EA045414B1 - SUBSTITUTED ALKYNYLENE COMPOUNDS AS ANTI-CANCER AGENTS - Google Patents

Description

Related applications

The present patent application claims priority to Indian Provisional Application No. 201841001978, filed on January 17, 2018, the contents of which are incorporated herein by reference in their entirety.

Field of technology

The present invention relates to new substituted alkynylene derivatives of formula (I) and pharmaceutically acceptable salts of these compounds.

Also according to the present invention there is provided a method of treating cancer or a proliferative disorder using these compounds.

State of the art

Cancer is characterized primarily by an increase in the number of abnormal cells derived from a specific normal tissue, the invasion of these abnormal cells into adjacent tissues, or the spread of malignant cells through the lymph or blood to regional lymph nodes and distant sites (metastases). Clinical data and molecular biology studies have shown that cancer is a multistage process, starting with small preneoplastic changes that, under certain conditions, can develop into neoplasia. Neoplastic lesions can develop in a clonal manner and develop with increasing invasiveness, growth, metastasis and heterogeneity, especially in those conditions where neoplastic cells escape the control of the host immune system (Roitt, I., Brostoff, J and Kale, D., Immunology , 17.1-17.12) ( ^3rd ed., Mosby, St. Louis, Mo., 1993).

Various types of cancer have been described in the medical literature. Examples include cancer of the lung, colon, rectum, prostate, breast, brain, and small intestine. The incidence of cancer increases as the population ages, new cancers emerge, and predisposed populations (eg, people affected by AIDS or overexposed to environmental conditions) grow. Cancer can be treated with surgery, chemotherapy, radiation therapy, hormonal therapy, targeted therapy, and synthetic lethality, but these cancer treatment options are limited and have serious side effects. For example, in the case of blood cancer (such as multiple myeloma), when traditional chemotherapy and bone marrow transplant are not suitable treatment options, there are very few options left as a treatment. Therefore, there is a great need for new methods and compositions that can be used to treat patients suffering from cancer.

Several publications are presented showing a variety of compounds used as anti-cancer agents, such as WO2017177316A1, Applicant 3R VALO, S.E.C., entitled Aminobenzoic acid derivatives for use as anti-inflammatory agents, anti-metastatic agents and/or anticancer agents for use as anti-inflammatory agents, antimetastatic agents and/or anti-cancer agents); WO2016161342A2, applicant Threshold Pharmaceuticals, entitled Nitrobenzyl derivatives of anti-cancer agents; WO2008039489 A2, applicant Celgene Corporation, entitled 5-Substituted quinazolinone derivatives and compositions comprising and methods of using the same (5-substituted quinazolinone derivatives, compositions containing these compounds, and methods of using them); WO2005047266 A1, applicant Lorus Therapeutics Inc. called Aryl imidazoles and their use as anti-cancer agents (Arylimidazoles and their use as anti-cancer agents); EP2632916B1 issued by INST Medical W&E HALL (AU), entitled Novel anti-cancer agents.

The publication by Ghorab et al. (Anticancer Agents Med Chem. 2017; 17(10):1411-1425), called Novel thiourea derivatives bearing sulfonamide moiety as anticancer agents through COX-2 inhibition. -2), a study of the anticancer activity of target compounds by inhibiting the COX-2 enzyme is described; in the publication by Gupta MK et al. (World J Gastroenterol 2003; 9(6): 1144-1155), entitled Mechanism and its regulation of tumor-induced angiogenesis, describes the state of research and evaluation of antiangiogenic therapy in human clinical trials; in the publication Boichuk S et al. (Anti-cancer Drugs, 2016, 27, No. 7, 620-34), called Ethyl-2-amino-pyrrole-3-carboxylates are novel potent anticancer agents that affect tubulin polymerization, induce G2/M cell-cycle arrest , and effectively inhibit soft tissue cancer cell growth in vitro (Ethyl-2-aminopyrrole-3-carboxylates, which are new effective anticancer agents that affect tubulin polymerization, induce G2/M cell cycle arrest and effectively inhibit the growth of soft tissue cancer cells in vitro), presents structurally novel antimitotic compounds demonstrating molecular and cellular mechanisms consistent with other antimitotic anticancer agents; in the publication of D. Rodriguez-Hernandez (Eur. J. Med. Chem., 2016, 115, 257-67), entitled Novel hederagenin-triazolyl derivatives as potential anti-cancer agents (New hederagenin-triazolyl derivatives as potential anti-cancer agents ), the synthesis of a number of new aryl-1H-1,2,3 is described

- 1 045414 triazol-4-yl-ester and amide derivatives of hederagenin; in the publication B.A. Dar et al. (Eur. J. Med. Chem., 2016, 111, 26-32), entitled Synthesis and screening of ursolic acid-benzylidine derivatives as potential anti-cancer agents. The promising biological activity of ursolic acid has been described, allowing its extensive chemical modification for the development of more effective antitumor agents.

The main aspect of cancer treatment is chemotherapy using anticancer agents. Although tremendous progress has been made in this field, since chemotherapy is rarely simple, there remains an unmet need for the development of new and improved compounds and compositions of anticancer agents that act through different mechanisms and pathways.

Brief description of the invention

One aspect of the present invention includes compounds of formula (I)

or a pharmaceutically acceptable salt of said compound; Where

A is (C ₆ -C ₁₄ )aryl or 5-10 membered heteroaryl containing from 1 to 4 heteroatoms selected from N, O and S;

X is NR _y or absent;

Y is O, S or NCN;

B is (C ₆ -C ₁₄ )aryl, (C ₃ -C ₁₀ )cycloalkyl or 3-15 membered heterocycloalkyl containing at least one heteroatom selected from O, N and S; wherein aryl, cycloalkyl or heterocycloalkyl are unsubstituted or substituted with one or more groups selected from (C ₁ -C ₆ )alkyl, halogen and oxo;

R ₁ represents (C ₁ -C ₆ )alkyl;

R2 represents hydrogen or unsubstituted (C ₁ -C ₆ )alkyl; or R1 and R2 together with the carbon atoms to which they are attached form a 3-5 membered cycloalkyl ring;

R ₃ represents -C(O)R _a , -S(O) ₂ R _a , -NHS(O) ₂ R _a , -NR _b C(O)R _a , =NOR _a , 5-10 membered heteroaryl , containing from 1 to 4 heteroatoms selected from N, O and S, 3-15 membered heterocycloalkyl containing at least one heteroatom selected from O, N and S, or (3-15 membered heterocycloalkyl containing at least at least one heteroatom selected from O, N and S)-(C ₁ -C ₆ )alkyl; wherein heteroaryl and heterocycloalkyl are unsubstituted or substituted with one or more groups selected from (C ₁ -C ₆ )alkyl, halogen, oxo or -C(O)R _x ;

R4 is (C ₁ -C ₆ )alkyl, halogen, halogen(C ₁ -C ₆ )alkyl, cyano, (C ₁ -C ₆ )alkoxy, (C ₆ C ₁₄ )aryloxy, (C ₁ -C ₆ ) alkoxy(C ₆ -C ₁₄ )aryl, hydroxy(C ₁ -C ₆ )alkyl, acetylene, acyl, hydroxy, (C ₃ C ₁₀ )cycloalkyl or -N(R _x ) ₂ ; wherein the cycloalkyl is unsubstituted or substituted with (C ₁ -C ₆ )alkyl;

R _a represents (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, halogen(C ₁ -C ₆ )alkyl, (C ₃ -C ₁₀ )cycloalkyl or 3-15 membered heterocycloalkyl containing at least one heteroatom selected from O, N and S; wherein (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, halogen(C ₁ -C ₆ )alkyl, (C ₃ -C ₁₀ )cycloalkyl and heterocycloalkyl are unsubstituted or substituted with one or more groups selected from (C ₁ -C ₆ )alkyl, halogen, (C ₆ -C ₁₄ )aryl, (C ₃ -C ₁₀ )cycloalkyl, halogen(C ₁ -C ₆ )alkyl, amino, amido, (C ₁ -C ₆ ) alkylamino, amino(C ₁ -C ₆ )alkyl, hydroxyl, cyano, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₆ -C ₁₄ )aryl, (C ₆ -C ₁₄ )aryloxy , hydroxy(C ₁ -C ₆ )alkyl, carboxyl group, -C(O)OR11, -C(O)SR11, -SC(O)R ₁₁ -oxo group (=O) and -C(O)R _X ;

R _x represents hydrogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkenyl, acyl or -C(O)-(C ₃ -C ₁₀ )cycloalkyl;

R _y represents hydrogen or (C ₁ -C ₆ )alkyl;

R _b represents hydrogen, (C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )alkenyl;

R11 represents (C ₁ -C ₆ )alkyl;

m represents 0, 1, 2 or 3.

In another aspect, the present invention relates to a method of treating cancer or a proliferative disorder, comprising administering a therapeutically effective amount of a compound of formula (I) as described above, or a pharmaceutically acceptable salt of said compound, to a patient in need of said treatment.

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Detailed Description of the Invention

The present invention provides substituted alkynylene compounds, called compounds of formula (I), suitable as anticancer agents. In addition, the present invention provides pharmaceutical compositions containing the above compounds and derivatives of the above compounds as therapeutic agents.

Each embodiment is presented for the purpose of explaining the present invention and not for the purpose of limiting the present invention. In fact, one skilled in the art will appreciate the various modifications and changes that can be made to the compounds, compositions and methods herein described without departing from the scope or spirit of the present invention. For example, features shown or described as part of one embodiment may be applied to another embodiment to produce yet another embodiment. Thus, the present invention is intended to include such modifications and changes and their equivalents. Other objects, features and aspects of the present invention are disclosed or made explicit in the following detailed description. One of ordinary skill in the art will appreciate that the present discussion is a description of exemplary embodiments and should not be construed as limiting the broader aspects of the present invention.

In one embodiment of the present invention there is provided a compound of formula (I):

or a pharmaceutically acceptable salt or stereoisomer of the said compound; Where

A is aryl or heteroaryl;

X is N-Ry or absent;

Y is O, S or NCN;

B is aryl, cycloalkyl or heterocycloalkyl; wherein aryl, cycloalkyl or heterocycloalkyl are optionally substituted with one or more groups selected from alkyl, halogen and oxo;

R1 represents alkyl; and R2 is hydrogen or alkyl; or R1 and R2 together with the carbon atoms to which they are attached form a 3-5 membered cycloalkyl ring;

R3 is -C(O)R _a , -S(O)2R _a , -NHS(O)2R _a , -NR _b C(O)R _a , =NOR _a , heteroaryl, heterocycloalkyl or (heterocycloalkyl)alkyl- ; wherein heteroaryl and heterocycloalkyl are optionally substituted with one or more groups selected from alkyl, halogen, oxo or -C(O)R _x ;

R4 is alkyl, halogen, haloalkyl, cyano, alkoxy, aryloxy, alkoxyaryl, hydroxyalkyl, acetylene, acyl, hydroxy, cycloalkyl or -N(R _x )2; wherein cycloalkyl is optionally substituted with alkyl;

R _a is alkyl, alkenyl, haloalkyl, cycloalkyl or heterocycloalkyl; wherein alkyl, alkenyl, haloalkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more groups selected from alkyl, halogen, aryl, cycloalkyl, haloalkyl, amino, amido, alkylamino, aminoalkyl, hydroxyl, cyano, alkoxy, alkoxyaryl, aryloxy, hydroxyalkyl, carboxylic acid, ester, thioester, oxo group (=O) and -C(O)R _x ;

R _x represents hydrogen, alkyl, alkenyl, acyl or -C(O)cycloalkyl;

Ry represents hydrogen or alkyl;

Rb is hydrogen, alkyl or alkenyl;

m represents 0, 1, 2 or 3.

According to one embodiment, there is particularly provided a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer of the said compound, wherein X represents NH.

In some implementations, X is missing.

According to one embodiment, there is particularly provided a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer of the said compound, wherein Y is O.

According to one embodiment, there is particularly provided a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer of the said compound, wherein A is aryl.

In some embodiments, A is phenyl.

In some embodiments, A is phenyl substituted with m R ₄ groups. In some embodiments, m is 1, 2, or 3. In some specific embodiments, m is 1 or 2.

According to one embodiment, a compound of formula (I) or

- 3 045414 a pharmaceutically acceptable salt or stereoisomer of the said compound, wherein B is cycloalkyl or heterocycloalkyl, optionally substituted by one or more groups selected from alkyl, halogen or oxo.

In some embodiments, B is cycloalkyl or heterocycloalkyl; wherein the heterocycloalkyl is optionally substituted with an oxo group.

In some embodiments, B is a 5-6 membered heterocycloalkyl.

According to one embodiment, in particular, a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer of the said compound is provided, wherein R1 represents alkyl; and R2 is hydrogen.

In some embodiments, R1 and R2, together with the carbon atoms to which they are attached, form a 3-5 membered cycloalkyl ring.

In some embodiments, R1 and R2, together with the carbon atoms to which they are attached, form a cyclopropyl or cyclopentyl ring.

In some embodiments, R1 and R2, together with the carbon atoms to which they are attached, form cyclopropyl.

According to one embodiment, there is particularly provided a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer of the said compound, wherein R ₃ is -C(O)R _a , -NHS(O)2R _a or -NRbC(O)R _a .

According to one embodiment, there is particularly provided a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer of the said compound, wherein R ₃ is -C(O)R _a ; wherein R _a is as defined for the compound of formula (I).

In some embodiments, R _a is alkenyl, cycloalkyl, or heterocycloalkyl; wherein alkenyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more groups selected from alkyl, halogen, aryl, cycloalkyl, haloalkyl, amino, amido, alkylamino, aminoalkyl, hydroxyl, cyano, alkoxy, alkoxyaryl, aryloxy, hydroxyalkyl, carboxylic acid, ester , thioester, oxo group (=O) or -C(O)Rx.

According to one embodiment, there is particularly provided a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ₃ is heterocycloalkyl, optionally substituted with a -C(O)R _x group.

In some embodiments, Rb is hydrogen or alkyl.

One embodiment specifically provides a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4 is alkyl, halogen, haloalkyl or cycloalkyl, wherein cycloalkyl is optionally substituted with alkyl.

In another embodiment of the present invention there is provided a compound of formula (IA):

or a pharmaceutically acceptable salt or stereoisomer of the said compound;

where A, R1, R2, _R3 , _R4 , B, Xi m are as defined for the compound of formula (I).

According to one embodiment, there is particularly provided a compound of formula (IA) or a pharmaceutically acceptable salt or stereoisomer of the said compound, wherein X represents NH.

According to one embodiment, there is particularly provided a compound of formula (IA) or a pharmaceutically acceptable salt or stereoisomer of the said compound, wherein A is aryl.

In some embodiments, A is phenyl.

One embodiment specifically provides a compound of formula (IA) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein B is cycloalkyl or heterocycloalkyl, optionally substituted by one or more groups selected from alkyl, halogen or oxo.

One embodiment specifically provides a compound of formula (IA) or a pharmaceutically acceptable salt or stereoisomer of the same compound, wherein B is a 5- or 6-membered cycloalkyl.

According to one embodiment, there is particularly provided a compound of formula (IA), or a pharmaceutically acceptable salt or stereoisomer of the same compound, wherein B represents a cyclopentyl or cyclohexyl ring.

According to one embodiment, in particular, a compound of formula (IA) or a pharmaceutically acceptable salt or stereoisomer of the said compound is provided, where R ₃ represents -C(O)Ra, -S(O)2R, -NHS(O)2Ra, - NRbC(O)Ra or=NORa.

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According to one embodiment, there is particularly provided a compound of formula (IA) or a pharmaceutically acceptable salt or stereoisomer of the said compound, wherein R3 is

-NHS(O)2R _a or -NR _b C(O)R _a ; where Ra and R _b are as defined for the compound of formula (I).

One embodiment specifically provides a compound of formula (IA), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4 is alkyl, halogen, haloalkyl, or cycloalkyl, wherein cycloalkyl is optionally substituted with alkyl.

In another embodiment of the present invention there is provided a compound of formula (IB):

or a pharmaceutically acceptable salt or stereoisomer of the said compound; where A, R1, R2, R3, R ₄ , B and m are as defined for the compound of formula (I).

According to one embodiment, there is particularly provided a compound of formula (IB), or a pharmaceutically acceptable salt or stereoisomer of the same compound, wherein A is aryl.

According to one embodiment, there is particularly provided a compound of formula (IB) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein B is cycloalkyl or heterocycloalkyl, optionally substituted by one or more groups selected from alkyl, halogen or oxo.

According to one embodiment, there is particularly provided a compound of formula (IB) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein B is heterocycloalkyl, optionally substituted with one or more groups selected from alkyl, halogen or oxo.

