fused carbacyclic or heterocyclic ring, or a 5- to 10-membered mono- or bicyclic aryl ring, wherein the 5- to 10- membered aryl ring is optionally substituted with 1-3 substituents independently selected from alkyl, -F, -CI, -Br, -OH, -CN, nitro, alkoxy, -CF₃, -OCF₃, -S(CH₃), -O-alkyl, -S-alkyl, -S(0)-alkyl, -S(0₂)-alkyl, S(0₂)aryl, -CH₂-aryl, heteroaryl, alkanoyl, -O-aryl, -0-CH₂-aryl, -N(CH₃)₂, cycloalkyl, heterocycloalkyl, - C(0)cycloalkyl, -C(0)-heterocycloalkyl, wherein the substituents may combine to form a 5-7 membered fused and optional substituted carbacyclic or

heterocyclic ring;

R₂ is alkanoyl; arylalkanoyl; aryl sulfonyl; heteroaryl sulfonyl; alkoxycarbonyl;

arylalkoxycarbonyl; or a 5- to 10-membered mono- or bicyclic heteroaryl ring that contains 0-3 heteroatoms independently selected from the group consisting of N, O and S, wherein the 5- to 10-membered ring system is optionally substituted with 1-3 substituents independently selected from alkyl, -F, -CI, -Br, -OH, -CN, nitro, alkoxy, -CF₃, -OCF₃, -S(CH₃), -OCH₃, -S-alkyl, -S(0)-alkyl, -S(0₂)-alkyl, S(0₂)aryl, -CH₂-aryl, heteroaryl, alkanoyl, -O-aryl, -0-CH₂-aryl, -N(CH₃)₂, cycloalkyl, heterocycloalkyl, -C(0)cycloalkyl, -C(0)-heterocycloalkyl, or substituted lower alkyl wherein the substituents may combine to form an optionally substituted 5-7 membered fused carbacyclic or heterocyclic ring, or a 5- to 10-membered mono- or bicyclic aryl ring, wherein the 5- to 10- membered ring system is optionally substituted with 1-3 substituents

independently selected from alkyl, -F, -CI, -Br, -OH, -CN, nitro, alkoxy, -CF₃, - OCF₃, -S(CH₃), -OCH₃, -S-alkyl, -S(0)-alkyl, -S(0₂)-alkyl, S(0₂)aryl, -CH₂-aryl, heteroaryl, alkanoyl, -O-aryl, -0-CH₂-aryl, -N(CH₃)₂, cycloalkyl,

heterocycloalkyl, -C(0)cycloalkyl, -C(0)-heterocycloalkyl, or substituted lower alkyl wherein the substituents may combine to form an optionally substituted 5-

7 membered fused carbacyclic or heterocyclic ring;

R₃ is -H, or optionally substituted alkyl, that optionally incorporates a heteroatom

selected from N, O, and S; a is 0 or 1.

[0008] In a further embodiment of the present invention, provided is a compound according to formula I

(I),

or a pharmaceutically acceptable salt thereof,

wherein:

Ri is 2-pyridinyl optionally substituted with 1 or 2 substituents independently selected from Ci-C₄alkyl, wherein Ci-C₄-alkyl includes, but are not limited to, methyl, ethyl, propyl, z^'so-propyl, butyl, z^'so-butyl, tert-butyl, or

Ri is benzofuranyl or halophenyl, wherein the halo is preferable chloro;

X is F, CI, -OH, or -0-CH₃;

R₂ is a 5- to 10-membered mono- or bicyclic aryl or heteroaryl ring that contains 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O and S, wherein the 5- to 10-membered ring system is optionally substituted with 1, 2 or 3 substituents independently selected from Ci-C₄-alkyl, -F, -CI, -Br, -OH, - CN, nitro, -CF₃, -OCF₃, -0-Ci-C₄-alkyl, -SCH₃, -S(0)-CH₃, -S(0₂)-CH₃, - C0₂CH₃, -C(0)NH₂, -C(0)NH(CH₃), -C(0)N(CH₃)₂, phenyl, wherein the C C₄-alkyl is preferably methyl, ethyl, propyl, z^'so-propyl, butyl, z^'so-butyl, tert- butyl; the -0-Ci-C₄-alkyl is preferably methoxy, ethoxy, propoxy, z^'so-proxy, butoxy, z^'so-butoxy, ferz-butoxy, wherein the 5- to 10-membered ring system is preferably phenyl, pyridinyl, naphthyl, quinolinyl, or

R₂ is -C(0)-Ci-C₅-alkyl, -C0₂-Ci-C₅-alkyl, -C(0)-benzyl, -C0₂-benzyl, -C(O)- phenyl, -C0₂-phenyl, benzyl, phenylethyl, -S(0₂)-phenyl which is optionally further substituted with a substituent independent selected from methyl, ethyl, propyl, CI, F, Br, wherein Ci-C₅-alkyl includes methyl, ethyl, propyl, z^'so-propyl, butyl, z^'so-butyl, teri-butyl, pentyl, z^'so-pentyl, teri-pentyl, neo-pentyl; R₃ is H;

a is 0 or 1.

[0009] In a further embodiment of the present invention, provided is a compound according to formula la

(la), or a pharmaceutically acceptable salt thereof,

wherein:

X is -F, -CI, -CN, CF₃, -OH, or -0-CH₃;

Ri is a 5- to 10-membered mono- or bicyclic heteroaryl ring that contains 1-3

heteroatoms selected from the group consisting of N, O and S, wherein the 5- to 10-membered ring system is optionally substituted with 1-3 substituents independently selected from alkyl, -F, -CI, -Br, -OH, -CN, nitro, alkoxy, -CF₃, - 0-CF₃, -S(CH₃), -O-alkyl, -S-alkyl, -S(0)-alkyl, -S(0₂)-alkyl, -S(0₂)-aryl ,- CH₂-aryl, heteroaryl, alkanoyl, -O-aryl, -0-CH₂-aryl, -N(CH₃)₂, cycloalkyl, heterocycloalkyl, -C(0)cycloalkyl, -C(0)heterocycloalkyl, wherein the substituents may combine to form an optionally substituted 5-7 membered fused carbacyclic or heterocyclic ring, or a 5- to 10-membered mono- or bicyclic aryl ring, wherein the 5- to 10- membered aryl ring is optionally substituted with 1-3 substituents independently selected from alkyl, -F, -CI, -Br, -OH, -CN, nitro, alkoxy, -CF₃, -OCF₃, -S(CH₃), -O-alkyl, -S-alkyl, -S(0)-alkyl, -S(0₂)-alkyl, S(0₂)aryl, -CH₂-aryl, heteroaryl, alkanoyl, -O-aryl, -0-CH₂-aryl, -N(CH₃)₂, cycloalkyl, heterocycloalkyl, - C(0)cycloalkyl, -C(0)-heterocycloalkyl, wherein the substituents may combine to form a 5-7 membered fused and optional substituted carbacyclic or heterocyclic ring;

R₂ is alkanoyl; arylalkanoyl; aryl sulfonyl; heteroaryl sulfonyl; alkoxycarbonyl; arylalkoxycarbonyl; or a 5- to 10-membered mono- or bicyclic heteroaryl ring that contains 0-3 heteroatoms independently selected from the group consisting of N, O and S, wherein the 5- to 10-membered ring system is optionally substituted with 1-3 substituents independently selected from alkyl, -F, -CI, -Br, -OH, -CN, nitro, alkoxy, -CF₃, -OCF₃, -S(CH₃), -OCH₃, -S-alkyl, -S(0)-alkyl, -S(0₂)-alkyl, S(0₂)aryl, -CH₂-aryl, heteroaryl, alkanoyl, -O-aryl, -0-CH₂-aryl, -N(CH₃)₂, cycloalkyl, heterocycloalkyl, -C(0)cycloalkyl, -C(0)-heterocycloalkyl, or substituted lower alkyl wherein the substituents may combine to form an optionally substituted 5-7 membered fused carbacyclic or heterocyclic ring, or a 5- to 10-membered mono- or bicyclic aryl ring, wherein the 5- to 10- membered ring system is optionally substituted with 1-3 substituents

heterocycloalkyl, -C(0)cycloalkyl, -C(0)-heterocycloalkyl, or substituted lower alkyl wherein the substituents may combine to form an optionally substituted 5- 7 membered fused carbacyclic or heterocyclic ring;

selected from N, O, and S;

[00010] In another embodiment, provided is a compound according to formula la, or a pharmaceutically acceptable salt thereof,

wherein:

X is -F, -CI, -OH, or -0-CH₃;

Ri is a substituted or unsubstituted ring selected from the following list:

R4 where present is -H or lower alkyl;

R₂ is a 5- to 10-membered mono- or bicyclic heteroaryl ring that contains 0-3

heteroatoms independently selected from the group consisting of N, O and S, wherein the 5- to 10-membered ring system is optionally substituted with 1-3 substituents independently selected from alkyl, -F, -CI, -Br, -OH, -CN, nitro, alkoxy, -CF₃, -OCF₃, -S(CH₃), -OCH₃, -S-alkyl, -S(0)-alkyl, -S(0₂)-alkyl, S(0₂)aryl, -CH₂-aryl, heteroaryl, alkanoyl, -O-aryl, -0-CH₂-aryl, -N(CH₃)₂, cycloalkyl, heterocycloalkyl, -C(0)cycloalkyl, -C(0)-heterocycloalkyl, or substituted lower alkyl wherein the substituents may combine to form an optionally substituted 5-7 membered fused carbacyclic or heterocyclic ring, or a 5- to 10-membered mono- or bicyclic aryl ring, wherein the 5- to 10- membered ring system is optionally substituted with 1-3 substituents

R₃ is -H, or optionally substituted alkyl, that optionally incorporates a heteroatom selected from N, O, and S;

In a further embodiment, provided is a compound according to formula la, or a pharmaceutically acceptable salt thereof, wherein:

Ri is 2-pyridinyl or substituted 2-pyridinyl;

X is F, CI, -OH, or -0-CH₃;

R₂ is optionally mono- or disubstituted mono- or bicyclic aryl, optionally mono- or disubstituted mono- or bicyclic heteroaryl,

R₃ is H;

In a further embodiment of the present invention, provided is a compound according to formula la, or a pharmaceutically acceptable salt thereof, wherein:

Ri is benzofuranyl or halophenyl, wherein the halo is preferably chloro; X is F, CI, -OH, or -0-CH₃;

R₂ is a 5- to 10-membered mono- or bicyclic aryl or heteroaryl ring that contains 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O and S, wherein the 5- to 10-membered ring system is optionally substituted with 1, 2 or 3 substituents independently selected from Ci-C₄-alkyl, -F, -CI, -Br, -OH, - CN, nitro, -CF₃, -OCF₃, -0-Ci-C₄-alkyl, -SCH₃, -S(0)-CH₃, -S(0₂)-CH₃, - C0₂CH₃, -C(0)NH₂, -C(0)NH(CH₃), -C(0)N(CH₃)₂, phenyl, wherein the Ci- C₄-alkyl is preferably methyl, ethyl, propyl, z^'so-propyl, butyl, z^'so-butyl, tert- butyl; the -0-Ci-C₄-alkyl is preferably methoxy, ethoxy, propoxy, z^'so-proxy, butoxy, z^'so-butoxy, ferz-butoxy, wherein the 5- to 10-membered ring system is preferably phenyl, pyridinyl, naphthyl, quinolinyl, or

R₂ is -C(0)-Ci-C₅-alkyl, -C0₂-Ci-C₅-alkyl, -C(0)-benzyl, -C0₂-benzyl, -C(O)- phenyl, -C0₂-phenyl, benzyl, phenylethyl, -S(0₂)-phenyl which is optionally further substituted with a substituent independent selected from methyl, ethyl, propyl, CI, F, Br, wherein Ci-C₅-alkyl includes methyl, ethyl, propyl, z^'so-propyl, butyl, z^'so-butyl, tert-butyl, pentyl, z^'so-pentyl, teri-pentyl, neo-pentyl,

R₃ is H.

[00011] In a further embodiment of the present invention, provided is a compound according to formula lb:

(lb),

or a pharmaceutically acceptable salt thereof,

wherein:

X is -F, -CI, -OH, or -0-CH₃;

Ri is an unsubstituted or substituted ring selected from the following list:

R4 where present is -H or lower alkyl

R₂ is a 5- to 10-membered mono- or bicyclic heteroaryl ring that contains 0-3

heteroatoms independently selected from the group consisting of N, O and S, wherein the 5- to 10-membered ring system is optionally substituted with 1-3 substituents independently selected from alkyl, -F, -CI, -Br, -OH, -CN, nitro, alkoxy, -CF₃, -OCF₃, -S(CH₃), -OCH₃, -S-alkyl, -S(0)-alkyl, -S(0₂)-alkyl, S(0₂)aryl, -CH₂-aryl, heteroaryl, alkanoyl, -O-aryl, -0-CH₂-aryl, -N(CH₃)₂, cycloalkyl, heterocycloalkyl, -C(0)cycloalkyl, -C(0)-heterocycloalkyl, or substituted lower alkyl or a 5- to 10-membered mono- or bicyclic aryl ring, wherein the 5- to 10- membered ring system is optionally substituted with 1-3 substituents

heterocycloalkyl, -C(0)cycloalkyl, -C(0)-heterocycloalkyl, or substituted lower alkyl;

R₃ is -H

[00012] In a further embodiment, provided is a compound according to formula lb, or a pharmaceutically acceptable salt thereof, wherein:

Ri is 2-pyridinyl or substituted 2-pyridinyl;

X is F, CI, -OH, or -0-CH₃;

R₃ is H;

[00013] In a further embodiment of the present invention, provided is a compound according to formula lb, or a pharmaceutically acceptable salt thereof, wherein:

R₂ is a 5- to 10-membered mono- or bicyclic aryl or heteroaryl ring that contains 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O and S, wherein the 5- to 10-membered ring system is optionally substituted with 1, 2 or 3 substituents independently selected from Ci-C₄-alkyl, -F, -CI, -Br, -OH, - CN, nitro, -CF₃, -OCF₃, -0-Ci-C₄-alkyl, -SCH₃, -S(0)-CH₃, -S(0₂)-CH₃, - C0₂CH₃, -C(0)NH₂, -C(0)NH(CH₃), -C(0)N(CH₃)₂, phenyl, wherein the C C -alkyl is preferably methyl, ethyl, propyl, z^'so-propyl, butyl, z^'so-butyl, tert- butyl; the -0-Ci-C -alkyl is preferably methoxy, ethoxy, propoxy, z^'so-proxy, butoxy, zso-butoxy, ferz-butoxy, wherein the 5- to 10-membered ring system is preferably phenyl, pyridinyl, naphthyl, quinolinyl, or

R₂ is -C(0)-Ci-C₅-alkyl, -C0₂-Ci-C₅-alkyl, -C(0)-benzyl, -C0₂-benzyl, -C(O)- phenyl, -C0₂-phenyl, benzyl, phenylethyl, -S(0₂)-phenyl which is optionally further substituted with a substituent independent selected from methyl, ethyl, propyl, CI, F, Br, wherein Ci-C₅-alkyl includes methyl, ethyl, propyl, z^'so-propyl, butyl, z^'so-butyl, teri-butyl, pentyl, z^'so-pentyl, teri-pentyl, neo-pentyl,

R₃ is H.

[00014] In a still further embodiment of the present invention, provided is a pharmaceutical composition, comprising a therapeutically effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[00015] It is to be understood that the terminology employed herein is for the purpose of describing particular embodiments, and is not intended to be limiting. Further, although any methods, devices and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods, devices and materials are now described.

[00016] As used herein, the term "alkyl", alone or in combination with other groups, refers to a branched or straight-chain monovalent saturated aliphatic

hydrocarbon radical of one to twenty carbon atoms, preferably one to sixteen carbon atoms, more preferably one to ten carbon atoms.

[00017] As used herein, the term "alkenyl", alone or in combination with other groups, refers to a straight-chain or branched hydrocarbon residue having an olefinic bond of two to twenty carbon atoms, preferably two to sixteen carbon atoms, more preferably two to ten carbon atoms.

[00018] The term "cycloalkyl" refers to a monovalent mono- or polycarbocyclic radical of three to ten, preferably three to six carbon atoms. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl, indanyl and the like. In a preferred embodiment, the "cycloalkyl" moieties can optionally be substituted with one, two, three or four substituents, With the understanding that said substituents are not, in turn, substituted further unless indicated otherwise in the Examples or claims below. Each substituent can independently be, alkyl, alkoxy, halogen, amino, hydroxyl or oxygen (0=) unless otherwise specifically indicated. Examples of cycloalkyl moieties include, but are not limited to, optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclopentenyl, optionally substituted cyclohexyl, optionally substituted cyclohexylene, optionally substituted cycloheptyl, and the like or those which are specifically exemplified herein.

[00019] The term "heterocycloalkyl" denotes a mono- or poly cyclic alkyl ring, wherein one, two or three of the carbon ring atoms is replaced by a heteroatom such as N, O or S. Examples of heterocycloalkyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxanyl and the like. The heterocycloalkyl groups may be unsubstituted or substituted and attachment may be through their carbon frame or through their heteroatom(s) where appropriate, with the understanding that said substituents are not, in turn, substituted further unless indicated otherwise in the Examples or claims below.

[00020] The term "lower alkyl", alone or in combination with other groups, refers to a branched or straight-chain alkyl radical of one to nine carbon atoms, preferably one to six carbon atoms, more preferably one to four carbon atoms. This term is further exemplified by radicals such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s -butyl, isobutyl, i-butyl, n-pentyl, 3-methylbutyl, n-hexyl, 2-ethylbutyl and the like.

[00021] The term "aryl" refers to an aromatic mono- or polycarbocyclic radical of 6 to 12 carbon atoms having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalene, 1,2- dihydronaphthalene, indanyl, lH-indenyl and the like.

[00022] The alkyl, lower alkyl and aryl groups may be substituted or

unsubstituted. When substituted, there will generally be, for example, 1 to 4 substituents present, with the understanding that said substituents are not, in turn, substituted further unless indicated otherwise in the Examples or claims below. These substituents may optionally form a ring with the alkyl, lower alkyl or aryl group with which they are connected. Substituents may include, for example: carbon-containing groups such as alkyl, aryl, arylalkyl (e.g. substituted and unsubstituted phenyl, substituted and unsubstituted benzyl); halogen atoms and halogen-containing groups such as haloalkyl (e.g. trifluoromethyl); oxygen-containing groups such as alcohols (e.g. hydroxyl, hydroxyalkyl, aryl(hydroxyl)alkyl), ethers (e.g. alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl, more preferably, for example, methoxy and ethoxy), aldehydes (e.g.

carboxaldehyde), ketones (e.g. alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl, arylalkylcarbonyl, arycarbonylalkyl), acids (e.g. carboxy, carboxyalkyl), acid derivatives such as esters(e.g. alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl), amides (e.g. aminocarbonyl, mono- or di-alkylaminocarbonyl, aminocarbonylalkyl, mono-or di-alkylaminocarbonylalkyl, arylaminocarbonyl), carbamates (e.g. alkoxycarbonylamino, aryloxycarbonylamino, aminocarbonyloxy, mono-or di-alkylaminocarbonyloxy, arylminocarbonloxy) and ureas (e.g. mono- or di- alkylaminocarbonylamino or arylaminocarbonylamino); nitrogen-containing groups such as amines (e.g. amino, mono- or di-alkylamino, aminoalkyl, mono- or di- alkylaminoalkyl), azides, nitriles (e.g. cyano, cyanoalkyl), nitro; sulfur-containing groups such as thiols, thioethers, sulfoxides and sulfones (e.g. alkylthio, alkylsulfmyl, alkylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, arylthio, arysulfinyl, arysulfonyl, arythioalkyl, arylsulfinylalkyl, arylsulfonylalkyl); and heterocyclic groups containing one or more heteroatoms, (e.g. thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, hexahydroazepinyl, piperazinyl, morpholinyl, thianaphthyl, benzofuranyl,

isobenzofuranyl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolinyl, isoquinolinyl, naphthridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxalinyl, chromenyl, chromanyl, isochromanyl, phthalazinyl and carbolinyl).

[00023] The term "heteroaryl," refers to an aromatic mono- or polycyclic radical of 5 to 12 atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, and S, with the remaining ring atoms being C. One or two ring carbon atoms of the heteroaryl group may be replaced with a carbonyl group. Examples of such groups include, but are not limited to, pyrimidinyl, pyridyl, indoyl, quinolinyl, pyridon-2-yl, isoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, thienyl, furanyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, pyrazolidinyl, pyrazinyl, pyridazinyl, thianaphthyl, benzofuranyl, isobenzofuranyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, benzopyranyl, coumarinyl, isocoumarinyl, isoquinolinyl, naphthridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxalinyl, chromenyl, chromanyl, isochromanyl, phthalazinyl and the like.

[00024] The heteroaryl group described above may be substituted independently with one, two, or three substituents, with the understanding that said substituents are not, in turn, substituted further unless indicated otherwise in the Examples or claims below. These substituents may optionally form a ring with the heteroaryl group to which they are connected. Substituents may include, for example: carbon-containing groups such as alkyl, aryl, arylalkyl (e.g. substituted and unsubstituted phenyl, substituted and unsubstituted benzyl); halogen atoms and halogen-containing groups such as haloalkyl (e.g. trifluoromethyl); oxygen-containing groups such as alcohols (e.g. hydroxyl, hydroxyalkyl, aryl(hydroxyl)alkyl), ethers (e.g. alkoxy, aryloxy, alkoxyalkyl, aryloxy alkyl), aldehydes (e.g. carboxaldehyde), ketones (e.g. alkylcarbonyl,

alkylcarbonylalkyl, arylcarbonyl, arylalkylcarbonyl, arylcarbonylalkyl), acids (e.g.

carboxy, carboxyalkyl), acid derivatives such as esters (e.g. alkoxycarbonyl,

alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl), amides (e.g. aminocarbonyl, mono- or di-alkylaminocarbonyl, aminocarbonylalkyl, mono-or di- alkylaminocarbonylalkyl, arylaminocarbonyl), carbamates (e.g. alkoxycarbonylamino, aryloxycarbonylamino, aminocarbonyloxy, mono-or di-alkylaminocarbonyloxy, arylminocarbonloxy) and ureas (e.g. mono- or di- alkylaminocarbonylamino or arylaminocarbonylamino); nitrogen-containing groups such as amines (e.g. amino, mono- or di-alkylamino, aminoalkyl, mono- or di-alkylaminoalkyl), azides, nitriles (e.g. cyano, cyanoalkyl), nitro; sulfur-containing groups such as thiols, thioethers, sulfoxides and sulfones (e.g. alkylthio, alkylsulfinyl, alkylsulfonyl, alkylthioalkyl,

alkylsulfinylalkyl, alkylsulfonylalkyl, arylthio, arysulfinyl, arysulfonyl, arythioalkyl, arylsulfinylalkyl, arylsulfonylalkyl); and heterocyclic groups containing one or more heteroatoms, (e.g. thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl,

isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, hexahydroazepinyl, piperazinyl, morpholinyl, thianaphthyl, benzofuranyl, isobenzofuranyl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolinyl, isoquinolinyl, naphthridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxalinyl, chromenyl, chromanyl, isochromanyl, phthalazinyl, benzothiazoyl and carbolinyl).

