BENZENE FUSED HETEROCYCLIC COMPOUND AND USE THEREOF

The present disclosure provides a benzene fused heterocyclic compound of Formula (I): wherein (A) is a single or double bond; n is 0 or 1; X is —CH2—, O, NR1, or S; A is —C(Ra1)(Ra2)(Ra3) or —N(Ra1)(Ra2), wherein Ra1, Ra2 and Ra3 are independently selected from a group consisting of: H, alkyl, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, C1-C3 hydrocarbon, —RaaORbb, —C(O)ORaaRbb, —C(O)RaaRbb, —C(O)NRaaRbb, —SO2 RaaRbb and —SO2 NRaaRbb which are optionally substituted by at least one substituent independently selected from a group consisting of: alkyl, cycloalkyl, heterocyclic alkyl, aryl, —Ybb, —ArbbYbb, —ORcc, and —OArbbYbb, wherein Raa, Rbb and Rcc independently are nil, H, halogen, alkyl, or aryl, Ybb is CN or halogen, and Araa and Arbb independently are aryl or heteroaryl; R1 is H or alkyl; R2 is alkyl, cycloalkyl, heterocylic alkyl, aryl, heteroaryl, C1-C6 hydrocarbon optionally substituted by at least one substituent independently selected from a group consisting of: —R2aOR2b, —R2aC(O)OR2bR2c, —R2aC(O)R2bR2c, —R2aC(O)NR2bR2c, —R2aNR2bC(O)NR2cR2d, —R2aNR2bC(O)R2cR2d, —R2aNR2bC(O)OR2cR2d, —R2aSO2R2bR2c, —R2aNR2bSO2NR2cR2d and —R2aSO2NR2bR2c, optionally substituted by at least one substituent independently selected from a group consisting of alkyl, cycloalkyl, heterocyclic alkyl, heteroaryl, and aryl, wherein R2a, R2b, R2c and R2d are independently selected from nil, H, halogen, alkyl, cycloalkyl, heterocyclic alkyl, heteroaryl, aryl or C1-C6 hydrocarbons, optionally substituted by at least one substituent independently selected from a group consisting of —OR2e, ═O, ═S, —SO2R2e, —SO2NR2eR2f, —NR2gSO2NR2eR2f, —NR2gC(O)NR2eR2f, —C(O)NHR2e, —NHC(O)R2e, —NHC(O)OR2e, —NO2, —CO2R2e and —C(O)R2e, wherein R2e, R2f, and R2g independently are H or alkyl.

TECHNICAL FIELD

The technical field relates to benzene fused heterocyclic compounds and their uses, and in particular to the pharmaceutical compositions comprising the same and their use as autotaxin inhibitors.

BACKGROUND

Autotaxin (ATX) is a secreted enzyme of about 120 kDa in humans and is encoded by the ENPP2 gene. Autotaxin is also known as ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (NPP2 or ENPP2) or lysophospholipase D.

Lysophosphatidic acid (LPA) activates at least six G-protein coupled receptors, which promote cell proliferation, survival, migration and muscle contraction while autotaxin has lysophospholipase D activity that converts lysophosphatidylcholine into lysophosphatidic acid. Autotaxin is important in generating the lipid signaling molecule LPA.

Non-alcoholic fatty liver disease (NAFLD) is the buildup of extra fat in liver cells that is not caused by alcohol. Non-alcoholic steatohepatitis (NASH) is the most extreme form of NAFLD. Moreover, NASH is regarded as a major cause of cirrhosis of the liver of unknown cause, and ATX-LPA signaling has been implicated in hepatic fibrogenesis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, relentlessly progressive fibrotic disorder of the lungs occurring mainly in older adults. It is reported that in both murine and human fibrotic lungs, increased concentrations of ATX can be detected.

Autotaxin and LPA are also involved in numerous inflammatory-driven diseases such as asthma and arthritis. In addition, Autotaxin and LPA have been shown to be involved in many cancers.

Accordingly, development of autotaxin inhibitors for treating diseases such as cancer, NAFLD, IPF, etc. is needed.

SUMMARY

According to some embodiments, the present disclosure provides a benzene fused heterocyclic compound of Formula (I), or a pharmaceutical acceptable salt, solvate, hydrate, geometric isomer, enantiomer, diastereoisomer or racemate thereof:

According to other embodiments, the present disclosure also provides a pharmaceutical composition, comprising: a therapeutically effective amount of the benzene fused heterocyclic compound of the present disclosure; and a pharmaceutically acceptable carrier.

According to still other embodiments, the present disclosure further provides a method for inhibiting the activity of autotaxin in environment, comprising: contacting the environment an effective amount of the benzene fused heterocyclic compound of the present disclosure or the pharmaceutical composition of the present disclosure.

A detailed description is given in the following embodiments.

DETAILED DESCRIPTION

Novel Compounds

The present disclosure provides a benzene fused heterocyclic compound of Formula (I), or a pharmaceutical acceptable salt, solvate, hydrate, enantiomer, or diastereoisomer thereof:

In some embodiments of the present disclosure, the benzene fused heterocyclic compound of Formula (I) can be Formula (II), or a pharmaceutical acceptable salt, solvate, hydrate, enantiomer, or diastereoisomer thereof:

wherein - - - is a single or double bond;

n is 0 or 1;

Y1is —C(Ra1)(Ra2)— or —N(Ra1)—, wherein Ra1and Ra2are independently selected from a group consisting of:

Y3is nil, H, CN, halogen, alkyl, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl or C1-C3hydrocarbon, optionally substituted by at least one substituent independently selected from a group consisting of H, alkyl, and halogen;

Y4is nil, H, halogen, aryl or heteroaryl, optionally substituted by at least one substituent independently selected from a group consisting of H, alkyl, and halogen;

R1is H or alkyl;

Z is C or N;

wherein R3e, R3f, and R3gindependently are H or alkyl.

Definitions of Terms

“Heterocyclic alkyl” refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, phosphorus, and silicon (“3-10 membered heterocyclic alkyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Unless otherwise specified, each instance of heterocyclic alkyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclic alkyl”) or substituted (a “substituted heterocyclic alkyl”) with one or more substituents. In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a heterocyclic alkyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic alkyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.

Unless otherwise indicated, the term “aryl” means an aromatic ring or a partially aromatic ring system composed of carbon and hydrogen atoms. An aryl moiety may comprise multiple rings bound or fused together. Examples of aryl moieties include naphthyl, and phenyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is a substituted phenyl.

Unless otherwise indicated, the term “heteroaryl” means an aryl moiety wherein at least one of its carbon atoms has been replaced with a heteroatom (e.g., N, O or S). In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl. Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.

Unless otherwise indicated, the term “alkoxy” or “alkoxyl” means an —O— alkyl group. Examples of alkoxy groups include, but are not limited to, —OCH3, —OCH2CH3, —O(CH2)2CH3, —O(CH2)3CH3, —O(CH2)4CH3, and —O(CH2)5CH3. The term “lower alkoxy” refers to —O-(lower alkyl), such as —OCH3and —OCH2CH3.

The term “amino” refers to a moiety of the formula: —N(R)2, wherein each instance of R is independently a substituent described herein, or two instances of R are connected to form substituted or unsubstituted heterocyclyl. In certain embodiments, the amino is unsubstituted amino (i.e., —NH2). In certain embodiments, the amino is a substituted amino group, wherein at least one instance of R is not hydrogen.

Unless otherwise indicated, the term “substituted,” when used to describe a chemical structure or moiety, refers to a derivative of that structure or moiety wherein one or more of its hydrogen atoms is substituted with an atom, chemical moiety or functional group such as, but not limited to, —OH, —CHO, alkoxy, alkanoyloxy (e.g., —OAc), alkenyl, alkyl (e.g., methyl, ethyl, propyl, t-butyl), aryl, aryloxy, halo, or haloalkyl (e.g., —CCl3, —CF3, —C(CF3)3).

Unless otherwise indicated, one or more adjectives immediately preceding a series of nouns is to be construed as applying to each of the nouns. For example, the phrase “optionally substituted alky, cycloalkyl, heterocyclic alkyl, aryl, or heteroaryl” has the same meaning as “optionally substituted alky, optionally substituted cycloalkyl, optionally substituted heterocyclic alkyl, optionally substituted aryl, or optionally substituted heteroaryl.”

Unless otherwise indicated, “an effective amount” of a compound is an amount sufficient to provide a therapeutic or positive benefit in the treatment or management of a disease, environment or condition, or to delay or minimize one or more symptoms associated with the disease, environment or condition. An effective amount of a compound is an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment or management of the disease, environment or condition. The term “effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease, environment or condition, or enhances the therapeutic efficacy of another therapeutic agent.

The term “pharmaceutically acceptable carrier” refers to a carrier, whether diluent or excipient, that is compatible with the other ingredients of a formulation and not deleterious to the recipient thereof. A usable pharmaceutically acceptable carrier are disclosed in various references including Handbook of Pharmaceuticals Excipients edited by Raymond C Rowe, Paul J Sheskey, and Marian E Quinn. In a unlimited embodiment, said pharmaceutically acceptable carrier can be selected from the group consisting of inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Said compositions optionally further comprise at least one of additional biologically active compounds or agents.

“Geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cylcobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

Pharmaceutical Formulation

In some embodiments, the benzene fused heterocyclic compounds of the present disclosure are useful as the pharmaceutical active agents. More preferably, the compounds of the present disclosure are formulated into pharmaceutical formulations for administration. In some embodiments, the compounds of the present disclosure may be formulated for administering to an environment (such as a cell). In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula (I) or Formula (II) of the present disclosure.

In some embodiments, the compound of Formula (I) is present at a level of about 0.1% to 99% by weight, based on the total weight of the pharmaceutical composition. In some embodiments, the compound of Formula (I) is present at a level of at least 1% by weight, based on the total weight of the pharmaceutical composition. In certain embodiments, the compound of Formula (I) is present at a level of at least 5% by weight, based on the total weight of the pharmaceutical composition. In still other embodiments, the compound of Formula (I) is present at a level of at least 10% by weight, based on the total weight of the pharmaceutical composition. In still yet other embodiments, the compound of Formula (I) is present at a level of at least 25% by weight, based on the total weight of the pharmaceutical composition.

In general, the pharmaceutical composition of the present disclosure are prepared by uniformly and intimately admixing the compounds of the present disclosure with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture. In some embodiments, the pharmaceutically acceptable carrier is selected from the group consisting of inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and oils.

In some embodiments, the present disclosure provides the pharmaceutical compositions comprising the compounds of Formula (I) or Formula (II) described herein, or pharmaceutically acceptable salts thereof, in pharmaceutically acceptable carriers for any suitable route of administration, including but not limited to, oral, intravenous, intramuscular, cutaneous, subcutaneous, intrathecal, intradermal, transdermal, implantation, sublingual, buccal, rectal, vaginal, ocular, otic, nasal, inhalation, topical, buccal, parenteral and nebulization administration.

Synthesis of Novel Compounds

The benzene fused heterocyclic compounds in the present disclosure can be prepared by any of the methods known in the art. For example, the following schemes illustrate the typical synthetic routes for preparing the benzene fused heterocyclic compounds in the present disclosure.

EXAMPLES

For the preparation of Compounds 8-9, please refer to Scheme 1 and the following details:

6-bromoindanole (4.3 g/20.3 mmole) (Compound 1) and methylamine (20 mL, 9.8 M in MeOH), in methanol (50 mL) were charged into a round bottom flask and stirred for about 3.5 hours at room temperature to form a solution. Sodium borohydride (1.2 g) was slowly added to the solution at room temperature to form a mixture, and then the mixture is stirred and maintained for completion of the reaction overnight. After that, the solvent and excess methylamine in the mixture was removed under vacuum to produce a residue. Ice-water was added to the residue and then a brown black solid was found, filtered, collected and washed by NaHCO3(aq). Next, the solid was dried under vacuum to afford a product (4.04 g, 87% yield). The product was Compound 2 (6-bromo-N-methyl-2,3-dihydro-1H-inden-1-amine). The product was used in the next step without further purification.

TEA (1.88 mL, 2.0 eq.) and 4-nitrophenyl chloroformate (2.1 g, 1.5 eq.) were added to a mixture of Compound 2 (6-bromo-N-methyl-2,3-dihydro-1H-inden-1-amine) (1.526 g, 6.7487 mmol) and dry CH2Cl2(10.0 mL) at 0° C. The resulting reaction mixture was stirred at room temperature overnight and the completion of reaction was confirmed by TLC. The resulting crude product was purified by column chromatography (EtOAc/Hexanes=1/4) to give a yellow oil. The yellow oil was Compound 3 (4-nitrophenyl (6-bromo-2,3-dihydro-1H-inden-1-yl)(methyl) carbamate) (817 mg, 31%).

3,5-dichlorobenzyl alcohol (2929.3 mg, 2.0 eq.) and sodium tert-butoxide (1558.3 mg, 2.0 eq.) was added to a mixture of Compound 3 (4-nitrophenyl (6-bromo-2,3-dihydro-1H-inden-1-yl)(methyl) carbamate) (3.172 g, 8.1079 mmol) and dry THF (20.0 mL) at 0° C. The resulting mixture was stirred at room temperature overnight. When the reaction was completed (note: the color of the mixture solution converted from yellow to orange), the resulting mixture was acidified with 2 N HCl(aq.)(note: the color of the mixture solution converted from orange to white) and extracted with EtOAc. The organic phase was dried with Na2SO4and concentrated under reduced pressure to give a crude mixture. The crude mixture was purified by column chromatography (EtOAc/Hexanes=1/5) to give yellow oil. The yellow oil was Compound 4 (3,5-dichlorobenzyl (6-bromo-2,3-dihydro-1H-inden-1-yl)(methyl)carbamate) (3.117 g, 89.6%).

Na2CO3(274 mg, 3.0 eq.), Pd(dppf)Cl2(31.5 mg, 0.05 eq.) and N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (533 mg, 2.0 eq.) were added to a mixture of Compound 4 (3,5-dichlorobenzyl (6-bromo-2,3-dihydro-1H-inden-1-yl)(methyl) carbamate) (370 mg, 0.8622 mmol) and dry DMF (6.0 mL) at room temperature to form a reaction mixture. The reaction mixture was degassed and stirred under Ar(g)for 15 minutes at room temperature. After that, the reaction mixture was stirred at 100° C. overnight. TLC was used to confirm the completion of reaction. After that, water was added to the reaction mixture and then the reaction mixture was extracted with EtOAc to obtain an organic phase. The organic phase was dried with Na2SO4and concentrated under reduced pressure to give a crude mixture. The crude mixture was purified by column chromatography (EtOAc/Hexanes=1/8 to EtOAc/Hexanes=1/4) to give a green product. The green product was Compound 5, tert-butyl 4-(3-((((3,5-dichlorobenzyl)oxy)carbonyl)(methyl)amino)-2,3-dihydro-1H-inden-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (280 mg, 61%).

4 N HCl (in 1,4-dioxane, 2.5 mL) was added to a mixture of Compound 5 (tert-butyl 4-(3-((((3,5-dichlorobenzyl)oxy)carbonyl)(methyl)amino)-2,3-dihydro-1H-inden-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate) (280 mg, 0.5268 mmol) and dry CH2Cl2(6.0 mL) at 0° C. to form a reaction mixture. The reaction mixture was stirred at room temperature overnight. TLC was used to confirm the completion of reaction. Saturated NaHCO3was added to the reaction mixture and then the reaction mixture was extracted with CH2Cl2to obtain an organic phase. The organic phase was dried with Na2SO4and concentrated under reduced pressure to give a brown product. The brown product was Compound 6, 3,5-dichlorobenzyl methyl(6-(1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydro-1H-inden-1-yl)carbamate (165 mg, 73%).

Hydroxyazetidine hydrochloride (4.8 g, 43.8 mmol, 1 eq.) was added to a suspension of potassium carbonate (13.3 g, 96 mmol, 2.2 eq.) in water (32 mL) to form a reaction mixture. The reaction mixture is stirred at room temperature until complete dissolution, and then diluted with 35 mL of DCM and cooled to 0° C. prior to the dropwise introduction of chloroacetyl chloride (4.2 mL, 1.2 eq.) over 30 minutes. After 2 hours of stirring at room temperature, the reaction mixture is filtered, the organic layer is separated and saved, and the aqueous phase is extracted with a mixture of EtOAc and nBuOH (1:1) (6×16 mL), and the organic layer is obtained. The two organic layers were combined. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was suspended in acetone (48 mL) and stirred vigorously for 20 minutes and then was filtered. The filtrate was concentrated in vacuo to afford Compound 7, 2-chloro-1-(3-hydroxyazetidin-1-yl)ethan-1-one (4.2 g, 64%).

K2CO3(106 mg, 2.0 eq.) and Compound 7 (2-chloro-1-(3-hydroxyazetidin-1-yl)ethan-1-one) (74 mg, 1.3 eq.) were added to a mixture of Compound 6 (3,5-dichlorobenzyl methyl(6-(1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydro-1H-inden-1-yl)carbamate) (165 mg, 0.3825 mmol) and dry MeCN (2.5 mL) at room temperature to form a reaction mixture. The reaction mixture was stirred at 80° C. for 5 hours and allowed to cool to room temperature. After that, the reaction mixture was stirred at room temperature overnight. TLC was used to confirm the completion of reaction. The solvent in the reaction mixture was removed, and then water was added to the reaction mixture. After that, the reaction mixture was extracted with EtOAc. The resulting organic phase was dried with Na2SO4and concentrated under reduced pressure to give a crude mixture. The crude mixture was purified by column chromatography (MeOH/EtOAc=1/15 to MeOH/EtOAc=1/10) to give a white product. The white product was Compound 8, 3,5-dichlorobenzyl(6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydro-1H-inden-1-yl)(methyl)carbamate (49 mg, 23.5%).

HOBt (35.5 mg, 0.5 eq.), EDC (133 mg, 1.5 eq.), NMM (0.1 mL, 2.0 eq.), and 4-oxo-2-thioxo-3-thiazolidinylacetic acid (133 mg, 1.5 eq.) were added to a mixture of Compound 6 (3,5-dichlorobenzyl methyl(6-(1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydro-1H-inden-1-yl)carbamate) (200 mg, 0.4637 mmol) and dry CH2Cl2(6.0 mL). The reaction mixture was stirred at room temperature overnight. TLC was used to confirm the completion of reaction. After that, water was added to the mixture and the mixture was extracted with CH2Cl2. The resulting organic phase was dried with Na2SO4and concentrated under reduced pressure to give a crude mixture. The crude mixture was purified by column chromatography (EtOAc/Hexanes=1/1 to EtOAc/Hexanes=2/1) to give an orange product. The orange product was Compound 9, 3,5-dichlorobenzyl methyl(6-(1-(2-(4-oxo-2-thioxothiazolidin-3-yl)acetyl)-1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydro-1H-inden-1-yl)carbamate (190 mg, 68%).