According to one embodiment, there is particularly provided a compound of formula (IB) or a pharmaceutically acceptable salt or stereoisomer of the same compound, wherein B is a 5- or 6-membered heterocycloalkyl.

According to one embodiment, there is particularly provided a compound of formula (IB) or a pharmaceutically acceptable salt or stereoisomer of the same compound, wherein R ₃ is heterocycloalkyl, optionally substituted with a -C(O)R _x group.

One embodiment specifically provides a compound of formula (IB), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ₄ is alkyl, halogen, haloalkyl or cycloalkyl, wherein cycloalkyl is optionally substituted with alkyl.

In another embodiment, the present invention provides a compound of formula (IC):

or a pharmaceutically acceptable salt or stereoisomer of the said compound;

where A, R1, R2, R3, R4 and m are as defined for the compound of formula (I).

According to one embodiment, there is particularly provided a compound of formula (IC), or a pharmaceutically acceptable salt or stereoisomer of the compound, wherein A is aryl.

According to one embodiment, in particular, a compound of formula (IC) or a pharmaceutically acceptable salt or stereoisomer of the specified compound is provided, wherein R1 represents alkyl; R ₂ represents hydrogen or alkyl.

According to one embodiment, there is particularly provided a compound of formula (IC), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ₁ and R ₂ together with the carbon atoms to which they are attached form a cyclopropyl or cyclopentyl ring.

One embodiment specifically provides a compound of formula (IC), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is optionally substituted heteroaryl, heterocycloalkyl, or (heterocycloalkyl)alkyl-.

One embodiment specifically provides a compound of formula (IC), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is heterocycloalkyl, optionally substituted with a -C(O)R _x group.

One embodiment specifically provides a compound of formula (IC), or a pharmaceutically acceptable salt or stereoisomer of the same compound, wherein R ₃ is heterocycloalkyl, optionally substituted with a -C(O)R _x group.

According to one embodiment, a compound of formula (IC) or

- 5 045414 a pharmaceutically acceptable salt or stereoisomer of the said compound, wherein R4 is alkyl, halogen, haloalkyl or cycloalkyl, wherein cycloalkyl is optionally substituted with alkyl.

According to one embodiment, a compound of formula (IC) or a pharmaceutically acceptable salt or stereoisomer of the same compound is provided, wherein m is 2.

In another embodiment of the present invention there is provided a compound of formula (ID):

o or a pharmaceutically acceptable salt or stereoisomer of the said compound;

where A, R1, _R2 , R4, Ra and m are as defined for the compound of formula (I).

According to one embodiment, there is particularly provided a compound of formula (ID) or a pharmaceutically acceptable salt or stereoisomer of the said compound, wherein A is aryl.

According to one embodiment, in particular, a compound of formula (ID) or a pharmaceutically acceptable salt or stereoisomer of the specified compound is provided, wherein R1 represents alkyl; and R ₂ independently represents hydrogen.

According to one embodiment, there is particularly provided a compound of formula (ID) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ra represents alkenyl, cycloalkyl or heterocycloalkyl, wherein alkenyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more groups selected from halogen , aryl, haloalkyl or carboxylic acid.

One embodiment specifically provides a compound of formula (ID), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ₄ is alkyl, halogen, haloalkyl, or cycloalkyl, wherein cycloalkyl is optionally substituted with alkyl.

According to one embodiment, there is particularly provided a compound of formula (ID), or a pharmaceutically acceptable salt or stereoisomer of the same compound, wherein R4 is a halogen.

According to one embodiment, a compound of formula (ID) or a pharmaceutically acceptable salt or stereoisomer of the said compound is provided, wherein m is 2.

In another embodiment, the present invention provides a compound of formula (IE):

o or a pharmaceutically acceptable salt or stereoisomer of the said compound;

where A, R ₄ , R _a and m are as defined for the compound of formula (I).

According to one embodiment, there is particularly provided a compound of formula (IE) or a pharmaceutically acceptable salt or stereoisomer of the said compound, wherein A is aryl.

According to one embodiment, there is particularly provided a compound of formula (IE) or a pharmaceutically acceptable salt or stereoisomer of the said compound, wherein Ra represents alkenyl, cycloalkyl or heterocycloalkyl, wherein alkenyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more groups selected from halogen, aryl, haloalkyl or carboxylic acid.

One embodiment specifically provides a compound of formula (IE), or a pharmaceutically acceptable salt or stereoisomer of the compound, wherein R4 is a halogen.

According to one embodiment, there is particularly provided a compound of formula (IE) or a pharmaceutically acceptable salt or stereoisomer of the specified compound, where m represents 2.

In another embodiment of the present invention there is provided a compound of formula (IF):

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or a pharmaceutically acceptable salt or stereoisomer of the said compound;

where R4, Ra and m are as defined for the compound of formula (I).

According to one embodiment, there is particularly provided a compound of formula (IF) or a pharmaceutically acceptable salt or stereoisomer of the said compound, wherein Ra represents alkenyl, cycloalkyl or heterocycloalkyl, wherein alkenyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more groups selected from halogen , aryl, haloalkyl or carboxylic acid.

According to one embodiment, there is particularly provided a compound of formula (IF) or a pharmaceutically acceptable salt or stereoisomer of the said compound, wherein R ₄ represents a halogen.

According to one embodiment, there is particularly provided a compound of formula (IF) or a pharmaceutically acceptable salt or stereoisomer of the said compound, wherein m is 2.

In another embodiment of the present invention there is provided a compound of formula (IG):

or a pharmaceutically acceptable salt or stereoisomer of the said compound;

where R1, R2, R ₄ and m are as defined for the compound of formula (I).

According to one embodiment, there is particularly provided a compound of formula (IG) or a pharmaceutically acceptable salt or stereoisomer of the said compound, wherein R1 represents alkyl; R2 independently represents hydrogen.

According to one embodiment, there is particularly provided a compound of formula (IG) or a pharmaceutically acceptable salt or stereoisomer of the same compound, wherein R ₄ represents a halogen.

According to one embodiment, a compound of formula (IG) or a pharmaceutically acceptable salt or stereoisomer of the said compound is provided, wherein m is 2.

In another embodiment of the present invention there is provided a compound of formula (IH):

or a pharmaceutically acceptable salt or stereoisomer of the said compound;

where R4 and m are as defined for the compound of formula (I).

According to one embodiment, there is particularly provided a compound of formula (IH) or a pharmaceutically acceptable salt or stereoisomer of the same compound, wherein R ₄ represents a halogen.

According to one embodiment, there is particularly provided a compound of formula (IH), or a pharmaceutically acceptable salt or stereoisomer of the same compound, wherein R ₄ is chlorine.

According to one embodiment, there is particularly provided a compound of formula (IH) or a pharmaceutically acceptable salt or stereoisomer of the said compound, where m is 2.

In another embodiment, the present invention provides a compound, or a pharmaceutically acceptable salt or stereoisomer of the compound, selected from:

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Example Structure 1 I 0 e, Η I I Yj 0 ; 1a I 0 e, / ^A Y n ι I Yj CI-^^ (Isomer-1) o . 1b I about s. ^C1 \x^xx^ Η ι 1 Y Y _C |Y%Y (Isomer-2) . 2 A o _α t O ; 2a A o C, Υτ ⁿ ciTy (Isomer-1) J . 2b Oh s, УУ f l 01^4^ (Isomer-2) 4 3 oh oh VAλΥ ΤΖ O 2 4 o Y/f ^N % ^Ν γ^ Cl·^ ⁴ ^ Ο ; 5 Cl >^ ^N ^ ^N T Yj F'^YO ;

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In some embodiments, the present invention provides a pharmaceutical composition comprising at least one compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer of the compound, and a pharmaceutically acceptable carrier or excipient.

In some embodiments, the present invention provides a compound, or a pharmaceutically acceptable salt or stereoisomer of the compound, for use as a drug.

In some embodiments, the pharmaceutical composition of a compound of formula (I) further comprises at least one agent selected from an anticancer agent, a chemotherapeutic agent, and an antiproliferative compound.

In some embodiments, the compounds of the present invention are expected to be useful in the therapy of proliferative diseases such as cancer, including, without limitation, carcinoma, including breast, liver, lung, colon, kidney, bladder, including small cell lung cancer , non-small cell cancer of the lung, head and neck, thyroid, esophagus, stomach, pancreas, ovary, gallbladder, cervix, prostate and skin, including squamous cell carcinoma.

In some embodiments, the compounds of the present invention can be administered in the form of a pharmaceutical composition to a patient in need of treatment of hematologic malignancies, including, without limitation, leukemias and lymphomas, including, without limitation, hematopoietic tumors of lymphoid origin, acute lymphoblastic leukemia, acute lymphocytic leukemia, small cell lymphocytic lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, B-cell lymphoma, T-cell lymphoma, hairy cell lymphoma, myeloma, mantle cell lymphoma and Burkett lymphoma, hematopoietic tumors of myeloid origin, including acute and chronic myelogenous leukemia, myelodysplastic syndrome and promyelo cytic leukemia.

In some embodiments, the pharmaceutical composition is suitable for treating a patient with a proliferative disease. In some embodiments, the pharmaceutical composition is suitable for treating a patient with cancer. In some embodiments, the pharmaceutical composition is suitable for treating a patient with lymphoma. In some embodiments, the pharmaceutical composition is suitable for treating a patient with Hodgkin's lymphoma, Burkitt's lymphoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, or MALT-type lymphoma. In some embodiments, the pharmaceutical composition is suitable for treating a patient with diffuse large B-cell lymphoma.

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Pharmaceutical compositions.

In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable salt or stereoisomer of the compound, and a pharmaceutically acceptable carrier or excipient.

In some embodiments, the pharmaceutical composition of the present invention further comprises at least one agent selected from an anticancer agent, a chemotherapeutic agent, and an antiproliferative compound.

The compositions and methods of the present invention can be used to treat an individual in need of said treatment. In some embodiments, the individual is a mammal, such as a human or other mammal. When administered to an animal such as a human, the composition or compound is preferably administered in the form of a pharmaceutical composition containing, for example, a compound of the present invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiological buffered saline, or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are intended for administration to humans, in particular for invasive routes of administration (i.e., routes such as injection or implantation that preclude transport or diffusion across an epithelial barrier), the aqueous solution is pyrogen-free or substantially pyrogen-free . Excipients may be selected, for example, to provide delayed release of the agent or to selectively target one or more cell types, tissues or organs. The pharmaceutical composition may be in the form of dosage units such as tablet, capsule (including break-open capsule and gelatin capsule), granule, lyophilisate for reconstitution, powder, solution, syrup, suppository, injection and the like. The composition may also be contained in a transdermal delivery system, such as a skin patch. The composition may also be in a solution suitable for topical use, such as eye drops.

The pharmaceutically acceptable carrier may contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or enhance absorption of a compound, such as a compound of the present invention. Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose or dextrans, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The pharmaceutical composition formulation may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (drug) may also be a liposome or other polymer matrix into which, for example, a compound of the present invention may be included. Liposomes, such as liposomes containing phospholipids or other lipids, are non-toxic, physiologically acceptable and metabolizable carriers that are relatively easy to manufacture and administer.

The compositions can readily be presented in dosage unit form and can be prepared using any methods well known in the pharmaceutical field. The amount of active ingredient that can be combined with the carrier material to form a single dosage form will vary depending on the organism being treated and the particular route of administration. The amount of active ingredient that can be combined with the carrier material to form a single dosage form will generally be that amount of the compound that provides a therapeutic effect. In general, on a one hundred percent basis, the amount will range from about 1 percent to about 99 percent of the active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

Methods for preparing such formulations or compositions include the step of combining an active compound, such as a compound of the present invention, with a carrier and optionally one or more auxiliary ingredients. In general, the formulations are prepared by uniformly and thoroughly combining the compound of the present invention with liquid carriers or finely divided solid carriers, or both, and then, if necessary, molding the product.

The compositions of the present invention suitable for oral administration may take the form of capsules (including break-open capsules and gelatin capsules), wafers, pills, tablets, lozenges (with a flavored base, usually sucrose and gum acacia or tragacanth), lyophilisate, powders, granules, or in the form of a solution or suspension in an aqueous or non-aqueous liquid, or in the form of an oil-in-water or water-in-oil emulsion, or in the form of an elixir or syrup, or in the form of lozenges (with an inert base such as gelatin and glycerin, or sucrose and acacia gum) and/or in the form of oral rinses and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. The compositions or compounds may also be administered as a bolus, electuary, or paste.

In some embodiments, the present invention provides a combination comprising a compound of formula (I) and a pharmaceutically acceptable salt or stereoisomer of the compound, and one or more therapeutically active co-administered agents.

Some embodiments of the present invention provide the use of the compounds of the present invention for the preparation of a medicament for the treatment of cancer.

Methods of treatment.

In some embodiments, the present invention provides compounds for use as a drug.

Some embodiments of the present invention provide the use of the compounds of the present invention for the manufacture of a medicament.

In some embodiments, the present invention provides a method of treating cancer or a proliferative disease, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer of the compound.

In some embodiments, the present invention provides a method of inhibiting tumor cell growth and/or metastasis by administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer of the compound.

Some embodiments of the present invention provide methods for treating cancer or a proliferative disease by administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer of the compound.

In some embodiments, the cancer or proliferative disease is selected from solid tumor, benign or malignant tumor, brain, kidney, liver, stomach, vaginal, ovarian, stomach, breast, bladder, colon, prostate, pancreas, lung tumors , cervix, testicle, skin, bones or thyroid; sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, head and neck tumors, epidermal hyperproliferation, psoriasis, prostate hyperplasia, neoplasia, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphoma, stroke Zhkinskaya and non-Hodgkin's, breast carcinoma, follicular carcinoma, papillary carcinoma, seminoma, melanoma; hematologic malignancies selected from leukemia, diffuse large B-cell lymphoma (DLBCL), activated B-cell DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma/leukemia, acute lymphocytic leukemia, B- cellular prolymphocytic leukemia, lymphoplasmacytic leukemia, Waldenström's macroglobulinemia (WM), splenic marginal zone lymphoma, intravascular large B-cell lymphoma, plasmacytoma and multiple myeloma.

In some embodiments, the cancer or proliferative disease is selected from lymphoma, leukemia, breast cancer, lung cancer (non-small cell lung cancer), colon cancer, colorectal cancer, brain cancer (glioma, medulloblastoma, and ependymoma); familial adenomatous polyposis (FAP) and Barrett's esophagus.

Some embodiments of the present invention provide compounds of formula (I), a pharmaceutically acceptable salt or stereoisomer thereof, for use in the treatment of cancer, an inflammatory disease, an autoimmune disease, chronic graft-versus-host disease, a metabolic disorder, an inherited disease, a hormone-related disease, immunodeficiency disorders, conditions associated with cell death, destructive bone disorder, thrombin-induced platelet aggregation, liver disease or cardiovascular disorder.

In some embodiments, the present invention provides compounds of formula (I), a pharmaceutically acceptable salt or stereoisomer thereof, for use in the management of cytokine release syndrome associated with T cell recruitment therapy, including CAR-T therapy.

Some embodiments provide the use of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof for the manufacture of a medicament for the treatment of cancer, an inflammatory disease, an autoimmune disease, chronic graft-versus-host disease, a metabolic disorder, an inherited disease, a hormone-related disease, immunodeficiency disorders, conditions associated with cell death, destructive bone disorder, thrombin-induced platelet aggregation, liver disease or cardiovascular disorder.

In some embodiments, there is provided a method of managing cytokine release syndrome associated with T cell recruitment therapy, including CAR-T therapy, comprising administering a therapeutically effective amount of a compound of formula (I).

Some embodiments provide the use of the compounds of the present invention for the manufacture of a medicament for the treatment and prevention of a proliferative disease. In some embodiments, the proliferative disease is cancer. In some embodiments, the proliferative disease is a benign neoplasm, angiogenesis-associated disease, an inflammatory disease, an autoinflammatory disease, a chronic graft-versus-host disease, or an autoimmune disease. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is Hodgkin lymphoma. In some embodiments, the cancer is non-Hodgkin's lymphoma. In some embodiments, the cancer is Burkitt's lymphoma. In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the cancer is a MALT lymphoma. In some embodiments, the cancer is diffuse large B-cell terminal center B-cell lymphoma (GCB-DLBCL) or primary mediastinal B-cell lymphoma (PMBL). In some embodiments, the cancer is activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL).