[00025] As used herein, the term "alkoxy" means alkyl-O-; and "alkanoyl" means alkyl-CO-. Alkoxy substituent groups or alkoxy-containing substituent groups may be substituted by, for example, one or more alkyl groups, with the understanding that said substituents are not, in turn, substituted further unless indicated otherwise in the

Examples or claims below.

[00026] As used herein, the term "halogen" means a fluorine, chlorine, bromine or iodine radical, preferably a fluorine, chlorine or bromine radical, and more preferably a fluorine or chlorine radical.

[00027] Compounds of formula I can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates. The optically active forms can be obtained for example by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbents or eluant). The invention embraces all of these forms.

[00028] As used herein, the term "pharmaceutically acceptable salt" means any pharmaceutically acceptable salt of the compound of formula I. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, /?-toluenesulfonic and the like.

Particularly preferred are fumaric, hydrochloric, hydrobromic, phosphoric, succinic, sulfuric and methanesulfonic acids. Acceptable base salts include alkali metal (e.g. sodium, potassium), alkaline earth metal (e.g. calcium, magnesium) and aluminum salts.

[00029] In the practice of the method of the present invention, an effective amount of any one of the compounds of this invention or a combination of any of the compounds of this invention or a pharmaceutically acceptable salt thereof, is

administered via any of the usual and acceptable methods known in the art, either singly or in combination. The compounds or compositions can thus be administered orally (e.g., buccal cavity), sublingually, parenterally (e.g., intramuscularly, intravenously, or subcutaneously), rectally (e.g., by suppositories or washings), transdermally (e.g., skin electroporation) or by inhalation (e.g., by aerosol), and in the form or solid, liquid or gaseous dosages, including tablets and suspensions. The administration can be conducted in a single unit dosage form with continuous therapy or in a single dose therapy ad libitum. The therapeutic composition can also be in the form of an oil emulsion or dispersion in conjunction with a lipophilic salt such as pamoic acid, or in the form of a biodegradable sustained-release composition for subcutaneous or intramuscular administration.

[00030] Useful pharmaceutical carriers for the preparation of the compositions hereof, can be solids, liquids or gases. Thus, the compositions can take the form of tablets, pills, capsules, suppositories, powders, enterically coated or other protected formulations (e.g. binding on ion-exchange resins or packaging in lipid-protein vesicles), sustained release formulations, solutions, suspensions, elixirs, aerosols, and the like. The carrier can be selected from the various oils including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, particularly (when isotonic with the blood) for injectable solutions. For example, formulations for intravenous administration comprise sterile aqueous solutions or of the active ingredient(s) which are prepared by dissolving solid active ingredient(s) in water to produce an aqueous solution, and rendering the solution sterile. Suitable

pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, talc, gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodium stearate, glycerol

monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. The compositions may be subjected to conventional

pharmaceutical additives such as preservatives, stabilizing agents, wetting or

emulsifying agents, salts for adjusting osmotic pressure, buffers and the like. Suitable pharmaceutical carriers and their formulation are described in Remington's

Pharmaceutical Sciences by E. W. Martin. Such compositions will, in any event, contain an effective amount of the active compound together with a suitable carrier so as to prepare the proper dosage form for proper administration to the recipient.

[00031] The dose of a compound of the present invention depends on a number of factors, such as, for example, the manner of administration, the age and the body weight of the subject, and the condition of the subject to be treated, and ultimately will be decided by the attending physician or veterinarian. Such an amount of the active compound as determined by the attending physician or veterinarian is referred to herein, and in the claims, as a "therapeutically effective amount". For example, the dose of a compound of the present invention is typically in the range of about 1 to about 1000 mg per day. Preferably, the therapeutically effective amount is in an amount of from about 1 mg to about 500 mg per day.

[00032] It will be appreciated, that the compounds of general formula I in this invention may be derivatized at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo. Physiologically acceptable and metabolically labile derivatives, which are capable of producing the parent compounds of general formula I in vivo are also within the scope of this invention.

[00033] Compounds of the present invention can be prepared beginning with commercially available starting materials and utilizing general synthetic techniques and procedures known to those skilled in the art. Chemicals may be purchased from companies such as for example Aldrich, Argonaut Technologies, VWR and Lancaster.

[00034] The compounds of formula I can be prepared by the following General

Reaction Scheme:

Scheme 1

[00035] In scheme 1 compounds of formula 1, wherein R¹ is either R¹ of formula

I or a derivative in which the functionality in the desired R¹ of the compound I exists in latent form that can be converted to the desired R¹ of the invention by protecting group and functional group manipulation at a later stage of the synthesis. Skilled organic chemists will understand where and how such transformations are best achieved. The use of protecting groups in organic syntheses have been systematically reviewed, for example in Wuts, P. G. and Greene, T. W., Greene's Protective Groups in Organic Synthesis, 4 edition, Wiley, 2006. Compounds of formula I are known, and in many cases, commercially available compounds or can be prepared using well established methodology. For example 1, R¹ = 2-pyridinyl or 3-pyridinyl are available from several suppliers including Sigma-Aldrich.

[00036] In the case that commercial supplies are not readily available, aryl- and heteroaryl alkynes can be prepared from the corresponding aryl or heteroaryl carboxaldehydes using the Corey-Fuchs procedure (Corey, E. J. and Fuchs, P. L., Tetrahedron Lett. 1972, 3769; reviewed in: Han, Xiaojun. Editor(s): Li, Jie Jack. Name Reactions for Homologations (2009), (Pt. 1), 393-403. Publisher: John Wiley & Sons, Inc.). Alternatively, aryl and heteroaryl carboxaldehydes may be converted to aryl or heteroaryl alkynes by treatment with C-silylated -diazophosphines under neutral conditions (Ona, I., Xavier, B., Cazoria, A. M., et al., Journal of Organic Chemistry 2006, 71, 5320).

[00037] In cases where the appropriate carboxaldehydes are not readily available, aryl or heteroaryl aryl and heteroaryl alkynes may also be prepared from aryl or heteroaryl compounds functionalized with groups capable of undergoing transition metal catalyzed cross-coupling reactions with alkynes. Those skilled in the art will appreciate how to select the appropriate reaction partners. For example US Patent 7,462,619 describes the synthesis of 3-alkynyl pyridine from either 3-bromopyridine or 3-trifluoromethanesulfonyl pyridine through reactions with suitably functionalized alkynes catalyzed by transition metals, followed by deprotection of terminal alkynes bearing a protecting group at the terminal position. In the event the protecting group is trimethylsilyl (TMS), the compound may be treated with an aqueous base, for example potassium hydroxide or potassium carbonate in methanol to effect its removal. In the case where the alkyne is formed through a transition metal catalyzed reaction between an aryl or heteraryl ring bearing a suitable functionality for cross coupling reactions, for example a bromide, and 2-methyl-3-butyne-2-ol, deprotection to give a terminal alkyne can be achieve through heating in a suitable solvent, for example toluene, in the presence of catalytic amounts of a base, for example sodium hydride. The following references are among the many examples of such transformations in the published literature: Holmes, B. T., Pennington, W. T., Hanks, T. W., Synthetic Communications, 2003, 33, 2447-2461; Negishi, E.-L, Xu, C, Tan, Z., Kotora, M., Heterocycles 1997, 46, 209-214. One common variant is known as the Sonogashira coupling reaction, reviewed in Chinchilla, R., Najera, C, Recent Advances in Sonogashira reactions, Chemical Society Reviews, 2011, 40, 5084-5121. [00038] In scheme 1 compounds of formula 2, in which PG is a protecting group, for example a 1,1-dimethylethoxycarbonyl (Boc) group, are known, and in many cases, commercially available compounds or can be prepared using well established methodology. For example 2, a = 1 or 2, PG =l-(l,l-dimethylethoxy)carbonyl (Boc) and R^3' = H, are available from several suppliers including Sigma-Aldrich and Wuxi AppTec. In cases where compounds of formula 2, R³ is alkyl or substituted alkyl are desired, they can be prepared by known or by variation of known procedures. For example homochiral l-(l,l-dimethylethoxy)carbonyl-2-substituted-azetin-3-ones can be prepared by cyclization of -diazoketones derivatived from amino acids in the presence of rhodium acetate; Podlech, J., Seebach, D., Helv. Chim. ACTA 1995, 78, 1238-1246. 2-Alkyl- and 2-aryl-[(l,l-dimethylethoxy)carbonyl]-4-oxo-pyrroldines can be prepared by a number of procedures, among them, the oxidative cyclization of N- acetyl-2-allylbenzylamines followed by hydrolysis, protection and oxidation according to the procedure described in Hashihayata, T., Sakoh, H., et al. Chem. Pharm. Bull. 2002, 50, 423-425 or the rhodium catalyzed cyclization of -diazo-3-keto-5- substituted-5 -{para -to lyl-sulfmylamino)pentanoic esters as described in Dong, C, Wang, J., J. Org. Chem. 2008, 73, 1971-1974.

[00039] Reaction of compounds 1 and 2 to form the alcohol 3 can be achieved by treatment of a solution of the alkyne 1 in a suitable inert solvent, for example THF, with a base sufficiently strong to achieve deprotonation of the alkyne terminal CH. Common bases for this purpose include Grignard reagents, for example, ethyl magnesium bromide, or an organo lithium reagent, for example n-butyl lithium. These reactions are often run at a low temperature, for example -78°C. The thus formed anion is then allowed to react with the ketone 2 until reaction is complete and the newly formed compound 3 can be isolated using conventional technics, for example by quenching the reaction with an aqueous solution followed by extraction of the products into an organic solvent, washing with water, drying and chromatography over silica gel, if necessary. [00040] Conversion of compounds of structure 3 to the fluorides 4 can be achieved by combination of a solution of 3 to a solution of a fluorinating reagent, for example DAST (diethylaminosulfur trifluoride) in a suitable inert solvent, for example, dichloromethane, typically maintained at a low temperature, for example -78 °C during the early part of the reaction. Such reactions may be worked up using common procedures, for example, quenching with water, extraction and chromatography as appropriate.

[00041] Conditions for the removal of the protecting group in 4 to give a compound of structure 5, will depend on the particular choice of protecting group employed. Skilled organic chemists will be familiar with the various potential protecting and the procedures for their removal. In this regard, reference to a compendium of protecting groups such as Greene's Protecting Groups in Organic Synthesis, 4^th ed., cited above may be useful. In one convenient implementation, a Boc ((1,1- dimethylethoxy)carbonyl) group may be used. In this case, its removal to give a compound of structure 4 may be readily achieved by treatment with an acid, for example trifluoroacetic acid (TFA) in a suitable solvent, for example dichloromethane followed by a conventional workup.

[00042] Further transformation of compounds of structure 5 to compounds of the invention or compounds readily transformed to compounds of the invention through functional and protecting group transformations on R¹ and R² , R⁵ or R⁶ as appropriate will depend on the particular target compound desired. In the case that introduction of a sulfonyl group is desired to give a compound of structure 9, a compound of structure 5 may be treated with an activated sulfonyl derivative 6 in which Lv is a leaving group, for example a chloride. Such transformations are generally carried out in the presence of an organic or inorganic base, for example triethylamine in a suitable solvent such as dichloromethane. Skilled organic chemists will be familiar with the general reaction scope and be able to choose appropriate conditions for the target compound of interest.

[00043] In the event that an amide or carbamate of structure 10 is desired (R⁶ aryl, heteroaryl, alkyl, alkoxy, or arylalkoxy), a compound of structure 5 may be treated with an activated ester derivative 7 in which Lv is a suitable leaving group for acylation reactions, for example a halogen atom such as a chloride. Such reactions may be carried out under a wide variety of conditions well known to skilled organic chemists. In one set of conditions, an acyl chloride, 7, in which Lv is chloride can be allowed to react with the amine 5 in an inert solvent such as dichloromethane at a suitable temperature, for example room temperature in the presence of base, for example triethylamine followed by a convention workup involving quenching with an aqueous solution, extraction of the product into an organic solvent, drying, evaporation and optionally, chromatographic purification of the residue.

[00044] In case the desired compound is an N-aryl or N-heteroaryl derivative of structure 11, a compound of structure 5 may be reacted with a compound of structure 7 in which Lv represents a leaving group suitable for participation in a Buchwald reaction and R² represents a R² of the invention or incorporates functionality that can

transformed into a R² of the invention through manipulation of substituents and protecting groups after the coupling reaction. Typical groups include iodide, bromide and chloride. Reactions typically are run in the presence of a base, which can either be a strong base such as LiHMDS or a weaker base such as cesium carbonate in the presence of a palladium catalyst and suitable ligand. The selection of the base, solvent and ligand for a particular desired transformation may be guided by literature precedent. One useful review is: Surry, D. S. and Buchwald, S. L, Chem. Sci. 2011, 2, 27-50. For aryl and heteroaryl moieties with highly reactive leaving groups, for example 2- fluoropyridine, a direct reaction between that compound and compound 5 in the presence of a suitable base, for example potassium carbonate at an elevated temperature, for example 100-120°C can affect their transformation to a compound of structure 11.

Scheme 2

[00045] An alternative method for the preparation of compounds of formula I is shown in Scheme 2. In this case, a protect alkyne, for example TMS acetylene, 12, is reacted with a ketone 13 in which R³ is R³ of the invention or a derivative that can be later converted to R³ of the invention through manipulation of functionality and protecting groups as appropriate and R⁷ is either a protecting group or corresponds to R² as defined above with the proviso that in this incidence, R² does not carry any functionality that would be inconsistent with the reactions necessary to convert 13 to a compound of the invention. Compounds 12 and 13 can be reacted in the presence of a strong base as described above for the reaction of 1 and 2 in Scheme 1 to give a compound of structure 14. Conversion of 14 to 15 can be achieved by treatment with DAST as described in Scheme 1 with the proviso that it may be desirable to protect the alkynyl group as a Cobalt complex during this transformation as described in van Neil, M. B., Collins, I., Beer, M. S., et al, J. Med. Chem. 1999, 42, 2087-2104. The acetylenic protecting group, if present can be removed by oxidation, for example by treatment with cerium ammonium nitrate and the TMS group can be removed using conditions noted above. The resulting alkyne, 17, may then undergo a Buchwald type cross coupling reaction with a compound of structure 16 in which R is an R¹ of the invention or can be converted to an R¹ by functional group and protecting group manipulations, if necessary. Skilled organic chemists will appreciate the need for and implementation of such transformations. [00046] The invention will now be further described in the Examples below, which are intended as an illustration only and do not limit the scope of the invention.

EXAMPLES

Example 1

Preparation l-carboxylate:

1

Compound 1 (3.00g, 29.1mmol) was dissolved in dry THF (60mL). The solution was cooled to 0^°C , and EtMgBr solution (3.0M, 10.6mL, 32mmol) was added. The reaction mixture was stirred for lOmin at rt. and then heated to 40 ^°C for lh. Compound 2 (5.48g, 32.0mmol) in 20mL of THF was added. The mixture was stirred overnight at room temperature, quenched with saturated NH₄C1 solution and then extracted with EtOAc (2x50mL). The separated organic layer was dried over anhydrous Na₂S0₄, filtered and concentrated to dryness, which was purified by column on silica gel (PE/EA, 1/2) to give desired compound. (Yield: 56%).

Procedure for Preparation of tert- \\ty\ 3-fluoro-3-(pyridin-2-ylethynyl)azetidine-l- carboxylate

teri-Butyl 3-hydroxy-3-(pyridin-2-ylethynyl)azetidine-l-carboxylate (5.5g, 20.0mmol) was dissolved in dry dichloromethane (60mL). The solution was cooled to -78 ^°C, and DAST (6.5g, 40.0mmol) was added slowly. The reaction mixture was stirred for lh at - 78 ^°C and warmed to rt. After quenching with H₂0, the solution was extracted with dichloromethane (3^x50mL). The combined organic layers were dried over anhydrous Na₂S0₄, filtered, concentrated to dryness and purified by column on silica gel (eluted with EA/PE, 1/5, v/v) to give the desired compound which was identified by

comparison with a reference standard (H13883-133-2A) by TLC. (3.0g,Yield: 55.5%)

Example 2

Preparation of 2-alkynyl-3-methylpyridine:

Procedure for reparation of 3:

To a solution of 1 (3400. Omg, 20.0mmol) in 30mL of degassed Et₃N was added successively Cul (380.9mg, 2.0mmol), 2(2160.8mg, 22.0mmol), and PdCl₂(PPh₃)₂ (731.7mg, 1.Ommol). The mixture was then degassed for 20min under N₂ atmosphere and stirred at rt overnight. The reaction mixture was filtered. 60mL of H₂0 was added into the black filtrate. After stirring for lOmin, the solution was extracted with EtOAc (3x30mL). The organic layer was washed with brine (2><30mL) and dried over anhydrous Na₂S0₄, filtered and evaporated to give crude product, which was purified by filtering through a silica gel plug (Dichloromethane) to give desired product (2.5g, yield=65.8%).

Procedure for preparation of 4:

Compound 3 (2500mg, 13.2mmol) was dissolved in MeOH/Dichloromethane

(60mL/30mL). The solution was cooled to 0^°C and KOH (1482mg, 26.4mmol) was added. The reaction mixture stirred for 0.5h, and then quenched with H₂0, extracted with Dichloromethane (2><30mL). The combined organic layers were dried over anhydrous Na₂S0₄, filtered and concentrated to give desired compound (1.5g, yield=99.8%).

Example 3

Preparation of 3-fluoro-3- [(3-methylpyridin-2-yl)-ethynyl] azetidine

Procedure for preparation of 6:

Compound 4(585. Omg, 5.0mmol) was dissolved in dry THF (20mL). The solution was cooled to -78 ^°C , and BuLi(2.5M, 2.2mL, 5.5mmol) was added. The reaction mixture was stirred for lhr at the temperature and then a solution of compound 5 (941. Omg, 5.5mmol) in THF was added thereto. The reaction was stirred at -78 ^°C for 2h, quenched by adding IN NH₄CI, and extracted with EA. The combined organic phases were washed by water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by pre-TLC (l . lg, yield=78.5%).

Procedure for preparation of 7:

Compound 6(600. Omg, 2.08mmol) was dissolved in dry Dichloromethane (20mL). The solution was cooled to -78 ^°C , and DAST(670.6mg, 4.16mmol) was added. The reaction mixture was stirred for lh at -78 ^°C and warmed to rt. After quenched with H₂0, the solution was extracted with EtOAc(2x l5mL). The combined organic layers were dried over anhydrous Na₂S0₄, filtered and concentrated to dryness, which was purified by column on silica gel (eluted with EA/PE, 1/10, v/v) to give desired compound (400. Omg, yield=66.7%).

Procedure for preparation of 8:

Compound 7(116. Omg, 0.4mmol) was dissolved in dry Dichloromethane (4.0mL) and TFA (0.8mL). The solution was stirred at r.t for 2 hr, and concentrated to dryness. The residue was dissolved in a minimum of water, neutralized with saturated sodium carbonate (pH=8), extracted with EA. The combined organic phases were washed by water, brine, dried over sodium sulfate and concentrated. The residue was purified by pre-TLC to give 3-fluoro-3-[(3-methylpyridin-2-yl)-ethynyl]azetidine (50.0mg, yield=65.7%).

Example 4

Preparation o 3-fluoro-3-[(4-methylpyridin-2-yl)-ethynyl]azetidine

Procedure for preparation of 3:

To a solution of 1 (3400. Omg, 20.0mmol) in 30mL of degassed Et₃N was added successively Cul (380.9mg, 2.0mmol), 2(2160.8mg, 22.0mmol), and PdCl₂(PPh₃)₂ (731.7mg, 1.Ommol). The mixture was then degassed for 20min under N₂ atmosphere and stirred at rt overnight. The reaction mixture was filtered. 60mL of H₂0 was added into the black filtrate. After stirring for lOmin, the solution was extracted with EtOAc (3x30mL). The organic layer was washed with brine (2><30mL) and dried over anhydrous Na₂S0₄, filtered and evaporated to give crude product, which was purified by filtering through a silica gel plug (Dichloromethane) to give desired product (2.4g, yield=63.1%).

Procedure for preparation of 4:

Compound 3 (2.4g, 12.6mmol) was dissolved in MeOH/Dichloromethane

(40mL/20mL). The solution was cooled to 0^°C and KOH (1.4g, 25.2mmol) was added. The reaction mixture stirred for 0.5h, and then quenched with H₂0, extracted with Dichloromethane (2><3mL). The combined organic layers were dried over anhydrous Na₂S0₄, filtered and concentrated to give desired compound (1.2g, yield=81.5%). Procedure for preparation of 6:

Compound 4(585. Omg, 5.0mmol) was dissolved in dry THF (20mL). The solution was cooled to -78 ^°C , and BuLi(2.5M, 2.2mL, 5.5mmol) was added. The reaction mixture was stirred for lhr at the temperature and then a solution of compound 5 (941. Omg, 5.5mmol) in THF was added thereto. The reaction was stirred at -78 ^°C for 2h, quenched by adding IN NH₄CI, and extracted with EA. The combined organic phases were washed by water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by pre-TLC (1.0g, yield=71.4%).

Procedure for preparation of 7:

Compound 6(600. Omg, 2.08mmol) was dissolved in dry Dichloromethane (20mL). The solution was cooled to -78 ^°C , and DAST(670.6mg, 4.16mmol) was added. The reaction mixture was stirred for lh at -78 ^°C and warmed to rt. After quenched with H₂0, the solution was extracted with EtOAc(2x l5mL). The combined organic layers were dried over anhydrous Na₂S0₄, filtered and concentrated to dryness, which was purified by column on silica gel (eluted with EA/PE, 1/10, v/v) to give desired compound (380. Omg, yield=64.0%).