Spectral Data of Compound 8 and 9

Compounds 10-17 and 19-21 were produced by using the same methods of Schemes 1.1 to 1.7. Compounds 18, 22, 24-30 were produced by using the same methods of Schemes 1.1 to 1.6 and Scheme 1.8. Compound 23 was produced by using the same methods for Compound 10 by replacing chloroacetyl chloride with oxalyl chloride.

Spectral Data of Compounds 10-30

For the preparation of Compounds 33 and 34, please refer to Scheme 2 and the following details:

DIPEA (2.06 g, 15.93 mmol) and triphosgene (1.89 g, 6.37 mmol) were added to a solution of 3,5-dichlorobenzyl alcohol (2.82 g, 15.93 mmol) in DCM (100 mL) at 0° C. The reaction mixture was stirred at the same temperature for 30 minutes. After the 3,5-dichlorobenzyl alcohol was consumed, a solution of Compound 2 (6-bromo-N-methyl-2,3-dihydro-1H-inden-1-amine) (3.00 g, 13.27 mmol) and DIPEA (2.06 g, 15.93 mmol) in DCM (30 mL) was added into the reaction mixture. Then the reaction mixture was slowly warmed to room temperature and stirred overnight. After the reaction was completed, the solvent in the reaction mixture was removed under reduced pressure. The residue was diluted with saturated NH4Cl and extracted with EtOAc, and then resulting organic layers were combined. The combined organic layers were dried over MgSO4and concentrated in vacuo to obtain a crude product. The crude product was used as Compound 4 in the next step without further purification, and the yield thereof was 5.06 g (11.79 mmol).

CsCO3(0.15 g, 0.45 mmol), Boc-piperazine (0.08 g, 0.45 mmol), 2-(di-t-butylphosphino)biphenyl (0.01 g, 0.03 mmol) and Pd(OAc)2(7.0 mg, 0.03 mmol) were added to a solution of Compound 4 (3,5-dichlorobenzyl (6-bromo-2,3-dihydro-1H-inden-1-yl)(methyl)carbamate) (0.13 g, 0.30 mmol) in toluene (5 mL). The mixture was degassed with argon for 15 minutes, and then heated to reflux overnight. After the reaction was completed, the solvent in the mixture was removed under reduced pressure, and then the residue was filtered through celite and washed with EtOAc. After concentration in vacuo, a resulting crude product was purified via flash column chromatography on a silica gel column using 4:1 hexane-EtOAc as the eluent to give Compound 31, tert-butyl 4-(3-((((3,5-dichlorobenzyl)oxy)carbonyl)(methyl)amino)-2,3-dihydro-1H-inden-5-yl)piperazine-1-carboxylate, and the yield thereof was 0.12 g (0.22 mmol).

The Compound 31 (tert-butyl 4-(3-((((3,5-dichlorobenzyl)oxy)carbonyl)(methyl)amino)-2,3-dihydro-1H-inden-5-yl)piperazine-1-carboxylate) (0.12 g, 0.22 mmol) was added to a solution of 4N HCl in dioxane (5 mL) to form a mixture, and then stirred for 3 hours. After the reaction was completed, the solvent in the mixture was removed under reduced pressure, and then a crude product was obtained. The crude product was used as Compound 32 (3,5-dichlorobenzyl methyl(6-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl)carbamate) (yield, 0.10 g) in the next step without further purification.

K2CO3(0.18 g, 1.3 mmol), 2-chloro-1-(3-hydroxyazetidin-1-yl)ethan-1-one (0.04, 0.28 mmol) and a catalytic amount of KI were added to a solution of Compound 32 (3,5-dichlorobenzyl methyl(6-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl)carbamate) (0.10 g) in CH3CN (5 mL), and then the reaction mixture was heated to reflux overnight. After reaction was completed, the solvent in the reaction mixture was removed under reduced pressure. The residue was diluted with water and extracted with EtOAc, and the resulting organic layers were combined. The combined organic layers were dried over MgSO4and concentrated in vacuo to obtain a crude product. The crude product was purified via flash column chromatography on a silica gel column using 10:1 DCM-MeOH as the eluent to give Compound 33, 3,5-dichlorobenzyl (6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl)(methyl)carbamate, and the yield thereof was 0.06 g (0.11 mmol).

NMM (0.159 g, 1.58 mmol) and EDCI (0.11 g, 0.59 mmol) were added to a mixture of Compound 32 (3,5-dichlorobenzyl methyl(6-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl)carbamate) (0.2 g, 0.39 mmol), morpholin-4-ylacetic acid (0.09 g, 0.59 mmol), HOBt (0.01 g, 0.08 mmol) in DCM (20 mL) at 0° C. After addition, the reaction mixture was slowly warmed to room temperature and stirred overnight. After the reaction was completed, the solvent in the reaction mixture was removed under reduced pressure. The residue was diluted with saturated NH4Cl and extracted with EtOAc, and the resulting organic layers were combined. The combined organic layers were dried over MgSO4and concentrated in vacuo. The crude product was purified via flash column chromatography on a silica gel column using 4:1 DCM-EtOAc as the eluent to give Compound 34, 3,5-dichlorobenzyl methyl(6-(4-(2-morpholinoacetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl)carbamate, and the yield thereof was 0.19 g (0.34 mmol).

Spectral data of Compounds 33 and 34

A solution of 7-bromo-1-tetralone (1.5 g, 6.66 mmol) in 30 mL of MeOH was treated with methyl amine (6.8 mL, 66.6 mmol). After 5 minutes, acetic acid (0.15 mL) was added followed by sodium cyanoborohydride (0.5 g, 8.0 mmol). The reaction mixture was stirred overnight at ambient temperature. MeOH and excess methyl amine in the reaction mixture were removed by vacuo. After that, water and saturated aqueous sodium carbonate solution were added to the reaction mixture followed by extraction with dichloromethane (×2). The organic layers were combined and dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to obtain oil. The oil was purified via flash column chromatography over silica gel using 50% ethyl acetate in hexane as the eluent to afford Compound 35, 7-bromo-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine (1.0 g, 62%, 4.17 mmol).

Compounds 36-37 were produced by using the same methods for Compound 34. Compound 38 was produced by using the same methods for Compound 33 by replacing Compound 2 with Compound 35 in the corresponding schemes.

Spectral Data of Compounds 36-38

For the preparation of Compounds 43 and 44, please refer to Scheme 4 and the following details:

4-fluorobenzoyl isothiocyanate (0.28 g, 1.54 mmol) was added to a solution of Compound 2 (6-bromo-N-methyl-2,3-dihydro-1H-inden-1-amine) (0.29 g, 1.28 mmol) in ACN (10 mL) and stirred for 3 hours at room temperature to form a mixture. After reaction was completed, the solvent in the mixture was removed under reduced pressure. The residual was diluted with cold water and sit to get a precipitated solid. The precipitated solid was collected by filtration and washed with ether to afford a crude product. The crude product was used as Compound 39, N-((6-bromo-2,3-dihydro-1H-inden-1-yl)(methyl)carbamothioyl)-4-fluorobenzamide (0.44 g, 1.07 mmol), in the next step without further purification.

1N NaOH (3 mL) was added to a mixture of Compound 39 (N-((6-bromo-2,3-dihydro-1H-inden-1-yl)(methyl)carbamothioyl)-4-fluorobenzamide) (0.44 g, 1.07 mmol) and sodium chloroacetate (0.25 g, 2.14 mmol) in MeCN (10 mL) to form a reaction mixture, and then the reaction mixture was heated to reflux for 6 hours. After the reaction was completed, the solvent in the reaction mixture was removed under reduced pressure. The residue was diluted with saturated NaHCO3and extracted with EtOAc and the resulting organic layers were combined. The combined organic layers were dried over MgSO4and concentrated in vacuo to obtain a crude product. The crude product was purified via flash column chromatography on a silica gel column using 10:1 Hexane-EtOAc as the eluent to give Compound 40, N-(6-bromo-2,3-dihydro-1H-inden-1-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine (0.29 g, 0.72 mmol).

CsCO3(0.35 g, 1.08 mmol), Boc-piperazine (0.20 g, 1.08 mmol), 2-(di-t-butylphosphino)biphenyl (0.02 g, 0.07 mmol) and Pd(OAc)2(0.02 g, 0.07 mmol) were added to a solution of Compound 40 (N-(6-bromo-2,3-dihydro-1H-inden-1-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine) (0.29 g, 0.72 mmol) in toluene (10 mL) to form a mixture. The mixture was degassed with argon for 15 minutes, and then heated to reflux overnight. After the reaction was completed, the solvent in the mixture was removed under reduced pressure, and then the residue was filtered through celite and washed with EtOAc to obtain a crude product. After concentration in vacuo, the crude product was purified via flash column chromatography on a silica gel column using 10:1 Hexane-EtOAc as the eluent to give Compound 41, tert-butyl 4-(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2,3-dihydro-1H-inden-5-yl)piperazine-1-carboxylate (0.30 g, 0.59 mmol).