In any of the above embodiments, the cancer or proliferative disorder is selected from the group consisting of solid tumor, benign or malignant tumor, brain, kidney, liver, stomach, vaginal, ovarian, stomach, breast, bladder, colon, prostate, pancreas, lung, cervix, testicle, skin, bones or thyroid; sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, head and neck tumors, epidermal hyperproliferation, psoriasis, prostate hyperplasia, neoplasia, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphoma, stroke Zhkinskaya and non-Hodgkin's, breast carcinoma, follicular carcinoma, papillary carcinoma, seminoma, melanoma; hematologic malignancies selected from leukemia, diffuse large B-cell lymphoma (DLBCL), activated B-cell DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma/leukemia, acute lymphocytic leukemia, B- cellular prolymphocytic leukemia, lymphoplasmacytic leukemia, Waldenström's macroglobulinemia (WM), splenic marginal zone lymphoma, intravascular large B-cell lymphoma, plasmacytoma and multiple myeloma.

Some embodiments of the present invention provide the use of the compounds of the present invention to modulate signaling pathways affecting cancer, inflammatory disorders, or autoimmune diseases.

In some embodiments, the pathway affected by the compounds of the present invention includes growth-enhancing pathways derived from cell surface receptors.

In some embodiments, the growth-enhancing pathway affected by the compounds of the present invention includes the epidermal growth factor receptor (EGFR) signaling pathway.

In some embodiments, the compounds of the present invention inhibit one or more components of the EGFR signaling pathway, including K-Ras, B-Raf, MEK, and ERK.

In some embodiments, the growth-enhancing pathway affected by the compounds of the present invention includes the B-cell receptor (BCR) pathway.

In some embodiments, the compounds of the present invention inhibit one or more components of the BCR pathway, including the CARD11-BCL10-MALT1 (CBM) complex.

In some embodiments, the compounds of the present invention inhibit one or more components of the BCR pathway, resulting in inhibition of cleavage of MALTI protease substrates, including A20 and ReIB.

In some embodiments, the compounds of the present invention inhibit one or more components of the BCR pathway, resulting in inhibition of the transcription factor NFkB.

In some embodiments, the compounds of the present invention inhibit one or more components of the BCR pathway, resulting in inhibition of the secretion of cytokines such as IL-6 and IL-10.

In some embodiments, the pathway affected by the compounds of the present invention includes the T cell receptor (TCR) pathway.

In some embodiments, the compounds of the present invention inhibit one or more components of the TCR pathway, resulting in inhibition of the secretion of cytokines such as IL-17 and IFN-γ.

The treatment method(s) of the present invention comprises administering a safe and

- 20045414 an effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt or stereoisomer of the said compound, to a patient (in particular a human) in need of said treatment.

Some embodiments of the present invention provide the use of compounds of the present invention to manage cytokine release syndrome associated with T cell recruitment therapy.

Some embodiments of the present invention provide the use of the compounds of the present invention for the management of cytokine release syndrome associated with chimeric antigen receptor expressing T cell (CAR-T) therapy.

In some embodiments, a compound of formula (I) can be used to treat cancer, including lymphoma and leukemia.

In some embodiments, a compound of formula (I) can be used to treat cancer, including breast cancer.

In some embodiments, a compound of formula (I) can be used to treat cancer, including lung cancer, particularly non-small cell lung cancer.

In some embodiments, a compound of formula (I) can be used to treat cancer, including colon cancer and colorectal cancer.

In some embodiments, a compound of formula (I) can be used to treat cancer, including brain cancer, including glioma, medulloblastoma, and ependymoma.

In some embodiments, a compound of formula (I) can be used to treat cancer, including familial adenomatous polyposis (FAP).

In some embodiments, a compound of formula (I) can be used to treat cancer, including Barrett's esophagus.

Definitions.

Unless otherwise specified, all technical and scientific terms used herein have the meanings commonly understood by those skilled in the art. In the specification and appended claims, unless otherwise indicated, the following terms have the meanings indicated to facilitate understanding of the present invention.

Singular forms include plural references unless the context clearly requires otherwise.

The terms optional or optional mean that the following phenomenon or circumstance may or may not be observed, and that the description includes both cases of the presence of the phenomenon or circumstance and cases of its absence. For example, optionally substituted alkyl refers to alkyl that may be substituted, as well as the case where alkyl is not substituted.

The term substituted refers to moieties containing substituents that replace hydrogen at one or more carbon atoms in the main chain. It is understood that substitution or substituted includes the express assumption that said substitution is consistent with the permissible valences of the substituted atom and the substituent, and that the substitution results in the formation of a stable compound, for example, that does not undergo spontaneous transformations such as rearrangement, cyclization, elimination, etc. . As used herein, the term substituted includes all acceptable substituents for organic compounds. In broad terms, acceptable substituents include acyclic and cyclic, branched and straight-chain, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. There may be one or more permissible substituents, and they may be the same or different for the respective organic compounds. In the present invention, heteroatoms such as nitrogen may have hydrogen substituents and/or permissible organic substituents as described herein corresponding to the valences of the heteroatoms. Substituents may include any substituents as defined herein, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl or acyl), thiocarbonyl (such as thioester, thioacetate or thioformate), alkoxy, oxo, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heteroaryl, heterocycloalkyl, aralkyl, or an aromatic or heteroaromatic moiety. Those skilled in the art will understand that a substituent, in turn, may itself be substituted. Unless explicitly indicated by the term unsubstituted, references to chemical moieties should be considered to include substituted variants. For example, reference to an aryl group explicitly includes both substituted and unsubstituted variants.

The term alkyl as used herein refers to saturated aliphatic groups, including, without limitation, Ci-Cio linear alkyl groups or C3-C ₁₀ branched alkyl groups. Preferably, alkyl refers to _C1 -C6 linear alkyl groups or C3-C6 branched alkyl groups. Most preferably, the alkyl group is a C ₁ -C ₄ linear alkyl group or a C ₃ -C ₈ branched alkyl group. Examples of alkyl include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neopentyl, 1 -hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl and 4-octyl. The alkyl group may optionally be substituted.

The term heteroalkyl as used herein refers to a straight or branched alkyl group in which one or more carbon atoms are replaced by a heteroatom selected from S, O, P and N; where the alkyl group is as defined above. Examples of heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides and alkyl disulfides. The group may be a terminal group or a bridging group.

The term alkenyl as used herein refers to a carbon chain containing at least one carbon-carbon double bond, which chain may be straight, branched, or a combination thereof. Examples of alkenyl include, but are not limited to, vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, and 2-methyl-2-butenyl.

Likewise, alkenylene refers to a divalent alkenyl radical as defined above.

The term alkynyl refers to linear or branched carbon chains with one or more triple bonds and a number of atoms ranging from 2 to 6.

Likewise, alkenylene refers to a divalent alkynyl radical as defined above.

The term halo or halogen, alone or in combination with other terms, means fluorine, chlorine, bromine or iodine.

The term haloalkyl means an alkyl substituted with one or more halogen atoms, wherein the halogen and alkyl group are as defined above. The term halo, interchangeably with halogen, refers to F, Cl, Br or I. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl and 2,2,2-trifluoroethyl.

The term hydroxy or hydroxyl, alone or in combination with other terms, means OH.

The term hydroxyalkyl or hydroxyalkyl means alkyl substituted with one or more hydroxyl groups, the alkyl groups being as defined above. Examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl and propan-2-ol.

The term ester as used herein refers to the group -C(O)OR11, where R11 represents a hydrocarbyl group.

The term carboxy or carboxylic acid refers to the group represented by the formula CO2H.

The term thioester refers to the group -C(O)SR11 or -SC(O)R11, where R ¹¹ represents hydrocarbyl.

The term hydrocarbyl as used herein represents a group containing a carbon atom directly bonded to the remainder of the molecule, which is hydrocarbon in nature.

The term oxo as used herein refers to the =O group.

The term alkoxy as used herein refers to an -O-alkyl group, where the alkyl groups are as defined above. Examples of C ₁ -C ₁₀ -alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy or t-butoxy. The alkoxy group may optionally be substituted with one or more suitable groups.

The term alkoxyaryl as used herein refers to an -O-alkyl group that is attached to an aryl group, wherein the alkyl and aryl group are as defined herein.

The term cyano as used herein refers to the -CN group.

The term amino as used herein refers to the -NH2 group.

The term amide or amido as used herein refers to the -CONH2 group.

The term alkylamino or cycloalkylamino as used herein refers to a -NH2 group, the nitrogen atom of said group being bonded to one or two alkyl or cycloalkyl groups, respectively. Examples of alkylamino or cycloalkylamino groups include, but are not limited to, -NHCH3 and -NH-cyclopropyl. The term alkylamino also includes dialkylamino groups (eg -N(CH ₃ )2).

Aminoalkyl refers to an alkyl group as defined above, with one or more hydrogen atoms in the alkyl group replaced by an amino group as defined above. Examples of aminoalkyl groups include, but are not limited to, -CH2NH2, -CH2CH2NH2, -CH(CH ₃ )NH2, -CH2CH(CH ₃ )NH2. The aminoalkyl group may be unsubstituted or substituted by one or more suitable groups.

The term cycloalkyl as used herein, alone or in combination with other terms, means a -C ₃ -C ₁₀ saturated cyclic hydrocarbon ring. The cycloalkyl may be a single ring, typically containing from 3 to 7 carbon atoms in the ring. Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Alternatively, the cycloalkyl may be polycyclic or contain more than one ring. Examples of polycyclic cycloalkyls include bridged, fused and spirocyclic carbocyclyls.

The term heterocycloalkyl as used herein refers to a non-aromatic, saturated or partially saturated, monocyclic or polycyclic 3-15 membered ring system containing at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O )2, NH or C(O), while the remaining atoms in the ring are independently selected from the group consisting of carbon, oxygen, nitrogen and sulfur. The term heterocycloalkyl also refers to a bridged bicyclic ring system containing at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O) ₂ , NH or C(O). Examples of heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxidothiomorpholinyl, oxa piperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl , dihydropyranyl, indolinyl, indolinylmethyl, azabicyclooctanyl, azocinyl, chromanyl, xanthenyl and N-oxides of these compounds. The addition of a heterocycloalkyl substituent can occur via a carbon atom or a heteroatom. The heterocycloalkyl group may be optionally substituted with one or more suitable groups from the above groups. Preferably, heterocycloalkyl refers to a 5-6 membered ring selected from the group consisting of azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4- dioxanil and N -oxides of these compounds. More preferably, heterocycloalkyl includes azetidinyl, pyrrolidinyl, morpholinyl and piperidinyl. All heterocycloalkyls are optionally substituted with one or more of the above groups.

The term (heterocycloalkyl)alkyl as used herein refers to an alkyl group with an attached heterocycloalkyl group, where alkyl and heterocycloalkyl groups are as defined herein.

The term heteroaryl as used herein refers to an aromatic heterocyclic ring system containing from 5 to 20 ring atoms, for example 5 to 10 ring atoms, which may contain a single ring (monocyclic) or multiple rings (bicyclic, tricyclic or polycyclic), condensed or covalently linked. Preferably, the heteroaryl is a 5-6 membered ring. The rings may contain from 1 to 4 heteroatoms selected from N, O and S, the N or S atoms being optionally oxidized, or the N atom being optionally quaternized. Any suitable position on the ring of the heteroaryl moiety can be covalently linked to a desired chemical structure.

Examples of heteroaryl include, but are not limited to, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, N-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzofou wounded , benzothienyl, benzotriazinyl, phthalazinyl, tianthrene, dibenzofuranyl, dibenzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purinyl, pteridinyl, 9H-carbazolyl, α-carboline, indolizinyl, benzoisothiazolyl, benzo xazolyl, pyrrolopyridyl, pyrazolopyrimidyl , furopyridinyl, purinyl, benzothiadiazolyl, benzooxadiazolyl, benzotriazolyl, benzotriadiazolyl, carbazolyl, dibenzothienyl, acridinyl and the like. Preferably, heteroaryl refers to a 5-6 membered ring selected from the group consisting of furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, N-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl. More preferably, pyrazolyl, pyridyl, oxazolyl and furanyl. All heteroaryls are optionally substituted with one or more of the above groups.

The term aryl as used herein represents an optionally substituted monocyclic, bicyclic or polycyclic aromatic hydrocarbon system containing from about 6 to 14 carbon atoms. Examples of the C ₆ -C ₁ 4-aryl group include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, fluorenyl, indanyl, biphenylenyl and acenaphthyl. The aryl group may be unsubstituted or substituted by one or more suitable groups.

The term aryloxy as used herein refers to the group -O-aryl, where the aryl groups are as defined above. Examples of the aryloxy group include, but are not limited to, phenoxy or naphthyloxy.

The term acyl refers to the group R-CO-, where R represents an optionally substituted alkyl group as defined above. Examples of acyl groups include, but are not limited to, _CH3CO- , CH3CH2CO-, CH3CH2CH2CO- or (CH3)2CHCO-.

The term heteroatom as used herein means a sulfur, nitrogen or oxygen atom.

The term compound(s) as used herein includes compounds of the present invention.

The terms contains or containing in the present specification are generally used in the sense of inclusion, i.e. as allowing the presence of one or more features or components.

The term or as used herein means and/or unless otherwise specified.

- 23 045414

The term including, as well as its other forms such as include, includes and included, is non-limiting as used herein.

The term composition as used herein is intended to cover a product containing certain ingredients in certain amounts, as well as a product obtained, directly or indirectly, from a combination of certain ingredients in certain amounts. Pharmaceutically acceptable means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and must not be harmful to the recipient of the formulation.

The term pharmaceutical composition as used herein refers to a composition containing a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

The pharmaceutical composition typically contains from about 1% to 99%, for example from about 5% to 75%, or from about 10% to about 30% by weight of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. The amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in a pharmaceutical composition may range from about 1 mg to about 1000 mg, or from about 2.5 mg to about 500 mg, or from about 5 mg to about 250 mg, or any range within the wider range of 1 mg to 1000 mg, or above or below the above range.

The terms treat, treating and treatment as used herein refer to a method of alleviating or stopping a disease and/or its accompanying symptoms.

The terms prevent, prevent and prevent as used herein refer to a method of preventing the onset of a disease and/or its accompanying symptoms, or preventing the occurrence of a disease in a subject. Also, the terms prevent, prevent and prevent as used herein include delaying the onset of a disease and/or its accompanying symptoms, and reducing the risk of a disease occurring in a subject.

The term subject as used herein may be used interchangeably with the term patient and refers to an animal, preferably a mammal, and most preferably a human.

The term therapeutically effective amount as used herein refers to an amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer of the same compound, or a composition containing a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer of the same compound, effective to provide the desired therapeutic response in a particular person. a patient suffering from a disease or disorder, in particular when using the compound for diseases or disorders associated with cancer. In particular, the term therapeutically effective amount includes that amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof which, when administered, induces a beneficial change in the disease or disorder being treated, or is sufficient to prevent the development of, or alleviate to some extent symptoms of the disease or disorder being treated in the subject. With regard to the therapeutic amount of a compound, it should be considered that the amount of compound used for treatment should be low enough to avoid unnecessary or severe side effects, which is within the scope of sound medical judgment. The therapeutically effective amount of a compound or composition will vary depending on the particular condition being treated, the severity of the condition being treated or prevented, the duration of treatment, the nature of the concomitant therapy, the age and health status of the patient, the particular compound or composition used, and the particular pharmaceutical used. acceptable medium.

The term pharmaceutically acceptable salt refers to the product obtained by reacting a compound of the present invention with a suitable acid or base. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic bases, such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn and Mn salts. Examples of pharmaceutically acceptable non-toxic acid addition salts include amino and inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, 4-methylbenzenesulfonate or p-toluenesulfonate and the like salts. Certain compounds of the present invention (compounds of formula (I)) can form pharmaceutically acceptable salts with various organic bases such as lysine, arginine, guanidine, diethanolamine or metformin. Suitable base salts include, without limitation, aluminum, calcium, lithium, magnesium, potassium, sodium or zinc salts.

Pharmaceutically acceptable means suitable for the preparation of a pharmaceutical composition, i.e., generally safe, non-toxic and not biologically or otherwise objectionable, and includes substances suitable for pharmaceutical use in animals and humans.

The present invention also provides methods for preparing compound compositions

- 24 045414 according to the present invention for pharmaceutical administration.

In a preferred embodiment, when such pharmaceutical compositions are intended for administration to humans, in particular for invasive routes of administration (i.e., routes such as injection or implantation that preclude transport or diffusion across an epithelial barrier), the aqueous solution is pyrogen-free or substantially pyrogen-free. Excipients may be selected, for example, to provide delayed release of the agent or to selectively target one or more cell types, tissues or organs. The pharmaceutical composition may be in the form of dosage units such as tablet, capsule (including break-open capsule and gelatin capsule), granule, lyophilisate for reconstitution, powder, solution, syrup, suppository, injection and the like. The composition may also be contained in a transdermal delivery system, such as a skin patch. The composition may also be in a solution suitable for topical use, such as eye drops.