Procedure for preparation of 8:

8

Compound 7(116. Omg, 0.4mmol) was dissolved in dry Dichloromethane (4.0mL) and TFA (0.8mL). The solution was stirred at r.t for 2 hr, and concentrated to dryness. The residue was dissolved in a minimum of water, neutralized with saturated sodium carbonate (pH=8), extracted with EA. The combined organic phases were washed by water, brine, dried over sodium sulfate and concentrated. The residue was purified by pre-TLC to give 3-fluoro-3-[(4-methylpyridin-2-yl)-ethynyl]azetidine (40.0mg, yield=52.6%).

Example 5

Preparation o 3-fluoro-3-[(5-methylpyridin-2-yl)-ethynyl]azetidine

Procedure for preparation of 3:

To a solution of 1 (lOOOmg, 1.2mmol) in 15mL of degassed Et₃N was added

successively Cul 11 lmg, 0.58mmol), 2 (628mg, 6.4mmol), and Pd(PPh₃)₂Cl₂ (213mg, 0.29mmol). The mixture was then degassed for 20min under N₂ atmosphere and stirred at rt overnight. The reaction mixture was filtered. 60mL of H₂0 was added into the black filtrate. After stirring for lOmin, the solution was extracted with EtOAc (3^x30mL). The organic layer was washed with brine (2x30mL) and dried over anhydrous Na₂S0₄, filtered and evaporated to give crude product, which was purified by filtering through a silica gel plug (Dichloromethane) to give desired product 3 (0.6g, yield: 54.5%).

Procedure for preparation of 4:

Compound 3 (600mg, 3.17mmol) was dissolved in MeOH/Dichloromethane

(2mL/lmL). The solution was cooled to 0^°C and KOH (355mg, 6.34mmol) was added. The reaction mixture stirred for 0.5h, and then quenched with H₂0, extracted with Dichloromethane (2><3mL). The combined organic layers were dried over anhydrous Na₂S0₄, filtered and concentrated to give desired compound 4 (300mg, yield: 80.8%). Procedure for preparation of 6:

Compound 4 (174mg, 1.49mmol) was dissolved in dry THF (5mL). The solution was cooled to -78 ^°C , and n-BuLi solution (2.5M, 0.7mL, 1.63mmol) was added. The reaction mixture was stirred for lhr and then compound 5 (280mg, 1.63mmol) in 2mL of THF was added. The mixture was stirred for 2hrs, then quenched with saturated NH₄C1 solution and then extracted with EtOAc (2><20mL). The separated organic layer was dried over anhydrous Na₂S0₄, filtered and concentrated to dryness, which was purified by pre-TLC to give desired compound 6 (170mg, yield: 39.7%).

Procedure for preparation of 7:

6

Compound 6 (170mg, 0.59mmol) was dissolved in dry Dichloromethane (lOmL). The solution was cooled to -78 ^°C , and DAST(190mg, 1.18mmol) was added. The reaction mixture was stirred for lh at -78 ^°C and warmed to rt. After quenched with H₂0, the solution was extracted with EtOAc (2x 15mL). The combined organic layers were dried over anhydrous Na₂S0₄, filtered and concentrated to dryness, which was purified by pre-TLC to give desired compound 7 (1 lOmg, yield: 64.2%).

Procedure for preparation of 8:

To a solution of compound 7 (1 lOmg, 0.38mmol) in Dichloromethane (3ml), TFA

(lml)was added slowly under N₂ atmosphere at 0^°C .The mixture was stirred at r.t. for 2hrs. The reaction mixture was concentrated to dryness to afford the crude 3-fluoro-3- [(5-methylpyridin-2-yl)-ethynyl]azetidine (60mg, yield: 83.2%).

Example 6

Preparation of benzofuranY2-ylethyne Compound 210-:

Procedure for Preparation of Compound 4:

1 ³

To a solution of 1 (2.0g, 10.2mmol) in 30mL of Et3N degassed was added successively Cul (0.194g, 1.026mmol), 2(1. lg, 11.2mmol), and 3(0.37g, 0.51mmol). The mixture was then degassed for 20min under N₂ atmosphere and stirred at RT overnight. The reaction mixture was filtered. 60mL of H₂0 was added into the black filtrate. After stirring for lOmin, the solution was extracted with EtOAc (3^x30mL). The organic layer was washed with brine (2x30mL) and dried over anhydrous Na₂S0₄, filtered and evaporated to give crude product, which was purified by filtering through a silica gel plug (Dichloromethane) to give desired product. (1.9g, Yield: 86%)

Procedure for Preparation of Compound 5:

Compound 4(1.90g, 9.31mmol) was dissolved in MeOH-DCM(v/v: 2: 1) (20mL). The solution was cooled to 0^°C , and KOH (1.04g, 18.63mmol) was added. The reaction mixture was stirred for 5min at 0^°C , then allowed to warm to RT and stirred for 0.5 h again.

TLC showed that the SM was consumed absolutely. 20mL of water was added to the mixture. The mixture was partitioned. The aqueous phase was extracted with DCM (15mLx3). Combine organic phase was washed, dried over anhydrous Na₂S0₄ and concentrated to give benzofuran-2-ylethyne (1.3g,Yield: 98%).

Example 7

Procedure for Preparation of 3-fluoro-3-(benzofuran-2-yl)azetine:

Compound 5(500mg, 3.52mmol) was dissolved in dry THF (lOmL). The solution was cooled to -78^°C , and n-BuLi solution(2.5M in hexane,1.5mL, 3.87mmol)) was added drop wise. The reaction mixture was stirred for lh at -78 ^°C . Then compound 6(663mg, 3.87mmol) in 3mL of THF was added. The mixture was stirred at the same temperature for 12h. The reaction was quenched with saturated NH₄C1 solution and then extracted with EtOAc(2x20mL). The separated organic layer was dried over anhydrous Na₂S0₄, filtered and concentrated to dryness, which was purified by prep-TLC to give desired compound. (600mg ,Yield: 54.5%>) Procedure for Preparation of Compound 8:

Compound 7(200mg, 0.639mmol) was dissolved in dry Dichloromethane(3mL). The solution was cooled to -78 ^°C , and DAST(206mg, 1.278mmol) was added. The reaction mixture was stirred for lh at -78 ^°C and warmed to rt. After quenched with H₂0, the solution was extracted with Dichloromethane (2><3mL). The combined organic layers were dried over anhydrous Na₂S0₄, filtered and concentrated to dryness, which was purified by prep-TLC(eluted with EA/PE, 1/5, v/v) to give desired compound. (lOOmg, Yield: 49.7%)

LCMS: m/z, 260.1 [M-55(^tBu)]⁺.

Procedure for Preparation of Compound 8:

To a solution of 8 (lOOmg, 0.317mmol) in DCM (lOmL) was added TFA (2mL) drop wise at 0^°C . After addition, the reaction mixture was stirred continuously for 15min. at 0^°C . Then the mixture was allowed to warm to RT, and stirred for ~lh. The reaction was checked by LCMS. The reaction mixture was neutralized with saturated Na₂C0₃ until pH>8, then extracted with DCM (5^x50mL). The separated organic layer was dried over anhydrous Na₂S0₄, filtered and concentrated to dryness, which was purified by prep-TLC to give 3-fluoro-3-(benzofuran-2-yl)azetine (50mg, Yield: 73.5%).

Example Compound 63

Procedure for preparation of Compound 63:

Compound 63 To a solution of 1 (20mg, 0.1 lmmol), 2 (45mg, 0.22mmol) and CS₂CO₃ (180mg, 0.55mmol) in DMF (lmL) were added 2 mg of Pd(dba)₂ and 2 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was irradiated in the microwave at 120°C for lh. LCMS showed most of the SM was consumed completely. The reaction mixture was diluted with EA (5mL) and washed with brine (2mL) twice. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purified by p-TLC to give the desired compound Compound 63 (lOmg, yield: 37%).

LCMS: m/z, 253.1 (M+H)⁺;

1HNMR (d-CDCl3, 400MHz): δ 8.60~8.61(m, 1H), 7.67~7.71(m, 1H), 7.48~7.50(m, 1H), 7.22-7.31 (m, 3H), 6.79-6.84 (m, 1H), 6.48~6.51(m, 2H), 4.26-4.39 (m, 4H).

Example Compound 64

Procedure for preparation of Compound 64:

Compound 64

A mixture of compound 7 (20mg, 0.1 lmmol), compound 2(31mg, 0.13mmol), CS₂CO₃ (143mg, 0.44mmol), Pd(dba)₂(6mg, O.Olmmol) and Xanphos (5mg, O.Olmol) in

DMF(l .OmL) were degassed under N₂ and then heated to 100^°C for lh. After cooled, the reaction mixture was filtered. The filtrate was washed with H₂0, extracted with EtOAc. The organic layer was dried over anhydrous Na₂S0₄, filtered and concentrated to residue, which was purified by prep-TLC (EA/PE, 1/2, v/v) to give desired compound (15mg, 50% yield).

LCMS: m/z, 287.0(M+H)+;

1HNMR (400MHz, CDC1₃) δ 4.17-4.3 l(m, 4H), 6.26~6.28(m, 1H), 6.38(t, J=2.0Hz, 1H), 6.69~6.71(m, 1H), 7.07(t, J=8.0Hz, 1H), 7.19~7.24(m, 1H), 7.42 (d, J=7.2Hz, 1H), 7.60-7.65 (m, 1H), 8.53~8.55(m, 1H).

Example Compound 68 Preparation of 2-((l-(3-chlorophenyl)-3-fluoroazetidin-3-yl)ethynyl)pyridine

Compound 64, 67, 68 and 69:

Preparation of 2-((trimethylsilyl)ethynyl)pyridine:

To a solution of 2-bromopyridine (1800 mg, 11.4 mmol) in 30 mL of degassed Et₃N was added successively Cul 217 mg, 1.14 mmol), trimethylsilyl acetylene (1227 mg, 12.5 mmol) and bis(triphenylphosphine) palladium dichloride (417mg, 0.57mmol). The mixture was then degassed for 20min under N₂ atmosphere and stirred at rt overnight. The reaction mixture was filtered and 60 mL of H₂0 was added into the black filtrate. After stirring for 10 min, the solution was extracted with EtOAc (3><30 mL). The organic layer was washed with brine (2x30 mL) and dried over anhydrous Na₂S0₄, filtered and evaporated to give crude product, which was purified by filtering through a silica gel plug (Dichloromethane) to give 2-((trimethylsilyl)ethynyl)pyridine (1.6g, 81% yield).

Preparation of 2-ethynylpyridine:

2-((Trimethylsilyl)ethynyl)pyridine (175mg, 1.0 mmol) was dissolved in

MeOH/Dichloromethane (2mL/lmL). The solution was cooled to 0°C and KOH

(112mg, 2.0 mmol) was added. The reaction mixture stirred for 0.5 h, and then quenched with H₂0, extracted with Dichloromethane (2x3 mL). The combined organic layers were dried over anhydrous Na₂S0₄, filtered and concentrated to give 2- ethynylpyridine (80 mg, 80%> yield).

Preparation of tert-bwty\ 3-hydroxy-3-(pyridin-2-ylethynyl)azetidine-l-carboxylate:

2-Ethynylpyridine (800mg, 7.77 mmol) was dissolved in dry THF (30 mL). The solution was cooled to 0°C, and EtMgBr solution (3.0M, 2.85 mL, 8.54 mmol) was added. The reaction mixture was stirred for 10 min at rt. and then heated to 40 ^°C for lh. tert-Butyl 3-oxoazetidine-l-carboxylate (1.46g, 8.54 mmol) in 2 mL of THF was added. The mixture was stirred overnight at room temperature, quenched with saturated NH₄CI solution and then extracted with EtOAc (2x20 mL). The separated organic layer was dried over anhydrous Na₂S0₄, filtered and concentrated to dryness, and the residue was purified by column on silica gel (PE/EA, 1/2) to give tert-butyl 3-hydroxy-3-(pyridin-2- ylethynyl)azetidine-l-carboxylate (1.3g, 62% yield).

LCMS: m/z, 274.1(M+H)⁺;

Preparation of 3-fluoro-3-(pyridin-2-ylethynyl)azetidine:

tert-Butyl 3-hydroxy-3-(pyridin-2-ylethynyl)azetidine-l-carboxylate (600mg, 2.18 mmol) was dissolved in dry Dichloromethane (20mL). The solution was cooled to -78 ^°C , and DAST (702mg, 4.36 mmol) was added. The reaction mixture was stirred for lh at -

78 ^°C and warmed to rt. After quenching with H₂0, the solution was extracted with

Dichloromethane (2x 15mL). The combined organic layers were dried over anhydrous

Na₂S0₄, filtered and concentrated to dryness, and the residue was purified by column on silica gel (eluted with EA/PE, 1/10, v/v) to give tert-butyl 3-fluoro-3-(pyridin-2- ylethynyl)azetidine-l-carboxylate (Compound 68) (380mg, 64% yield).

LCMS: m/z, 276.3(M+H)⁺;

Procedure or preparation 0/2-((3-fluoroazetidin-3-yl)eth nyl)pyridine:

tert-Butyl 3-fluoro-3-(pyridin-2-ylethynyl)azetidine-l-carboxylate (250 mg, 0.9 mmol) was dissolved in Dichloromethane (5.0 mL), then 0.5 mL of TFA was added at 0^°C . The reaction mixture was stirred overnight at rt. The solvent was removed and the residue was washed with saturated Na₂C0₃ solution (pH=8), extracted with dichloromethane (3x5mL). The combined organic layers were dried over anhydrous Na₂S0₄, filtered and concentrated to give 2-((3-fluoroazetidin-3-yl)ethynyl)pyridine (140mg, 87%> yield). LCMS: m/z, 177.1(M+H)⁺;

Preparation of 2-((l-(3-chlorophenyl)-3-fluoroazetidin-3-yl)ethynyl)pyridine Compound 64:

A mixture of 2-((3-fluoroazetidin-3-yl)ethynyl)pyridine (20mg, 0.11 mmol), 3-chloro- iodobenzene (31mg, 0.13mmol), Cs₂C0₃ (143mg, 0.44mmol), Pd(dba)₂(6mg, O.Olmmol) and Xanphos (5mg, O.Olmol) in DMF(l .OmL) were degassed under N₂ and then heated to 100^°C for lh. After cooling, the reaction mixture was filtered. The filtrate was washed with H₂0, extracted with EtOAc. The organic layer was dried over anhydrous Na₂S0₄, filtered and concentrated to residue, which was purified by prep-TLC (EA/PE, 1/2, v/v) to give 2-((l-(3-chlorophenyl)-3-fluoroazetidin-3-yl)ethynyl)pyridine (15mg, 50% yield).

LCMS: m/z, 287.0(M+H)⁺;

Example Compound 91 Procedure for preparation of Compound 91:

Compound 91

A mixture of compound 1 (15mg, 0.085mmol), compound 2(23mg, O. lmmol), Cs₂C0₃ (l lOmg, 0.34mmol), Pd(dba)₂(5mg, 0.0085mmol) and Xanphos (4mg, 0.0085mol) in DMF(l .OmL) were degassed under N₂ and then heated to 100^°C for lh. After cooled, the reaction mixture was filtered. The filtrate was washed with H₂0, extracted with EtOAc. The organic layer was dried over anhydrous Na₂S0₄, filtered and concentrated to residue, which was purified by prep-TLC (EA/PE, 1/2, v/v) to give desired compound (13mg, 57% yield).

LCMS: m/z, 278.1(M+H)+;

1HNMR (400MHz, CDC1₃) δ 4.31~4.45(m, 4H), 6.67~6.73(m, 2H), 7.06-7.10(m, 1H), 7.31~7.35(m, 2H), 7.52(d, J=8.0Hz, 1H), 7.65~7.73(m, 1H), 8.56(d, J=4.8Hz, 1H). Example Compound 93

Procedure for preparation of Compound 93:

Compound 93

A mixture of compound 1 (15mg, 0.085mmol), compound 2(24mg, O. lmmol), CS₂CO₃ (l lOmg, 0.34mmol), Pd(dba)₂(5mg, 0.0085mmol) and Xanphos (4mg, 0.0085mol) in DMF(l .OmL) were degassed under N₂ and then heated to 100^°C for lh. After cooled, the reaction mixture was filtered. The filtrate was washed with H20, extracted with EtOAc. The organic layer was dried over anhydrous Na₂S0₄, filtered and concentrated to residue, which was purified by prep-TLC (EA/PE, 1/2, v/v) to give desired compound (12mg, 50% yield).

LCMS: m/z, 287.1(M+H)⁺;

1HNMR (400MHz, CDC1₃) δ 4.25~4.39(m, 4H), 6.41-6.44 (m, 2H), 7.19~7.23(m, 2H), 7.30~7.34(m, 1H), 7.52(d, J=7.2Hz, 1H), 7.70~7.74(m, 1H), 8.64(d, J=4.4Hz, 1H).

Example Compound 94

Procedure for preparation of Compound 94:

Compound 94

A mixture of compound 1 (15mg, 0.085mmol), compound 2(24mg, O. lmmol), CS₂CO₃ (l lOmg, 0.34mmol), Pd(dba)₂(5mg, 0.0085mmol) and Xanphos (4mg, 0.0085mol) in DMF(1.OmL) were degassed under N2 and then heated to 100^°C for lh. After cooled, the reaction mixture was filtered. The filtrate was washed with H₂0, extracted with EtOAc. The organic layer was dried over anhydrous Na₂S0₄, filtered and concentrated to residue, which was purified by prep-TLC (EA/PE, 1/2, v/v) to give desired compound

(lOmg, 42% yield).

LCMS: m/z, 287.1(M+H)⁺ 1HNMR (400MHz, CDC1₃) δ 4.41~4.58(m, 4H), 6.54(dd, J=1.6Hz, 8.0Hz, 1H), 6.78~6.83(m, 1H), 7.14~7.17(m, 1H), 7.22~7.24(m, 1H), 7.26~7.30(m, 1H), 7.51(d, J=4.0Hz, 1H), 7.68~7.72(m, 1H), 8.62(d, J=4.4Hz, 1H).

Example Compound 97

Procedure for preparation of Compound 97:

A mixture of compound 1 (15mg, 0.085mmol), compound 2(25mg, O. lmmol), Cs₂C0₃ (l lOmg, 0.34mmol), Pd(dba)₂(5mg, 0.0085mmol) and Xanphos (4mg, 0.0085mol) in DMF(l .OmL) were degassed under N₂ and then heated to 100^°C for lh. After cooled, the reaction mixture was filtered. The filtrate was washed with H₂0, extracted with EtOAc. The organic layer was dried over anhydrous Na₂S0₄, filtered and concentrated to residue, which was purified by prep-TLC (EA/PE, 1/1, v/v) to give desired compound (14mg, 56% yield).

LCMS: m/z, 298.1(M+H)⁺;

1HNMR (400MHz, CDC1₃) δ 4.32~4.44(m, 4H), 6.73~6.76(m, 1H), 7.24-7.28 (m, 1H), 7.30~7.35(m, 1H), 7.37(t, J=8.0Hz, 1H), 7.5 l(d, J=7.6Hz, 1H), 7.61~7.63(m, 1H), 7.65-7.73 (m, 1H), 8.63(d, J=4.8Hz, 1H).

Example Compound 98

Preparation of Compound

Experimental section:

Procedure for preparation of Compound 98:

A mixture of compound 1 (15mg, 0.085mmol), compound 2(25mg, O. lmmol), Cs₂C0₃ (l lOmg, 0.34mmol), Pd(dba)₂(5mg, 0.0085mmol) and Xanphos (4mg, 0.0085mol) in DMF(l .OmL) were degassed under N₂ and then heated to 100^°C for lh. After cooled, the reaction mixture was filtered. The filtrate was washed with H₂0, extracted with EtOAc. The organic layer was dried over anhydrous Na₂S0₄, filtered and concentrated to residue, which was purified by prep-TLC (EA/PE, 1/2, v/v) to give desired compound

(13mg, 52% yield).

LCMS: m/z, 296.1(M+H)⁺;

1HNMR (400MHz, CDC1₃) δ 4.24~4.44(m, 4H), 6.32~6.35(m, 1H), 6.66 (s, 1H), 6.75(d, J=8.0Hz, 1H), 7.26~7.35(m, 1H), 7.50(d, J=7.6Hz, 1H), 7.64~7.73(m, 1H), 8.62(d, J=4.8Hz, 1H).

Example Compound 99 Procedure for preparation of C mpound 99:

Compound 99

Compound 1 (15mg, 0.085mmol) and Et₃N(34mg, 0.34mmol) were dissolved in

Dichloromethane(l .OmL), then compound 2(17mg, 0.17mmol) was added. The reaction mixture was stirred for lh at rt. The reaction mixture was washed with H₂0. The separated organic layer was dried over anhydrous Na₂S0₄, filtered and concentrated to residue, which was purified by prep-TLC (EA/PE, 5/1, v/v) to give desired compound (14mg, 78% yield).

LCMS: m/z, 233.1(M+H)⁺;

1HNMR (400MHz, CDC1₃) δ 1.93(s, 3H), 4.31~4.65(m, 4H), 7.29~7.33(m, 1H), 7.50(d, J=7.6Hz, 1H), 7.64~7.73(m, 1H), 8.60-8.68 (m, 1H). Example Compound 100

Procedure for preparation of Compound 100:

common intermediate

1 2 Compound 100

To a solution of compound 1 (15mg, 0.09mmol) and Et₃N (34mg, 0.34mmol) in Dichloromethane (3ml), then the compound 2 (18mg, O.lOmmol) was added, the mixture was stirred at r.t. overnight. The reaction was quenched by adding water and extracted with EA. The combine organic phases were washed by water, brine, dried over anhydrous Na₂S0₄ and concentrated to dryness. The residue was purified by pre- TLC to obtain the title compound Compound 100 (17.6mg, yield: 65%).

LCMS: m/z, 317.0(M+H)⁺;

1HNMR (d-CDC-3, 400MHz): δ 8.52-8.54 (m, 1H), 7.80-7.82 (m, 2H), 7.50-7.64 (m, 4H), 7.25-7.38 (m, 1H), 7.20-7.25 (m, 1H), 4.20-4.25 (m, 2H), 4.07-4.18 (m, 2H).