Compound 41 (Tert-butyl 4-(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2,3-dihydro-1H-inden-5-yl)piperazine-1-carboxylate) (0.30 g, 0.59 mmol) was added to a solution of 4N HCl in dioxane (5 mL), and then stirred for 3 hours to form a mixture. After the reaction was completed, the solvent in the mixture was removed under reduced pressure to obtain a crude product. The crude product was used as Compound 42 in the next step without further purification.

K2CO3(0.49 g, 3.52 mmol), 2-chloro-1-(3-hydroxyazetidin-1-yl)ethan-1-one (0.09 g, 0.59 mmol) and a catalytic amount of KI were added to a solution of Compound 42 (4-(4-fluorophenyl)-N-methyl-N-(6-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl)thiazol-2-amine) (0.5 mmol) in DMF (5 mL), and then the reaction mixture was heated to 80° C. overnight to obtain a mixture. After the reaction was completed, the solvent in the mixture was evaporated off by air-drying. The residue was diluted with water and extracted with EtOAc, and the resulting organic layers were combined. The combined organic layers were dried over MgSO4and concentrated in vacuo to obtain a crude product. The crude product was purified via flash column chromatography on a silica gel column using 10:1 DCM-MeOH as the eluent to give Compound 43, 2-(4-(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2,3-dihydro-1H-inden-5-yl)piperazin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethan-1-one (0.23 g, 0.45 mmol).

Compound 44 was produced by using the same methods for Compound 43.

Spectral Data of Compounds 43 and 44

For the preparation of Compounds 50-54, please refer to Scheme 5 and the following details:

Benzoyl isothiocyanate (0.72 g, 4.42 mmol) was added to a solution of Compound 2 (6-bromo-N-methyl-2,3-dihydro-1H-inden-1-amine) (1.00 g, 4.42 mmol) in ACN (40 mL) and stirred for 3 hours at room temperature to obtain a reaction mixture. After the reaction was completed, the reaction mixture was diluted with cold water and sit to get a precipitated solid. The precipitated solid was collected by filtration and washed with ether to afford a crude product. The crude product was used as Compound 45 in the next step without further purification.

A solution of Compound 45 (N-((6-bromo-2,3-dihydro-1H-inden-1-yl)(methyl)carbamothioyl) benzamide) (4.0 mmol) in MeOH (20 mL) was added to a solution of methylamine in MeOH (20 mL) and stirred at room temperature overnight to form a mixture. After reaction was completed, the solvent in the mixture was removed under reduced pressure to obtain a crude product. The crude product was used as Compound 46 in the next step without further purification.

Pyridine (0.20 g, 2.53 mmol) was added to a solution of 4-fluorobenzoylacetonitrile (0.34 g, 2.10 mmol) in EtOH (10 mL) and heated to 80° C. for 15 minutes to form a reaction mixture. The reaction mixture was cooled to room temperature and a solution of Compound 46 (1-(6-bromo-2,3-dihydro-1H-inden-1-yl)-1-methylthiourea) (0.30 g, 1.05 mmol) and I2(0.63 g, 2.50 mmol) in EtOH (10 mL) was added therein. After addition, the reaction mixture was stirred at room temperature overnight. After the reaction was completed, the solvent in the reaction mixture was removed under reduced pressure. The residue was diluted with 1M Na2S2O3and extracted with EtOAc, and the resulting organic layers were combined. The combined organic layers were dried over MgSO4and concentrated in vacuo to obtain a crude product. The crude product was purified via flash column chromatography on a silica gel column using 10:1 DCM-MeOH as the eluent to give Compound 47, 2-((6-bromo-2,3-dihydro-1H-inden-1-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile and the yield thereof was 0.23 g (0.45 mmol).

CsCO3(0.19 g, 0.60 mmol), Boc-piperazine (0.11 g, 0.60 mmol), 2-(di-t-butylphosphino)biphenyl (0.01 g, 0.04 mmol) and Pd(OAc)2(0.01 g, 0.04 mmol) were added to a solution of Compound 47 (2-((6-bromo-2,3-dihydro-1H-inden-1-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile) (0.17 g, 0.40 mmol) in toluene (5 mL) to form a mixture. The mixture was degassed with argon for 15 minutes, and then heated to reflux overnight. After the reaction was completed, the solvent in the mixture was removed under reduced pressure, and then the residue was filtered through celite and washed with EtOAc to obtain a crude product. After concentration in vacuo, the crude product was purified via flash column chromatography on a silica gel column using 10:1 Hexane-EtOAc as the eluent to give Compound 48, tert-butyl 4-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2,3-dihydro-1H-inden-5-yl)piperazine-1-carboxylate (0.08 g, 0.16 mmol).

Compound 48 (Tert-butyl 4-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2,3-dihydro-1H-inden-5-yl)piperazine-1-carboxylate) (0.08 g, 0.16 mmol) was added to a solution of 4N HCl in dioxane (5 mL), and then stirred for 3 hours to form a mixture. After the reaction was completed, the solvent in the mixture was removed under reduced pressure to obtain a crude product. The crude product was used as Compound 49 in the next step without further purification.

K2CO3(0.13 g, 0.94 mmol), 2-chloro-1-(3-hydroxyazetidin-1-yl)ethan-1-one (0.03 g, 0.19 mmol) and a catalytic amount of KI were added to a solution of Compound 49 (4-(4-fluorophenyl)-2-(methyl(6-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl)amino)thiazole-5-carbonitrile) in DMF (5 mL), and then the reaction mixture was heated to 80° C. overnight. After the reaction was completed, the solvent in the reaction mixture was evaporated off by air-drying. The residue was diluted with water and extracted with EtOAc, and the resulting organic layers were combined. The combined organic layers were dried over MgSO4and concentrated in vacuo to obtain a crude product. The crude product was purified via flash column chromatography on a silica gel column using 10:1 DCM-MeOH as the eluent to give Compound 50, 4-(4-fluorophenyl)-2-((6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl)(methyl)amino)thiazole-5-carbonitrile, and the yield thereof was 0.06 g (0.11 mmol).

Compound 52 was produced by using the same methods for Compound 50.

Compounds 51 and 53 were produced by using the same methods for Compound 50 by replacing Compound 2 with Compound 35 in the corresponding schemes. Compound 54 was produced by using the same methods of Schemes 5.1 to 5.5 and 1.8 with the corresponding starting material.

Spectral Data of Compounds 50-54

For the preparation of Compounds 58-61, please refer to Scheme 6 and the following details:

Compound 55 was produced with the same methods for Compound 47 by replacing 4-fluorobenzoylacetonitrile with 4-chlorobenzoylacetonitrile. Na2CO3(0.08 g, 0.77 mmol), N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (0.16 g, 0.52 mmol), and Pd(dppf)Cl2(0.01 g, 0.01 mmol) were added to a solution of Compound 55 (2-((6-bromo-2,3-dihydro-1H-inden-1-yl)(methyl)amino)-4-(4-chlorophenyl)thiazole-5-carbonitrile) (0.12 g, 0.26 mmol) in DMF (5 mL) to form a mixture. The mixture was degassed with argon for 15 minutes, and then heated to 100° C. overnight. After the reaction was completed, the solvent in the mixture was evaporated off by air-drying, and then the residue was filtered through celite and washed with EtOAc to obtain a crude product. After concentration in vacuo, the crude product was purified via flash column chromatography on a silica gel column using 10:1 Hexane-EtOAc as the eluent to give Compound 56, tert-butyl 4-(3-((4-(4-chlorophenyl)-5-cyanothiazol-2-yl)(methyl)amino)-2,3-dihydro-1H-inden-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.14 g, 0.25 mmol).

Compound 56 (tert-butyl 4-(3-((4-(4-chlorophenyl)-5-cyanothiazol-2-yl)(methyl)amino)-2,3-dihydro-1H-inden-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate) (0.14 g, 0.25 mmol) was added to a solution of 4N HCl in dioxane (5 mL), and then stirred for 3 hours to form a mixture. After the reaction was completed, the solvent in the mixture was removed under reduced pressure to obtain a crude product. The crude product was used as Compound 57 in the next step without further purification.

K2CO3(0.36 g, 2.57 mmol), 2-chloro-1-(3-hydroxyazetidin-1-yl)ethan-1-one (0.05 g, 0.31 mmol) and a catalytic amount of KI were added to a solution of Compound 57 (4-(4-chlorophenyl)-2-(methyl(6-(1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydro-1H-inden-1-yl)amino)thiazole-5-carbonitrile) in DMF (5 mL), and then the reaction mixture was heated at 80° C. overnight. After the reaction was completed, the solvent in the mixture was evaporated off by air-drying. The residue was diluted with water and extracted with EtOAc, and the resulting organic layers are combined. The combined organic layers were dried over MgSO4and concentrated in vacuo to obtain a crude product. The crude product was purified via flash column chromatography on a silica gel column using 10:1 DCM-MeOH as the eluent to give Compound 58, 4-(4-chlorophenyl)-2-((6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydro-1H-inden-1-yl)(methyl)amino)thiazole-5-carbonitrile, and the yield thereof was 0.06 g (0.11 mmol).