The term stereoisomers refers to any enantiomers, diastereoisomers or geometric isomers of the compounds of formula (I) if they are chiral or contain one or more double bonds. When the compounds of formula (I) and related formulas are chiral, they may exist in racemic or optically active enantiomeric form. It should be understood that the present invention covers all stereochemical isomeric forms, including diastereomeric, enantiomeric and epimeric forms, as well as d-isomers and I-isomers and mixtures thereof. Individual stereoisomers of compounds can be synthesized from commercially available starting materials containing chiral centers, or by synthesizing mixtures of enantiomeric products followed by resolution, such as conversion to a mixture of diastereoisomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatography columns, or any other a suitable method known in the art. Starting compounds with defined stereochemistry are commercially available or can be prepared and separated using techniques known in the art. In addition, the compounds of the present invention may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, (E) (entgegen) and (Z) (zusammen) isomers, as well as corresponding mixtures of isomers.

The compounds of the present invention can be administered as a single drug or as a pharmaceutical composition in which the compound is mixed with various pharmacologically acceptable materials.

The compounds of the present invention are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared using procedures well known in the pharmaceutical field and contain at least one compound of the present invention. The pharmaceutical compositions of the present invention contain one or more compounds of the present invention and one or more pharmaceutically acceptable excipients. In general, pharmaceutically acceptable excipients are approved by regulatory authorities or are generally considered safe for use in humans or animals. Pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents, viscosity increasing agents and solvents.

The pharmaceutical composition can be administered by oral, parenteral or inhalation routes. Examples of parenteral administration include injection, subcutaneous, transmucosal, nasal and pulmonary routes of administration.

Examples of suitable carriers include, but are not limited to, water, saline solutions, alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, calcium sulfate, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia gum, stearic acid, lower alkyl and cellulose ethers, silicic acid, fatty acids, fatty acid amines, monoglycerides and diglycerides of fatty acids, esters of fatty acids and polyoxyethylene.

The pharmaceutical compositions may also contain one or more pharmaceutically acceptable auxiliary agents, wetting agents, suspending agents, preservatives, buffering agents, sweeteners, flavoring agents, coloring agents, or any combination of the foregoing agents.

Pharmaceutical compositions may be in conventional form, for example, tablets, capsules, solutions, suspensions, injectables or topical products. In addition, the pharmaceutical composition of the present invention can be formulated to provide a desired release profile.

Administration of the compounds of the present invention in pure form or in an appropriate pharmaceutical composition can be accomplished using any of the accepted routes for administering pharmaceutical compositions. The route of administration may be any route that provides effective transport of the active compound of the present invention to a suitable or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, buccal, dermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular, or topical.

Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or granule form), lozenges and lozenges.

Liquid formulations include, but are not limited to, syrups, emulsions, and sterile injectable liquids such as suspensions or solutions.

Topical dosage forms of the compounds include ointments, pastes, creams, lotions, powders, solutions, eye or ear drops, impregnated dressings, and may contain appropriate conventional additives such as preservatives, solvents to promote drug penetration.

The pharmaceutical compositions of the present invention can be prepared using conventional techniques known in the literature.

Suitable dosages of the compounds for use in treating diseases or disorders described herein can be determined by one skilled in the art. Therapeutic doses are generally determined based on varying dose trials in humans, based on preliminary data obtained from animal studies. Doses should be sufficient to obtain the desired therapeutic benefit without causing unwanted side effects. The route of administration, dosage forms and suitable pharmaceutical excipients can also be used and adjusted by those skilled in the art. All changes and modifications are considered to be within the scope of the present invention.

In one embodiment, the compounds of the present invention may also contain different isotope ratios for one or more of the atoms that make up the compounds. For example, the present invention also covers isotopically tagged embodiments that are identical to the illustrated embodiments except that one or more atoms in the compound are replaced by atoms whose atomic mass or mass number differs from the predominant atomic mass or mass number for the atom in nature. . All isotopes of any of these atoms or elements are included within the scope of the compounds of the present invention and the uses of said compounds. Examples of isotopes that may be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as ^2H (D), ^3H , ^nC , ^13C , ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³² P, ³³ P, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I and ¹²⁵ I. Isotopically labeled compounds of the present invention can generally be obtained using techniques similar to those shown in the diagrams and/or examples below, by replacing an unlabeled reagent with an isotopically labeled reagent.

The following abbreviations have the following definitions: BBr ₃ - boron tribromide; DCM - dichloromethane; DMA - dimethylacetamide; DMSO - dimethyl sulfoxide; DIPEA - N,N-diisopropylethylamine; DPPA diphenylphosphoryl azide; EDCl or EDC.HCl - 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; NaHCO ₃ - sodium bicarbonate; EtOH - ethanol; EtI - ethyl iodide; dioxane.HCl - hydrochloric acid in dioxane; Na ₂ SO ₄ - sodium sulfate; NaHMDS - sodium bis(trimethylsilyl)amide; Na ₂ CO ₃ - sodium carbonate; Na ₂ S ₂ O ₃ - sodium thiosulfate; H ₂ O - water; ush - widened; A - angstrom; °C - degree Celsius; conc. - concentrated; CHCl ₃ - chloroform; CDCl ₃ //chloroform-d - deuterated chloroform; DMSO-d ₆ - deuterated dimethyl sulfoxide; CH ₂ Cl ₂ - DCM - dichloromethane; DMF - N,Ndimethylformamide; Et ₂ O - diethyl ether; g - gram; h - hour; HOBT - hydroxybenzotriazole; 1H - proton; HCl - hydrochloric acid; Hz - hertz; IPA - isopropyl alcohol; J is the interaction constant; LC-MS - liquid chromatography - mass spectroscopy; LiCl - lithium chloride; LiOH lithium hydroxide; HATU - 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate; HPLC - high performance liquid chromatography; chiral HPLC - chiral high performance liquid chromatography; MeOH - methanol; M - molar; MHz - megahertz (frequency); MS - mass spectroscopy; mmol - millimole; ml - milliliter; min - minute; mole - mole; M+ - molecular ion; m/z is the ratio of mass to charge; N - normality; NMR - nuclear magnetic resonance; NMM - N-methylmorpholine; Et ₃ N or TEA - triethylamine; ppm - parts per million; ct/CT - room temperature; c - singlet; d - doublet, t - triplet; kv - quartet; m - multiplet; dd - doublet of doublets; td - triplet of doublets; kvd - quartet of doublets; ddd - doublet of doublets of doublets; dt - doublet of triplets; ddt - doublet of doublets of triplets; p - pentet; TBTU - O-(benzotriazol-1-yl)-N,N,N',N'tetramethyluronium tetrafluoroborate; TLC - thin layer chromatography; THF - tetrahydrofuran; % percent; µm - micrometer; µl - microliter; µmol - micromole; δ - delta; without - anhydrous; and ± is a racemic mixture.

General methods of obtaining.

The following general guidance applies to all experimental procedures described. Unless otherwise stated, experiments were performed under a positive nitrogen pressure atmosphere, the temperature indicated being the ambient temperature (i.e., oil bath temperature). Reagents and solvents obtained from suppliers were used as is without additional drying or purification.

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The molarities given for reagent solutions are approximate and have not been verified by preliminary titration with a standard. All reactions were stirred using a magnetic stirrer armature. Cooling to sub-zero temperatures was carried out with acetone/dry ice or ice/salt. Magnesium sulfate and sodium sulfate were used interchangeably to dry the solvent after the reaction. Removing solvents under reduced pressure or vacuum or concentrating the reaction mixture meant distilling off the solvents on a rotary evaporator.

The compounds of the present invention can be prepared using chemical synthetic methods, examples of which are given herein. It is understood that the order of steps in the methods may vary, that the specific reagents, solvents, and reaction conditions specified may be substituted for others, and that vulnerable moieties may be protected and then removed as needed.

The specific method for synthesizing the compounds of the present invention is described in detail in the experimental section.

The present invention will be illustrated by several examples, which should not be construed as limiting the scope of the present invention.

The present invention relates to novel substituted alkynylene derivatives of formula (I) useful as anticancer agents and to pharmaceutical compositions that can be used in the methods of the present invention for the treatment or prevention of proliferative diseases and conditions, including various types of lymphomas.

Each embodiment is presented for the purpose of explaining the present invention and not for the purpose of limiting the present invention. In fact, those skilled in the art will appreciate that various modifications and changes may be made regarding the compounds, compositions and methods of the present invention without departing from the scope and spirit of the present invention. For example, a feature demonstrated or described as part of one embodiment may be applied to another embodiment to result in an additional embodiment. It is therefore intended that the present invention include such modifications and changes and their equivalents. Other objects, features and aspects of the present invention are disclosed or made explicit in the following detailed description. One of ordinary skill in the art will appreciate that the present discussion is a description of exemplary embodiments and should not be construed as limiting the broader aspects of the present invention.

experimental part

Unless otherwise stated, recovery involves partitioning the reaction mixture between the organic and aqueous phases, separating the layers and drying the organic layer over anhydrous sodium sulfate, filtering and evaporating the solvent. Purification, unless otherwise specified, involves purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether of suitable polarity as the mobile phase.

The analysis of the compounds of the present invention, unless otherwise stated, was carried out using general methods well known to those skilled in the art. Although the present invention has been described with reference to certain preferred embodiments, other embodiments will be apparent to one skilled in the art upon consideration of the present description. Below, the present invention will be described using the following examples, which describe in detail the analysis of the compounds according to the present invention.

One skilled in the art will appreciate that many modifications, both materials and methods, can be practically implemented without departing from the scope of the present invention. Some intermediates were carried forward by TLC without further characterization unless otherwise noted.

MS (mass spectral) data indicated in the examples were obtained using equipment - API 2000 LC/MS/MS/Triplequad; Agilent Technologies/LC/MS/DVL/Singlequad; Shimadzu LCMS2020/Singlequad.

The NMR data shown in the examples were obtained using 1H NMR equipment: Varian 400 MHz and Varian 300 MHz.

HPLC in the presented examples was carried out using Agilent Technologies 1200 Series equipment; Agilent Technologies 1100 Series; Shimadzu(UFLC) Prominance; Shimadzu Nexera-UHPLC.

Compounds were purified using CombiFlash® unless otherwise stated.

Intermediate 1: aryl halides.

The following compounds are generally commercially available or can be prepared using techniques well known to those skilled in the art. The following products were used to synthesize the compounds of the present invention and/or their intermediates.

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Intermediate connection Structure IUPAC 1a Oh^L t t 1,2-dichloro-4-iodobenzene 1b cix^^x^i IJ 2-chloro-1-fluoro-4-iodobenzene 1s dx^-xL 1 j 2-chloro-4-iodo-1(trifluoromethyl)benzene 1d a^^xL XT 2-chloro-4-iodo-1-methylbenzene 1e T Ϊ 4-bromo-2-chloro-1-fluorobenzene 1f Λχ/ ¹ / ^sCl 2-chloro-5-iodothiophene ig Clx^br XX Ph'^O'^'^ 1-(benzyloxy)-4-bromo-2-chlorobenzene 1h ci^^^Br Ph^J 0 4-bromo-2-chloro-1-phenoxybenzene 1i F^Nx^^^Br T Ϊ 5-bromo-2-chloroaniline 1j Cl ji X 1-bromo-2,4-dichlorobenzene 1k G ₃ S^xL xx 4-iodo-2-(trifluoromethyl)benzonitrile eleven 2-iodonaphthalene 1m oi 1-iodonaphthalene 1n CQ e o / 2-bromo-6-methoxynaphthalene 1o HJi J H 5-iodo-1H-indazole 1p ^N= \ ^N'xjx,l ΙζΤΓ 4-iodo-1-methyl-1 N-indazole 1q τ x Cl 2-bromo-1-chloro-4-iodo benzene

Intermediate 1r: 4-bromo-1-chloro-2-(1-methylcyclopropyl)benzene

Step 1: 5-bromo-2-chloro-N-methoxy-N-methylbenzamide.

With stirring, N,O-dimethylhydroxylamine hydrochloride (5.46 g, 56.07 mmol), HATU ( 26.6 g, 84.10 mmol) and DIPEA (18.1 g, 140.16 mmol) at RT and stirred for 16 h at RT. After the reaction was completed, the resulting mixture was poured into ice water; the solid was filtered and purified on a combiflash® silica gel column (hexane/EtOAc=90/10) to give the title compound (11.0 g, 82%). LCMS: m/z=277.5 [M] ⁺ .

Step 2: 1-(5-bromo-2-chlorophenyl)ethan-1-one.

With stirring to a solution of 5-bromo-2-chloro-N-methoxy-N-methylbenzamide (step 1) (11.0 g,

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39.49 mmol) in THF (100 ml) was added methylmagnesium bromide (3.0 M in THF) (19.7 ml, 59.24 mmol) at 0°C in an inert atmosphere and stirred for 16 h at RT. After completion of the reaction, the mixture was poured into 1N HCl and extracted with diethyl ether. The ether layer was dried, concentrated and purified on a combiflash® silica gel column (hexane/EtOAc=95/5) to give the title compound (7.0 g, 76.0%). LCMS: m/z=not ionized. The resulting product was used in the next step without further purification.

Step 3: 4-bromo-1-chloro-2-(prop-1-en-2-yl)benzene.

While stirring, n-butyllithium (2.0 M in hexane) (37.5 mL, 75.10 mmol) was added to a solution of methyltriphenylphosphonium bromide (26.8 g, 75.10 mmol) in THF (50 mL) at 0°C . The reaction mixture was stirred for 5 min at 0°C and 1-(5-bromo-2-chlorophenyl)ethan-1-one (step 2) (7.0 g, 30.04 mmol) in THF (50 ml) was added. at 0°C and stirred for 16 h at RT. After completion of the reaction, the mixture was poured into 1N HCl and extracted with diethyl ether. The ether layer was dried and concentrated to give the crude compound. The crude compound was purified on a combiflash® silica gel column (hexane/EtOAc=95/5) to give the title compound (5.0 g, 71.42%). The resulting compound was used in the next step without further purification.

Step 4: 4-bromo-1-chloro-2-(1-methylcyclopropyl)benzene.

With stirring, a solution of diethylzinc (1.0 M in hexane) (43.2 ml, 43.2 mmol) in DCM (25 ml) was slowly added to a solution of TFA (4.9 g, 43.2 mmol) in DCM (15 ml ) at 0°C and stirred for 20 min at 0°C. A solution of diiodomethane (11.5 g, 43.2 mmol) in DCM (30 ml) was added to the reaction mixture at 0°C and stirred for 20 min at 0°C. A solution of 4bromo-1-chloro-2-(prop-1-en-2-yl)benzene (step 3) (2.0 g, 8.65 mmol) in DCM (30 ml) was added to the reaction mixture at RT and stirred within 16 hours with CT scan. The reaction mixture was then diluted with pentane and washed with 1N HCl, saturated NaHCO ₃ solution and brine. The organic layer was dried and concentrated to give the title compound (2.0 g, 94.3%). LCMS: m/z=He ionized.

Intermediate 1s: 4-bromo-2-chloro-N,N-diethylaniline

With stirring, NaHMDS (11.5 mL, 69.68 mmol) was added to a solution of 4-bromo-2-chloroaniline (1.8 g, 8.82 mmol) in dry THF (20 mL), followed by EtI (0.9 ml, 2.95 mmol) at CT. The reaction mixture was stirred at RT for 1 hour. The reaction mixture was poured into aqueous NH ₄ Cl and extracted with EtOAc (2x50 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (1.5 g, 75%) , LCMS: m/z=264.0 [M+2]+.

Intermediate 1t: 5-bromo-2-chloro-N,N-diethylaniline

The target compound was prepared as described in the procedure for the preparation of intermediate-1s. Yield: 76%; LCMS: m/z=262.2 [M+H] ⁺ .

Intermediate 1u: 1-chloro-4-iodo-5-methoxy-2-(1-methylcyclopropyl)benzene.

Step 1: 4-chloro-2-methoxy-5-(1-methylcyclopropyl)aniline.

The target intermediate was synthesized as described in US20140288045 A1 and used in the next step.

Step 2: 1-chloro-4-iodo-5-methoxy-2-(1-methylcyclopropyl)benzene.

With stirring, a solution of 4-chloro-2-methoxy-5-(1-methylcyclopropyl)aniline (0.8 g, 3.97 mmol) in conc. HCl (3.8 ml) and water (3.8 ml) was added to a solution of NaNO ₂ (0.3 g, 4.53 mmol) in water at -5°C. After stirring for 15 min, potassium iodide solution (1.2 g, 7.55 mmol) was added. The reaction mixture was stirred at RT for 30 min. The reaction mixture was extracted with EtOAc (2x50 ml), dried over Na ₂ SO ₄ , concentrated and purified on a combiflash® silica gel column (hexane/ethyl acetate=95/5) to give the title compound (0.8 g, 74%), LCMS: m /z=264.0 [M+2] ⁺ .