Example Compound 115 Procedure for preparation of Compound 115:

Compound 115

To a solution of l(17.6mmol, O. lmmol) and 2(36mg, 0.15mmol) was added Pd(dba)₂ (6mg,0.01mmol), Xantphos (6mg,0.01mmol) and Cs₂CO₃(98mg,0.3mmol). The suspension was degassed under vacuum and purged with N2 several times. The mixture was stirred at 100^°C for lh, cooled to rt, LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (80mL) and washed with brine (20mL) three times. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purification with prep-TLC to afford the title product (lOmg, yield: 30%).

LCMS: m/z, 336.1 (M+H)⁺; 1HNMR (400 MHz, CDC1₃): δ 4.17-4.45 (m, 4H), 6.13-6.24 (m, 1H), 6.27-6.33 (m, 1H), 6.57-6.60 (m, 1H), 7.14-7.25 (m, 2H), 7.42-7.44 (m, 1H), 7.61~7.65(m, 1H). > 8.54-8.55 (m, 1H).

Example Compound 116

To a solution of 1(17.6mgl, O. lmmol) and 2(36mg, 0.15mmol) was added

Pd(dba)₂(6mg,0.01mmol), Xantphos (6mg,0.01mmol) and

Cs₂CO₃(98mg,0.3mmol)..The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 100^°C for lh, cooled to rt, LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (80mL) and washed with brine (20mL) three times. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purification with prep-TLC to afford the title product (lOmg, yield: 30%)

LCMS: m/z, 321.1 (M+H)⁺;

1HNMR (400 MHz, CDC1₃): δ 4.23-4.37 (m, 4H), 6.54-6.59 (m, 2H), 6.97~6.99(m, 1H), 7.22-7.29 (m, 2H), 7.42-7.44 (m, 1H), 7.61~7.66(m, 1H), 8.53-8.56 (m, 1H).

Example Compound 117

Procedure for preparation of Compound 117:

To a solution of l(17.6mmol, O. lmmol) and 2(32.7mg, 0.15mmol) was added Pd (dba)₂ (6mg, O.Olmmol), Xantphos (6mg,0.01mmol) and Cs₂C0₃(98mg, 0.3mmol). The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 100^°C for lh, cooled to rt, LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (80mL) and washed with brine (20mL) three times. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purification with prep-TLC to afford the title product (7mg, yield: 27%).

LCMS: m/z, 267.2 (M+H)⁺;

1HNMR (400 MHz, CDC1₃): δ 2.32 (s, 3H), 4.23-4.38 (m, 4H), 6.31~6.32(m, 1H), 6.64-6.66 (m, 1H), 7.12-7.16 (m, 2H), 7.31-7.34 (m, 1H), 7.51-7.52 (m, 1H), 7.71-7.75 (m, 1H), 8.63-8.64 (m, 1H).

Example Compound 118 Procedure for preparation of Compound 118):

1 Compound 118

To a solution of l(17.6mmol, O. lmmol) and 2(40mg, 0.15mmol) was added Pd₂(dba)₃ (6mg,0.01mmol), Xantphos. (6mg,0.01mmol) and Cs₂CO₃(98mg,0.3mmol). The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 100^°C for lh, cooled to rt, LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (80mL) and washed with brine (20mL) three times. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purification with prep-TLC to afford the title product (1 lmg, yield: 39%).

LCMS: m/z, 383.2 (M+H)⁺;

1HNMR (400 MHz, CDC1₃): δ 3.80 (s, 3H), 4.24-4.39 (m, 4H), 6.02~6.03(m, 1H), 6.10~6.12(m, 1H), 6.6437-6.40 (m, 1H), 7.14-7.18 (m, 1H), 7.28-7.29 (m, 1H), 7.48~7.50(m, 1H), 7.67~7.71(m, 1H), 8.61-8.62 (m, 1H). Example Compound 120

Procedure for preparation of Compound 120:

To a solution of 1 (lOmg, 0.057mmol), 2 (31mg, 0.114mmol) and CS₂CO₃ (95mg, 0.29mmol) in DMF (lmL) were added 2 mg of Pd(dba)₂ and 2 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for lh. LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (5mL) and washed with brine (2mL) twice. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purified by p-TLC to give the desired compound Compound 120 (6mg, yield: 33.3%).

LCMS: m/z, 321.0 (M+H)⁺;

1HNMR:(d-CDCl₃, 400MHz): δ 8.65(s, 1H), 7.67(t, J=7.2, 1H), 7.45(d, J=7.6, 1H), 7.27(t, J=6.0, 1H), 6.70(s, 1H), 6.23(d, J=1.2, 2H), 4.14~4.30(m, 4H).

Example Compound 121

Procedure for preparation of Compound 121:

1 Compound 121 To a solution of 1 (lOmg, 0.057mmol), 2 (25mg, 0.114mmol) and Cs₂C0₃ (95mg, 0.29mmol) in DMF (lmL) were added 2 mg of Pd(dba)₂ and 2 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for 2h. LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (5mL) and washed with brine (2mL) twice. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purified by p-TLC to give the desired compound Compound 121 (5mg, yield: 27.8%).

LCMS: m/z, 321.0 (M+H)⁺,

1HNMR:(d-CDCl₃, 400MHz): 8.86(s, 1H), 7.80(t, J=7.0, 1H), 7.56(d, J=8.0, 1H), 7.37(t, J=5.6, 1H), 7.25(s, 1H), 6.49(d, J=2.4, 1H), 6.28(dd, Ji=2.8,J₂=8.4, 1H), 4.11~4.33(m, 4H).

Example Compounds 132, 141, 142 Preparation of l-(3-chlorophenyl)-3-fluoro-3-(2-pyridylethynyl)pyrrolidine

Compound 132& Compound 140& Compound 141

& Compound 142 & Compound 146

Compound 140 Compound 146

Experimental section:

Procedure for preparation of Compound 140,

1 Compound 140 To a solution of l(500mg, 4.9mmol) in THF(20mL) was added n-BuLi(3ml, 7.4mmol) at -78°C , the mixture was stirred at -78°C for lh, the compound 2(l . lg,5.8mmol) in THF(2ml) was added. The mixture was stirred at -78°C for 30min, The mixture was stirred for overnight at room temperature, quenched with saturated NH₄CI solution and then extracted with EtOAc(2x20mL). The separated organic layer was dried over anhydrous Na₂S0₄, filtered and concentrated to dryness, which was purified by Prep- TLC to give desired compound(500mg,yield:36%).

LCMS: m/z, 289.2 (M+H)⁺;

1HNMR (400 MHz, CDC1₃): δ 1.41 (s, 9H), 2.25-2.29 (m, 2H), 3.49~3.85(m, 4H), 5.29, 5.68 (s, 1H, total ), 7.17-7.22 (m, 1H), 7.30-7.38 (m, 1H), 7.58-7.64 (m, 1H),

8.49-8.52 (m, 1H).

Procedure for preparation of Compound 146:

Compound 140 Compound 146

Compound Compound 140 (500mg, 1.74mmol) was dissolved in dry CH₂Cl₂(20mL). The solution was cooled to -78°C , and DAST(560mg, 3.476mmol) was added. The reaction mixture was stirred for lh at -78°C and warmed to rt. After quenched with H₂0, the solution was extracted with EtOAc(2xl5mL). The combined organic layers were dried over anhydrous Na₂S0₄, filtered and concentrated to dryness, which was purified by column on silica gel (eluted with EA/PE, 1/10, v/v) to give desired

compound(350mg, yield:59%)

LCMS: m/z, 291.2 (M+H)⁺;

1HNMR (400 MHz, CDC1₃): δ 1.40 (s, 9H), 2.18-2.34 (m, 1H), 2.39-2.5 l(m, 1H), 3.41~3.54(m, 3H), 3.71-3.98 (m, 1H), 7.21-7.24 (m, 1H), 7.41~7.43(m, 1H),

7.60~7.65(m, 1H), 8.54-8.55 (m, 1H).

Procedure for preparation of 3:

3

Compound 146

To a solution of Compound 146 (350mg,1.2mmol) in DCM(5ml) was added TFA(lml) at 0°C .The mixture was stirred at rt for 1.5h. The solvent was removed, diluted with CH₂CI₂ (40ml), and washed with saturated Na₂C0₃ (20ml), The organic phase was dried over Na₂S0₄, concentrated to afford the title product (200mg, yield: 87%).

Procedure for preparation of Compounds 132, 141 and 142:

Compound 132

Compound 141

Compound 142

To a solution of 3 (19mg, O.l lmmol), 4 (35.1mg, 0.15mmol) and Cs₂C0₃ (98mg, 0.3mmol) in DMF (lmL) were added 6 mg of Pd(dba)₂ and 6 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for 3h under N₂. LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EtOAc (20mL) and washed with brine (lOmL) three times. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purified by Prep-TLC to give the racemic compound Compound 132 (8mg, yield: 26%).6mg Compound 132 was used for SFC to afford two enantiomers: 1.50mg of Compound 141, 1.43mg of Compound 142.

Compound 132

MS: m/z, 301.1 (M+H)⁺:

1HNMR:(CDCl₃,400MHz): δ 2.45~2.62(m, 1H), 2.66~2.75(m, 1H), 3.49~3.52(m, 2H), 3.81-3.88 (m, 2H), 6.41~6.44(m, 1H), 6.53~6.54(m, 1H), 6.69~6.71(m, 1H),

7.13~7.17(m, 1H), 7.28~7.32(m, 1H), 7.50~7.51(m, 1H), 7.68~7.72(m, 1H),

8.63~8.67(m, 1H).

Compound 141 MS: m/z, 301.1 (M+H)⁺;

1HNMR:(CDCl₃,400MHz): δ 2.37~2.55(m, 1H), 2.59~2.69(m, 1H), 3.46~3.50(m, 2H), 3.74-3.80 (m, 2H), 6.46~6.47(m, 1H), 6.62~6.64(m, 1H), 6.69~6.71(m, 1H),

7.06~7.10(m, 1H), 7.22~7.25(m, 1H), 7.43~7.45(m, 1H), 7.62~7.66(m, 1H),

8.55~8.56(m, 1H).

Compound 142

MS: m/z, 301.1 (M+H)⁺;

1HNMR:(CDCl₃,400MHz): δ 2.38~2.54(m, 1H), 2.57~2.67(m, 1H), 3.45~3.49(m, 2H), 3.74-3.80 (m, 2H), 6.34~6.36(m, 1H), 6.46~6.47(m, 1H), 6.62~6.64(m, 1H),

7.06~7.10(m, 1H), 7.19~7.25(m, 1H), 7.43~7.45(m, 1H), 7.61~7.66(m, 1H),

8.55~8.56(m, 1H).

The racemic compound Compound 132 (6mg) was dissolved in MeOH(1.5ml). This sol ution was injected via the pump on a 5cm by 50cm Chiralcel OJ 250x30mm I.D. ,20um.

The chromatography was achieved at 38°C at a flow - rate of 50ml/min and UV detecte d was at 220nm.The mobile phase consists of a mixture of A: Supercritical C0₂ , B:ME OH(contained 0.1% NH₃.H₂0), A:B =65:35 at 50ml/min. Under the applied chromatogr aphy conditions, two enantiomers was isolated from a first fraction collected between 8 ~9.5min and 9.8~12min, after 3 injections of a total 6mg of racemate. the fractions cont aining the corresponding enantiomerics were combined to yield 1.50mg of and 1.43mg of with an enantiomeric purity of 98.9% and 96.5%, respectively. The enantiomeric puri ty was determined on an analytical Column: Chiralpak AD-H 250x4.6mm I.D., 5um M obile phase: ethanol(0.05% DEA) in C0₂ from5% to 40% Flow rate: 2.35mL/min, Wav elength: 220nm.

Example Compound 134

Procedure for preparation of Compound 134:

Compound 134

To a solution of 1(17.6mg, O.lmmol) and 2(35mg, 0.15mmol) in DMF(lml) was added Pd(dba)₂ (6mg,0.01mmol), Xantphos (6mg,0.01mmol) and Cs₂CO₃(98mg,0.3mmol). The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 100^°C for lh, cooled to rt, LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (80mL) and washed with brine (20mL) three times. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purification with prep-TLC to afford the title product (15mg, yield: 50%).

LCMS: m/z, 316.1 (M+H)⁺;

1HNMR (400 MHz, CDC1₃): δ 4.29~4.42(m, 4H), 6.34~6.37(m, IH), 6.99-6.01 (m, IH), 7.24-7.27 (m, IH), 7.43~7.45(m, IH), 7.63-7.67 (m, IH), 8.55-8.56 (m, IH).

Example Compound 135

Experimental section:

Procedure for preparation of 2:

2

To a solution of l(35mmol, 0.22mmol) and 2(65mg, 0.3mmol) in DMF(lml)was added Pd(dba)₂ (12mg,0.02mmol), Xantphos (12mg,0.02mmol) and Cs₂CO₃(200mg,0.6mmol). The suspension was degassed under vacuum and purged with N2 several times. The mixture was stirred at 100^°C for lh, cooled to rt, the solution was extracted with EtOAc (3x30mL). The organic layer was washed with brine (2><30mL) and dried over anhydrous Na₂S0₄, filtered and evaporated to give crude product, which was purified with prep-TLC to afford the title product(15mg, yield: 30%) Procedure for preparation of Compound 135:

2

Compound 135

To a stirred solution of 1(15 mg, 0.054 mmol) in dioxane (2 ml) were added

NaB0₃ ^'4H₂0 (57 mg, 0.44mmol) and H₂0 (2mL). The mixture was stirred at 80 ^°C fori 6 h, cooled, H₂0 was added and the mixture was extracted with Dichloromethane. The title product was checked by LC/MS. Then the reaction mixture was diluted with EA (80mL) and washed with brine (20mL) three times. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purification with prep-TLC to afford the title product (5mg, yield: 31%)

LCMS: m/z, 296.1 (M+H)⁺;

1HNMR (400 MHz, CDC1₃): δ 4.23~4.38(m, 4H), 5.5 l(s, 1H), 5.89(s, 1H),

6.55~6.58(m, 1H), 6.92-6.93 (m, 1H), 7.06-7.08 (m, 1H), 7.21~7.26(m, 2H), 7.43-7.45 (m, 1H), 7.62~7.67(m, 1H), 8.54-8.56 (m, 1H). Example Compound 137

Procedure for preparation of Compound 137:

Compound 137

A mixture of compound 8 (19.0mg, O.lmmol), 2 (26.1mg, O.l lmmol), Xantphos (5.8mg, O.Olmmol) and Cs₂C0₃(65.1mg, 0.2mmol)in DMF (lmL) was degassed 3 times under N₂, and then Pd₂(dba)₃(9.2mg, O.Olmmol) was added to the mixture under N₂. The reaction mixture was heated at 100^°C under N₂ and stirred for 2h. The reaction mixture was quenched by added water and extracted with EA. The combined organic phases were washed by water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by pre-TLC (8.9mg, yield=29.6%).

LCMS: m/z 301.1 [M+H]⁺ 1HNMR (CDC13 400 MHz): δ 2.29 (s, 3H), 4.16-4.31 (m, 4H), 6.25(dd, J=3.2, 8.0Hz, IH), 6.37 (t, J=2.2Hz, IH), 6.68 (dd, J=2.8, 8.0Hz, IH), 7.04 (d, J=5.2Hz, IH), 7.07 (d, J=8.0Hz, IH), 7.26 (s, IH), 8.38 (d, J=5.2Hz, IH).

Example Compound 138

Preparation of Compound 138:

Procedure for preparation of Compound 138:

Compound 138

To a solution of 3-fluoro-3-[(5-methylpyridin-2-yl)-ethynyl]azetidine (15mg,

0.079mmol), 9 (38mg, 0.158mmol) and Cs₂C0₃ (129mg, 0.395mmol) in DMF (2mL) were added 1 mg of Pd(dba)₂ and 1 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for 2hrs.The reaction was quenched by adding water and extracted with EA. The combine organic phases were washed by water, brine, dried over anhydrous Na₂S0₄ and concentrated to dryness. The residue was purified by pre-TLC to obtain the title compound Compound 138 (2.42mg, yield: 10.2%).

LCMS: m/z, 301.0(M+H)⁺;

1HNMR (d-CDCl₃, 400MHz): δ 8.37-8.38 (m, IH), 7.42-7.44 (m, IH), 7.32(d, J=8Hz, IH), 7.08 (t, J=8Hz, IH), 6.69-6.71 (m, IH), 6.38 (t, J=2Hz, IH), 6.26-6.29 (m, IH), 4.24-4.31 (m, 2H), 4.17-4.22 (m, 2H), 2.30 (s, 3H).

Example Compound 144

Synthetic Scheme

Procedure for preparation of Compound 144:

A mixture of compound 1 (15mg, 0.085mmol), compound 2(25mg, O. lmmol), CS₂CO₃ (l lOmg, 0.34mmol), Pd(dba)₂(5mg, 0.0085mmol) and Xanphos (4mg, 0.0085mol) in DMF(l .OmL) were degassed under N₂ and then heated to 100^°C for lh. After cooled, the reaction mixture was filtered. The filtrate was washed with H₂0, extracted with EtOAc. The organic layer was dried over anhydrous Na₂S0₄, filtered and concentrated to residue, which was purified by prep-TLC (EA/PE, 1/2, v/v) to give desired compound (5mg, 21% yield).

LCMS: m/z, 310.2(M+H)⁺;

1HNMR (400MHz, CDC1₃): δ 2.40~2.70(m, 2H), 3.45~3.49(m, 2H), 3.75 (d, J=13.6Hz, 2H), 6.33~6.37(m, 1H), 6.48(s, 1H), 6.62(dd, J=1.2Hz, 8.0Hz, 1H), 7.23~7.25(m, 1H), 7.44(d, J=8.0Hz, 1H), 7.63~7.67(m, 1H), 8.56(dd, J=0.8Hz, 4.8Hz, 1H).

Example Compound 145

Preparation of Compound 145:

Compound 145

Experimental section:

Procedure for preparation of Compound 145:

Cs₂C0₃ Compoud 145

A mixture of compound 1 (15mg, 0.085mmol), compound 2(24mg, O. lmmol), Cs₂C0₃ (l lOmg, 0.34mmol), Pd(dba)₂(5mg, 0.0085mmol) and Xanphos (4mg, 0.0085mol) in DMF(l .OmL) were degassed under N₂ and then heated to 100^°C for lh. After cooled, the reaction mixture was filtered. The filtrate was washed with H₂0, extracted with EtOAc. The organic layer was dried over anhydrous Na₂S0₄, filtered and concentrated to residue, which was purified by prep-TLC (EA/PE, 1/2, v/v) to give desired compound (5mg, 21% yield).

LCMS: m/z, 303.1(M+H)⁺; 1HNMR (400MHz, CDC1₃): δ 2.39~2.67(m, 2H), 3.44(dd, J=4.4Hz, 9.6Hz, 2H), 3.70~3.80(m, 2H), 6.10~6.12(m, 1H), 6.22~6.27(m, 1H), 6.92~6.99(m, 1H), 7.24(dd, J=4.8Hz, 8.0Hz, 1H), 7.44(d, J=7.6Hz, 1H), 7.61~7.66(m, 1H), 8.55(dd, J=0.8Hz, 4.8Hz, 1H).

Example Compound 149

Procedure for preparation of Compound 149:

common intermediate

1 Compound 149

To a solution of compound 1 (15mg, 0.079mmol) and Et₃N (32mg, 0.32mmol) in Dichloromethane (3ml), then the compound 2 (17mg, 0.095mmol) was added, the mixture was stirred at r.t. overnight. The reaction was quenched by adding water and extracted with EA. The combine organic phases were washed by water, brine, dried over anhydrous Na₂S0₄ and concentrated to dryness. The residue was purified by pre- TLC to obtain the title compound Compound 149 (17.64mg, yield: 67.6%).

LCMS: m/z, 331.1(M+H)⁺;

1HNMR (d-CDCl₃, 400MHz): δ 8.51-8.52 (m, 1H), 7.77-7.79 (m, 2H), 7.59-7.63 (m, 1H), 7.52-7.54 (m, 1H), 7.46-7.50 (m, 2H), 7.36-7.38 (m, 1H), 7.20-7.24 (m, 1H), 3.77-3.85 (m, 1H), 3.56-3.70 (m, 2H), 3.31-3.37 (m, 1H), 2.36-2.45 (m, 1H),

2.15-2.31 (m, 1H).

Example Compound 150

Preparation of Compound 150:

common intermediate

1 Compound 150

Experimental section:

Procedure for preparation of Compound 150:

common intermediate

1 2 Compound 150

To a solution of compound 1 (15mg, 0.079mmol) and Et₃N (32mg, 0.32mmol) in Dichloromethane (3ml), then the compound 2 (18mg, 0.095mmol) was added, the mixture was stirred at r.t. overnight. The reaction was quenched by adding water and extracted with EA. The combine organic phases were washed by water, brine, dried over anhydrous Na₂S0₄ and concentrated to dryness. The residue was purified by pre- TLC to obtain the title compound Compound 150 (12.22mg, yield: 44.9%).

LCMS: m/z, 345.1(M+H)⁺;

1HNMR (d-CDCl3, 400MHz): δ 8.51-8.53 (m, 1H), 7.63-7.67 (m, 2H) 7.59-7.62 (m, 1H), 7.36-7.38 (m, 1H), 7.25-7.27 (m, 2H), 7.20-7.24 (m, 1H), 3.75-3.83 (m, 1H),

3.53~3.68(m, 2H) > 3.31-3.36 (m, 1H), 2.39-2.45 (m, 1H), 2.36 (s, 3H), 2.14-2.31 (m, 1H).

Example Compound 151 Synthetic Scheme

Preparation of Compound 151:

Experimental section:

Procedure for preparation of Compound 151:

common intermediate Compound 151

1

To a solution of compound 1 (15mg, 0.079mmol) and Et₃N (32mg, 0.32mmol) in Dichloromethane (3ml), then the compound 2 (20mg, 0.095mmol) was added, the mixture was stirred at r.t. overnight. The reaction was quenched by adding water and extracted with EA. The combine organic phases were washed by water, brine, dried over anhydrous Na₂S0₄ and concentrated to dryness. The residue was purified by pre- TLC to obtain the title compound Compound 151 (14.96mg, yield: 51.9%).

Example Compound 152

Synthetic Scheme

Preparation of Compound 152:

Compound 152

Experimental section:

Procedure for preparation of Compound 152:

Compound 152

A mixture of compound 1 (38.0mg, 0.2mmol), 2 (52.2mg, 0.22mmol), Xantphos (11.6mg, 0.02mmol) and Cs₂CC>3(130.2mg, 0.4mmol)in DMF (lmL) was degassed 3 times under N₂, and then Pd₂(dba)₃(9.218.4mg, 0.02mmol) was added to the mixture under N₂. The reaction mixture was heated at 100^°C under N₂ and stirred overnight. The reaction mixture was quenched by added water and extracted with EA. The combined organic phases were washed by water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by pre-TLC (7.5mg, yield=25.0%).