To a stirred suspension of NaH (0.86 g, 60% in mineral oil, 20 mmol) in 20 mL dimethyl carbonate was added dropwise a solution of Compound 1 (6-bromoindanone) (1.0 g, 4.73 mmol) in 30 mL dimethyl carbonate and DMF 1 mL. The mixture was refluxed at 80° C. for 16 hours. After cooling to room temperature, and then H2O (80 mL) was added. The aqueous phase was separated and extracted with CH2Cl2(3×50 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The crude oil thus obtained was subjected to chromatography (silica gel, 2:1 hexane/CH2Cl2) to yield 1.06 g (83%) of Compound 59a (methyl 6-bromo-1-oxo-2,3-dihydro-1H-indene-2-carboxylate).

A solution of Compound 59a (methyl 6-bromo-1-oxo-2,3-dihydro-1H-indene-2-carboxylate) (0.27 g, 1.0 mmol) in dry DMSO (5 ml) was stirred under argon and cooled in a water bath. K2CO3(0.28 g, 2.0 mmol) was added and the resulting suspension stirred for a further 15 minutes, lodoethane (0.31 g, 2.0 mmol) was added and the mixture was stirred for 16 hours at rt. Ethyl acetate and excess dilute aqueous hydrochloric acid were added. The organic layer was separated, dried and evaporated to give a brown solid (Compound 59b) (0.25 g, 84%). The crude product of Compound 59b was used in next step without further purification.

To a solution of Compound 59b (methyl 6-bromo-2-ethyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate) (3.70 g, 14.46 mmol) in AcOH (30 mL) was added H2O (2 mL) and conc. HCl (10 mL). After addition, the reaction mixture was refluxed for overnight. After reaction was completed, the solvent AcOH was removed under reduced pressure. The residual was dissolved in EtOAc and washed with Sat. NaHCO3and brine. The combined organic layers were dried over MgSO4and concentrated in vacuo to get a crude product of Compound 59c (2.71 g, 11.33 mmol). The Compound 59c was used in the next step without further purification.

Compound 59 was produced by using the same methods for Compound 58 by replacing with the corresponding starting materials. Compounds 60 and 61 were produced by using the same methods for Compounds 58 and 59, respectively, by replacing Compound 1 with Compound 59c in the corresponding schemes.

Spectral Data of Compounds 58-61

For the preparation of Compound 66, please refer to Scheme 7 and the following details:

TEA (0.42 g, 4.13 mmol) and diphenylphosphorylazide (0.68 g, 2.48 mmol) were added to a solution of 5-bromobenzofuran-3-carboxylic acid (0.50 g, 2.06 mmol) and 3,5-dichlorobenzylalcohol (0.43 g, 2.48 mmol) in toluene (20 mL). After addition, the reaction mixture was heated to reflux overnight. After the reaction was completed, the solvent was removed under reduced pressure. The residue was diluted with EtOAc and washed with saturated NH4Cl, saturated NaHCO3and brine, and the resulting organic layers were combined. The combined organic layers were dried over MgSO4and concentrated in vacuo. The crude product was purified via flash column chromatography on a silica gel column using 10:1 Hexane-EtOAc as the eluent to give Compound 62, 3,5-dichlorobenzyl (5-bromobenzofuran-3-yl)carbamate (0.53 g, 1.28 mmol).

NaH (0.07 g) was added to a solution of Compound 62 (3,5-dichlorobenzyl (5-bromobenzofuran-3-yl)carbamate) (0.53 g, 1.28 mmol) in MeCN (20 mL) at 0° C. and stirred for 30 minutes at the same temperature to form a reaction mixture, and then MeI (1 mL) was added into the reaction mixture. After addition, the reaction mixture was slowly warmed to room temperature and stirred for 1 hour. After the reaction was completed, the solvent in the reaction mixture was removed under reduced pressure. The residue was diluted with EtOAc and washed with saturated NH4Cl, saturated NaHCO3and brine, and the resulting organic layers are combined. The combined organic layers were dried over MgSO4and concentrated in vacuo to obtain a crude product. The crude product was purified via flash column chromatography on a silica gel column using 10:3 Hexane-EtOAc as the eluent to give Compound 63, 3,5-dichlorobenzyl (5-bromobenzofuran-3-yl)(methyl)carbamate (0.44 g, 1.03 mmol).

CsCO3(0.50 g, 1.54 mmol), Boc-piperazine (0.29 g, 1.54 mmol), 2-(di-t-butylphosphino)biphenyl (0.03 g, 0.10 mmol) and Pd(OAc)2(0.02 g, 0.01 mmol) were added to a solution of Compound 63 (3,5-dichlorobenzyl (5-bromobenzofuran-3-yl)(methyl)carbamate) (0.44 g, 1.03 mmol) in toluene (10 mL) to form a mixture. The mixture was degassed with argon for 15 minutes, and then heated to reflux overnight. After the reaction was completed, the solvent in the mixture was removed under reduced pressure, and then the residue was filtered through celite and washed with EtOAc to obtain a crude product. After concentration in vacuo, the crude product was purified via flash column chromatography on a silica gel column using 10:3 Hexane-EtOAc as the eluent to give Compound 64, tert-butyl 4-(3-((((3,5-dichlorobenzyl)oxy)carbonyl)(methyl)amino)benzofuran-5-yl)piperazine-1-carboxylate, and the yield thereof was 0.23 g (0.43 mmol).

Compound 64 (tert-butyl 4-(3-((((3,5-dichlorobenzyl)oxy)carbonyl)(methyl)amino) benzofuran-5-yl)piperazine-1-carboxylate) (0.23 g, 0.43 mmol) was added to a solution of 4N HCl in dioxane (10 mL), and then stirred for 3 hours to form a mixture. After the reaction was completed, the solvent in the mixture was removed under reduced pressure to produce a crude product. The crude product was used as Compound 65 in the next step without further purification.

NMM (0.17 g, 1.70 mmol) and EDCI (0.12 g, 0.64 mmol) were added to a mixture of Compound 65 (3,5-dichlorobenzyl methyl(5-(piperazin-1-yl)benzofuran-3-yl)carbamate) (0.4 mmol), Rhodanine-3-acetic acid (0.12 g, 0.64 mmol), HOBt (0.01 g, 0.09 mmol) in DCM (10 mL) at 0° C. After addition, the reaction mixture was slowly warmed to room temperature and stirred overnight. After the reaction was completed, the solvent in the in the reaction mixture was removed under reduced pressure. The residue was diluted with EtOAc and washed with saturated NH4Cl, saturated NaHCO3and brine, and the resulting organic layers were combined. The combined organic layers were dried over MgSO4and concentrated in vacuo to obtain a crude product. The crude product was purified via flash column chromatography on a silica gel column using 10:2 DCM-EtOAc as the eluent to give Compound 66, 3,5-dichlorobenzyl methyl(5-(4-(2-(4-oxo-2-thioxothiazolidin-3-yl)acetyl)piperazin-1-yl)benzofuran-3-yl)carbamate (0.17 g, 0.28 mmol).

Spectral Data of Compound 66

For the preparation of Compound 69, please refer to Scheme 8 and the following details:

Na2CO3(0.07 g, 0.69 mmol), N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (0.14 g, 0.46 mmol), and Pd(dppf)Cl2(0.02 g, 0.02 mmol) were added to a solution of Compound 63 (3,5-dichlorobenzyl (5-bromobenzofuran-3-yl)(methyl)carbamate) (0.10 g) in DMF (10 mL) to form a mixture. The mixture was degassed with argon for 15 minutes, and then heated at 100° C. overnight. After the reaction was completed, the solvent in the mixture was evaporated off by air-drying, and then the residue was filtered through celite and washed with EtOAc to obtain a crude product. After concentration in vacuo, the crude product was purified via flash column chromatography on a silica gel column using 10:1 Hexane-EtOAc as the eluent to give Compound 67, tert-butyl 4-(3-((((3,5-dichlorobenzyl)oxy)carbonyl)(methyl)amino)benzofuran-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.07 g, 0.14 mmol).

Compound 67 (tert-butyl 4-(3-((((3,5-dichlorobenzyl)oxy)carbonyl)(methyl)amino) benzofuran-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate) (0.07 g, 0.14 mmol) was added to a solution of 4N HCl in dioxane (10 mL), and then stirred for 3 hours to form a mixture. After the reaction was completed, the solvent in the mixture was removed under reduced pressure to obtain a crude product. The crude product was used as Compound 68 in the next step without further purification.

NMM (0.04 g, 0.41 mmol) and EDCI (0.04 g, 0.20 mmol) were added to a mixture of Compound 68 (3,5-dichlorobenzyl methyl(5-(1,2,3,6-tetrahydropyridin-4-yl)benzofuran-3-yl)carbamate) (0.14 mmol), Rhodanine-3-acetic Acid (0.04 g, 0.20 mmol), HOBt (4.0 mg, 0.03 mmol) in DCM (10 mL) at 0° C. After addition, the reaction mixture was slowly warmed to room temperature and stirred overnight. After the reaction was completed, the solvent in the reaction mixture was removed under reduced pressure. The residue was diluted with EtOAc and washed with saturated NH4Cl, saturated NaHCO3and brine, and the resulting organic layers were combined. The combined organic layers were dried over MgSO4and concentrated in vacuo to obtain a crude product. The crude product was purified via flash column chromatography on a silica gel column using 10:2 DCM-EtOAc as the eluent to give Compound 69, 3,5-dichlorobenzyl methyl(5-(1-(2-(4-oxo-2-thioxothiazolidin-3-yl)acetyl)-1,2,3,6-tetrahydropyridin-4-yl)benzofuran-3-yl)carbamate, and the yield thereof was 0.03 g (0.05 mmol).