Intermediate 1v: 1-chloro-4-iodo-2-methoxy-5-(1-methylcyclopropyl)benzene

The above intermediate was prepared essentially using the method described in US2014/288045A1 and step 2 in the synthesis of intermediate-1u with appropriate changes in reagents, amounts of reagents, solvents and reaction conditions. Yield: 59%; LCMS: no ionization. Transferred to the next stage.

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The following compounds are generally commercially available or can be prepared using techniques well known to those skilled in the art. The following products were used to synthesize the compounds of the present invention and/or intermediates.

Intermediate connection Structure IUPAC 2a ^<^nh ₂ But-Z-in-2-amine (+) 2b ^^νη ₂ 2-methylbut-3-yne-2-amine 2s ^^νη ₂ pent-1-in-3-amine (±) 2d ^<ζΐΗ ₂ 4-methylpent-1-yne-3-amine (±)

The following compounds are generally commercially available or can be prepared using techniques well known to those skilled in the art. The following products were used to synthesize the compounds of the present invention and/or intermediates.

Intermediate connection Structure IUPAC Behind ^T^NHBoc T ret-butyl-but-Z-in-2ylcarbamate (±) 3b ^^MNVos Tert-butyl-(1ethynylcyclopropyl)carbamate

Intermediate 3 c: tert-butyl (1-ethynylcyclopentyl)carbamate

Step 1: 1 -((tert-butoxycarbonyl)amino)cyclopentane-1-carboxylic acid.

While stirring, a 1N solution of NaOH in water (26.0 mL) and di-tert- butyl dicarbonate (1.40 mL, 6.101 mmol) at RT and stirred for 14 hours. The reaction mixture was poured into ice water and extracted with DCM. The combined DCM layers were washed with water and brine and dried over sodium sulfate; evaporated under reduced pressure to give the title compound (crude 1.201 g). LCMS: m/z=230.3 [M+H]+.

Step 2: 1-((tert-butoxycarbonyl)amino)cyclopentane-1-carbonic (isobutylcarbonic) anhydride.

While stirring, 4-methylmorpholine (0.58 mL, 5.286 mmol) was added to a suspension of 1-((tert-butoxycarbonyl)amino)cyclopentane-1-carboxylic acid (1.20 g, 5.234 mmol) in dimethoxyethane (30.0 mL). , isobutyl chloroformate (0.68 mL, 5.286 mmol) at -15°C and stirred for 1 hour. The reaction mixture was allowed to warm to RT and stirred for an additional 1 hour, then the reaction mixture was evaporated under reduced pressure to give the title compound (crude 1.782 g). The resulting crude compound was used in the next step without further purification.

Step 3: tert-butyl (1-(hydroxymethyl)cyclopentyl)carbamate.

Sodium borohydride (0.78 g, 27.019 mmol) was added to a suspension of 1-((tert-butoxycarbonyl)amino)cyclopentane-1-carboxylic (isobutylcarbonic) anhydride (1.780 g, 5.404 mmol) in dimethoxyethane (20.0 mL) with stirring. in water (3.0 ml) at -5°C dropwise and stirred at RT for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined ethyl acetate layers were washed with water, brine, dried over sodium sulfate and evaporated under reduced pressure to give the title compound (0.903 g, 77.84%).

The resulting compound was used in the next step without further analysis.

Step 4: tert-butyl (1-formylcyclopentyl)carbamate.

While stirring, Dess-Martin periodinane (2.51 g, 5.918 mmol) was added in portions at 0° to a suspension of tert-butyl-(1-(hydroxymethyl)cyclopentyl)carbamate (0.980 g, 4.552 mmol) in dichloromethane (25.0 ml). C and then stirred at RT for 2 hours. The reaction mixture was poured into hexane, filtered through Celite® and washed with DCM. The collected filtrate was dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by a Combiflash® silica gel column (hexane/ethyl acetate=90/10) to obtain the title compound (0.540 g, 55.67%). Resulting connection

- 30 045414 was used in the next stage without additional analysis.

Step 5: tert-butyl (1-ethynylcyclopentyl)carbamate.

While stirring, dimethyl (2-oxopropyl)phosphonate (0.466 g, 2.813 mmol) was added to a suspension of 4-acetamidobenzenesulfonyl azide (0.732 g, 3.047 mmol) in acetonitrile (30.0 mL) at 0 °C and stirred at RT for 2 h Add tert-butyl (1formylcyclopentyl)carbamate (0.980 g, 4.552 mmol) in ethanol (30.0 mL) dropwise to the reaction mixture at RT and stir for 2 hours. The reaction mixture is filtered through a pad of Celite®. The collected filtrate was evaporated under reduced pressure. The resulting residue was purified by a Combiflash® silica gel column (hexane/ethyl acetate=95/05) to obtain the title compound (0.300 g, 61.22%). LCMS: not ionized. The resulting product was used without further purification.

The following compounds are generally commercially available or can be prepared using techniques well known to those skilled in the art. The following products were used to synthesize the compounds of the present invention and/or intermediates.

Intermediate connection Structure IUPAC 4a I^^NBoc HN^ Tert-butyl-piperazine-1carboxylate 4b ^x^NHBoc h ₂ n^^ Cis-tert-butyl-((1 s,4s)-4aminocyclohexyl)carbamate (±). 4s BocN^>— / \lH Tert-butyl-3-(piperazin-1-yl)azetidine-1-carboxylate 4d 4e ^ ^NHHN ? 0 ¹ /NH piperazin-2-one (1R,2R)-N1,N2- dimethylcyclohexane-1,2-diamine 4f TFA H 0 0 1-(2,2,2-trifluoroacetyl)-1A ⁴ piperidin-4-one

Intermediate 5: tert-butyl 4-(chlorocarbonyl)piperazine-1-carboxylate o

CI^N^

O ¹

To a solution of tert-butyl-piperazine-1-carboxylate (10.0 g, 53.76 mmol) in DCM (50 ml) was added pyridine (6.37 g, 80.64 mmol) and triphosgene (7.97 g, 26 .88 mmol, dissolved in 50 ml DCM) at 0°C. The resulting yellow solution was stirred at RT for 1 hour. The reaction mixture was partitioned between DCM and 1N HCl (150 ml); the DCM layer was dried and concentrated to give the title compound (11.8 g, 89%). The resulting compound was used in the next step without further purification.

The following intermediates were prepared essentially using the method described in Bioorganic & Medicinal Chemistry Letters, 2000, Vol. 10, No. 20, pp. 2357-2360, with appropriate changes in reagents, amounts of reagents, solvents and reaction conditions.

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Intermediate connection Structure IUPAC 5a ABOUT ^^NHBoc T ret-butyl-(1-(chlorocarbonyl)piperidin-4-yl)carbamate 5b ABOUT WNBoc T ret-butyl-3-(4-(chlorocarbonyl)piperazin-1-yl)azetidine-1carboxylate

The following compounds are generally commercially available or can be prepared using techniques well known to those skilled in the art. The following products were used to synthesize the compounds of the present invention and/or intermediates.

Intermediate connection Structure IUPAC 6a O CIH.HN^J 1-(piperazin-1-yl)prop-2-en-1-one 6b TFA.HN^ O ABOUT Ethyl-(E)-4-oxo-4-(4-(2,2,2trifluoroacetyl)-4A ⁴ -piperazin-1 yl)-but-2-enoate 6s TFA.N^ 4-(1H-imidazol-1-yl)piperidin-1ium 2,2,2-trifluoroacetate 6d TFAHN^o And 1 -(1 -(2,2,2-trifluoroacetyl)-1I4piperidin-4-yl)-1H-pyrrole-2,5dione

Intermediate 6e: N-(2-(2,2,2-trifluoroacetyl)-2-azabicyclo[2.2.1]heptan-5yl)acrylamide (±).

Step 1: tert-butyl 5-acrylamido-2-azabicyclo[2.2.1]heptane-2-carboxylate (±).

To a suspension of tert-butyl-5-amino-2-azabicyclo[2.2.1]heptane-2-carboxylate(±) (0.300 g, 1.41 mmol) in dichloromethane (10 ml) and triethylamine (0.580 ml, 4.23 mmol) acryloyl chloride (0.127 g, 1.41 mmol) was added at 0°C and stirred for 1 hour at room temperature. The reaction mixture was diluted with dichloromethane and washed with saturated NaHCO ₃ solution, dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by a CombiFlash® silica gel column (ethyl acetate=100%) to give the title compound (0.180 g, 48%). LCMS: m/z=167.3 [M100] ⁺ .

Step 2: N-(2-(2,2,2-trifluoroacetyl)-2-azabicyclo[2.2.1]heptan-5-yl)acrylamide (±).

To a solution of tert-butyl-5-acrylamido-2-azabicyclo[2.2.1]heptane-2-carboxylate (±) (0.180 g, 0.670 mmol) in dichloromethane (5 ml) was added TFA (0.2 ml) at 0° C and stirred at room temperature for 4 hours, then the reaction mixture was concentrated to give the title compound (crude, 0.280 g). LCMS: m/z=167.1 [M-100] ⁺

Intermediate 6f: K-(2-azabicyclo[2.2.1]heptan-5-yl)ethensulfonamide (TFA salt)(±).

Step 1: tert-butyl 5-(vinylsulfonamido-2-azabicyclo[2.2.1]heptane-2-carboxylate (±).

To a suspension of tert-butyl-5-amino-2-azabicyclo[2.2.1]heptane-2-carboxylate (±) (0.500 g, 2.350 mmol) and triethylamine (0.970 ml, 7.060 mmol) was added chloroethylsulfonyl chloride (0.383 g, 2. 35 mmol) at 0°C and stirred for 1 hour at room temperature. The reaction mixture was diluted with dichloromethane and washed with saturated NaHCO ₃ solution, dried over anhydrous sodium sulfate and concentrated to give the crude compound, which was purified on a CombiFlash® silica gel column (ethyl acetate=100%) to give the title compound (0.250 g, 35. 8%). HCMS:

m/z=203.2 [M+H-100]+.

Step 2: N-(2-azabicyclo[2.2.1]heptan-5-yl)ethensulfonamide (TFA salt) (±).

To a solution of tert-butyl-5-(vinylsulfonamido-2-azabicyclo[2.2.1]heptane-2-carboxylate (±) (0.250 g, 0.827 mmol) in dichloromethane (10 ml) was added TFA (0.5 ml) at 0 °C and stirred at room temperature for 4 hours. The reaction mixture was concentrated to give the title compound (0.300 g, crude) LCMS: m/z=203.2 [M+H-100] ⁺ .

Intermediate 6g: N-allyl-N-(piperidin-4-yl)acrylamide (TFA salt)

The target intermediate was synthesized following the procedure described in Organic Letters, 2013, Vol. 15, No. 8, pp. 1986-1989.

Intermediate 6h: (E)-3-(dimethylαamino)-2-(piperazine-1-carbonyl) acrylonitrile TFA salt

Step 1: tert-butyl 4-(2-cyanoacetyl)piperazine-1-carboxylate.

With stirring, TBTU (10.77 g, 33.548 mmol) was added to a suspension of 2-cyanoacetic acid (2.85 g, 33.548 mmol) in acetonitrile (50.0 mL) at RT and stirred for 2 hours. After 2 hours, tert β-butyl-piperazine-1-carboxylate (5.00 g, 26.838 mmol) at RT and stirred for an additional 14 hours. The reaction mixture was evaporated under reduced pressure and the resulting residue was partitioned between water and EtOAc (1:1). The combined EtOAc layers were washed with water and brine. Dried over Na ₂ SO ₄ and evaporated under reduced pressure. The resulting residue was purified by a Combiflash® silica gel column (DCM/MoOH=99/1) to give the title compound (2.80 g, 41.27%). LCMS: m/z=254.30 [M] ⁺ .

Step 2: tert-butyl 4-(2-cyano-3-(dimethylamino)acryloyl)piperazine-1-carboxylate.

DMF-DMA (10.0 mL, 75.277 mmol) was added to a suspension of tert-butyl 4-(2-cyanoacetyl)piperazine-1-carboxylate (1.00 g, 3.947 mmol) in DMF (10.0 mL) with stirring. at RT and heated to 100°C for 5 hours. The reaction mixture was poured into ice water and extracted with EtOAc. The combined EtOAc layers were washed with brine and water. Dry over Na2SO4 and evaporate under reduced pressure to give the title compound (0.902 g, crude). LCMS: m/z=309.38 [M+H] ⁺ .

Step 3: (E)-3-(dimethylamino)-2-(piperazine-1-carbonyl)acrylonitrile TFA salt.

While stirring, TFA (0.50 mL, 6.529 mmol) at RT and stirred for 5 hours. The reaction mixture was evaporated under reduced pressure and the resulting residue was triturated with diethyl ether to give the title compound (0.195 g, crude). LCMS: m/z=209.30 [M+H] ⁺ .

Intermediate 6i: 3-oxo-3-(piperazin-1-yl)propanenitrile (TFA salt)

While stirring, TFA (0.50 mL, 6.529 mmol) was added to a suspension of tert-butyl 4-(2-cyanoacetyl)piperazine-1-carboxylate (0.30 g, 1.184 mmol) in DCM (5.0 mL) at RT and stirred for 14 hours. The reaction mixture was evaporated under reduced pressure, and the resulting residue was triturated with diethyl ether to give the title compound (0.280 g, crude). LCMS: m/z=154.19 [M] ⁺¹ .

The following compounds are generally commercially available or can be prepared using techniques well known to those skilled in the art. The following products were used to synthesize the compounds of the present invention and/or intermediates.

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Intermediate connection Structure IUPAC 7a ABOUT L^NBoc 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid 7b About ^but ^^\v° ^s 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid 7s ABOUT J-Q ^^^NHBoc trans-(1 g,4 g)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid(±) 7d ABOUT Il NHBoc % 1 -((tert-butoxycarbonyl)amino)cyclopentane-1carboxylic acid

Intermediate 8: tert-butyl 4-(but-3-yn-2-ylcarbamoyl)piperazine-1-carboxylate (±).

To a solution of but-3-yn-2-amine (±) (intermediate 2a) (5.00 g, 72.34 mmol) in dichloromethane (100 mL) was added with stirring and QT tert-butyl-4(chlorocarbonyl) )piperazine-1-carboxylate (intermediate 5) (17.90 g, 72.34 mmol) and DIPEA (37.60 ml, 217 mmol). After stirring for 16 hours at RT, the reaction mixture was washed with saturated NaHCO ₃ solution and brine. The dichloromethane layer was collected, dried and concentrated. The resulting crude material was purified by a Combiflash® silica gel column (hexane/ethyl acetate=65/35) to give the title compound (8.00 g, 39.4%). LCMS: m/z=282.2 [M+H]+.

The following intermediates were prepared essentially using the method described for intermediate 8 with appropriate changes in reagents, amounts of reagents, solvents and reaction conditions. Data characterizing the compounds are given in the table below.

Intermediate connection Structure IUPAC Output (%)/analytical data 8a \/o ^Н k^NBoc T ret-butyl-4-((2methylbut-3-in-2-yl)carbamoyl)piperazine 1-carboxylate Exit: 28.2% LCMS: n/a 8b % O ^H k^NBoc Tert-butyl-4-(pent-1yn-3-ylcarbamoyl)piperazine-1carboxylate (±) Yield: 22.8% LCMS: m/z = 240.2 [M-56]+ 8s γ ^{0 Н} L^,NBoc T ret-butyl-4-((4methylpent-1-in-3-yl)carbamoyl)piperazine 1-carboxylate (±) Yield:8.0% LCMS: no ionization 8d I O ^H VnBoc T ret-butyl-3-(4-(but-3yn-2-ylcarbamoyl)piperazin-1-yl)azetidine-1carboxylate (±) Yield: 42.0% LCMS: m/z =337.2 [M+H]+ 8e I o ^H L 1 ⁴ —NHBoc T ret-butyl-(1 -(but-3in-2-ylcarbamoyl)piperidin-4-yl)carbamate (±) Output: crude LCMS: n/a

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8f „ About ^H %.NBoc Tert-butyl-4-((1ethynylcyclopropyl)carbamoyl)piperazine 1-carboxylate Exit: crude LCMS: n/a

Intermediate 9: tert-butyl 4-(but-3-yn-2-ylcarbamoyl)piperidine-1-carboxylate (±)

With stirring, to a solution of but-3-yn-2-amine (intermediate 2a) (0.5 g, 7.042 mmol) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (intermediate 7a) (1.61 g, 7.042 mmol) in dichloromethane (50 ml) was added diisopropylethylamine (3.73 ml, 21.126 mmol) and HATU (3.21 g, 8.450 mmol) at 0°C. After stirring for 4 hours at RT, the reaction mixture was washed with saturated sodium bicarbonate solution. The dichloromethane layer was dried and concentrated. The crude compound was purified on a Combiflash® silica gel column (hexane/ethyl acetate=75/25) to give the title compound (0.600 g, 30%). The product was used in the next step without further purification.