LCMS: m/z 301.1 [M+H]⁺;

1HNMR (d-CDC13 400 MHz): δ 2.40-2.63 (m, 2H), 3.44-3.48 (m, 2H), 3.72 (s, 1H), 3.78 (d, J=3.6Hz, 1H), 6.38(dd, J=3.6, 12.0Hz, 2H), 7.1 (d, J=12.0Hz, 2H), 7.22-7.25 (m, 1H), 7.43 (d, J=8.0Hz, 1H), 7.61 (dt, J=2.4, 8.0Hz, 1H), 8.54 (d, J=3.6Hz, 1H).

Example Compound 153 Preparation of Compound 153:

Compound 153

Experimental section:

Procedure for preparation of Compound 153:

Compound 153

To a solution of compound 1(19. Omg, 0. Immol) in DCM (lmL) was added successively TEA (20.2mg, 0.2mmol) and compound 2 (18.7mg, 0.1 Immol) at 0 °C. The solution was stirred under N₂ at r.t. for 0.5h. The reaction mixture was quenched by water and extracted with EA, the organic phase was washed by brine, dried over Na₂S0₄, filtered and concentrated. The residue was purified by pre-TLC (7.5mg, yield=23.1%).

LCMS: m/z 325.2 [M+H]⁺.

Example Compound 154 Preparation of Compound 154:

Compound 154

Experimental section:

Procedure for preparation of Compound 154:

To a solution of 1 (15mg, 0.079mmol), 2 (32mg, 0.158mmol) and Cs₂C0₃ (128mg, 0.395mmol) in DMF (lmL) were added 2 mg of Pd(dba)₂ and 2 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for lh. LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (lOmL) and washed with brine (2mL) twice. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purified by p-TLC to give the desired compound Compound 154 (lOmg, yield: 40%).

LCMS: m/z, 317.1 (M+H)⁺;

1HNMR:(d-CDCl₃, 400MHz): δ 8.66(s, 1H), 8.19(t, J=4.6, 1H), 7.82(d, J=4.6, 1H), 7.71(t, J=7.6, 1H), 7.46~7.53(m, 4H), 7.38(t, J=8.0, 1H), 7.30(t, J=6.4, 1H), 7.05(d, J=7.2, 1H), 3.73~3.97(m, 3H), 3.38~3.43(m,lH ), 2.65~2.74(m, 2H).

Example Compound 155

Preparation of Compound 155,

Experimental section:

Procedure for preparation of Compound 155:

To a solution of 1 (15mg, 0.079mmol), 2 (32mg, 0.158mmol) and Cs₂C0₃ (128mg, 0.395mmol) in DMF (lmL) were added 2 mg of Pd(dba)₂ and 2 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for lh. LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (lOmL) and washed with brine (2mL) twice. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purified by p-TLC to give the desired compound Compound 155 (12mg, yield: 48%).

LCMS: m/z, 317.2 (M+H)⁺;

1HNMR:(d-CDCl₃, 400MHz): δ 8.64(s, 1H), 7.56~7.67(m, 4H), 7.47(d, J=7.2, 1H), 7.30(t, J=7.6, 2H), 7.11~7.15(m, 1H), 6.88(d, J=8.0, 1H), 6.69(s, 1H), 3.83~3.94(m, 2H), 3.61(d, J=7.6, 2H), 2.43~2.65(m, 2H).

Example Compound 156

Preparation of Compound 156:

Compound 156

Experimental section:

Procedure for preparation of Compound 156:

Cs₂C0₃,DMF

1 Compound 156

To a solution of 1 (15mg, 0.079mmol), 2 (32mg, 0.158mmol) and Cs₂C0₃ (128mg, 0.395mmol) in DMF (lmL) were added 2 mg of Pd(dba)₂ and 2 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for lh. LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (lOmL) and washed with brine (2mL) twice. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purified by p-TLC to give the desired compound Compound 156 (8mg, yield: 32%).

LCMS: m/z, 318.1 (M+H)⁺;

1HNMR:(d-CDCl₃, 400MHz): δ 8.56~8.59(m, 2H), 7.90~7.96(m, 2H), 7.64(t, J=7.2, 1H), 7.45(d, J=7.6, 1H), 7.24(t, J=6.2, 2H), 7.10(d, J=8.8, 1H), 6.59(d, J=1.6, 1H), 3.85~3.95(m, 2H), 3.58~3.64(m, 2H), 2.44~2.73(m, 2H).

Example Compound 157

Preparation of Compound 157:

Compound 157

Experimental section:

Procedure for preparation of Compound 157:

Compound 157

To a solution of 1 (15mg, 0.079mmol) in 2 (5mL) was added K₂C0₃ (78mg, 0.57mmol). The mixture was stirred at 110°C for 6h. The LCMS showed the starting material was consumed completely. Then the reaction mixture was filtered and the filter cake was washed with 5mL of Dichloromethane. The filtrate was concentrated to dryness which was purified by p-TLC to obtain the title compound Compound 157 (9mg, yield:

42.8%).

LCMS: m/z, 268.1 (M+H)⁺;

1HNMR:(d-MeOD, 400MHz): δ 8.65(b, 1H), 8.10(d, J=5.6, 1H), 7.66(t, J=7.2, 1H), 7.41~7.47(m, 2H), 7.19~7.27(m, 1H), 6.55(t, J=6.4, 1H), 6.33(d, J=8.4, 1H),

3.72~4.08(m, 2H), 3.55~3.61(m, 2H), 2.41~2.66(m, 2H). Example Compound 158

Preparation of Compound 158:

common intermediate Cs₂C0₃,DMF

Compound 158

Experimental section:

Procedure for preparation of Compound 158:

Compound 158

To a solution of 1 (15mg, 0.079mmol), 2 (32mg, 0.158mmol) and CS₂CO₃ (128mg, 0.395mmol) in DMF (lmL) were added 2 mg of Pd(dba)₂ and 2 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for lh. LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (lOmL) and washed with brine (2mL) twice. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purified by p-TLC to give the desired compound Compound 158 (8mg, yield: 38%).

LCMS: m/z, 268.1 (M+H)⁺;

1HNMR: (d-CDCl3, 400MHz): δ 8.55(d, J=4.4, 1H), 7.94-8.15(m, 2H), 7.64(t, J=5.8, 1H), 7.45(d, J=7.2, 1H), 7.23(d, J=3.2, 2H), 6.89(d, J=6.4, 1H), 3.85(s, 1H), 3.79(s, 1H), 3.52~3.56(m, 2H), 2.42-2.7 l(m, 2H).

Example Compound 159

Preparation of Compound 159:

Compound 159

Experimental section:

Procedure for preparation of Compound 159:

Compound 159 To a solution of 1 (15mg, 0.079mmol), 2 (35mg, 0.158mmol) and CS₂CO₃ (128mg, 0.395mmol) in DMF (lmL) were added 2 mg of Pd(dba)₂ and 2 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for lh. LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (lOmL) and washed with brine (2mL) twice. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purified by p-TLC to give the desired compound Compound 159 (lOmg, yield: 38.4%).

LCMS: m/z, 335.1 (M+H)⁺;

1HNMR:(d-CDCl₃, 400MHz): δ 8.59(s, 1H), 7.64(d, J=6.8, 1H), 7.45(d, J=7.2, 1H), 7.26(s, 1H), 7.17(s, 1H), 6.52(s, 1H), 6.30(dd, J=8.8, 1H), 3.70~3.80(m, 2H),

3.40~3.46(m, 2H), 2.38~2.68(m, 2H).

Example Compound 160

Preparation of Compound 160:

Compound 160

Experimental section:

Procedure for preparation of Compound 160:

Compound 160

To a solution of 1 (15mg, 0.079mmol), 2 (35mg, 0.158mmol) and Cs₂C0₃ (128mg, 0.395mmol) in DMF (lmL) were added 2 mg of Pd(dba)₂ and 2 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for lh. LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (lOmL) and washed with brine (2mL) twice. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purified by p-TLC to give the desired compound Compound 160 (12mg, yield: 46.1%).

LCMS: m/z, 335.1 (M+H)⁺;

1HNMR (d-CDCl3, 400MHz): δ 8.59(s, 1H), 7.65(d, J=7.6, 1H), 7.45(d, J=7.6, 1H), 7.26(s, 1H), 6.63(s, 1H), 6.32 (s, 2H), 3.76(s, 1H), 3.69(s, 1H), 3.45(d, J=9.2, 2H), 2.37~2.65(m, 2H).

Example Compound 161

Preparation of Compound 161:

Experimental section:

Procedure for preparation of Compound 161:

A mixture of compound 1 (15mg, 0.085mmol), compound 2(24mg, O. lmmol), CS₂CO₃ (l lOmg, 0.34mmol), Pd(dba)₂(5mg, 0.0085mmol) and Xanphos (4mg, 0.0085mol) in DMF(l .OmL) were degassed under N₂ and then heated to 100^°C for lh. After cooled, the reaction mixture was filtered. The filtrate was washed with H₂0, extracted with EtOAc. The organic layer was dried over anhydrous Na₂S0₄, filtered and concentrated to residue, which was purified by prep-TLC (EA/PE, 1/2, v/v) to give desired compound (6mg, 25% yield).

LCMS: m/z, 303.0(M+H)+;

1HNMR (400MHz, CDC1₃): δ 2.47~2.73(m, 2H), 3.49~3.55(m, 2H), 3.78(s, 1H), 3.85(s, 1H), 6.02~6.06(m, 2H), 6.15~6.19(m, 1H), 7.30~7.34(m, 1H), 7.51(d, J=8.0Hz, 1H), 7.69~7.73(m, 1H), 8.63(d, J=4.4Hz, 1H).

Example Compound 162

Preparation of Compound 162:

Cs₂C0₃ Compound 162

Experimental section:

Procedure for preparation of Compound 162:

^Cs2^c°3 Compound 162

A mixture of compound 1 (15mg, 0.085mmol), compound 2(22mg, O. lmmol), CS₂CO₃ (l lOmg, 0.34mmol), Pd(dba)₂(5mg, 0.0085mmol) and Xanphos (4mg, 0.0085mol) in DMF(l .OmL) were degassed under N₂ and then heated to 100^°C for lh. After cooled, the reaction mixture was filtered. The filtrate was washed with H₂0, extracted with EtOAc. The organic layer was dried over anhydrous Na₂S0₄, filtered and concentrated to residue, which was purified by prep-TLC (EA/PE, 1/2, v/v) to give desired compound (6mg, 25% yield).

LCMS: m/z, 286.1(M+H)+;

1HNMR (400MHz, CDC1₃): δ 2.48~2.64(m, 1H), 2.70~2.79(m, 1H), 3.54~3.63(m, 2H), 3.84(s, 1H), 3.90(s, 1H), 6.52~6.55(m, 1H), 7.32(dd, J=5.2Hz, 7.2Hz, 1H), 7.52(d, J=7.6Hz, 1H), 7.68~7.71(m, 1H), 7.81(s, 1H), 7.88(s, 1H), 8.63(d, J=0.8Hz, 4.8Hz, 1H).

Example Compound 165 Preparation of Compound 165:

1 Compound 165

Experimental section:

Procedure for preparation of Compound 165:

1 Compound 165

To a solution of compound 1 (15mg, 0.079mmol) and Et₃N (32mg, 0.32mmol) in Dichloromethane (3ml), then the compound 2 (lOmg, 0.095mmol) was added, the mixture was stirred at r.t. overnight. The reaction was quenched by adding water and extracted with EA. The combine organic phases were washed by water, brine, dried over anhydrous Na₂S0₄ and concentrated to dryness. The residue was purified by pre- TLC to obtain the title compound Compound 165 (6.83mg, yield: 33.3%).

LCMS: m/z, 261.1(M+H)⁺;

1HNMR (d-CDC-3, 400MHz): δ 8.55 (s, 1H), 7.61-7.67 (m, 1H), 7.43 (d, J=8Hz, 1H), 7.20-7.26 (m, 1H), 3.97-4.16 (m, 1H), 3.54-3.90 (m, 3H), 2.56-2.63 (m, 2H),

2.34-2.55 (m, 1H), 1.10-1.19 (m, 6H).

Example Compound 166

Procedure for preparation of Compound 166:

2 Compound 166

To a solution of compound 1 (15mg, 0.079mmol) and Et₃N (32mg, 0.32mmol) in Dichloromethane (3ml), then the compound 2 (lOmg, 0.095mmol) was added, the mixture was stirred at r.t. overnight. The reaction was quenched by adding water and extracted with EA. The combine organic phases were washed by water, brine, dried over anhydrous Na₂S0₄ and concentrated to dryness. The residue was purified by pre- TLC to obtain the title compound Compound 166 (9.66mg, yield: 44.7%).

LCMS: m/z, 275.1(M+H)⁺:

1HNMR (d-CDC-3, 400MHz): δ 8.54-8.55 (m, 1H), 7.61-7.64 (m, 1H), 7.43 (d, J=8Hz, 1H), 7.23-7.25 (m, 1H), 4.16 (b, 1H), 3.87-3.90 (m, 1H), 3.79-3.82 (m, 1H), 3.64-3.71 (m, 1H), 2.51 (b, 1H), 2.28 (b, 1H), 1.18-1.22 (m, 9H).

Example Compound 167

Preparation of Compound 167:

2 Compound 167 Experimental section:

Procedure for preparation of Compound 167:

Compound 167

To a solution of compound 1 (15mg, 0.079mmol) and Et₃N (32mg, 0.32mmol) in Dichloromethane (3ml), then the compound 2 (12mg, 0.095mmol) was added, the mixture was stirred at r.t. overnight. The reaction was quenched by adding water and extracted with EA. The combine organic phases were washed by water, brine, dried over anhydrous Na₂S0₄ and concentrated to dryness. The residue was purified by pre- TLC to obtain the title compound Compound 167 (16.02mg, yield: 74.2%).

LCMS: m/z, 275.1(M+H)⁺;

1HNMR (d-CDCl3, 400MHz): δ 8.60 (s, 1H), 7.69-7.70 (m, 1H), 7.47-7.49 (m, 1H), 7.26-7.32 (m, 1H), 3.89-4.38 (m, 2H), 3.58-3.85 (m, 2H), 2.39-2.68 (m, 2H),

2.22-2.30 (m, 2H), 1.62-1.65 (m, 2H), 1.34-1.39 (m, 2H), 0.92 (t, J=7.2Hz, 3H).

Example Compound 168

Preparation of Compound 168:

common intermediate

1 Compound 168

Experimental section:

Procedure for preparation of Compound 168:

common intermediate

1 Compound 168

To a solution of compound 1 (15mg, 0.079mmol) and 3 (36mg, 0.095mmol) ' 4 (31mg, 0.237mmol) in DCM (3ml), then the compound 2 (1 lmg, 0.095mmol) was added, the mixture was stirred at r.t. overnight. The reaction was quenched by adding water and extracted with EA. The combine organic phases were washed by water, brine, dried over anhydrous Na₂S0₄ and concentrated to dryness. The residue was purified by pre- TLC to obtain the title compound Compound 168 (12.16mg, yield: 53.3%). LCMS: m/z, 289.2(M+H)⁺;

1HNMR (d-CDCl₃, 400MHz): δ 8.53-8.55 (m, 1H), 7.61-7.65 (m, 1H), 7.41-7.44 (m, 1H), 7.20-7.25 (m, 1H), 3.79-4.32 (m, 2H), 3. 65-3.76 (m, 2H), 2.20-2.24 (m, 2H), 2.15-2.19 (m, 2H), 1.47-1.53 (m, 3H), 0.84-0.87 (m, 6H).

Example Compound 169

Preparation of Compound 169:

common intermediate

1 Compound 169

Experimental section:

Procedure for preparation of Compound 169:

common intermediate

1 Compound 169

To a solution of 1 (30mg, 0.158mmol), 2 (72mg, 0.316mmol) and Cs₂C0₃ (256mg, 0.79mmol) in DMF (2mL) were added 1 mg of Pd(dba)₂ and 1 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for 2hrs. The reaction was quenched by adding water and extracted with EA. The combine organic phases were washed by water, brine, dried over anhydrous Na₂S0₄ and concentrated to dryness. The residue was purified by pre-TLC to obtain the title compound Compound 169 (16.23mg, yield: 35.3%).

LCMS: m/z, 292.1(M+H)⁺;

1HNMR (d-CDCl₃, 400MHz): δ 8.54-8.56 (m, 1H), 7.62-7.66 (m, 1H), 7.43-7.46 (m, 1H), 7.20-7.26 (m, 2H), 6.91-6.93 (m, 1H), 6.65~6.68(m, 2H), 3.78 (d, J=27.2Hz, 2H), 3.47-3.51 (m, 2H), 2.62-2.71 (m, 1H), 2.40-2.57 (m, 1H).

Example Compound 170

Preparation of Compound 170:

common intermediate Compound 170

Experimental section:

Procedure for preparation of Compound 170:

common intermediate Compound 170 To a solution of 1 (15mg, 0.079mmol), 2 (32mg, 0.158mmol) and CS₂CO₃ (129mg, 0.395mmol) in DMF (2mL) were added 1 mg of Pd(dba)₂ and 1 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for 2hrs. The reaction was quenched by adding water and extracted with EA. The combine organic phases were washed by water, brine, dried over anhydrous Na₂S0₄ and concentrated to dryness. The residue was purified by pre-TLC to obtain the title compound Compound 170 (6.56mg, yield: 31.2%).

LCMS: m/z, 267.1(M+H)⁺;

1HNMR (CDC1₃, 400MHz): δ 8.54-8.56 (m, 1H), 7.61-7.65 (m, 1H), 7.43-7.45 (m, 1H), 7.16-7.24 (m, 3H), 6.67 (t, J=7.4Hz, 1H), 6.49-6.51 (m, 2H), 3.76-3.83 (m, 2H), 3.47-3.51 (m, 2H), 2.10-2.64 (m, 2H).

Example Compound 171

Preparation of Compound 171:

common intermediate

1 Compound 171 Experimental section:

Procedure for preparation of Compound 171:

common intermediate

1 2 Compound 171

To a solution of 1 (15mg, 0.079mmol), 2 (35mg, 0.158mmol) and Cs₂C0₃ (129mg, 0.395mmol) in DMF (2mL) were added 1 mg of Pd(dba)₂ and 1 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for 2hrs. The reaction was quenched by adding water and extracted with EA. The combine organic phases were washed by water, brine, dried over anhydrous Na₂S0₄ and concentrated to dryness. The residue was purified by pre-TLC to obtain the title compound Compound 171 (6.62mg, yield: 29.4%).

LCMS: m/z, 285.1(M+H)⁺;

1HNMR (d-CDCl3, 400MHz): δ 8.61-8.63 (m, 1H), 7.68-7.73 (m, 1H), 7.50-7.52 (m, 1H), 7.30-7.32 (m, 1H), 7.14-7.20 (m, 1H), 6.41-6.45 (m, 1H), 6.22-6.32 (m, 2H), 3.81 (s, 1H), 3.87 (s, 1H), 3.53-3.56 (m, 2H), 2.59-2.66 (m, 1H), 2.38-2.55 (m, 1H).

Example Compound 172 Preparation of Compound 172:

Compound 172

Experimental section:

Procedure for preparation of Compound 172:

Compound 172 To a solution of 1 (15mg, 0.05mmol) in dioxane (lmL) were added NaB0_3. 4H₂0

(15mg, O. lmmol) and H₂0 (lmL).The mixture was stirred at 80^°C for 16hr.The reaction was quenched by adding water and extracted with Dichloromethane. The combine organic phases were washed by water, brine, dried over anhydrous Na₂S0₄ and concentrated to dryness. The residue was purified by pre-TLC to obtain the title compound Compound 172 (6.08mg, yield: 38.2%).

LCMS: m/z, 310.1(M+H)⁺;

1HNMR (d-CDCl3, 400MHz): δ 8.54-8.56 (m, 1H), 7.62-7.66 (m, 1H), 7.44-7.48 (m, 1H), 7.20-7.25 (m, 2H), 6.98-7.01 (m, 2H), 6.61-6.64 (m, 1H), 6.06 (b, 1H), 5.59 (b, 1H), 3.76-3.86 (m, 2H), 3.49-3.58 (m, 2H), 2.39-2.69 (m, 2H).

Example Compound 173

Preparation of Compound 173:

common n erme a e

Experimental section:

Procedure for preparation of 2:

common intermediate

To a solution of 1 (60mg, 0.2mmol) in dry THF (2mL) was added NaH (12mg, 0.3mmol) at 0°C. After stirring for 30min at room temperature, a solution of CH₃I (42mg, 0.3mmol) in dry THF (lmL) was added drop-wise. The ensuing mixture was stirred at room temperature for 2h. TLC and LCMS showed the starting material was converted to the desired product completely. Then the reaction mixture was quenched with ice and extracted with EA (5mL) three times. The combined organic layers were washed with brine, dried over anhydrous Na₂S0₄, concentrated to dryness which was purified by p-TLC to give the desired compound 2 (50mg, yield: 79.3%).

LCMS: m/z, 303.2 (M+H)⁺.

Procedure for preparation of 3:

To a solution of 2 (50mg, 0.165mmol) in dry Dichloromethane (2mL) was added TFA (0.4mL) drop wise at 0°C. Then the reaction mixture was stirred at room temperature for 2h and concentrated to residue. Then the residue was treated with saturated aqueous Na C0₃ till pH=10 and extracted with Dichloromethane (5mL><3). The combined organic layers were dried over anhydrous Na₂S0₄, filtered and concentrated to dryness which was purified by p-TLC to give the desired compound 3 (25mg, yield: 75.7%). LCMS: m/z, 203.2 (M+H)⁺.

Procedure for preparation of Compound 173:

ompound 173

To a solution of 3 (lOmg, 0.05mmol), 4 (24mg, O. lmmol) and Cs₂C0₃ (80mg,

0.25mmol) in DMF (lmL) were added 1 mg of Pd(dba)₂ and 1 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for lh. LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (lOmL) and washed with brine (2mL) twice. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purified by p-TLC to give the desired compound Compound 173 (6mg, yield: 40%).