Spectral Data of Compound 69

For the preparation of Compounds 73 and 74, please refer to Scheme 9 and the following details:

A suspension of 2,4-difluorophenol (8 g, 0.0615 mol), 1,2-dibromoethane (37.5 mL, 81.75 g, 0.435 mol) and K2CO3(27.49 g, 0.198 mol) in acetonitrile (80 mL) was stirred at 60° C. overnight under a nitrogen atmosphere to form a reaction mixture. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by column chromatography over silica gel, using 5% ethyl acetate in petroleum ether as eluent, to give an intermediate compound (9.93 g), 1-(2-Bromoethoxy)2,4-difluorobenzene, as a colorless liquid, and the yield thereof was 9.93 g. A mixture of 6-bromo-N-methyl-2,3-dihydro-1H-inden-1-amine (0.5 g, 2.2 mmol), the above intermediate compound (1-(2-Bromoethoxy)2,4-difluorobenzene) (0.79 g, 3.3 mmol), KI (0.35 g, 2.2 mmol) and potassium carbonate (0.73 g, 5.28 mmol) in dry N,N′-dimethylformamide (15 mL) was stirred overnight at 100° C. The mixture was vacuum concentrated and the residue was dissolved in water (25 mL), extracted with ethyl acetate (3×20 mL) and washed with water, and the resulting organic layers were combined. The organic layer was dried and evaporated to give a crude product. The crude product was purified via flash column chromatography on a silica gel column using 5:1 to 2:1 n-Hex-EtOAc as the eluent to give Compound 70, 6-bromo-N-(2-(2,4-difluorophenoxy)ethyl)-N-methyl-2,3-dihydro-1H-inden-1-amine (0.516 g, 61%).

CsCO3(0.623 g, 1.91 mmol), Boc-piperazine (0.34 g, 1.83 mmol), 2-(di-t-butylphosphino)biphenyl (0.046 g, 0.15 mmol) and Pd(OAc)2(0.041 g, 0.18 mmol) were added to a solution of Compound 70 (6-bromo-N-(2-(2,4-difluorophenoxy)ethyl)-N-methyl-2,3-dihydro-1H-inden-1-amine) (0.585 g, 1.53 mmol) in toluene (3 mL) to form a mixture. The mixture was degassed with argon for 15 minutes, and then heated at 80° C. overnight. After the reaction was completed, the solvent in the mixture was removed under reduced pressure, and then the residue was filtered through celite and washed with EtOAc to obtain a crude product. After concentration in vacuo, the crude product was purified via flash column chromatography on a silica gel column using 1:1 Hexane-EtOAc as the eluent to give Compound 71, tert-butyl 4-(3-((2-(2,4-difluorophenoxy)ethyl)(methyl)amino)-2,3-dihydro-1H-inden-5-yl)piperazine-1-carboxylate (0.26 g, 35%).

4 N HCl (in 1,4-dioxane, 1.5 mL) was added to a solution of Compound 71 (tert-butyl 4-(3-((2-(2,4-difluorophenoxy)ethyl)(methyl)amino)-2,3-dihydro-1H-inden-5-yl)piperazine-1-carboxylate) (258 mg, 0.529 mmol) in dry CH2Cl2(4.0 mL) at 0° C. to form a mixture. The mixture was stirred at room temperature overnight. TLC was used to confirm the completion of reaction. After that, saturate NaHCO3was added to the mixture, and then the mixture was extracted with CH2Cl2. The resulting organic phase was dried with Na2SO4and concentrated under reduced pressure to give a crude product which was brown (226 mg, 99%). The crude product was used as Compound 72, N-(2-(2,4-difluorophenoxy)ethyl)-N-methyl-6-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-amine in the next step without further purification.

K2CO3(0.07 g, 0.15 mmol), 2-chloro-1-(3-hydroxyazetidin-1-yl)ethan-1-one (0.05, 0.32 mmol) were added to a solution of Compound 72 (N-(2-(2,4-difluorophenoxy)ethyl)-N-methyl-6-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-amine) (0.10 g) in MeCN (2 mL), and then the reaction mixture was heated at 80° C. for 5 hours. After the reaction was completed, the solvent in the reaction mixture was removed under reduced pressure. The residue was diluted with water and extracted with EtOAc, and the resulting organic were combined. The combined organic layers were dried over MgSO4and concentrated in vacuo to obtain a crude product. The crude product was purified via flash column chromatography on a silica gel column using 20:1 DCM-MeOH as the eluent to give Compound 73, and the yield thereof was 32 mg (25%).

Spectral Data of Compounds 73 and 74

For the preparation of Compound 82, please refer to Scheme 10 and the following details:

Ethyl diazoacetate (1.38 g, 12.09 mmol) dropwise was added to a mixture of 5-bromo-2-hydroxybenzaldehyde (1.21 g, 6.05 mmol) and 50% w/w HBF4.Et2O (0.20 g, 0.60 mmol) in DCM (30 mmol) at 0° C. to form a reaction mixture. After addition, the reaction mixture was slowly warmed to room temperature and stirred for 1 hour. After the hemiacetal intermediate was formed, concentrated H2SO4(3 mL) was added into the reaction mixture and stirred for further 1 hour. After the reaction was completed, the solvent in the reaction mixture was removed under reduced pressure. The residual was neutralized with saturated NaHCO3and extracted with EtOAc; and the resulting organic layers were combined. The combined organic layers were dried over MgSO4and concentrated in vacuo to obtain a crude product. The crude product was used as Compound 75, ethyl 5-bromobenzofuran-3-carboxylate, in the next step without further purification.

1N LiOH (6 mmol) was added to a solution of ethyl 5-bromobenzofuran-3-carboxylate (1.00 g, 3.72 mmol) in THF (20 mmol) and stirred overnight at room temperature to form a mixture. After the reaction was completed, the solvent in the mixture was removed under reduced pressure. The residue was acidified with 1N HCl, and the precipitated solid therefrom was collected by filtration and washed with cold water and hexane to obtain a crude product. The crude product acid was used as Compound 76, 5-bromobenzofuran-3-carboxylic, in the next step without further purification.

TEA (0.51 g, 5.02 mmol) and isobutyl chloroformate (0.68 g, 4.98 mmol) were added to a solution of 5-bromobenzofuran-3-carboxylic acid (1.00 g, 4.15 mmol) in THF (20 mL) at 0° C. and stirred for 2 hours at the same temperature to obtain a mixture. After the reaction was completed, the solvent in the mixture was removed under reduced pressure. The residue was dissolved in EtOAc and washed with 1N HCl, saturated NaHCO3and brine, and the resulting organic layers were combined. The combined organic layers were dried over MgSO4and concentrated in vacuo to obtain a crude mixed anhydride. The crude mixed anhydride was used in the next step without further purification.

NaBH4(0.16 g, 4.15 mmol) was added to a solution of mixed anhydride in MeOH (20 mL) at 0° C. After addition, the reaction mixture was slowly warmed to room temperature and stirred overnight. After the reaction was completed, the solvent in the mixture was removed under reduced pressure. The residue was diluted with saturated NH4Cl and extracted with EtOAc, and the resulting organic layers were combined. The combined organic layers were dried over MgSO4and concentrated in vacuo to obtain crude (5-bromobenzofuran-3-yl)methanol. The crude (5-bromobenzofuran-3-yl)methanol was used in the next step without further purification. SOCl2(5 mL) was added to a solution of (5-bromobenzofuran-3-yl)methanol in Et2O (20 mL) and stirred for 3 hours at room temperature to form a mixture. After the reaction was completed, the solvent in the mixture was removed under reduced pressure to obtain a crude product. The crude product was purified via flash column chromatography on a silica gel column using 10:1 Hexane-EtOAc as the eluent to give Compound 78, 5-bromo-3-(chloromethyl) benzofuran (0.56 g, 2.26 mmol).

The 3-(4-chlorophenyl)-3-oxopropanenitrile (1 g, 5.58 mmol) was dissolved in N,N-Dimethylformamide dimethyl acetal (2 mL) and stirred at room temperature for 1 hour. After reaction was completed, the solvent was removed under reduced pressure. The residual was dissolved in EtOAc and washed with water and brine. The combined organic layers were dried over MgSO4and concentrated in vacuo. The crude product 78a, (E)-2-(4-chlorobenzoyl)-3-(dimethylamino)acrylonitrile (1.15 g, ˜88%), was used in the next step without further purification.

To a solution of Compound 78a ((E)-2-(4-chlorobenzoyl)-3-(dimethylamino)acrylonitrile) (1.15 g, 4.9 mmol) in EtOH (10 mL) was added conc. HCl (0.1 mL) and hydrazine hydrate (0.3 g). After addition, the reaction mixture was refluxed for 3 hours. After reaction was completed, the solvent was removed under reduced pressure. The residual was diluted with cold water and sit to get a precipitated solid. The precipitated solid was collected by filtration to obtain a crude product of Compound 78b (0.81 g, yield=81%). Compound 78b was used in the next step without further purification.