The following intermediates were prepared essentially using the method described for intermediate 9 with appropriate changes in reagents, amounts of reagents, solvents and reaction conditions.

Intermediate connection Structure IUPAC Output (%)/analytical data 9a °\\ N Sun y—NH T ret-butyl-3-(but-3-in-2ylcarbamoyl)pyrrolidine-1carboxylate (±) Yield: 35% LCMS: n/a 9b I o n II ^^NHBoc T ret-butyl-((1 g,4 g)-4-(but3-in-2-ylcarbamoyl)cyclohexyl)carbamate (±) Output: crude LCMS: n/a

Intermediate 10: tert-butyl (1-((4-chloro-2-methoxy-5-(1methylcyclopropyl)phenyl)ethynyl)cyclopropyl)carbamate

Solution of 1-chloro-4-iodo-5-methoxy-2-(1-methylcyclopropyl)benzene (1u) (0.600 g, 2.11 mmol), tert-butyl (1-ethynylcyclopropyl)carbamate (intermediate 3b) (0.460 g , 2.53 mmol) and triethylamine (0.642 ml, 6.439 mmol) in DMF (10 ml) were purged with argon for 20 min. CuI (0.79 g, 4.15 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.080 g, 0.423 mmol) were then added and the reaction mixture was again purged with argon for 10 min. The reaction mixture was stirred for 2 hours at 90°C. The reaction mixture was then filtered through a pad of celite. The collected filtrate was partitioned between ethyl acetate and water (1:1). The EtOAc layer was dried, concentrated and purified on a combiFlash® silica gel column (hexane/EtOAc=80/20) to give the title compound (0.480 g, 57.61%). LCMS: m/z=276.3 [M-100] ⁺ .

The following intermediates were prepared essentially using the method described for Intermediate 10 with appropriate changes in reagents, amounts of reagents, solvents, and reaction conditions.

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Intermediate connection Structure IUPAC Output (%)/analytical data 10a Cl C.I. 'NHBoc T ret-butyl-(1 -((3,4dichlorophenyl)ethynyl)-cyclopropyl)carbamate Yield: 62%; LCMS: m/z = 226.1 [M+H-SOOG T ret-butyl-(4-(3-chloro- Yield: 50.8%; 10b NHBoc 4-phenoxyphenyl)-but- LCMS: m/z 3-in-2-yl)-carbamate =315.9 Cl (±) [M+N-56]+. Yus C.I. V Cl NHBoc T ret-butyl-(1 -((3,4dichlorophenyl)ethynyl)-cyclopentyl)carbamate Yield: 59%; LCMS: m/z = not ionized Tert-butyl-(1-((4- 10d Cl ^xNHBoc chloro-3-(1methylcyclopropyl)phenyl)-ethynyl)cyclopropyl)carbamate Yield: 63%; LCMS: m/z = not ionized NHBoc T ret-butyl-(4-(4-chloro- 3-(1- Yield: 81.5%; 10th YY methylcyclopropyl)- LCMS: m/z = Cl J.U. phenyl)-but-3-in-2yl)-carbamate(±) 234.2[M+N-100]+ 10f sK Cl and NHBoc Tert-butyl-(4-(2,4dichlorophenyl)-but-3yn-2-yl)-carbamate (±) Yield: 27%; LCMS: m/z = n/o 10g Cl Ύ J ^NHBoc T ret-butyl-(4-(3-chloro4-(diethylamino)phenyl)-but-3-in-2yl)-carbamate(±) Yield: 37%; LCMS: m/z = 351.3[M+H]+.

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10h Ύ J ^T'NHBoc T ret-butyl-(4-(4-chloro3-(diethylamino)phenyl)-but-3-in-2yl)-carbamate (±) T ret-butyl-(4-(4- Yield: 60%; LCMS: m/z = 351.2[M+H]+. r'NHBoc cyano-3- Yield: 10.79% 10i Τι T (trifluoromethyl)- LCMS: m/z = II\ phenyl)-but-3-in-2yl)-carbamate(±) 339.33 [M+H]+. ^NHBoc tert-butyl-(4-(4- Yield: 42.3% 10j fluorophenyl)-but-3-yne- LCMS: m/z = II J 2-yl)-carbamate 264.3 [M+H]+. 10k λα VA o/ N HBOC Tert-butyl-(1-((6methoxynaphthalene-2yl)-ethynyl)cyclopropyl)carbamate Output: crude LCMS: m/z = 236.2 [M-100J+. 101 ‘7 ^NHBoc Tert-butyl-(1(naphthalene-1ylethynyl)cyclopropyl)carbamate Yield: 99% LCMS: m/z = 206 [M-100]+ Tert-butyl-(1-((3- Yield: 73% 10m IJ ^NHBoc bromo-4-chlorophenyl)- ethynyl)-cyclopropyl)- LCMS: m/z = 372.3[M+2]+ Cl carbamate 10n Cl^y Cl ^NHBoc Tert-butyl-(4-(3,4- dichlorophenyl)-but-3in-2-yl)-carbamate Yield: 36.8%, LCMS: m/z =214.2 [M-100] ⁺ •^NHBoc Tert-butyl-(1-((4- chloro-5-methoxy-2-(1- Yield: 80% 10o [ιΎ^ methylcyclopropyl)- LCMS: m/z II J phenyl)-ethynyl)- =276.9 [M-100] ⁺ /0 cyclopropyl)carbamate

Boc protected intermediates (10b, 10n and 10k) were treated with dioxane.HC1 for 16 h at RT. The reaction mixture was concentrated and the crude product was triturated with diethyl ether to give the corresponding hydrochloride salt (11, 11a, 11b).

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Intermediate connection Structure IUPAC Output (%)/analytical data eleven ^r^NHjHCI Cl jlj Cl 4-(3-chloro-4phenoxyphenyl)-but-3-yne2-amine hydrochloride (±) Yield: 100% LCMS: m/z =271.9 [M+H]+. 11a ^<^NH ₂ .HCI XT Cl 4-(3,4-dichlorophenyl)-but- Z-in-2-amine (±) Yield: 93% LCMS: m/z =214.0[M]+. 11b about cxi / 1-((6-methoxynaphthalene-2yl)-ethynyl)-cyclopropan1-amine hydrochloride Crude LCMS: m/z =236.3 [M+1]+. (free base)

Boc-protected intermediates (10, 10a, 10c-10j) were treated with dioxane.HCl for 16 h at RT. The reaction mixture was concentrated, the crude product was dissolved in dichloromethane and washed with aqueous bicarbonate to give the corresponding amine free base (intermediates 11c-11x)._____________________________________________

Intermediate connection Structure IUPAC Yield (%)/analytical data 11s th 1-(naphthalene-1ylethynyl)cyclopropan-1-amine Yield: 89%; LCMS: m/z = 208.2[M+H]+. 11d J t Cl'^^ 1-((3-bromo-4chlorophenyl)-ethynyl)cyclopropan-1-amine Yield: 99% LCMS: 270.2 [M+H] 11th o L> O °СЛ Ζ I 1-((4-chloro-2-methoxy-5(1-methylcyclopropyl)phenyl)-ethynyl)cyclopropan-1-amine Yield: 90% LCMS: 276.3 [M+H] 11o o \ / \ A CHK Ζ g? 1-((4-chloro-5-methoxy-2(1-methyl cyclopropyl)phenyl)-ethynyl)cyclopropan-1-amine Yield: 85%; LCMS: 276.3 [M+N] 11r Xj CI^Y Cl 1-((3,4-dichlorophenyl)ethynyl)-cyclopropane-1- amine Yield: 92.5%; LCMS: m/z =226.2 11q C.M. T O 1-((3,4-dichlorophenyl)ethynyl)-cyclopentane-1- amine Output: crude LCMS: n/a 11g A/ ^^^nh ₂ XX Cl M-(1-((4-chloro-3-(1methylcyclopropyl)phenyl)-ethynyl)cyclopropyl)-12chloroanamine Yield: 94% LCMS: m/z =246.3 [M+H]+.

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11s o\O A- z 4-(4-chl op-3-(1methylcyclopropyl)phenyl)-but-3-yn-2-amine (±) Yield: 92%; LCMS: m/z = not ionized 11t 1 Cl 4-(2,4-dichlorophenyl)but-3-yn-2-amine (±) Yield: 99%; LCMS: m/z =214 [M]+. 11u JI J 4-(3-aminobut-1-in-1yl)-2-chloro-M, Mdiethylaniline (±) Yield:83%; LCMS: m/z =251.1 [M+H]+. 11v it 5-(3-aminobut-1-in-1yl)-2-chloro-M, Mdiethylaniline (±) Yield:80%; LCMS: m/z =251.2 [M+H]+. 11w I J 4-(3-aminobut-1-yn-1yl)-2-(trifluoromethyl)benzonitrile (±) Output: crude LCMS: m/z =239.21 [M+H]+. 11x ^^nh ₂ 4-(4-fluorophenyl)-but-3yn-2-amine Output: crude; LCMS: m/z =164.2 [M]+ ¹ .

Intermediate 12: Phenyl-(4-(3,4-dichlorophenyl)but-3-yn-2-yl)carbamate (±)

With stirring, phenyl chloroformate (1.23 g, 7.89 mmol) was added to a suspension of intermediate 11 (1.3 g, 6.07 mmol) in THF (30 mL) at 0 °C and stirred for 16 h at RT. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO ₃ . The combined EtOAc layers were washed with water and brine, dried over Na ₂ SO ₄ and evaporated under reduced pressure. The resulting residue was purified by a Combiflash® silica gel column (hexane/ethyl acetate=80/20) to give the title compound (1.5 g, 73.9%). LCMS: m/z=214.2 [M-120] ⁺ .

The following intermediates were prepared essentially using the method described for intermediate 12 with appropriate changes in reagents, amounts of reagents, solvents and reaction conditions.

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Prome creepy Exit (%)/ new Structure IUPAC analytically connect e data opinion Phenyl-(4-(3-chloro-4- Yield: 71.7%; 12a ^H Г £ i T phenoxyphenyl)-but-3- LCMS: m/z Cl in-2-yl)-carbamate (±). =392.0 [M+H]+. ⁰ Wil У AX JI Phenyl-(1-((3,4- Yield:58% 12b H dichlorophenyl)-ethynyl)- LCMS: m/z = not I.A. Cl cyclopropyl)-carbamate ionized LL°iWl X/II Phenyl-(1-((3,4- Yield:65% ASlAxA/ 12s N O ^CI \XX H dichlorophenyl)-ethynyl)- LCMS: m/z = IJ Cl'^^ cyclopentyl)-carbamate not ionized „ 0 fWl Phenyl-(1-((4-chloro-3-(1- Yield: 84%; 12d V JJ k IJ L/ nA/ ⁴ ^ ^L -H methylcyclopropyl)- LCMS: m/z = A j phenyl)-ethynyl)- not ionized Cl cyclpropyl)-carbamate 10 Phenyl-(4-(4-chloro-3-(1 - 19l i>AW methylcyclopropyl)- Yield: 85%; IJ phenyl)-but-3-yn-2-yl)- LCMS: m/z = Cl^ ⁴ ^ carbamate(±). 234 [M+N-120G 1 θ AAl with A JAa Phenyl-(4-(2,4- Yield: 60%; 12f I N 0 H dichlorophenyl)-but-3- LCMS: m/z = A J Cl in-2-yl)-carbamate (±). But 10 ...... Phenyl-(4-(3-chloro-4- 19η ^A _N A ₀ AA CIa/x/AH (diethylamino)-phenyl)- Yield: 54%; II LCMS: m/z = II J but-Z-in-2-yl)- carbamate(±). 371.2 [M+H] ⁺ 1 0 A Phenyl-(4-(4-chloro-3- 19h % 1 A 1 J (diethylamino)-phenyl)- Yield: 14%; 1 Ζί 1 χ ^Ν χχΧ^ h LCMS: m/z = H I but-Z-in-2-yl)- II J Cl carbamate (±). 371.2 [M+H] ⁺ 1 0 r^Wl Phenyl-(4-(4-cyano-3- 12i 1 A A J Α^Ν οΑ^ (trifluoromethyl)- Yield: 36.3%; ^g зС^^>^ HTT phenyl)-but-3-yn-2-yl)- LCMS: m/z = nc^AA carbamate (±). 359.32 [M+N] ⁺ 10 A l AJ Phenyl-(4-(4- Yield: 32.7%; 12j ^H fluorophenyl)-but-3-yne-2- LCMS: m/z = A J yl)-carbamate 284.3[M+H]+. V-, 0 Ax AC V Λ AJ Phenyl-(1-(naphthalene-1- Yield: 94%; 12k SyAi ylethynyl)- LCMS: m/z = And cyclopropyl)-carbamate 208.2[M-120]+. _w o Aki AA AJ Phenyl-(1-((3-bromo-4- Yield: 90%; 121 ^Br axA^ H chlorophenyl)-ethynyl)- LCMS: m/z = A A Cl cyclopropyl)-carbamate 272.1[M-120]+.

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12m ο \D Ο b Phenyl-(1 -((4-chloro-2μ is xy-5-(1methylcyclopropyl)phenyl)-ethynyl)cyclopropyl)-carbamate Yield: 56%; LCMS: m/z = 396.3[M+H]+. 12η <p V u L J η ί τ Phenyl-(1 -((4-chloro-5methoxy-2-(1methylcyclopropyl)phenyl)-ethynyl)cyclopropyl)-carbamate Yield: 69%; LCMS: m/z = 396.3[M+H]+. 12ο q ΖΙ /° Phenyl-(1-((6methoxynaphthalene-2yl)-ethynyl)cyclopropyl)-carbamate Crude LCMS: m/z = 358.3 [M+H]+.

Intermediate 13: Phenyl(E)-N'-cyano-N-(4-(3,4-dichlorophenyl)-but-3-yn-2yl)carbamimidate (±)

With stirring, triethylamine (0.833 yl, 5.988 mmol) was added to a solution of intermediate 11 (0.5 g, 1.996 mmol) and diphenylcyanocarbonimidate (0.475 g, 1.996 mmol) in acetonitrile (30 ml) at RT and stirred for 16 h at RT . After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by a combiflash® silica gel column (hexane/ethyl acetate=75/25) to give the title compound (0.5 g, 70%). LCMS: m/z 358.2 [M] ⁺ .

Intermediate 14: 1,2-dichloro-4-(3-isocyanatobut-1-yn-1-yl)benzene (±)

With stirring, to a solution of intermediate 11a (0.200 g, 0.833 mmol) in DCM (10 ml) was added triphosgene (0.0915 g, 0.308 mmol) and sat. NaHCO ₃ solution (10 ml) at 0°C. The reaction mixture was then stirred for 1 hour at RT. After completion of the reaction, the DCM layer was separated and concentrated to give the title compound (0.200 g, crude). The resulting product was used in the next step without further purification.

Intermediate 15: tert-butyl 4-((1-((3,4-dichlorophenyl)ethynyl)cyclopentyl)carbamoyl)piperazine-1-carboxylate.

While stirring, tert-butyl piperazine-1-carboxylate (0.098 g, 0.529 mmol) and triethylamine (0.20 mL, 1.443 mmol) were added to a suspension of intermediate 12c (0.180 g, 0.481 mmol) in DMSO (5.0 mL). at RT and heated to 60°C for 16 hours. The reaction mixture was poured into ice water and extracted with EtOAc. The combined EtOAc layers were combined, washed with brine, water, dried over Na ₂ SO ₄ and evaporated under reduced pressure. The resulting residue was purified by a Combiflash® silica gel column (hexane/ethyl acetate=60/40) to give the title compound (0.204 g, 30.44%). LCMS: m/z=366.3 [M+H-100] ⁺ .

The following intermediates were prepared essentially using the method described for intermediate 15.