LCMS: m/z, 313.1 (M+H)⁺;

1HNMR (d-CDCl3, 400MHz): δ 8.52(d, J=4.8, 1H), 7.57~7.61(m, 1H), 7.38(d, J=7.6, 1H), 7.18(t, J=5.6, 1H), 7.04(t, J=8.0, 1H), 6.57(dd, Ji=1.2, J₂=8.0, 1H), 6.43(t, J=2.0, 1H), 6.32(dd, Ji=2.0,J₂=8.4, 1H), 3.57~3.63(m, 2H), 3.37~3.42(m, 5H), 2.31~2.46(m, 2H). Example Compound 174

Preparation of Compound 174:

common intermediate Cs₂C0₃, DIVl F

Compound 174

Experimental section:

Procedure for preparation of Compound 174:

Compound 174

To a solution of 1 (lOmg, 0.05mmol), 2 (20mg, O. lmmol) and CS₂CO₃ (80mg,

0.25mmol) in DMF (lmL) were added 1 mg of Pd(dba)₂ and 1 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for lh. LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (lOmL) and washed with brine (2mL) twice. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purified by p-TLC to give the desired compound Compound 174 (7mg, yield: 50%).

LCMS: m/z, 279.2 (M+H)⁺;

1HNMR:(d-CDCl₃, 400MHz): δ 8.60(s, 1H), 7.65~7.69(m, 1H), 7.46(d, J=7.6, 1H), 7.22~7.28(m, 3H), 6.70(t, J=7.6, 1H), 6.56(d, J=8.0, 1H), 3.68~3.74(m, 2H),

3.48~3.50(m, 5H), 2.40~2.53(m, 2H).

Example Compound 175

Preparation of Compound 175:

1 Compound 175

Experimental section:

Procedure for preparation of Compound 175):

1 Compound 175 To a solution of l(21mg, 0.1 lmmol) and 2(35mg, 0.15mmol) was added Pd(dba)₂ (6mg, O.Olmmol), Xantphos (6mg,0.01mmol) and Cs₂CC>3(98mg, 0.3mmol). The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 100^°C for lh, cooled to rt, LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (80mL) and washed with brine (20mL) three times. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purification with prep-TLC to afford the title product (lOmg, yield: 35%).

LCMS: m/z, 297.1 (M+H)⁺;

1HNMR (400 MHz, CDC1₃): δ 2.44~2.74(m, 2H), 3.49~3.50(m, 4H), 3.81(s, 3H), 3.83~3.89(m, 2H), 6.11~6.12(m, 1H), 6.18-6.20 (m, 1H), 6.31~6.34(m, 1H), 7.14-7.19 (m, 1H), 7.29-7.32 (m, 1H), 7.51~7.53(m, 1H), 7.69-7.73 (m, 1H), 8.62-8.64 (m, 1H).

Example Compound 176

Preparation of Compound 176:

1 Compound 176

Experimental section:

Procedure for preparation of Compound 176-:

1 Compound 176

To a solution of l(21mg, 0.1 lmmol) and 2(35mg, 0.15mmol) was added Pd (dba)₂ (6mg, O.Olmmol), Xantphos (6mg,0.01mmol) and Cs₂CC>3(98mg, 0.3mmol). The suspension was degassed under vacuum and purged with N₂ several times. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 100^°C for lh, cooled to rt, LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (80mL) and washed with brine (20mL) three times. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purification with prep-TLC to afford the title product (lOmg, yield: 39%).

LCMS: m/z, 351.1 (M+H)⁺;

1HNMR (400 MHz, CDC1₃): δ 2.39~2.70(m, 2H), 3.47~3.51(m, 2H), 3.75-3.82(m, 2H), 6.27~6.29(m, 1H), 6.37~6.39(m, 1H), 6.50~6.52(m, 1H), 7.14-7.25 (m, 2H), 7.43-7.46 (m, 1H), 7.62-7.66 (m, 1H), 8.55~8.57(m, 1H).

Example Compound 177

Synthetic Scheme

Pre aration of Compound 177:

1 Compound 177

Experimental section:

Procedure for preparation of Compound 177:

Compound 177

To a solution of l(21mg, 0.1 Immol) and 2(35mg, 0.15mmol) was added Pd(dba)₂ (6mg, O.Olmmol) ,xphose (6mg, O.Olmmol) and Cs₂CC>3(98mg, 0.3mmol). The suspension was degassed under vacuum and purged with N₂ several times. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 100^°C for lh, cooled to rt, LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (80mL) and washed with brine (20mL) three times. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purification with prep-TLC to afford the title product (lOmg, yield: 39%).

LCMS: m/z, 330.1 (M+H)⁺;

1HNMR (400 MHz, CDC1₃): δ 2.43~2.74(m, 2H), 3.51~3.59(m, 2H), 3.79-3.86(m, 2H), 6.41~6.45(m, 1H), 7.11-7.12 (m, 1H), 7.19-7.27 (m, 12H), 7.44~7.46(m, 1H),

7.63-7.67 (m, 1H), 8.55-8.57 (m, 1H).

Example Compound 178

Preparation of Compound 178

1 Compound 178

Experimental section:

Procedure for preparation of Compound 178:

Compound 178

To a solution of l(21mg, 0.1 Immol) and 2(42mg, 0.15mmol) was added Pd(dba)₂ (6mg, O.Olmmol), Xantphos (6mg,0.01mmol) and Cs₂C0₃(98mg, 0.3mmol). The suspension was degassed under vacuum and purged with N₂ several times. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 100^°C for lh, cooled to rt, LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (80mL) and washed with brine (20mL) three times. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purification with prep-TLC to afford the title product (1 lmg, yield: 29%).

LCMS: m/z, 345.1 (M+H)⁺;

1HNMR (400 MHz, CDC1₃): δ 2.43~2.74(m, 2H), 3.05(s, 3H), 3.58~3.67(m, 2H), 3.88~3.95(m, 2H), 6.75~6.78(m, IH), 7.06-7.07 (m, IH), 7.24-7.25 (m, 2H),

7.30~7.33(m, IH), 7.39-7.43 (m, IH), 7.70~7.74(m, IH), 8.62-8.64 (m, IH).

Example Compound 179

Preparation of Compound 179:

Compound 179

Experimental section:

Procedure for preparation of Compound 179:

Compound 179

To a solution of l(21mg, 0.1 lmmol) and 2(40mg, 0.15mmol) was added Pd (dba)₂ (6mg, O.Olmmol), Xantphos (6mg,0.01mmol) and Cs₂C0₃(98mg, 0.3mmol). The suspension was degassed under vacuum and purged with N₂ several times. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 100^°C for lh, cooled to rt, LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (80mL) and washed with brine (20mL) three times. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purification with prep-TLC to afford the title product (12mg, yield: 32%).

LCMS: m/z, 335.1 (M+H)⁺;

1HNMR (400 MHz, CDC1₃): δ 2.43~2.70(m, 2H), 3.51~3.55(m, 2H), 3.79-3.86(m, 2H), 6.61~6.68(m, 2H), 6.89~6.91(m, 1H), 7.22-7.297 (m, 2H), 7.44-7.46 (m, 2H),

7.62~7.66(m, 1H), 8.57-8.61 (m, 1H).

Example Compound 180

Preparation of Compound 180

1

Compound 180

Experimental section:

Procedure for preparation of Compound 180:

Compound 180

To a solution of l(21mg, 0.1 lmmol) and 2(40mg, 0.15mmol) was added Pd(dba)₂(6mg, O.Olmmol), Xantphos (6mg, O.Olmmol) and Cs₂C0₃(98mg, 0.3mmol). The suspension was degassed under vacuum and purged with N₂ several times. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 100^°C for lh, cooled to rt, LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (80mL) and washed with brine (20mL) three times. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purification with prep-TLC to afford the title product (lOmg, yield: 28%).

LCMS: m/z, 325.2 (M+H)⁺;

1HNMR (400 MHz, CDC1₃): δ 2.44~2.77(m, 2H), 3.59~3.64(m, 2H), 3.88~3.95(m, 5H), 6.73~6.75(m, 1H), 7.23-7.33 (m, 3H), 7.40-7.42 (m, 2H), 7.51~7.53(m, 1H),

7.69~7.73(m, 1H), 8.62-8.63 (m, 1H). Example Compound 181

Preparation of Compound 181:

Compound 181

To a solution of l(21mg, 0.1 lmmol) and 2(40mg, 0.15mmol) was added Pd(dba)₂ (6mg, O.Olmmol), Xantphos (6mg, O.Olmmol) and Cs₂CC>3(98mg, 0.3mmol). The suspension was degassed under vacuum and purged with N₂ several times. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 100^°C for lh, cooled to rt, LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (80mL) and washed with brine (20mL) three times. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purification with prep-TLC to afford the title product (5mg, yield: 14%).

LCMS: m/z, 338.2 (M+H)⁺;

1HNMR (400 MHz, CDC1₃): δ 2.43~2.70(m, 2H), 2.92-3.03(s, 6H), 3.45~3.54(m, 2H), 3.76~3.83(m, 2H), 6.49-6.5 l(m, 2H), 6.64~6.66(m, 1H), 7.16-7.25 (m, 2H), 7.43-7.45 (m, 1H), 7.61~7.65(m, 1H), 8.54-8.56 (m, 1H).

Example Compound 182

Preparation of Compound 182:

Compound 182

Experimental section:

Procedure for preparation of Compound 182:

1 Compound 182 To a solution of l(21mg, 0.1 lmmol) and 2(40mg, 0.15mmol) was added Pd(dba)₂(6mg, O.Olmmol), Xantphos (6mg,0.01mmol) and Cs₂CC>3(98mg, 0.3mmol). The suspension was degassed under vacuum and purged with N₂ several times. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 100^°C for lh, cooled to rt, LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (80mL) and washed with brine (20mL) three times. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purification with prep-TLC to afford the title product (7mg, yield: 19%).

LCMS: m/z, 324.2 (M+H)⁺;

1HNMR (400 MHz, CDC1₃): δ 2.44-2.7 l(m, 2H), 2.93-3.07(s, 3H), 3.46~3.54(m, 2H), 3.76~3.83(m, 2H), 6.49-6.5 l(m, 2H), 6.64~6.66(m, 1H), 7.16-7.25 (m, 2H), 7.43-7.45 (m, 1H), 7.61~7.65(m, 1H), 8.54-8.56 (m, 1H).

Example Compound 184 Pre aration o Com ound 184:

Compound 184 Experimental section:

Procedure for preparation of Compound 184:

Compound 184

A mixture of compound 1 (38.0mg, 0.2mmol), 2 (52.2mg, 0.22mmol), Xantphos

(11.6mg, 0.02mmol) and Cs₂CC>3(130.2mg, 0.4mmol)in DMF (lmL) was degassed 3 times under N₂, and then Pd₂(dba)₃(9.218.4mg, 0.02mmol) was added to the mixture under N₂. The reaction mixture was heated at 100^°C under N2 and stirred overnight. The reaction mixture was quenched by added water and extracted with EA. The combined organic phases were washed by water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by pre-TLC (7.5mg, yield=25.0%).

LCMS: m/z 301.1 [M+H]⁺;

1HNMR (d-CDC13 400 MHz): δ 2.42-2.63 (m, 2H), 3.42 (dt, J=2.8, 8.4Hz, IH), 3.73-3.86 (m, 2H), 4.16 (dd, J=12.0, 32.0Hz, IH), 6.83 (dt, J=1.4, 8.1Hz, IH), 7.15 (dt, J=1.6, 7.2Hz, IH), 7.26-7.33 (m, 2H), 7.50 (d, J=8.0Hz, IH), 7.67 (dt, J=1.6, 7.6Hz, IH), 8.61 (d, J=3.6Hz, IH).

Example Compound 185

Preparation of Compound 185:

Compound 185

Experimental section:

Procedure for preparation of Compound 185:

Compound 185

To a solution of compound 1(19. Omg, O. lmmol) in DCM (lmL) was added successively TEA (20.2mg, 0.2mmol) and compound 2 (17. Omg, 0.1 lmmol) at 0 °C. The solution was stirred under N₂ at r.t. for 0.5h. The reaction mixture was quenched by water and extracted with EA, the organic phase was washed by brine, dried over Na₂S0₄, filtered and concentrated. The residue was purified by pre-TLC (10.5mg, yield=34.1%).

LCMS: m/z 309.2 [M+H]⁺;

1HNMR (d-CDC13 400 MHz): δ 2.18-2.47 (m, 2H), 3.56-3.83 (m, 5H), 3.96-4.16 (m, 1H), 7.17-7.28 (m, 6H), 7.40 (d, J=7.6Hz, 1H), 7.60-7.65 (m, 1H), 8.53 (d, J=7.6Hz, 1H).

Example Compound 187

Preparation of Compound 187:

Compound 187

Experimental section:

Procedure for preparation of Compound 187:

Compound 187

To a solution of compound 1(19. Omg, O. lmmol) in DCM (lmL) was added successively TEA (20.2mg, 0.2mmol) and compound 2 (11.9mg, 0.1 lmmol) at 0°C. The solution was stirred under N₂ at r.t. for 0.5h. The reaction mixture was quenched by water and extracted with EA, the organic phase was washed by brine, dried over Na₂S0₄, filtered and concentrated. The residue was purified by pre-TLC (11.5mg, yield=43.9%).

LCMS: m/z 263.1 [M+H]⁺;

1HNMR (d-CDCl₃ 400 MHz): 5 1.19 (t, J=7.2Hz, 3H), 2.22-2.38 (m, IH), 2.46-2.53 (m, IH), 3.48-3.56 (m, IH), 3.59-3.75 (m, 2H), 3.87~4.00(m, IH), 4.06 (q, J=7.2Hz, 2H), 7.21 (dd, J=4.8, 7.2Hz, IH), 7.41 (d, J=7.8Hz, IH), 7.60 (dt, J=1.6, 8.0Hz, IH), 8.53 (d, J=4.8Hz, IH).

Example Compound 188

Preparation of Compound 188:

Compound 188

Experimental section:

Procedure for preparation o Compound 188:

Compound 188

To a solution of compound l(19.0mg, O.lmmol) in DCM (lmL) was added successively TEA (20.2mg, 0.2mmol) and compound 2 (17.2mg, 0.1 lmmol) at 0°C. The solution was stirred under N₂ at r.t. for 0.5h. The reaction mixture was quenched by water and extracted with EA, the organic phase was washed by brine, dried over Na₂S0₄, filtered and concentrated. The residue was purified by pre-TLC (11.5mg, yield=43.9%).

LCMS: m/z 311.1 [M+H]⁺;

1HNMR (d-CDCl₃ 400 MHz): δ 2.28-2.63 (m, 2H), 3.61-3.93 (m, 3H), 4.03-4.16 (m, IH), 7.06 (dd, J=1.2, 7.2Hz, 2H), 7.11 (t, J=8.0Hz, IH), 7.22 (t, J=6.0Hz, IH), 7.27 (t, J=8.0Hz, IH), 7.42 (d, J=7.8Hz, IH), 7.61 (dt, J=0.8, 8.0Hz, IH), 8.54 (d, J=4.8Hz, IH). Example Compound 191

Preparation of Compound 191:

1 Compound 191

Experimental section:

Procedure for preparation of Compound 191:

1 Compound 191 To a solution of l(21mg, 0.1 lmmol) and 2(42mg, 0.15mmol) was added Pd (dba)₂ (6mg, O.Olmmol), Xantphos (6mg,0.01mmol) and Cs₂CC>3(98mg, 0.3mmol). The suspension was degassed under vacuum and purged with N₂ several times. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 100^°C for lh, cooled to rt, LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (80mL) and washed with brine (20mL) three times. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purification with prep-TLC to afford the title product (1 lmg, yield: 35%).

LCMS: m/z, 281.2 (M+H)⁺;

1HNMR (400 MHz, CDC1₃): δ 2.42 (s, 3H), 2.61-2.73 (m, 2H), 3.57~3.58(m, 2H), 3.83~3.89(m, 2H), 6.38~6.39(m, 2H), 6.56-6.58 (m, 1H), 7.13-7.17 (m, 1H), 7.29-7.32 (m, 1H), 7.50-7.52 (m, 1H), 7.69-7.73 (m, 1H), 8.632-8.63 (m, 1H).

Example Compound 192

Preparation of Compound 192:

Compound 192

Experimental section: Procedure for preparation of Compound 192:

Compound 192

To a solution of compound 1(19. Omg, O. lmmol) in DCM (lmL) was added successively TEA (20.2mg, 0.2mmol) and compound 2 (15. Omg, 0.1 lmmol) at 0°C. The solution was stirred under N₂ at r.t. for 0.5h. The reaction mixture was quenched by water and extracted with EA, the organic phase was washed by brine, dried over Na₂S0₄, filtered and concentrated. The residue was purified by pre-TLC (10.5mg, yield=36.1%).

LCMS: m/z 291.1 [M+H]⁺;

1HNMR (d-CDCl₃ 400 MHz): δ 0.85 (t, J=7.2Hz, 3H), 1.28-1.37 (m, 2H), 1.51-1.59 (m, 2H), 2.23-2.53 (m, 2H), 3.48-3.75 (m, 3H), 3.87-4.05 (m, 3H), 7.21 (dd, J=5.4, 7.0Hz, IH), 7.41 (d, J=8.0Hz, IH), 7.60 (dt, J=1.6, 8.0Hz, IH), 8.53 (d, J=4.4Hz, IH).

Example Compound 193

Preparation of Compound 193:

Compound 193

A mixture of compound 1 (38. Omg, 0.2mmol), 2 (54.9mg, 0.22mmol), Xantphos (11.6mg, 0.02mmol) and Cs₂CO₃(130.3mg, 0.4mmol)in DMF (2mL) was degassed 3 times under N₂, and then Pd₂(dba)₃(18.4mg, 0.02mmol) was added to the mixture under N₂. The reaction mixture was heated at 100^°C under N2 and stirred for 2h. The reaction mixture was quenched by added water and extracted with EA. The combined organic phases were washed by water, brine, dried over sodium sulfate, filtered and

concentrated. The residue was purified by pre-TLC. (15.6mg, yield=25.0%).

LCMS: m/z 312.1 [M+H]⁺;

1HNMR (d-CDCl₃ 400 MHz): δ 2.50-2.74 (m, 2H), 3.59-3.63 (m, 2H), 3.86-3.93 (m, 2H), 6.78(dd, J=2.6, 8.2Hz, 1H), 7.24-7.34 (m, 3H), 7.49-7.55 (m, 2H), 7.67(dt, J=1.8, 8.1Hz, 1H), 8.60-8.62 (m, 1H).

Example Compound 194

Preparation of Compound 194:

Experimental section:

Procedure for preparation of 2:

1 2

To a solution of l(21mg, 0.1 lmmol) and 2(40mg, 0.15mmol) was added Pd₂(dba)₃ (6mg, O.Olmmol), Xantphos (6mg,0.0 lmmol) and Cs₂C0₃(98mg, 0.3mmol). The suspension was degassed under vacuum and purged with N₂ several times. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 100^°C for lh, cooled to rt, LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (80mL) and washed with brine (20mL) three times. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purification with prep-TLC to afford the title product (20mg,yield:47%).

Procedure for preparation of 0194:

Compound 194

To s solution of l(20mg, 0.052mmol) in DCM(5ml) was added TFA(lml) at 0^°C .The mixture was stirred at rt for 1.5h, then, the solvent was removed, diluted with

EtOAc(2x20mL) and washed with brine. The separated organic layer was dried over anhydrous Na₂S0₄, filtered and concentrated to dryness, which was purified by prep- TLC to give desired compound(5mg, yield: 10%).

LCMS: m/z, 282.1 (M+H)⁺;

1HNMR (400 MHz, CDC1₃): δ 2.35~2.64(m, 2H), 3.44~3.48(m, 2H), 3.5(s, 2H), 3.73~3.79(m, 3H), 5.83~3.84(m, 1H), 5.941~5.962(m, 1H), 6.03~6.06(m, 1H), 6.95~6.99(m, 1H), 6.03~6.06(m, 1H), 6.95-6.99 (m, 1H), 7.21-7.24 (m, 1H),

7.43~7.45(m, 1H), 7.61~7.65(m, 1H), 8.55-8.56 (m, 1H).

Example Compound 196

Preparation of Compound 196:

Experimental section:

Procedure for preparation of Compound 196:

ompoun

To a solution of 1 (15mg, 0.079mmol), 2 (36mg, 0.158mmol) and Cs₂C0₃ (128mg, 0.395mmol) in DMF (lmL) were added 2 mg of Pd(dba)₂ and 2 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for lh. LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (lOmL) and washed with brine (2mL) twice. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purified by p-TLC to give the desired compound Compound 196 (6mg, yield: 22.2%).

LCMS: m/z, 343.1 (M+H)⁺;

1HNMR:(d-CDCl₃, 400MHz): 8.63(s, IH), 7.69~7.73(m, IH), 7.61(t, J=2.2, 2H), 7.52(t, J=3.8, IH), 7.43(t, J=7.2, 2H), 7.29~7.36(m, 3H), 6.97(d, J=8.0, IH), 6.75(t, J=2.0, IH), 6.57(dd, Ji=2.0,J₂=8.4, IH), 3.97(s, IH), 3.90(s, IH), 3.59~3.67(m, 2H), 2.50~2.76(m, 2H).

Example Compound 197

Procedure or preparation of Compound 197:

Compound 197

A mixture of compound 1 (15mg, 0.078mmol), compound 2(20mg, 0.117mmol) and K2C03 (32mg, 0.234mmol) in DMF (1.OmL) were heated to 100 ^°C for 2h. After cooled, the crude was purified by prep-TLC(EA/PE, 1/3, v/v) to give desired compound (1 lmg, 50% yield).

LCMS: m/z, 281.1(M+H)⁺;

1HNMR (400MHz, CDC1₃): δ 2.46(t, J=6.8Hz, IH), 2.52(t, J=6.8Hz, IH), 2.61~2.68(m, IH), 2.94~3.06(m, 2H), 3.19~3.27(m, IH), 3.71(d, J=3.2Hz, 2H), 7.24~7.36(m, 6H), 7.45(d, J=8.0Hz, IH), 7.67(t, J=8.0Hz, IH), 8.59(d, J=4.4Hz, IH).

Example Compound 198

Procedure or preparation of Compound 198:

Compound 198 A mixture of compound 1 (15mg, 0.078mmol), compound 2(22mg, 0.117mmol) and K2C03 (32mg, 0.234mmol) in DMF (l .OmL) were heated to 100 ^°C for 2h. After cooled, the crude was purified by prep-TLC (EA/PE, 1/3, v/v) to give desired compound (lOmg, 45% yield).