NaH (0.18 g) was added to a solution of Compound 78b (0.16 g, 0.79 mmol) in DMF (10 mL) at 0° C. and stirred for 30 minutes at the same temperature to form a reaction mixture, and then the Compound 78 (5-bromo-3-(chloromethyl)benzofuran) (0.16 g, 0.65 mmol) was added into the reaction mixture. After addition, the reaction mixture was slowly warmed to room temperature and stirred overnight. After the reaction was completed, the solvent in the reaction mixture was evaporated off by air-drying, and then the residue was diluted with saturated NH4Cl and extracted with EtOAc, and the resulting organic layers were combined. The combined organic layers were dried over MgSO4and concentrated in vacuo to produce a crude product. The crude product was purified via flash column chromatography on a silica gel column using 5:1 Hexane-EtOAc as the eluent to give Compound 79, 1-((5-bromobenzofuran-3-yl)methyl)-3-(4-chlorophenyl)-1H-pyrazole-4-carbonitrile (0.18 g, 0.42 mmol).

Na2CO3(0.29 g, 2.74 mmol), boronic ester (0.56 g, 1.81 mmol) and Pd(dppf)Cl2(0.07 g, 0.09 mmol) were added to a solution of 1-((5-bromobenzofuran-3-yl)methyl)-3-(4-chlorophenyl)-1H-pyrazole-4-carbonitrile (0.37 g, 0.90 mmol) in DMF (10 mL). The mixture was degassed with Ar for 15 minutes, and then heated at 100° C. overnight. After the reaction was completed, the solvent in the mixture was evaporated off by air-drying, and then the residue was filtered through celite and washed with EtOAc to obtain a crude product. After concentration in vacuo, the crude product was purified via flash column chromatography on a silica gel column using 5:1 Hexane-EtOAc as the eluent to give Compound 80, tert-butyl 4-(3-((3-(4-chlorophenyl)-4-cyano-1H-pyrazol-1-yl)methyl)benzofuran-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.26 g, 0.50 mmol).

Tert-butyl 4-(3-((3-(4-chlorophenyl)-4-cyano-1H-pyrazol-1-yl)methyl)benzofuran-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.26, 0.50 mmol) was added to a solution of 4N HCl in dioxane (10 mL), and then stirred for 3 hours to form a mixture. After the reaction was completed, the solvent in the mixture was removed under reduced pressure to obtain a crude product. The crude product was used as Compound 81, 3-(4-chlorophenyl)-1-((5-(1,2,3,6-tetrahydropyridin-4-yl)benzofuran-3-yl)methyl)-1H-pyrazole-4-carbonitrile, in the next step without further purification.

K2CO3(0.20 g, 1.45 mmol), alkyl chloride (0.07 g, 0.47 mmol) and a catalytic amount of KI were added to a solution of 3-(4-chlorophenyl)-1-((5-(1,2,3,6-tetrahydropyridin-4-yl)benzofuran-3-yl)methyl)-1H-pyrazole-4-carbonitrile in DMF (3 mL), and then the reaction mixture was heated at 80° C. overnight. After the reaction was completed, the solvent in the reaction mixture was evaporated off by air-drying. The residue was diluted with water and extracted with EtOAc, and the resulting organic layers were combined. The combined organic layers were dried over MgSO4and concentrated in vacuo to obtain a crude product. The crude product was purified via flash column chromatography on a silica gel column using 10:1 EtOAc-MeOH as the eluent to give, Compound 82, 3-(4-chlorophenyl)-1-((5-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-1,2,3,6-tetrahydropyridin-4-yl)benzofuran-3-yl)methyl)-1H-pyrazole-4-carbonitrile, and the yield thereof was 0.09 g (0.17 mmol).

Spectral Data of Compound 82

For the preparation of Compound 85, please refer to Scheme 11 and the following details:

To a cold solution of 5-bromo-2-fluorobenzonitrile (7.43 g, 37.15 mmol) in DMF at 0° C. was added dropwise methyl 2-mercaptoacetate (6.65 mL, 74.3 mmol). The reaction mixture was stirred at 0° C. for 30 minutes, and then potassium tert-butoxide (8.4 g, 74.5 mmol) was added over 15 minutes with vigorous stirring. After stirring at 0° C. for 0.5 hour, allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was quenched with ice-water. The resulting precipitate was collected by filtration and dried to give 9.8 g of white solid of Compound 83 (methyl 3-amino-5-bromobenzo[b]thiophene-2-carboxylate) in 92% yield.

To a solution of Compound 83 (methyl 3-amino-5-bromobenzo[b]thiophene-2-carboxylate) (0.76 g, 2.66 mmol, 1 eq) in 1-methyl-2-pyrrolidinone (4.5 mL) was added piperazine (1.56 mL, 14.1 mmol, 5.3 eq). The reaction was stirred at 130° C. overnight. Ice was added, and the mixture was extracted with ethyl acetate. The organic extracts were washed twice with water, dried, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel eluting with 30% ethyl acetate in hexanes to provide Compound 84 (5-bromobenzo[b]thiophen-3-amine) (460 mg, 76%).

Compound 85 was produced by starting with Compound 84 and followed by Schemes 2.1, 7.2, and 8.1 to 8.3, accordingly.

Spectral Data of Compound 85

To a solution of LAH (0.17 g, 4.40 mmol) in THF (30 mL) was added 3-Chloro-5-methylbenzoic acid (0.50 g, 2.93 mmol) slowly at 0° C. After addition, the reaction mixture was slowly warmed to RT and stirred for 3 hours. After reaction was completed, the solvent was removed under reduced pressure. The residue was quenched with 1N HCl and extracted with EtOAc. The combined organic layers were dried over MgSO4and concentrated in vacuo to afford Compound 86 (3-Chloro-5-methylbenzyl alcohol) (0.45 g, 2.87 mmol, 98% yield). The crude product was used in the next step without further purification.

Compound 87, 88, 89, 90 and 91 are synthesized by using the same method as in Scheme 12.1.

To a mixture of 5′-Bromo-2′-hydroxyacetophenone (2.1 g, 9.95 mmol) and HBF4.Et2O (0.32 g, 1 mmol) in DCM (15 mL) was slowly added a solution of ethyl diazoacetate (1.8 g, 15.77 mmol) in DCM (15 mL) at 0° C. After addition, the reaction mixture was slowly warmed to RT and stirred for 2 hours. Then the reaction mixture was added conc. H2SO4(1.3 g) and stirred for further 20 min. After reaction was completed, the reaction mixture was neutralized with Na2CO3and the solvent was removed under reduced pressure. The crude product was purified via flash column chromatography on a silica gel column using 10:1 Hexane-EtOAc as the eluent to give Compound 98 (ethyl 5-bromo-2-methylbenzofuran-3-carboxylate) (2.30 g, 8.12 mmol, 82% yield).

To a solution of Compound 98 (0.74 g, 2.62 mmol) in THF (20 mL) and MeOH (20 mL) was added 1N LiOH (5 mL). After addition, the reaction mixture was heated to reflux for 2 hours. After reaction was completed, the solvent was removed under reduced pressure. The residual was acidified with 1N HCl. The precipitated solid was collected by filtration to afford Compound 99 (5-bromo-2-methylbenzofuran-3-carboxylic acid) (0.52 g, 2.06 mmol, yield 78%)

To a solution of Compound 99 (0.50 g, 1.96 mmol) and 3,5-Bis(trifluoromethyl)benzyl alcohol (0.42 g, 2.35 mmol) in toluene (30 mL) was added TEA (0.40 g, 3.92 mmol) and diphenylphosphorylazide (0.65 g, 2.35 mmol). After addition, the reaction mixture was heated to reflux for overnight. After reaction was completed, the solvent was removed under reduced pressure. The residual was diluted with EtOAc and washed with Sat. NH4Cl, Sat. NaHCO3and brine. The combined organic layers were dried over MgSO4and concentrated in vacuo to afford Compound 100 (3,5-bis(trifluoromethyl)benzyl (5-bromo-2-methylbenzofuran-3-yl)carbamate) (0.94 g, 1.90 mmol, 97% yield). The product was used in next step without further purification.

To a solution of Compound 100 (0.50 g, 1.01 mmol) in ACN (20 mL) was added NaH (0.06 g, 1.51 mmol) at 0° C. and stirred for 30 min at the same temperature, then MeI (0.50 mL) was added into the reaction mixture. After addition, the reaction mixture was slowly warmed to RT and stirred for 1 hr. After reaction was completed, the solvent was removed under reduced pressure. The residual was diluted with EtOAc and washed with Sat. NH4Cl, Sat. NaHCO3and brine. The combined organic layers were dried over MgSO4and concentrated in vacuo. The crude product was purified via flash column chromatography on a silica gel column using 10:3 Hexane-EtOAc as the eluent to give Compound 101 (3,5-bis(trifluoromethyl)benzyl (5-bromo-2-methylbenzofuran-3-yl)(methyl)carbamate) (0.38 g, 0.74 mmol, 73% yield).

Compound 102 was synthesized by using the same methods as in Scheme 1.4, 1.5 and 1.8 with Compound 101. Compound 103 was synthesized by using the same methods for Compound 102.

Compound 104 was synthesized by using the same method in Scheme 13.4 with ethyl iodide.

Compound 105 was synthesized by using the same methods as in Scheme 1.4, 1.5 and 1.8 with Compound 104.

To a mixture of 4-Bromo-2-iodoaniline (1.38 g, 4.6 mmol) ethyl acetoacetate (0.67 g, 5.1 mmol), CuI (0.1 g, 0.52 mmol), and BINOL (0.2 g, 0.70 mmol) was added Cs2CO3(1.5 g, 4.60 mmol) in DMSO. After addition, the reaction mixture was heated at 50° C. for overnight. After reaction was completed, the reaction mixture was diluted with Sat. NH4Cl and EtOAc. The organic layer was washed with brine and dried over MgSO4to afford Compound 106 (ethyl 5-bromo-2-methyl-1H-indole-3-carboxylate) (1.17 g, 4.15 mmol, yield 90%). The product was used in next step without further purification.