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Prome creepy Exit (%)/ new Structure IUPAC analytically connect e data opinion 15a ] I o An h 1 ^NBoc T ret-butyl-4-((4-(3-chloro-4phenoxyphenyl)-but-3-yn-2yl)-carbamoyl)-piperazine 1-carboxylate (±). Yield: 54%; LCMS: m/z =484.2 [M+H]+. T ret-butyl-4-((4-(3-chloro-4- A- (diethylamino)-phenyl)-but- Yield: 66%; 15b SK XX ^H A' V? 3-in-2-yl)-carbamoyl)- LCMS: m/z = 0 ¹ piperazine-1-carboxylate 464.2 [M+HJ+. (±). T ret-butyl-4-((4-(4-chloro-3- 1° li/s (diethylamino)-phenyl)-but- Yield:80%; 15s cr N N H L 0 ¹ 3-yn-2-yl)-carbamoyl)piperazine-1-carboxylate LCMS: m/z = 463.4 [M+H]+. (±). 15d J cr xY X 0 ^HU 'yA 0 ¹ T ret-butyl-4-((4-(2,4dichlorophenyl)-but-3-yn-2yl)-carbamoyl)-piperazine1-carboxyl at(±). Yield: 78%; LCMS: m/z = 425.9 [M]+. 15th Clx. T Cl^ X o A nA HH \SHNVos Cis-tert-butyl-((1 s,4s)-4(3-(4-(3,4-dichlorophenyl)but-3-yn-2-yl)-ureido)cyclohexyl)-carbamate (±) Yield: 90%; LCMS: m/z =354.2[M+H] ⁺ 15f ck cK b 1 O An h I ^NH M-(4-(3,4-dichlorophenyl)but-3-yn-2-yl)-3oxopiperazine-1carboxamide (±). Yield: 99%; LCMS: m/z = 340.1 [M]+. 15g cr xY 10 An h L x^NBoc T ret-butyl-4-((4-(4-chloro-3(1-methylcyclopropyl)phenyl)-but-3-yn-2-yl)carbamoyl)-piperazine-1 carboxylate (±). Yield: 68.7%; LCMS: m/z = 446.4 [M+H]+. 15h jcr 0 Nm- H N.. VnBoc T ret-butyl-3-(4-((4-(4-chloro3-(1 -methylcyclopropyl)phenyl)-but-3-in-2-yl)carbamoyl)-piperazine-1 - Yield: 58%; LCMS: m/z = 502.4 [M+H]+.

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yl)-azetidine-1carboxylate(±). 15i ο _r ^Η L^Boc T ret-butyl-4-((1-((3,4dichlorophenyl)-ethynyl)cyclopropyl)-carbamoyl)piperazine-1-carboxylate Output: 100%; LCMS: m/z =381.8 [M+H] ⁺ 15j ABOUT zv ||q k^NBoc Cl^ T ret-butyl-4-((1-((4-chloro-3(1-methylcyclopropyl)phenyl)-ethynyl)cyclopropyl)-carbamoyl)piperazine-1-carboxylate Yield: 56%; LCMS: no analyzed 15k l\ O AA ^H Ύ L^NBoc T ret-butyl-3-(4-((1-((4chloro-3-(1methylcyclopropyl)phenyl)-ethynyl)cyclopropyl)-carbamoyl)piperazin-1-yl)-azetidine 1-carboxylate Yield: 57%; LCMS: m/z = 513.4[M]+. 151 V7 ⁰ J//·. ^h ^nboc T ret-butyl-4-((1-((6methoxynaphthalin-2-yl)ethynyl)-cyclopropyl)carbamoyl)-piperazine-1carboxylate Output: crude LCMS: m/z = 450.4 [M]+. 15m 0\IZ ,—z z—> from o Tert-butyl-4-((1(naphthalene-1-ylethynyl)cyclopropyl)-carbamoyl)piperazine-1-carboxylate Yield: 40%; LCMS: m/z = 420.4[M+H]+ 15η 15ο 15ρ £ o V ? ABOUT h °gch\ > > > >° >O >° O 0 o FROM FROM ooo ooo T ret-butyl-4-((1-((3-bromo-4chlorophenyl)-ethynyl)cyclopropyl)-carbamoyl)piperazine-1-carboxylate T ret-butyl-4-((1-((4-chloro-2methoxy-5-(1methylcyclopropyl)phenyl)-ethynyl)cyclopropyl)-carbamoyl)piperazine-1-carboxylate T ret-butyl-4-((1-((4-chloro-5methoxy-2-(1methylcyclopropyl)phenyl)-ethynyl)cyclopropyl)-carbamoyl)piperazine-1-carboxylate Yield: 54%; LCMS: m/z = 426[M-56]+ Yield: 74%; LCMS: m/z = 488.4[M+]+ Yield: 80%; LCMS: m/z = 488.2[M+]+

Intermediate 15q: tert-butyl 4-((1-((4-chloro-3-ethynylphenyl)ethynyl)cyclopropyl)carbamoyl)piperazine-1-carboxylate

Step 1: tert-butyl 4-((1-((4-chloro-3-((trimethylsilyl)ethynyl)phenyl)ethynyl)cyclopropyl)carbamoyl)piperazine-1-carboxylate

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A solution of tert-butyl 4-((1-((3-bromo-4-chlorophenyl)ethynyl)cyclopropyl)carbamoyl)piperazine-1carboxylate (15n) (0.150 g, 0.311 mmol), ethynyltrimethylsilane (0.046 g, 2.53 mmol ) and triethylamine (2 ml) in DMF (1 ml) were purged with argon for 10 min. CuI (0.006 g, 0.031 mmol) and tetrakis(triphenylphosphine)-palladium(0) (0.022 g, 0.031 mmol) were then added at RT. The reaction mixture was kept in a microwave oven at 140°C with stirring for 4 hours. The reaction mixture was then concentrated under reduced pressure. The resulting crude product was purified on a combiFlash® silica gel column (hexane/EtOAc=60/40) to give the title compound (0.080 g, not pure). LCMS: m/z=500.5 [M+H]+.

Step 2: tert-butyl 4-((1-((4-chloro-3-ethynylphenyl)ethynyl)cyclopropyl)carbamoyl)piperazine-1carboxylate

With stirring, to a solution of tert-butyl 4-((1-((4-chloro-3-((trimethylsilyl)ethynyl)phenyl)ethynyl)cyclopropyl)carbamoyl)piperazine-1-carboxylate (0.080 g, 0.160 mmol) in methanol (1 ml), K2CO3 (0.133 g, 0.480 mmol) was added and stirred for 1 hour at room temperature. The reaction mixture was concentrated and purified on a Combiflash® silica gel column (hexane/EtOAc=60/40) to give the title compound (0.070 g, not pure). LCMS: m/z=428.3 [M+H].

Intermediate 15r: N-(4-(3,4-dichlorophenyl)-but-3-yn-2-yl)-4-oxopiperidin-1carboxamide (±).

With stirring, triethylamine (0.12 mL, 0.897 mmol) at RT and stirred for 14 hours. The reaction mixture was poured into ice water and extracted with EtOAc. The combined EtOAc layers were washed with water and brine, dried over Na ₂ SO ₄ and evaporated under reduced pressure. The resulting residue was purified on a Combiflash® silica gel column (DCM/MeOH=98/02) to give the title compound (0.095 g, 94.05%) as a solid. LCMS: m/z=339.3 [M+H] ⁺ .

Intermediate 15s: N-(4-(3,4-dichlorophenyl)-but-3-yn-2-yl)-4-(hydroxyimino)piperidine-1-carboxamide (±).

With stirring, a suspension of N-(4-(3,4-dichlorophenyl)-but-3-yn-2-yl)-4-oxopiperidin-1 carboxamide (intermediate 15I) (0.090 g, 0.265 mmol) in ethanol (4 .0 ml), saturated sodium bicarbonate (0.036 g, 0.531 mmol) and hydroxylamine hydrochloride (0.036 g, 0.531 mmol) were added at 0°C. The reaction mixture was left to warm to RT, stirred for 14 hours, and then evaporated under reduced pressure. The resulting residue was placed in water, extracted with EtOAc, the combined EtOAc layers were washed with brine, dried over Na ₂ SO ₄ and evaporated under reduced pressure (0.090 g, 45.74%). LCMS: m/z=354.3 [M+H] ⁺ .

Intermediate 15t: tert-butyl 4-((4-(3,4-dichlorophenyl)-but-3-yn-2yl)carbamoyl)piperazine-1-carboxylate (±)

Solution of 1,2-dichloro-4-iodobenzene (intermediate 1a) (5.6 g, 20.75 mmol), tert-butyl4-(but-3-yn-2-ylcarbamoyl)piperazine-1-carboxylate (intermediate 8) (7 g, 24.91 mmol) and triethylamine (8.66 ml, 62.25 mmol) in DMF (100 ml) were purged with argon for 20 min. Copper iodide (0.79 g, 4.15 mmol) and tetrakis(triphenylphosphine)-palladium(0) (2.39 g,

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2.07 mmol) and again purged the reaction mixture with argon for 10 min. The reaction mixture was stirred for 2 hours at 80°C. After completion of the reaction, the mixture was poured into ice water and extracted with EtOAc. The EtOAc layers were dried, concentrated and purified on a combiFlash® silica gel column (hexane/EtOAc=40/60) to give the title compound (7.0 g, 79.8%). LCMS: m/z=426.1 [M] ⁺ .

The following intermediates were prepared essentially using the method described for intermediate 15t with appropriate changes in reagents, amounts of reagents, solvents and reaction conditions.

Intermediate connection Structure IUPAC Output (%)/analytical data 15i About °h ZI λ) oh oh T ret-butyl-4-((4-(3,4dichlorophenyl)-2methylbut-3-in-2-yl)carbamoyl)piperazine-1carboxylate Yield:50.3% LCMS: m/z =384.1[M-56]+ 15v % θ O ⁱⁿ “ T ret-butyl-4-((1-(3,4dichlorophenyl)-pent-1yn-3-yl)-carbamoyl)piperazine-1carboxylate (±) Yield:54.2% LCMS: m/z =440.1 [M+H]+ 15w With, %/NBoc Tert-butyl-4-((1-(3,4dichlorophenyl)-4methylpent-1-in-3-yl)carbamoyl)piperazine-1carboxylate (±) Yield:50.78% LCMS: m/z =398.8 [M-56]+ 15x 1 O s, ^N N Vos T ret-butyl-4-((4-(3chloro-4-fluorophenyl)but-3-in-2-yl)carbamoyl)piperazine-1carboxylate(±) Yield: 35.7% LCMS: m/z =410.1 [M+H]+ 15v 1 θ c, ^H ^ ^nb ° ^c F ₃ C' ^A ^ T ret-butyl-4-((4-(3chloro-4(trifluoromethyl)phenyl)-but-3-yn-2yl)-carbamoyl)piperazine-1carboxylate(±) Yield: 64%; LCMS: m/z =404.0 [M-56]+

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15z i o s. ^{H Boc} H ₃ C%^ T ret-butyl-4-((4-(3chloro-4-methylphenyl)but-3-yn-2-yl)carbamoyl)piperazine-1carboxylate (±) Yield: 43.16% LCMS: m/z =350.2 [M-56J+ 15aa I 0 _r , ^H LJ, Yj \^NBoc T ret-butyl-3-(4-((4(3,4-dichlorophenyl)but-3-in-2-yl)carbamoyl)piperazin-1-yl)azetidine-1carboxylate(±) Yield:40% LCMS: m/z =481.1 [M+H]+ 15ab O o co °4 ZT vy Tert-butyl 4-((4(naphthalene-2-yl)-but3-in-2-yl)carbamoyl)piperazine-1carboxylate(±) Yield: 53.0% LCMS: m/z = 408.3 [M+H]+ 15ac I 0 ^H I___NBoc Ν J| JN\^H T ret-butyl-4-((4-(1 Nindazol-5-yl)-but-3in-2-yl)-carbamoyl)piperazine-1carboxylate Yield:56% LCMS: m/z =398.1 [M+H]+ 15ad \ Z'z λΧυ >° 00 o o Tert-butyl-4-((4-(1methyl-1H-indazol-4yl)-but-3-in-2-yl)carbamoyl)piperazine-1carboxylate(±) Yield:54% LCMS: m/z =412.1 [M+H]+

- 46 045414

15ae I o _ra Lu n ι I TT ^^NHBoc T ret-butyl-(1 -((4-(3,4dichlorophenyl)-but-3in-2-yl)-carbamoyl)piperidin-4-yl)carbamate(±) Yield:50% LCMS: m/z =440 [M+H]+ 15af I θ Ay /У' ^H L ,NBoc / ^S Cl T ret-butyl-4-((4-(5chlorothiophen-2-yl)-but3-in-2-yl)carbamoyl)piperazine-1carboxylate (±) Yield:57.14% LCMS: m/z =398.3 [M+H]+ 15ag I O _ri Ary sk/¾. η ι ¹ || n B° ^c T ret-butyl-4-((4-(4(benzyloxy)-3chlorophenyl)-but-3-in2-yl)-carbamoyl)piperazine-1carboxylate (±) Yield:45.5% LCMS: m/z =498.6 [M+N]+ 15ah 1 0 _c| ^H T,NBoc T ret-butyl-4-((4-(3chloro-4-fluorophenyl)but-3-in-2-yl)carbamoyl)piperazine-1carboxylate (±) Yield:24.13% LCMS: m/z =410 [M+H]+ 15ai I o Ji L^NBoc Cl T ret-butyl-4-((4-(3amino-4-chlorophenyl)but-3-in-2-yl)carbamoyl)piperazine-1carboxylate(±) Yield:23.66% LCMS: m/z =407.3 [M+N]+

Intermediate 15aj: tert-butyl 4-((4-(3-acetamido-4-chlorophenyl)-but-3-yn-2yl)carbamoyl)piperazine-1-carboxylate (±).

With stirring, triethylamine (0.150 g, 1.47 mmol) and acetyl chloride were added to a solution of intermediate 15ai (0.200 g, 0.492 mmol) in DCM (25 mL) at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated under reduced pressure. The resulting crude product was purified on a combiFlash® silica gel column (60% EA in hexane) to give the title compound (0.150 g, 68.1%) as a white solid. LCMS: m/z=349.3 [M+H-100] ⁺ .

Intermediate 15a: tert-butyl-4-((4-(4-chloro-3-(cyclopropanecarboxamido)-phenyl)but-3-yn-2-yl)carbamoyl)piperazine-1-carboxylate (±).

The title compound was prepared essentially using the procedure described for the preparation of intermediate-15aj using intermediate 15ai Yield: 64.3%; LCMS: m/z=375.3 [M+H-100] ⁺ .

The following intermediates were prepared essentially using the method described for intermediate 15t with appropriate changes in reagents, amounts of reagents, solvents, and reaction conditions.

Intermediate connection Structure IUPAC Output (%)/analytical data 16 I° ^Н k^NBoc T ret-butyl-4-((4-(3,4dichlorophenyl)-but-3-yn2-yl)-carbamoyl)piperidine-1carboxylate (±) Output:41 LCMS: m/z = 425.0[M+H]+ 16a I ⁰ II \ ^^NHBoc ci^ ⁴ ^ T rans-tert-butyl-((1 g,4g)4-((4-(3,4-dichlorophenyl)but-3-in-2-yl)- Output: 91 LCMS: m/z = 438.9[M+H]+ carbamoyl)cyclohexyl)-carbamate (±)

Intermediate 16b: tert-butyl 3-(((S)-4-(3,4-dichlorophenyl)-but-3-yn-2-yl)carbamoyl)pyrrolidine-1-carboxylate hydrochloride (±); and intermediate 16c: tert-butyl 3-(((S)-4-(3,4-dichlorophenyl)-but-3-yn-2-yl)carbamoyl)pyrrolidine-1-carboxylate hydrochloride (±)

The target compounds were prepared using the procedure described for the preparation of intermediate-8 using intermediate 9a and intermediate 1a to obtain a mixture of isomers as the crude product. The crude compound was further purified by preparative TLC to obtain isomer 16b (yield: 15%; LCMS: n/a) and isomer 16c (yield: 14%; LCMS: n/a) separately.

Intermediate 16d: tert-butyl-(1-((4-(3,4-dichlorophenyl)-but-3-yn-2yl)carbamoyl)cyclopentyl)carbamate (±).

C.I.

With stirring, a suspension of intermediate 11a (0.150 g, 0.5986 mmol) and 1((tert-butoxycarbonyl)amino)cyclopentane-1-carboxylic acid (intermediate 7d) (0.137 g, 0.5986 mmol) in DMF (4 .0 ml) EDCI (0.126 g, 0.6585 mmol), HOBT (0.089 g, 0.6585 mmol) and triethylamine (0.025 ml, 1.7960 mmol) were added at 0°C and stirred for 14 h at RT. After completion of the reaction, the reaction mixture was poured into ice water and extracted with EtOAc. The combined EtOAc layers were washed with water and brine, dried over Na ₂ SO ₄ and evaporated under reduced pressure. The resulting crude product was purified on a Combiflash® silica gel column (hexane/ethyl acetate=70/30) to give the title compound (0.102 g crude). LCMS: m/z=325.2 [M-100].

Intermediate 17: K-(4-(3,4-dichlorophenyl)-but-3-yn-2-yl)piperazin-1-carboxamide hydrochloride (±).