LCMS: m/z, 295.1(M+H)+;

1HNMR (400MHz, CDC1₃): δ 2.49(t, J=7.2Hz, 1H), 2.53(t, J=7.2Hz, 1H), 2.64~2.70(m, 1H), 2.74~2.85(m, 4H), 2.99~3.09(m, 2H), 3.29~3.37(m, 1H), 7.19~7.29(m, 6H), 7.47(d, J=7.6Hz, 1H), 7.67(t, J=6.0Hz, 1H), 8.61(d, J=4.8Hz, 1H).

Example Compound 202

Procedure or preparation of Compound 202:

common nterme ate

1 2 Compound 202

To a solution of 1 (lOmg, 0.053mmol), 2 (26mg, 0.106mmol) and Cs₂C0₃ (86mg, 0.265mmol) in DMF (2mL) were added 1 mg of Pd(dba)₂ and 1 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for lhr. The reaction was quenched by adding water and extracted with EA. The combine organic phases were washed by water, brine, dried over anhydrous Na₂S0₄ and concentrated to dryness. The residue was purified by pre-TLC to obtain the title compound Compound 202 (2.02mg, yield: 12.4%).

LCMS: m/z, 310.1(M+H)⁺;

1HNMR (d-CDCl₃, 400MHz): δ 8.57 (s, 1H), 7.64-7.67 (m, 1H), 7.45-7.47 (m, 1H), 7.32-7.37 (m, 1H), 7.25-7.28 (m, 1H), 6.18-6.27 (m, 2H), 3.74-3.85 (m, 2H),

3.53-3.57 (m, 2H), 2.63-2.74 (m, 1H), 2.42-2.59 (m, 1H).

Example Compound 203

Preparation of Compound 203:

common intermediate

1 Compound 203 Experimental section:

Procedure for preparation of Compound 203:

common intermediate

1 2 Compound 203

To a solution of 1 (30mg, 0.157mmol), 2 (70mg, 0.315mmol) and CS₂CO₃ (256mg, 0.785mmol) in DMF (2mL) were added 1 mg of Pd(dba)₂ and 1 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for lhr. The reaction was quenched by adding water and extracted with EA. The combine organic phases were washed by water, brine, dried over anhydrous Na₂S0₄ and concentrated to dryness. The residue was purified by pre-TLC to obtain the title compound Compound 203 (4.74mg, yield: 10.6%).

LCMS: m/z, 285.1(M+H)⁺;

1HNMR (d-CDCl₃, 400MHz): δ 8.54-8.56 (m, 1H), 7.61-7.66 (m, 1H), 7.44 (d, J=8Hz, 1H), 7.19-7.25 (m, 1H), 6.88-6.92 (m, 2H), 6.39-6.43 (m, 2H), 3.78-3.83 (m, 1H), 3.73-3.78 (m, 1H), 3.44-3.47 (m, 2H), 2.54-2.63 (m, 1H), 2.42-2.47 (m, 1H).

Example Compound 204

Preparation of Compound 204:

1 2 Compound204

Experimental section:

Procedure or preparation of Compound 204:

Compound 204

To a solution of 1 (30mg, 0.157mmol), 2 (78mg, 0.315mmol) and Cs₂C0₃ (256mg, 0.785mmol) in DMF (2mL) were added 1 mg of Pd(dba)₂ and 1 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for lhr. The reaction was quenched by adding water and extracted with EA. The combine organic phases were washed by water, brine, dried over anhydrous Na₂S0₄ and concentrated to dryness. The residue was purified by pre-TLC to obtain the title compound Compound 204 (5.15mg, yield: 10.5%).

LCMS: m/z, 310.1(M+H)⁺;

1HNMR (d-CDC-3, 400MHz): δ 8.55-8.57 (m, 1H), 7.64-7.68 (m, 1H), 7.45-7.48 (m, 1H), 7.38-7.42 (m, 1H), 7.24-7.28 (m, 1H), 6.39-6.44 (m, 1H), 6.24-6.28 (m, 1H), 4.12-4.20 (m, 1H), 4.03-4.09 (m, 1H), 3.70-3.82 (m, 2H), 2.60-2.69 (m, 1H),

2.35-2.53 (m, 1H).

Example Compound 205

Procedure for preparation of Compound 205:

Cs₂C0₃,DMF

1 Compound 205

To a solution of 1 (15mg, 0.079mmol), 2 (35mg, 0.158mmol) and CS₂CO₃ (128mg, 0.395mmol) in DMF (lmL) were added 2 mg of Pd(dba)₂ and 2 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for lh. LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (lOmL) and washed with brine (2mL) twice. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purified by p-TLC to give the desired compound Compound 205 (6mg, yield: 27.2%).

LCMS: m/z, 285.1 (M+H)⁺;

1HNMR:(d-CDCl₃, 400MHz): 8.55(d, J=5.2, 1H), 7.61~7.65(m, 1H), 7.44(d, J=7.6, 1H), 7.19~7.24(m, 1H), 6.91~6.96(m, 2H), 6.59~6.68(m, 2H), 3.81~4.06(m, 2H),

3.46~3.64(m, 2H), 2.36~2.62(m, 2H).

Example Compound 207

Experimental section: Procedure for preparation of Compound 207:

ompoun

To a solution of 1 (15mg, 0.079mmol), 2 (44mg, 0.158mmol) and CS₂CO₃ (128mg, 0.395mmol) in DMF (lmL) were added 2 mg of Pd(dba)₂ and 2 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for lh. LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (lOmL) and washed with brine (2mL) twice. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purified by p-TLC to give the desired compound Compound 207 (lOmg, yield: 37%).

LCMS: m/z, 343.1 (M+H)⁺;

1HNMR (CDC1₃, 400MHz): 8.55(d, J=5.2, 1H), 7.62~7.66(m, 1H), 7.44~7.49(m, 5H), 7.31~7.38(m, 2H), 7.21~7.25(m, 2H), 6.57(d, J=8.8, 2H), 3.88(s, 1H), 3.81(s, 1H), 3.52~3.57(m, 2H), 2.43~2.66(m, 2H).

Example Compound 210

Procedure for Preparation of Compound 210:

Compound 2 0

A mixture of compound 9(15mg, 0.07mmol), 10(22mg, 0.07mmol), Xantphos (12mg, 0.021mmol) and CsC03(137mg, 0.42mmol)in DMF (5mL) was degassed 3 times under N2, and then Pd(dba)₃(6mg, 0.007mmol) was added to the mixture under N₂. The reaction mixture was heated at 100^°C under N2 and stirred for 2h. The reaction mixture was checked by LCMS after it was cooled to RT. The mixture was partitioned with H20 (5mL) and EA (5mL). Organic phase was dried, concentrated and purified by prep-TLC to give ~5mg of crude desired product. The cruder product was treated together with H14535-019,031 to afford 6mg of desired product with 97% purity for delivery. (Yield: 26.5%)

LCMS: m/z, 326.0 (M+H)⁺;

1HNMR (CDC1₃, 400MHz): δ 7.90(s, 1H), 7.65(s, 1H), 7.52(m, 1H), 7.43 (m, 1H), 7.30(m, 1H), 7.20(m, 1H), 7.00(s, 1H), 6.45(d, J=7.6Hz 1H), 4.35(m, 4H).

Example Compound 212 Preparation of Compound 212:

Experimental section:

Procedure for preparation of Compound 212

A mixture of compound 1 (15mg, 0.085mmol), compound 2(23mg, O. lmmol), Cs₂C0₃ (l lOmg, 0.34mmol), Pd(dba)₂(5mg, 0.0085mmol) and Xanphos (4mg, 0.0085mol) in DMF(l .OmL) were degassed under N₂ and then heated to 100^°C for lh. After cooled, the reaction mixture was filtered. The filtrate was washed with H₂0, extracted with EtOAc. The organic layer was dried over anhydrous Na₂S0₄, filtered and concentrated to residue, which was purified by prep-TLC (EA/PE, 2/1, v/v) to give desired compound (4mg, 20% yield).

LCMS: m/z, 298.1(M+H)+;

1HNMR (400MHz, CDC1₃): δ 2.46~2.76(m, 2H), 3.54~3.63(m, 1H), 3.78(s, 1H), 3.81(s, 3H), 3.91(s, 1H), 6.35(t, J=2.4Hz, 1H), 7.26-7.3 l(m, 1H), 7.52(d, J=8.0Hz, 1H), 7.65(d, J=2.4Hz, 1H), 7.68~7.73(m, 1H), 7.75(d, J=2.4Hz, 1H), 7.88(s, 1H), 8.63(d, J=5.2Hz, 1H). Example Compound 214

Procedure for preparation of Compound 214:

common intermediate

Compound 214

2

To a solution of 1 (lOmg, 0.053mmol), 2 (25mg, 0.106mmol) and CS2CO3 (86mg, 0.265mmol) in DMF (2mL) were added 1 mg of Pd(dba)₂ and 1 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for lhr. The reaction was quenched by adding water and extracted with EA. The combine organic phases were washed by water, brine, dried over anhydrous Na₂S0₄ and concentrated to dryness. The residue was purified by pre-TLC to obtain the title compound Compound 214 (1.74mg, yield: 10.9%).

LCMS: m/z, 303.1(M+H)⁺;

1HNMR (d-CDCl₃, 400MHz): δ 8.61-8.62 (m, 1H), 7.67-7.72 (m, 1H), 7.51 (d, J=8Hz, 1H), 7.26-7.31 (m, 1H), 6.74-6.84 (m, 3H), 4.10-4.20 (m, 1H), 3.79-3.92 (m, 2H), 3.53-3.57 (m, 1H), 2.31-2.57 (m, 2H).

Example Compound 215

Procedure for preparation of Compound 215:

1 Compound 215 To a solution of 1 (30mg, 0.157mmol), 2 (81mg, 0.315mmol) and Cs₂C0₃ (256mg, 0.785mmol) in DMF (2mL) were added 1 mg of Pd(dba)₂ and 1 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for lhr. The reaction was quenched by adding water and extracted with EA. The combine organic phases were washed by water, brine, dried over anhydrous Na₂S0₄ and concentrated to dryness. The residue was purified by pre-TLC to obtain the title compound Compound 215 (6.15mg, yield: 12.3%). LCMS: m/z, 319.0(M+H)⁺;

1HNMR (d-CDCl₃, 400MHz): δ 8.62-8.63 (m, 1H), 7.68-7.72 (m, 1H), 7.50-7.52 (m, 1H), 7.28-7.32 (m, 1H), 7.09-7.12 (m, 1H), 6.91-6.93 (m, 2H), 4.06-4.17 (m, 1H), 3.68-3.77 (m, 2H), 3.33-3.38 (m, 1H), 2.46-2.69 (m, 2H).

Example Compound 216

Procedure for preparation of Compound 216:

common intermediate

1 2 Compound 216

To a solution of 1 (30mg, 0.157mmol), 2 (78mg, 0.315mmol) and Cs₂C0₃ (256mg, 0.785mmol) in DMF (2mL) were added 1 mg of Pd(dba)₂ and 1 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for lhr. The reaction was quenched by adding water and extracted with EA. The combine organic phases were washed by water, brine, dried over anhydrous Na₂S0₄ and concentrated to dryness. The residue was purified by pre-TLC to obtain the title compound Compound 216 (4.24mg, yield: 8.7%).

LCMS: m/z, 310.1(M+H)⁺;

1HNMR (d-CDCl3, 400MHz): δ 8.55-8.57 (m, 1H), 7.63-7.67 (m, 1H), 7.46 (d, J=8Hz, 1H), 7.19-7.28 (m, 2H), 6.44 (t, J=8Hz, 1H), 6.34 (d, J=8Hz, 1H), 4.04-4.23 (m, 2H), 3.77-3.85 (m, 2H), 2.60-2.69 (m, 1H), 2.36-2.53 (m, 1H).

Example Compound 217

Procedure for preparation of Compound 217:

common intermediate Cs₂C0₃,DMF

1

Compound 217

To a solution of 1 (15mg, 0.079mmol), 2 (35mg, 0.158mmol) and Cs₂C0₃ (128mg, 0.395mmol) in DMF (lmL) were added 2 mg of Pd(dba)₂ and 2 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for lh. LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (lOmL) and washed with brine (2mL) twice. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purified by p-TLC to give the desired compound Compound 217 (6mg, yield: 27.2%).

LCMS: m/z, 286.1 (M+H)⁺;

1HNMR (CDC1₃, 400MHz): δ 8.62(d, J=4.8, 1H), 8.17(d, J=5.6, 1H), 8.08(d, J=5.2, 1H), 7.69~7.74(m, 1H), 7.52(d, J=8.0, 1H), 7.31~7.33(m, 1H), 6.47(dd, Ji=5.6,J₂=8.0, 1H), 4.03~4.15(m, 2H), 3.71~3.78(m, 2H), 2.58~2.74(m, 1H), 2.40~2.46(m, 1H).

Example Compound 218

Procedure for preparation of Compound 218:

Compound 218

To a solution of 1 (15mg, 0.079mmol), 2 (30mg, 0.158mmol) and Cs₂C0₃ (128mg, 0.395mmol) in DMF (lmL) were added 2 mg of Pd(dba) and 2 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for 6h. LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (lOmL) and washed with brine (2mL) twice. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purified by p-TLC to give the desired compound Compound 218 (4mg, yield: 16.6%).

LCMS: m/z, 302.0 (M+H)⁺;

1HNMR:(d-CDCl₃, 400MHz): δ 8.55(d, J=4.4, 1H), 7.89(s, 1H), 7.80(s, 1H),

7.62~7.66(m, 1H), 7.44(d, J=8.0, 1H), 6.74(t, J=2.0, 1H), 3.83(s, 1H), 3.76(d, J=3.2, 1H), 3.49~3.54(m, 2H), 2.42~2.72(m, 2H).

Example Compound 219

Procedure for preparation of Compound 219:

Compound 219

To a solution of 1 (15mg, 0.079mmol), 2 (38mg, 0.158mmol) and CS₂CO₃ (128mg, 0.395mmol) in DMF (lmL) were added 2 mg of Pd(dba)₂ and 2 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for lh. LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (lOmL) and washed with brine (2mL) twice. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purified by p-TLC to give the desired compound Compound 219 (4mg, yield: 16.6%).

LCMS: m/z, 303.1 (M+H)⁺;

1HNMR:(d-CDCl₃, 400MHz): δ 8.55(d, J=4.8, 1H), 7.61~7.65(m, 1H), 7.44(d, J=7.6, 1H), 7.19~7.25(m, 1H), 6.81~6.88(m, 1H), 7.25~7.32(m, 2H), 3.83~4.05(m, 2H), 3.46~3.60(m, 2H), 2.33~2.63(m, 2H).

Example Compound 220

Procedure for preparation of Compound 220:

To a solution of 1 (15mg, 0.079mmol), 2 (30mg, 0.158mmol) and Cs₂C0₃ (128mg, 0.395mmol) in DMF (lmL) were added 2 mg of Pd(dba)₂ and 2 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for 6h. LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (lOmL) and washed with brine (2mL) twice. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purified by p-TLC to give the desired compound Compound 220 (5mg, yield: 20.8%).

LCMS: m/z, 309.1 (M+H)⁺;

1HNMR:(d-CDCl₃ (400MHz): δ 8.54~8.55(m, 1H), 7.61~7.65(m, 1H), 7.44(d, J=7.6, 1H), 7.21~7.24(m, 1H), 7.12(t, J=5.8, 1H), 6.56(d, J=7.6, 1H), 6.32~6.36(m, 2H), 3.84(s, 1H), 3.77(s, 1H), 3.45~3.53(m, 2H), 2.75~2.82(m, 1H), 2.56~2.66(m, 1H), 2.37~2.53(m, 1H), 1.19(d, J=4.8,6H).

Example Compound 221 Procedure for preparation of Compound 221:

To a solution of 1 (15mg, 0.079mmol), 2 (33mg, 0.158mmol) and Cs₂C0₃ (128mg, 0.395mmol) in DMF (lmL) were added 2 mg of Pd(dba)₂ and 2 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for 6h. LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (lOmL) and washed with brine (2mL) twice. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purified by p-TLC to give the desired compound Compound 221 (3mg, yield: 12%).

LCMS: m/z, 323.2 (M+H)⁺;

1HNMR (CDC1₃, 400MHz): δ 8.62(d, J=4.8, 1H), 7.68~7.73(m, 1H), 7.52(d, J=7.6, 1H), 7.30(t, J=6.4, 1H), 7.20(t, J=8.0, 1H), 6.79(d, J=7.2, 1H), 6.58(s, 1H), 6.41(d, J=5.6, 1H), 3.92(s, 1H), 3.86(s, 1H), 3.56~3.60(m, 2H), 2.61~2.74(m, 1H), 2.47~2.56(m, 1H), 1.32(s,9H).

Example Compound 222

Procedure for preparation of Compound 222

Compound 222

To a solution of 1 (15mg, 0.079mmol), 2 (33mg, 0.158mmol) and Cs₂C0₃ (128mg, 0.395mmol) in DMF (lmL) were added 2 mg of Pd(dba)₂ and 2 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for 6h. LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (lOmL) and washed with brine (2mL) twice. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purified by p-TLC to give the desired compound Compound 222 (6mg, yield: 24%).

LCMS: m/z, 325.2 (M+H)⁺;

1HNMR:(CDC1₃, 400MHz): 8.54(d, J=3.6, 1H), 7.61~7.65(m, 1H), 7.43(d, J=8.0, 1H), 7.21~7.24(m, 1H), 7.06(t, J=8.2, 1H), 6.23(dd, Ji=2.0,J₂=8.0, 1H), 6.09(dd,

Ji=2.2,J₂=8.2, 1H), 6.04(t, J=2.4, 1H), 4.45-4.5 l(m, 1H), 3.80(s, 1H), 3.74(s, 1H), 3.42~3.50(m, 2H), 2.55~2.65(m, 1H), 2.36~2.53(m, 1H), 1.27(t, J=4.8,6H).

Example Compound 223 (structure mistake) Preparation of Compound 223:

Experimental section:

Procedure for preparation of 3:

1

Compound 1 (500mg, 3.68mmol) was dissolved in dry THF (lOmL). The solution was cooled to -78 0^°C , and n-BuLi solution(2.5M in hexane,2.2mL, 5.52mmol)) was added drop wise. The reaction mixture was stirred for lh at -78 ^°C . Then compound 2(1.06g, 5.33mmol) in 2mL of THF was added. The mixture was stirred at the same temperature for lh. The reaction was quenched with saturated NH₄C1 solution and then extracted with EtOAc(2x l0mL). The separated organic layer was dried over anhydrous Na₂S0₄, filtered and concentrated to dryness, which was purified by prep-TLC to give desired compound(450mg,yield: 37%)

Procedure r preparation of 4:

Compound l(321mg, lmmol) was dissolved in dry Dichloromethane(15mL). The solution was cooled to -78 ^°C , and DAST(322mg, 2mmol) was added. The reaction mixture was stirred for 30min at -78 ^°C and warmed to rt. After quenched with H₂0, the solution was extracted with EtOAc(2x l5mL). The combined organic layers were dried over anhydrous Na₂S0₄, filtered and concentrated to dryness, which was purified by column on silica gel (eluted with EA/PE, 1/10, v/v) to give desired compound(150mg, yield:46%).

Procedure or preparation of 5:

To a solution of 1 (150mg, 0.46mmol) in dry Dichloromethane (5ml) was added TFA (lml) drop wise at 0°C. Then the reaction mixture was stirred at rt for2h and concentrated to residue. Then the residue was treated with saturated aqueous Na₂C0₃ till pH=10 and extracted with Dichloromethane (50mLx lO). The combined organic layers were dried over anhydrous Na₂S0₄, filtered and concentrated to give the desired product (50mg, yield: 48%).

Procedure for preparation of Compound 223:

Compound 223

To a solution of 1 (23mg, O.lmmol), 2 (34mg, 0.15mmol) and CS₂CO₃ (98mg, 0.3mmol) in DMF (lmL) were added 6 mg of Pd(dba)₂ and 6 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 100 ^°C for lh under N₂. LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (20mL) and washed with brine (lOmL) three times. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purified by prep-TLC to give the title compound (lOmg, yield: 31%).

LCMS: m/z, 265.1(M+H)⁺;

1HNMR (400 MHz, CDC1₃): δ 2.42~2.69(m, 1H), 2.75~2.77(m, 1H), 3.56-3.60 (m, 2H), 3.75~3.90(m, 2H), 6.52~6.56(m, 1H), 7.26-7.3 l(m, 1H), 7.26~7.38(m, 2H), 7.48~7.49(m, 1H), 7.81~7.83(m, 1H), 7.87-7.88 (m, 1H).

Example Compound 224 Preparation of Compound 224:

Procedure for preparation of 2:

1 2

The compound l(500mg, 2.7mmol) was diluted with anhydrous MeOH (15 ml) and catalytic amount of PPTS (lOmg g) was added. The reaction mixture was stirred for 1 h and then diluted with Dichloromethane and work up with saturated NaHC0₃ solution. The layers were separated and the aqueous layer was extracted with Dichloromethane (2 x 15ml). The combined organic fractions were dried over Na₂S0₄, filtered, and concentrated in vacuo to afford title product (500mg, 79%).

Procedure for preparation of 3:

2 3

To a solution of 2 (500mg, 1.89 mol) in MeOH (15 ml) was added Pd/C (15 mg) under N₂. The suspension was degassed under vacuum and purged with H2 several times, The mixture was stirred under H2 balloon at rt for3hours. The suspension was filtered through a pad of Celite and filter cakewas washed with MeOH (lOmL). The combined filtrates were concentrated to dryness to give product (180mg, 72%).

Procedure for preparation of 5:

3 5

To a solution of 3(13 lmg, lmmol), 4 (304mg, 1.5mmol) and Cs₂C0₃ (980mg, 3mmol) in DMF (5mL) were added 60 mg of Pd(dba)₂ and 60 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for 3h under N₂. LCMS showed the SM was consumed completely. Then the reaction mixture was diluted with EA (20mL) and washed with brine (lOmL) three times. The organic solution was dried over anhydrous Na₂S0₄, filtered, concentrated under reduced pressure and purified by prep-TLC to give the title compound (50mg, yield: 24%).