To a solution of Compound 106 (1.17 g, 4.15 mmol) in DMF was added NaH (0.25 g, 6.23 mmol) at 0° C. and stirred for 10 min, then to the reaction mixture was added MeI (0.88 g, 6.23 mmol). After addition, the reaction mixture was slowly warmed to RT and stirred for 30 min. After reaction was completed, the reaction mixture was diluted with Sat. NH4Cl. The precipitated solid was collected by filtration and washed with water to afford Compound 107 (ethyl 5-bromo-1,2-dimethyl-1H-indole-3-carboxylate) (1.13 g, 3.83 mmol, 92% yield). The product was used in next step without further purification.

To a solution of Compound 107 (1.13 g, 3.83 mmol) in MeOH/THF (40 mL, 3:1) was added 2N NaOH (10 mL). After addition, the reaction mixture was refluxed for overnight. After reaction was completed, the solvent was removed under reduced pressure, then acidified with 1N HCl. The precipitated solid was collected by filtration and washed with water to afford Compound 108 (5-bromo-1,2-dimethyl-1H-indole-3-carboxylic acid) (0.98 g, 3.65 mmol, 95% yield). The product was used in next step without further purification.

Compound 109 was synthesized by using the same methods as in Scheme 13.3, 13.4, Scheme 1.4, 1.5, and 1.8 with Compound 108.

To a mixture of 5-Bromo-2-hydroxy-3-methoxybenzaldehyde (4.6 g, 19.91 mmol) and HBF4.Et2O (0.64 g, 2 mmol) in DCM (50 mL) was slowly added a solution of ethyl diazoacetate (3.6 g, 31.54 mmol) in DCM (20 mL) at 0° C. After addition, the reaction mixture was slowly warmed to RT and stirred for overnight. Then the reaction mixture was added conc. H2SO4(2.6 g) and stirred for further 2 hours. After reaction was completed, the reaction mixture was neutralized with Na2CO3and the solvent was removed under reduced pressure. The crude product was purified via flash column chromatography on a silica gel column using 10:1 Hexane-EtOAc as the eluent to give Compound 110 (ethyl 5-bromo-7-methoxybenzofuran-3-carboxylate) (1.9 g, 6.35 mmol, 32% yield).

To a solution of Compound 110 (0.96 g, 3.21 mmol) in MeOH/THF (40 mL, 3:1) was added 2N NaOH (10 mL). After addition, the reaction mixture was refluxed for overnight. After reaction was completed, the solvent was removed under reduced pressure, then acidified with 1N HCl. The precipitated solid was collected by filtration and washed with water to afford Compound 111 (5-bromo-7-methoxybenzofuran-3-carboxylic acid) (0.80 g, 2.95 mmol, 92% yield). The product was used in next step without further purification.

Compound 112 was synthesized by using the same methods as in Scheme 13.3, 13.4, Scheme 1.4, 1.5, and 1.8 with Compound 111.

To the anhydrous dimethyl carbonate (50 mL) was added NaH (2.2 g), and then to the reaction mixture was added a solution of 6-Bromo-1-indanone (3.0 g, 14.21 mmol) in dimethyl carbonate (10 mL). After addition, the reaction mixture was added DMF (1 mL) and then heated at 80° C. for overnight. After reaction was completed, the dimethyl carbonate was removed under reduced. pressure. The residual was diluted with water and the precipitated solid was collected by filtration to afford Compound 114 (methyl 6-bromo-1-oxo-2,3-dihydro-1H-indene-2-carboxylate) (2.7 g, 10.03 mmol, yield 71%). The product was used in next step without further purification.

To a solution of Compound 114 (2.7 g, 10.03 mmol) in DMSO (50 mL) was added K2CO3(2.8 g, 20.26 mmol) and MeI (3.0 g, 21.14 mmol). After addition, the reaction mixture was stirred for overnight. After reaction was completed, the reaction was diluted with water and the precipitated solid was collected by filtration to afford Compound 115 (methyl 6-bromo-2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate) (2.6 g, 9.18 mmol, yield 91%). The product was used in next step without further purification.

Compound 115 (2.6 g, 9.18 mmol) was dissolved in a mixture of cone. HCl (10 mL) and AcOH (30 mL) and heated at 65° C. for 5 hours. After reaction was completed, the dimethyl carbonate was removed under reduced. pressure. The residual was quenched with Sat. NaHCO3and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4and concentrated in vacuo to afford Compound 116 (6-bromo-2-methyl-2,3-dihydro-1H-inden-1-one) (1.55 g, 6.89 mmol, yield 75%). The product was used in next step without further purification.

Compound 117 was synthesized by using the same methods as in Scheme 1.1, 1.2, 1.3, 1.4, 1.5, and 1.8 with Compound 116.

Compound 118 was synthesized by using the same methods as in Scheme 16.1, 16.2, 16.3 with ethyl iodide. With similar methods for the synthesis of Compound 117, Compound 119 was synthesized by using the precursor Compound 118.

Compound 120 and 121 are synthesized by using the same methods as the synthesis for Compound 119 with the corresponding precursors for Compound 18 and 22, respectively.

N-hydroxyacetamide (2.63 g, 35.0 mmol) was dissolved in DMF (100 mL), and then t-BuOK (3.93 g, 35.0 mmol) was added in one portion. The temperature rose to 30° C. The mixture was stirred for 1 h, and 5-bromo-2-fluorobenzonitrile (7 g, 35.0 mmol) was added. The reaction mixture was stirred for overnight. An additional portion of t-BuOK (1.96 g, 17.5 mmo) was added and the reaction was allowed to stir overnight. The mixture was poured into brine and CH2Cl2and the layers were separated. The organic phase was dried over MgSO4and concentrated in vacuo. The residue was purified by flash column chromatography using EtOAc/Hexane (1/2) to afford the Compound 122 (5-Bromobenzo[d]isoxazo-3-amine) (4.59 g, 62%) as a white-off solid.

Compound 126 was synthesized by using the same method in Scheme 17.4 with ethyl iodide.

Compound 127, 128, 129 are synthesized by using the same methods as in Scheme 1.5, and 1.8 with Compound 124, 125, 126, respectively.

Compound 130 was synthesized by using the same methods for Compound 9 by replacing methyl amine with ethyl amine in Scheme 1.1.

Compound 131 was synthesized by using the same methods for Compound 127 with precursor Compound 89.

Compound 132 and 133 are synthesized by using the same methods for Compound 128 and 129, respectively, with precursor Compound 89.

To a solution of triethyl phosphonoacetate (0.82 mL, 4.13 mmol) in dried THF was added NaH (330 mg, 8.26 mmol) slowly at 0° C. under nitrogen atmosphere. After stirring at 0° C. for 30 mins, 3,5-dichlorobenzaldehyde (723 mg, 4.13 mmol) was added to the reaction solution and warmed to room temperature. After stirring for 2 hours, H2O was added to the reaction solution and extracted with ethyl acetate. After evaporation, the crude product was purified by silica gel column chromatography using ethyl acetate/Hexane=1/10 as elution to yield the ester product of Compound 134 (800 mg, 80%) as a white solid.

A mixture solution of Compound 134 and 5% Pd/C in methanol was stirred at room temperature under H2atmosphere overnight. After filtration and concentration, the residue was dissolved in MeOH, followed by the addition of 1N NaOH(aq). The mixture solution was stirred at room temperature overnight. The reaction was quenched with 1N HCl(aq). After evaporation, the crude product of Compound 135 was used in next step without further purification.

A mixture solution of Compound 2 (150 mg, 0.664 mmol), EDCI (192 mg, 0.996 mmol), HOBt (52 mg, 0.332 mmol) and NMM (0.2 mL, 1.996 mmol) and Compound 135 (250 mg, 0.968 mmol) in DCM was stirred at room temperature overnight. The reaction solution was diluted with DCM, washed with sat. NH4Cl(aq), dried over Na2SO4and concentrated in vacuo. The residue was purified by flash column chromatography using EtOAc/Hexane (1/1) to afford the desired product of Compound 136 (360 mg, 51%).

Compound 137 was synthesized by using the same methods as in Scheme 1.4, 1.5, and 1.8 with Compound 136.

Compound 138 was synthesized by using the same methods for Compound 22 with the corresponding precursor 4-oxo-2-thioxo-3-thiazolidinylacetic acid.

A solution of Compound 6 (195 mg, 0.452 mmol) in dried CH2Cl2(10 mL) was stirred at 0° C., followed by addition of Et3N (0.13 mL, 0.942 mmol) and 3-chlorocarbonyl-1-methanesulfonyl-2-imidazolidinone (157 mg, 0.678 mmol). The reaction mixture was stirred at room temperature overnight and monitored by TLC. The mixture was added water and extracted with CH2Cl2. The organic phase was dried with MgSO4and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using CH2Cl2/ethyl acetate=3/1 as elution to yield the desired product of Compound 139 (97 mg, 35%) as a yellow oil.

Autotaxin activity was measured by choline release from LPC in presence or absence of compound.

The inhibition rates of the compounds of the present disclosure on the activity of autotaxin enzyme are shown in Table 1.