Procedure for preparation of 5:

5 6

To a solution of 1 (80 mg, 0.39 mmol) in dry Dichloromethane (3ml) was added TFA (lmL) drop wise at 0^°C . Then the reaction mixture was stirred at rt for 2h and concentrated to residue. Then the residue was treated with saturated aqueous Na₂C0₃ till pH=10 and extracted with Dichloromethane (50mLx 10). The combined organic layers were dried over anhydrous Na₂S0₄, filtered and concentrated to give the desired product (30mg, yield: 48%).

Procedure for preparation of Compound 224:

6 Compound 224

Compound l(24mg, 0.24mmol) was dissolved in dry THF (5mL). The solution was cooled to -78 ^°C , and n-BuLi solution(2.5M in hexane,0.12ml, 0.29mmol)) was added drop wise. The reaction mixture was stirred for lh at -78 ^°C . Then compound 2(30mg, 0.19mmol) in 2mL of THF was added. The mixture was stirred at the same temperature for lh. The reaction was quenched with saturated NH₄C1 solution and then extracted with EtOAc(2x lOmL). The separated organic layer was dried over anhydrous Na₂S0₄, filtered and concentrated to dryness, which was purified by prep-TLC to give desired compound(15mg, yield:27%)

LCMS: m/z, 319.0(M+H)⁺;

1HNMR (400 MHz, CDC1₃): δ 2.43~2.54(m, 2H), 3.50~3.66(m, 4H), 3.79-3.82 (m, 1H), 6.55~6.69(m, 2H), 6.71~6.73(m, 1H), 7.22~7.27(m, 3H), 7.44~7.6(m, 1H), 7.65~7.69(m, 1H), 8.57~8.58(m, 1H).

Example Compound 225

Procedure for preparation of Compound 225:

common intermediate

Compound 225

1

To a solution of 1 (30mg, 0.157mmol), 2 (81mg, 0.315mmol) and Cs₂C0₃ (256mg, 0.785mmol) in DMF (2mL) were added 1 mg of Pd(dba)₂ and 1 mg of Xantphos. The suspension was degassed under vacuum and purged with N₂ several times. The mixture was stirred at 120°C for lhr. The reaction was quenched by adding water and extracted with EA. The combine organic phases were washed by water, brine, dried over anhydrous Na₂S0₄ and concentrated to dryness. The residue was purified by pre-TLC to obtain the title compound Compound 225 (8.52mg, yield: 17.9%).

LCMS: m/z, 319.1(M+H)⁺;

1HNMR (d-CDCl3, 400MHz): δ 8.55-8.56 (m, 1H), 7.62-7.66 (m, 1H), 7.43-7.46 (m, 1H), 7.22-7.25 (m, 1H), 6.85-6.88 (m, 1H), 6.70-6.83 (m, 1H), 6.46-6.50 (m, 1H), 3.82-4.16 (m, 2H), 3.59-3.66 (m, 1H), 3.49-3.54 (m, 1H), 2.34-2.63 (m, 2H).

Example Compound 226 Procedure for Preparation of Compound 226:

Compound 226

A mixture of compound 1(15 mg, 0.07 mmol), 2(14 mg, 0.07 mmol), Xantphos (12 mg, 0.021 mmol) and CsC03(137mg, 0.42 mmol)in DMF (5 mL) was degassed 3 times under N2, and then Pd(dba)3(6 mg, 0.007 mmol) was added to the mixture under N2. The reaction mixture was heated at 100^°C under N₂ and stirred for 2h. The reaction mixture was checked by LCMS after it was cooled to RT. The mixture was partitioned with H20 (5mL) and EA(5mL). The organic phase was dried, concentrated and purified by prep-TLC to afford 3 mg (15%) of desired product with 97% purity.

LCMS: m/z, 292.1 (M+H)⁺;

1HNMR (CDC1₃, 400MHz): δ 7.52(m, 1H), 7.40(m, 1H), 7.30(m, 1H), 7.20 (m, 3H), 6.96(s, 1H), 6.75(m, 1H), 6.45(m, 2H), 4.25(m, 4H). Example 8

Functional Calcium Clux Assay Methodology

[00047] For functional assays, HEK293 cells stably expressing recombinant rat mGluR5 were seeded in 384-well plates and dye loaded using Fluo-8. Cells were then washed to remove the un-incorporated dye. Antagonist evaluation was performed following a 15 min incubation of the test compound followed by the addition of submaximal concentration of glutamate. Intracellular calcium ([Ca²⁺]i) measurements were performed using a fluorometric imaging plate reader (FLIPR, Molecular Devices). The glutamate-evoked increase in [Ca²⁺]i in the presence of the test compounds was compared to the response to glutamate alone (the positive control). Antagonist inhibition curves were fitted with a 4-parameter logistic equation giving IC₅₀ values, and Hill coefficients using an iterative nonlinear curve fitting algorithm. [00048] The tables below provide IC50 data in this assay. In the activity column,

A = IC50 >1,000 and < 5,000 nM; B = IC₅₀ >500 and <1,000 nM and C = IC₅₀ <500 nM. 00049] Table 1

Table 2

153 B

154 c

155 B

156 A

157 c

158 c

159 A

160 B

CI

161 C

F

162 C

165 A

166 B

167 C

Example 9

Radioligand Binding Assay Using Membrane Preparations Expressing Rat mGluR5 [00051] The radiolabeled allosteric antagonist [³H]-2-Methyl-6-

(phenylethynyl)pyridine (MPEP, American Radiolabeled Chemical) was used to evaluate the ability of test compounds to interact with the MPEP site on mGluR5 as described in Rodriguez et al. [Mol Pharmacol 78: 1105-1123, 2010]. Membranes were prepared from HEK293 cells expressing rat mGluR5. Radioligand binding assays were performed in 96-well plates (Corning) containing binding buffer (15mM Tris pH 7.4,

120mM NaCl, lOOmM KCl, 25mM MgCl₂, 25 mM CaCl₂) with a final assay volume of 250 and 40μg membranes/well. [00052] Saturation isotherms were determined by incubation in presence of 12 increasing concentrations of [³H]-MPEP (0.1-100 nM), while competition experiments were performed with a fixed concentration (4nM) of [³H]-MPEP in presence of 12 increasing concentrations of test compound (1-30,000 nM). Incubations were performed at 4°C for lh. Nonspecific binding was estimated using 100 μΜ MTEP. At the end of incubation, membranes were filtered over GF/C filter plates (Perkin Elmer) presoaked in 0.1% BSA for 2h at room temperature. Filter plates were then washed 5 times with ice cold buffer (15mM Tris, pH 7.4 plus 0.1% BSA) using the Packard Filtermate Harvester and dried overnight in a 37°C oven. Fifty μΕ microscint 20 (PerkinElmer) were added to each well and the plates were incubated on an orbital shaker for 15 min before counting on a Microbeta Trilux for 2 min/well.

[00053] It is to be understood that the invention is not limited to the particular embodiments of the invention described above, as variations of the particular embodiments may be made and still fall within the scope of the appended claims.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof,

wherein:

X is -F, -CI, -CN, CF₃, -OH, or -0-CH₃;

Ri is a 5- to 10-membered mono- or bicyclic heteroaryl ring that contains 1-3

selected from N, O, and S;

a is 0 or 1.

2. The compound according to claim 1 , of structure la, wherein:

(la),

or a pharmaceutically acceptable salt thereof,

wherein:

X is -F, -CI, -CN, CF₃, -OH, or -0-CH₃;

Ri is a 5- to 10-membered mono- or bicyclic heteroaryl ring that contains 1-3

heteroatoms selected from the group consisting of N, O and S, wherein the 5- to 10-membered ring system is optionally substituted with 1-3 substituents independently selected from alkyl, -F, -CI, -Br, -OH, -CN, nitro, alkoxy, -CF₃, - 0-CF₃, -S(CH₃), -O-alkyl, -S-alkyl, -S(0)-alkyl, -S(0₂)-alkyl, -S(0₂)-aryl ,- CH₂-aryl, heteroaryl, alkanoyl, -O-aryl, -0-CH₂-aryl, -N(CH₃)₂, cycloalkyl, heterocycloalkyl, -C(0)cycloalkyl, -C(0)heterocycloalkyl, wherein the substituents may combine to form an optionally substituted 5-7 membered fused carbacyclic or heterocyclic ring, or a 5- to 10-membered mono- or bicyclic aryl ring, wherein the 5- to 10- membered aryl ring is optionally substituted with 1-3 substituents independently selected from alkyl, -F, -CI, -Br, -OH, -CN, nitro, alkoxy, -CF₃, -OCF₃, -S(CH₃),

-O-alkyl, -S-alkyl, -S(0)-alkyl, -S(0₂)-alkyl, S(0₂)aryl, -CH₂-aryl, heteroaryl, alkanoyl, -O-aryl, -0-CH₂-aryl, -N(CH₃)₂, cycloalkyl, heterocycloalkyl, - C(0)cycloalkyl, -C(0)-heterocycloalkyl, wherein the substituents may combine to form a 5-7 membered fused and optional substituted carbacyclic or

heterocyclic ring;

R₃ is -H, or optionally substituted alkyl, that optionally incorporates a heteroatom selected from N, O, and S.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein:

X is -F, -CI, -OH, or -0-CH₃;

Ri is a substituted or unsubstituted ring selected from the following list:

R4 where present is -H or lower alkyl

R₂ is a 5- to 10-membered mono- or bicyclic heteroaryl ring that contains 0-3

selected from N, O, and S.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein: Ri is 2-pyridinyl or substituted 2-pyridinyl; X is F, -OH, or -0-CH₃; R₂ is optionally mono- or disubstituted mono- or bicyclic aryl, or optionally mono- or disubstituted mono- or bicyclic hereroaryl

R₃ is H.

5. The compound according to claim 1, of formula lb,

(lb),

or a pharmaceutically acceptable salt thereof,

wherein:

X is -F, -CI, -OH, or -0-CH₃; Ri is an unsubstituted or substituted ring selected from the following list:

R4 where present is -H or lower alkyl

R₂ is a 5- to 10-membered mono- or bicyclic heteroaryl ring that contains 0-3

heteroatoms independently selected from the group consisting of N, O and S, wherein the 5- to 10-membered ring system is optionally substituted with 1-3 substituents independently selected from alkyl, -F, -CI, -Br, -OH, -CN, nitro, alkoxy, -CF₃, -OCF₃, -S(CH₃), -OCH₃, -S-alkyl, -S(0)-alkyl, -S(0₂)-alkyl, S(0₂)aryl, -CH₂-aryl, heteroaryl, alkanoyl, -O-aryl, -0-CH₂-aryl, -N(CH₃)₂, cycloalkyl, heterocycloalkyl, -C(0)cycloalkyl, -C(0)-heterocycloalkyl, or substituted lower alkyl, wherein the substituents may combine to form an optionally substituted 5-7 membered fused carbacyclic or heterocyclic ring, or; a 5- to 10-membered mono- or bicyclic aryl ring, wherein the 5- to 10- membered ring system is optionally substituted with 1-3 substituents

heterocycloalkyl, -C(0)cycloalkyl, -C(0)-heterocycloalkyl, or substituted lower alkyl, wherein the substituents may combine to form an optionally substituted 5- 7 membered fused carbacyclic or heterocyclic ring; R₃ is -H.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein: Ri is 2-pyridinyl or substituted 2-pyridinyl; X is F, -OH, or -0-CH₃; R₂ is optionally mono- or disubstituted mono- or bicyclic aryl, or optionally mono- or disubstituted mono- or bicyclic hereroaryl.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein Ri is 2-pyridinyl or substituted 2-pyridinyl.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is:

2-((3 -fluoro- 1 -phenylpyrrolidin-3 -yl)ethynyl)pyridine,

2- (( 1 -(3 -chlorophenyl)-3 -fluoropyrrolidin-3 -yl)ethynyl)pyridine,

3- fluoro-5-(3-fluoro-3-(pyridin-2-ylethynyl)pyrrolidin-l-yl)benzonitrile,

2-((l -(3, 4-difluorophenyl)-3 -fluoropyrrolidin-3 -yl)ethynyl)pyridine,

2-((l-(4-chlorophenyl)-3-fluoropyrrolidin-3-yl)ethynyl)pyridine,

2-((3 -fluoro- 1 -(naphthalen- 1 -yl)pyrrolidin-3 -yl)ethynyl)pyridine,

2-((3 -fluoro- 1 -(naphthalen-2-yl)pyrrolidin-3 -yl)ethynyl)pyridine,

2-((3 -fluoro- 1 -(pyridin-3 -yl)pyrrolidin-3 -yl)ethynyl)pyridine,

6-(3-fluoro-3-(pyridin-2-ylethynyl)pyrrolidin-l-yl)quinolone,

2-((3 -fluoro- 1 -(pyridin-2-yl)pyrrolidin-3 -yl)ethynyl)pyridine,

2-((l-(3,4-dichlorophenyl)-3-fluoropyrrolidin-3-yl)ethynyl)pyridine,

2-((l-(3,5-dichlorophenyl)-3-fluoropyrrolidin-3-yl)ethynyl)pyridine,

2- (( 1 -(3 ,5 -difluorophenyl)-3 -fluoropyrrolidin-3 -yl)ethynyl)pyridine,

3 -fluoro-5 -(3 -fluoro-3-(pyridin-2-ylethynyl)pyrrolidin- 1 -yl)pyridine,

3- (3-fluoro-3-(pyridin-2-ylethynyl)pyrrolidin-l-yl)benzonitrile,

2-((3 -fluoro- 1 -(3 -fluorophenyl)pyrrolidin-3 -yl)ethynyl)pyridine,

2-((3 -fluoro- 1 -(3 -methoxyphenyl)pyrrolidin-3 -yl)ethynyl)pyridine, 2-((3 -fluoro- 1 -(3 -fluoro-5 -nitrophenyl)pyrrolidin-3 -yl)ethynyl)pyridine, 2-((3 -fluoro- 1 -(3 -(trifluoromethyl)phenyl)pyrrolidin-3 -yl)ethynyl)pyridine, 2-((l-(2-chlorophenyl)-3-fluoropyrrolidin-3-yl)ethynyl)pyridine,

2-((3 -fluoro- 1 -(m -to lyl)pyrrolidin-3 -yl)ethynyl)pyridine,

2-((3 -fluoro- 1 -(3 -nitrophenyl)pyrrolidin-3 -yl)ethynyl)pyridine,

3 -(3 -fluoro-3 -(pyridin-2-ylethynyl)pyrrolidin- 1 -yl)aniline,

2-((l-(3-benzylphenyl)-3-fluoropyrrolidin-3-yl)ethynyl)pyridine,

2-((l -([ 1 , 1 '-biphenyl]-3-yl)-3-fluoropyrrolidin-3-yl)ethynyl)pyridine,

2-fluoro-4-(3-fluoro-3-(pyridin-2-ylethynyl)pyrrolidin-l-yl)benzonitrile, 2-((3 -fluoro- 1 -(4-fluorophenyl)pyrrolidin-3 -yl)ethynyl)pyridine,

4-fluoro-2-(3-fluoro-3-(pyridin-2-ylethynyl)pyrrolidin-l-yl)benzonitrile, 2-((3 -fluoro- 1 -(2-fluorophenyl)pyrrolidin-3 -yl)ethynyl)pyridine,

2-((l -([ 1 , 1 '-biphenyl]-4-yl)-3-fluoropyrrolidin-3-yl)ethynyl)pyridine,

3 -(3 -fluoro-3 -(pyridin-2-ylethynyl)pyrrolidin- 1 -yl)-5 -methoxypyridine,

2-((l -(2,6-difluorophenyl)-3-fluoropyrrolidin-3-yl)ethynyl)pyridine,

2-((l-(2-chloro-4-fluorophenyl)-3-fluoropyrrolidin-3-yl)ethynyl)pyridine,

2- fluoro-6-(3-fluoro-3-(pyridin-2-ylethynyl)pyrrolidin-l-yl)benzonitrile,

3 - chloro-5 -(3 -fluoro-3 -(pyridin-2-ylethynyl)pyrrolidin- 1 -yl)pyridine,

2-(( 1 -(2,5 -difluorophenyl)-3 -fluoropyrrolidin-3 -yl)ethynyl)pyridine,

2-((3-fluoro-l-(3-isopropylphenyl)pyrrolidin-3-yl)ethynyl)pyridine,

2-(( 1 -(3 -(teri-butyl)phenyl)-3 -fluoropyrrolidin-3 -yl)ethynyl)pyridine,

2- ((3-fluoro-l-(3-isopropoxyphenyl)pyrrolidin-3-yl)ethynyl)pyridine,

3- fluoro-4-(3-fluoro-3-(pyridin-2-ylethynyl)pyrrolidin-l-yl)pyridine,

2-((l-(3-chloro-2-fluorophenyl)-3-fluoropyrrolidin-3-yl)ethynyl)pyridine, 2-((3-fluoro-l-(3-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)ethynyl)pyridine.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is:

tert-bu yl 3-fluoro-3-(pyridin-2-ylethynyl)pyrrolidine-l-carboxylate,

benzyl 3 -fluoro-3 -(pyridin-2-ylethynyl)pyrrolidine- 1 -carboxylate,

3 -(3 -fluoro-3 -(pyridin-2-ylethynyl)pyrrolidin- 1 -yl)benzamide,

3 -(3 -fluoro-3 -(pyridin-2-ylethynyl)pyrrolidin- 1 -yl)benzenesulfonamide, methyl 3 -(3 -fluoro-3 -(pyridin-2-ylethynyl)pyrrolidin- 1 -yl)benzoate,

3 -(3 -fluoro-3 -(pyridin-2-ylethynyl)pyrrolidin- 1 -yl)-N,N-dimethylbenzamide, 3 -(3 -fluoro-3 -(pyridin-2-ylethynyl)pyrrolidin- 1 -yl)-N-methylbenzamide.

ethyl 3-fluoro-3-(pyridin-2-ylethynyl)pyrrolidine- 1 -carboxylate,

butyl 3 -fluoro-3 -(pyridin-2-ylethynyl)pyrrolidine- 1 -carboxylate,

3 -(3 -fluoro-3 -(pyridin-2-ylethynyl)pyrrolidin- 1 -yl)-N-phenylbenzamide, phenyl 3-(3-fluoro-3-(pyridin-2-ylethynyl)pyrrolidin-l-yl)benzoate.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is:

2-((3 -fluoro- 1 -tosylpyrrolidin-3 -yl)ethynyl)pyridine,

2-((3 -fluoro- l-(phenylsulfonyl)pyrrolidin-3-yl)ethynyl)pyridine,

2-((l-((3-chlorophenyl)sulfonyl)-3-fluoropyrrolidin-3-yl)ethynyl)pyridine.

1 1. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, in which said compound is:

1 -(3 -fluoro-3 -(pyridin-2-ylethynyl)pyrrolidin- 1 -yl)-2-methylpropan- 1 -one,

1 -(3-fluoro-3-(pyridin-2-ylethynyl)pyrrolidin- 1 -yl)-2,2-dimethylpropan- 1 -one,

1 -(3 -fluoro-3 -(pyridin-2-ylethynyl)pyrrolidin- 1 -yl)pentan- 1 -one,

1 -(3 -fluoro-3 -(pyridin-2-ylethynyl)pyrrolidin- 1 -yl)-4-methylpentan- 1 -one,

1- (3-fluoro-3-(pyridin-2-ylethynyl)pyrrolidin-l-yl)-2-phenylethanone,

2-((3-fluoro-l-phenethylpyrrolidin-3-yl)ethynyl)pyridine,

2- ((l-benzyl-3-fluoropyrrolidin-3-yl)ethynyl)pyridine.

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, in which said compound is:

2-((3 -fluoro- 1 -phenylazetidin-3 -yl)ethynyl)pyridine,

2- ((l-(4-chlorophenyl)-3-fluoroazetidin-3-yl)ethynyl)pyridine.

3- (3-fluoro-3-(pyridin-2-ylethynyl)azetidin- 1 -yl)benzonitrile,

2-((3 -fluoro- 1 -(3 -fluorophenyl)azetidin-3 -yl)ethynyl)pyridine,

2-((l-(3-chlorophenyl)-3-fluoroazetidin-3-yl)ethynyl)pyridine,

2-((l-(2-chlorophenyl)-3-fluoroazetidin-3-yl)ethynyl)pyridine,

2- ((3-fluoro-l-(3-nitrophenyl)azetidin-3-yl)ethynyl)pyridine,

3 - fluoro-5 -(3 -fluoro-3-(pyridin-2-ylethynyl)azetidin- 1 -yl)benzonitrile,

2-((3 -fluoro- 1 -(3 -(trifluoromethoxy)phenyl)azetidin-3 -yl)ethynyl)pyridine, 2-((3 -fluoro- 1 -(3 -(trifluoromethyl)phenyl)azetidin-3 -yl)ethynyl)pyridine, 2-((3 -fluoro- 1 -(m-tolyl)azetidin-3 -yl)ethynyl)pyridine,

2-((3 -fluoro- 1 -(3 -methoxyphenyl)azetidin-3 -yl)ethynyl)pyridine,

2-(( 1 -(3 ,5 -dichlorophenyl)-3 -fluoroazetidin-3 -yl)ethynyl)pyridine,

2-((l-(3,4-dichlorophenyl)-3-fluoroazetidin-3-yl)ethynyl)pyridine,

2-((3-fluoro-l-(3-fluoro-5-nitrophenyl)azetidin-3-yl)ethynyl)pyridine,

2-(( 1 -(3 -chlorophenyl)-3 -fluoroazetidin-3 -yl)ethynyl)-5 -methylpyridine,

2- (( 1 -(3 -chlorophenyl)-3 -fluoroazetidin-3 -yl)ethynyl)-4-methylpyridine,

3 - (benzofuran-2-ylethynyl)- 1 -(3 -chlorophenyl)-3 -fluoroazetidine .

13. A compound of claim 1 in the free base or pharmaceutically acceptable salt form, for use as a pharmaceutical.

14. A compound of claim 1 in free base or pharmaceutically acceptable salt form, for use in the prevention, treatment or delay of progression of disorders associated with irregularities of glutamatergic signal transmission in the digestive tract, urinary tract or central nervous system mediated in full or in part by mGluR5 receptors.

15. A pharmaceutical composition, comprising a compound of claim 1 in free base or pharmaceutically acceptable salt form, in association with a pharmaceutical carrier or diluent.

16. A method of treating disorders associated with irregularities of the glutamatergic signal transmission, and the nervous system disorders mediated full or in part by mGluR5 receptors, which method comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim 1 in free base or pharmaceutically acceptable salt form.