With stirring, to a solution of tert-butyl 4-((4-(3,4-dichlorophenyl)-but-3-yn-2yl)carbamoyl)piperazine-1-carboxylate (7.0 g, 16.43 mmol) in dioxane (100 ml) was added dioxane.HCl (70 ml) at 15°C. The reaction mixture was stirred for 16 hours at RT. The reaction mixture was concentrated and the crude product was triturated with diethyl ether to give the desired product (5.9 g,

- 48 045414 crude), which was used in the next stage.

The following intermediates were prepared essentially using the method described for intermediate 17._____________________________________________

Prome creepy Exit (%)/ new Structure IUPAC analytically connect e data opinion N-(4-(3,4- \/O dichlorophenyl)-2- 17a methylbut-Z-in-2-yl)- LCMS: m/z = I J ,ΝΗ.ΗΟΙ piperazine-1- 340.1 [M+H]+ Cl'^^ carboxamide hydrochloride N-(1-(3,4- Exit: ⁰ II dichlorophenyl)-pent-1- 17b in-3-yl)-piperazine-1- crude II 1 H 1 SHCHN.NS1 LCMS: m/z = carboxamide hydrochloride (±) But Ύ' about N-(1-(3,4- Exit: 17s AR Η 1 dichlorophenyl)-4- crude JI J _schn.na methylpent-1-in-Z-yl)- LCMS: m/z = Cl^^^ piperazine-1- 353.95 [M+N] ⁺ carboxamide (free hydrochloride (±) base) Exit: Ν-(4-(3-χπορ-4- crude 17d 1 O fluorophenyl)-but-3-yne-2- LCMS: m/z = II I Η 1 „NH.HCI yl)-piperazine-1- 310.1 [M+H] ⁺ carboxamide (free hydrochloride (±) base) Ν-(4-(3-χπορ-4- Exit: 10 (trifluoromethyl)- crude 17th Cl./. η Γ _XNH.HCI phenyl)-but-3-yn-2-yl)- LCMS: m/z I J piperazine-1- =359.7 [M+N]+ F ₃ C'^ ^/ ι Ο carboxamide hydrochloride (±) Ν-(4-(3-χπορ-4- (free base) Exit: 1 A methylphenyl)-but-3-yne- crude 17f 2-yl)-piperazine-1- Cl^^. 1 J Η I ^NH.HCI LCMS: m/z HjC^^A carboxamide hydrochloride (±) =n/a 4-(azetidin-3-yl)-Н-(4- Yield: 87% ¹⁰ (3,4-dichlorophenyl)-but- LCMS: m/z 17g ci.^A yАШ N'd ^Η Μ 3-yn-2-yl)-piperazine-1- =381.2 [M+N] ⁺ JI\ Cl'^^ ¹⁰ Ynh.hci carboxamide hydrochloride (±) N-(4-(naphthalene-2-yl)- but-Z-in-2-yl)- (free base) Exit: crude 17h ,Α.Α.,/' LCMS: m/z ^Η L „NH.HCI piperazine-1- =308.2 [M+N]+ carboxamide (free base) hydrochloride (±)

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17i I 0 ^H % ^NHHCI H N-(4-(1 H-indazol-5-yl)but-3-in-2-yl)piperazin-1carboxamide hydrochloride (±) Yield: 89% LCMS: m/z =297.9 [M+H] ⁺ (free base) 17j I o N=, A X C^NH.HCI N-(4-(1 -methyl-1Hindazol-4-yl)-but-3-in2-yl)-piperazin-1carboxamide hydrochloride (±) Yield: 74% LCMS: m/z =311.8[M+H]+ (free base) 17k I 0 ^H I 1 Ji J ^^NH ₂ HCl 4-amino-N-(4-(3,4dichlorophenyl)-but-3in-2-yl)-piperazin-1carboxamide hydrochloride (±) Output: crude LCMS: m/z =340.1 [M+H]+ (free base) 171 1° L,NH.HCI /® Cl M-(4-(5-chlorothiophen-2yl)-but-3-yn-2-yl)piperazine-1carboxamide hydrochloride (±) Output: crude LCMS: m/z =n/o 17m T T0 <4 ZI M-(4-(4-(benzyloxy)-3chlorophenyl)-but-3-in-2yl)-piperazine-1carboxamide hydrochloride (±) Output: crude LCMS: m/z =n/o 17n Cl ^H k^NH.HCI N-(4-(3-chloro-4fluorophenyl)-but-3-in-2yl)-piperazine-1carboxamide hydrochloride (±) Yield: 94.5% LCMS: m/z =310.3 [M+N]+

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17ο o c, ^CH C/NHHCI C|·^ N-(1-((3,4- dichlorophenyl)-ethynyl)cyclopropyl)piperazine-1carboxamide hydrochloride Yield: 83.6%; LCMS: m/z =338.2 [M]+. 17ρ / \ 0 _p| ^H Cx- ^nh - ^hc| N-(1-((3,4- dichlorophenyl)-ethynyl)cyclopentyl)piperazine-1carboxamide hydrochloride Yield: 88% LCMS: m/z = 368.2[M]+. 17q I ⁰ _r , /Al ^H C/NH.HCI ό N-(4-(3-χπορ-4phenoxyphenyl)-but-3in-2-yl)-piperazin-1carboxamide hydrochloride (±) Output: crude LCMS: m/z = 384.1 [M+HJ+. 17r 0 ^HY /NH.HCI M-(1-((4-chloro-3-(1methylcyclopropyl)phenyl)-ethynyl)cyclopropyl)piperazine-1carboxamide hydrochloride Output: crude LCMS: m/z = 358.3 [M+HJ+. 17s Г\ ° r> γχ ^{H e} v _C| /W Vnh 4-(azetidin-3-yl)-N-(1((4-chloro-3-(1methylcyclopropyl)phenyl)-ethynyl)cyclopropyl)piperazine-1carboxamide Output: 100%; LCMS: m/z = 413.3 [M+H]+

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17t I O r> ^H k/NH Cl N-(4-(4-xnop-3-(1- methylcyclopropyl)phenyl)-but-3-yn-2-yl)piperazine-1- carboxamide (±) Output: 100%; LCMS: m/z = 346.3 [M+H]+ 17u I ⁰ □fy ^h □nh.hci 4-(azetidin-3-yl)-N-(4(4-chloro-3-(1methylcyclopropyl)phenyl)-but-3-in-2-yl)piperazin-1carboxamide hydrochloride (±) Yield: 92.6%; LCMS: m/z = 401.4[M+N]+ 17v I 0 Λ f| <^nhhci Cl N-(4-(2,4- dichlorophenyl)-but-3in-2-yl)-piperazine-1carboxamide hydrochloride (±) Yield: 94%; LCMS: m/z = 325.7 [M+H]+ 17w I° _c| ^H kk ^HHc| N-(4-(3-χπορ-4(diethylamino)-phenyl)but-3-in-2-yl)piperazine-1carboxamide hydrochloride(±) Output: crude LCMS: m/z = 362.3 [M+H]+ 17x I ⁰ Cl'^ M-(4-(4-chloro-3(diethylamino)-phenyl)but-3-in-2-yl)piperazin-1carboxamide hydrochloride Output: crude LCMS: m/z = 363.0 [M+H]+ 17y ₀ _/\χΝΗ ₂ HCI _c Cl HH IJ Cl^^^ Hnc-1-((1s,4s)-4-((l2chloranyl)-amino)cyclohexyl)-3-(4-(3,4dichlorophenyl)-but-3yn-2-yl)-urea (±). Yield: 92% LCMS: no ionized 17z ,-, ^{0 H} Cx ^-NHHCI N-(1-((6- methoxynaphthalene-2yl)-ethynyl)cyclopropyl)piperazine-1carboxamide hydrochloride crude LCMS: m/z = 350.3 [M+H]+ (free base)

The following intermediates 17aa-17ad were prepared by treating the corresponding Boc-protected TFA precursors in DCM and concentration in vacuo.

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Intermediate connection Structure IUPAC Output (%)/analytical data 17aa V-7 ⁰ / ⁵ ¾¾. \/ and ___ Μγ ⁿ k/NH TFA M-(1-(naphthalene-1ylethynyl)cyclopropyl)piperazine-1carboxamide (TFA salt) Yield: 85.6%; LCMS: m/z = 320.3 [M+H] ⁺ (free base) 17аб V-7 ⁰ || ^^ %/NH.TFA N-(1-((4-chloro-3ethynylphenyl)-ethynyl)cyclopropyl)piperazine-1- Output: crude LCMS: m/z = 328.3 [M+H] ⁺ carboxamide (TFA salt) (free base) 17ac <i GA^| ^Hk /NH.TFA M-(1-((4-chloro-2methoxy-5-(1methylcyclopropyl)phenyl)-ethynyl)cyclopropyl)piperazine-1carboxamide (TFA salt) Yield: 99% LCMS: m/z = 388.3 [M+H] ⁺ (free base) 17ad t ^H k^NH.TFA si-'d^ Ν-(1-((4-χπορ-5- methoxy-2-(1methylcyclopropyl)phenyl)-ethynyl)cyclopropyl)piperazine-1carboxamide (TFA salt) Yield: 96% LCMS: m/z = 388.3 [M+H] ⁺ (free base)

Compounds of intermediates (17ae and 17af) were prepared by treating the corresponding HCl salt with sodium carbonate.____________________________________________________________

Intermediate Structure IUPAC Yield (%)/ analytical connected ie data tion I O N-(4-(3-acetamido-4- Exit: 1 A_ chlorophenyl)-but-3-yne-2- 85.8% 17ae yl)-piperazine-1- LCMS: m/z Cl carboxamide (±) =349.3 [M+N]+ N-(4-(4-chloro-3- Λ ι Ω Exit: °v 1 i (cyclopropinecarboxam 84.7% 17af Η ΐ X ido)-phenyl)-but-3-yne-2- LCMS: m/z = H\ yl)-piperazine-1- 375.3 [M+H]+ carboxamide (±)

Intermediate 17ag: trans-3-(4-(3,4-dichlorophenyl)-but-3-yn-2-yl)-1-methyl-1-(2-53 045414 (methylamino)cyclohexyl)urea (±) .

With stirring, to a suspension of intermediate 12 (0.150 g, 0.157 mmol) and transN1,N2-dimethylcyclohexane-1,2-diamine (±) (intermediate 4e) (0.095 g, 0.718 mmol) in DMSO (5.0 ml) was added trimethylamine (0.18 mL, 2.992 mmol) at RT and stirred for 18 hours. The reaction mixture was poured into ice water and extracted with EtOAc. The combined EtOAc layers were washed with water and brine, dried over Na ₂ SO ₄ and evaporated under reduced pressure. The resulting residue was purified by a Combiflash® silica gel column (DCM/MeOH=93/07) to obtain the title compound (0.060 g, 35.08%) as a solid. LCMS: m/z=382.30 [M+H]+.

The following compounds were prepared essentially using the method described for intermediate 17 with appropriate changes in reagents and reaction conditions.

Intermediate connection Structure IUPAC Output (%)/analytical data I ⁰ N-(4-(3,4-dichlorophenyl)- 18 С1\/ Ύ ⁿ L _XNH.HCI but-3-in-2-yl)-piperidin- 4-carboxamide Yield: 83% LCMS: n/a Cl^ ⁴ hydrochloride (±) 18a ΎCl^^ 1 ⁰ gA N ⁿ NH.HCI N-(4-(3,4-dichlorophenyl)but-3-in-2-yl)-pyrrolidine3-carboxamide hydrochloride (±)(isomer-1) Exit: crude LCMS: n/a ¹⁰ N-(4-(3,4-dichlorophenyl)- Exit: 18b Cl^T ^N । N.H. but-3-in-2-yl)-pyrrolidin- 3-carboxamide crude LCMS: n/a Cl^ .HCI hydrochloride (±)(isomer-2) 18s Cl^, j Cl^ 1 O .HCI trans-(1 g,4 g)-4-amino-M-(4(3,4-dichlorophenyl)-but-3in-2-yl)-cyclohexane-1carboxamide hydrochloride (±) Yield: 92% LCMS: m/z = 340.2 [M+H-100]+ 18d sg ⁿ CI NH2 b 1-amino-N-(4-(3,4dichlorophenyl)-but-3-in-2yl)-cyclopentane-1carboxamide (±) Output: crude LCMS: m/z = 325.2[M]+

Example 1: 4-acryloyl-X-(4-(3,4-dichlorophenyl)-but-3-yn-2-yl)piperazine-1-carboxamide (±).

With stirring, a suspension of N-(4-(3,4-dichlorophenyl)-but-3-yn-2-yl)piperazin-1-carboxamide hydrochloride (intermediate 17) (5.9 g, 16.34 mmol) in DCM (70 ml) was added with triethylamine (4.95 g, 49.02 mmol) and acryloyl chloride (1.92 g, 21.24 mmol) at 15°C. The reaction mixture was stirred at RT for 3 hours. After completion of the reaction, the reaction mixture was washed with sat. NaHCO ₃ solution and salt solution. The DCM layer was concentrated to give the crude compound, which was purified on a combiflash® silica gel column (DCM/MeOH=97/3) to give the title compound (3.2 g, 51.5%). HPLC: 98.7%; LCMS: m/z=379.9 [M+H] ⁺ .

^1H NMR (400 MHz, CDCl3): δ 7.53 (d, J=1.86 Hz, 1H), 7.40 (d, J=8.31 Hz, 1H), 7.31-7.22 (m, 1H), 6.59 (dd, J=10.49, 16.79 Hz, 1H), 6.37 (dd, J=1.82, 16.87 Hz, 1H), 5.78 ( dd, J=1.84, 10.52 Hz, 1H), 4.97 (kv, J=7.14 Hz, 1H), 4.67 (d, J=7.87 Hz, 1H), 3, 84-3.37 (m, 8H), 1.53 (d, J=6.87 Hz, 3H)

- 54 045414

The compounds of Examples 1a and 1b were isolated from Example 1 using chiral preparative

HPLC according to the following method, obtaining two separate isomers (isomer-1 and isomer-2 of example 1)

Method:

Column: LUX AMYLOSE-2 (21.2 x 250 mm-5 µm);

Mobile phase: hexane (A), 0.1% TFA in ethanol (B);

Flow rate: 20 ml/min;

Isocratic mode: 80:20.

Example 1a: 4-acryloyl-N-(4-(3,4-dichlorophenyl)-but-3-yn-2-yl)piperazine-1-carboxamide (isomer-1).

Yield: 46.6%; HPLC: 99.09%; LCMS: m/z=379.9 [M+H]+;

Example 1b: 4-acryloyl-N-(4-(3,4-dichlorophenyl)-but-3-yn-2-yl)piperazine-1-carboxamide (isomer 2).

Yield: 46.0%; HPLC: 99.09%; LCMS: m/z=379.9 [M+H] ⁺ ;

Example 2: 4-acryloyl-N-(1-(3,4-dichlorophenyl)-pent-1-yn-3-yl)piperazine-1-carboxamide (±).

Example 2 was prepared according to the procedure described for the preparation of Example 1, with appropriate changes in reagents, amounts of reagents, solvents and reaction conditions. Yield: 64%; HPLC: 97.47%; LCMS: m/z=394.0 [M+H] ⁺ ;

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.48 (d, J=1.89 Hz, 1H), 7.35 (d, J=8.31 Hz, 1H), 7.28-7, 17 (m, 1H), 6.53 (dd, J=10.47, 16.79 Hz, 1H), 6.31 (dd, J=1.87, 16.79 Hz, 1H), 5.73 (dd, J=1.87, 10.48 Hz, 1H), 4.80 (td, J=5.81, 7.82 Hz, 1H), 4.64 (d, J=8.12 Hz, 1H), 3.82 - 3.30 (m, 8H), 1.90-1.41 (m, 2H), 1.04 (t, J=7.37 Hz, 3H).

The racemic mixture obtained above was purified by chiral preparative HPLC to obtain the individual isomers (2a and 2b).

Example

Structure

Yield (%) and Analytics

Isomer-2

Yield: 50%; LCMS: m/z 394.2 [M+H] ⁺ ; HPLC: 98.4%

Yield: 50%; LCMS: m/z =394.2 [M+H] ⁺ ; HPLC: 97.6%;

The following examples were prepared according to the procedure described for the preparation of Example 1, with appropriate changes in reagents, amounts of reagents, solvents and reaction conditions.

- 55 045414

Example Structure Yield (%) and Analytics 3 Cm ZI LA o o Yield: 22.4%; HPLC: 94.52%; LCMS: m/z =394.2 [M+H] ⁺ ; ^1H NMR (400 MHz.SES) δ 7.59 (dd, J = 0.95, 1.96 Hz, 1H), 7.39 (dd, J = 0.93, 8.41 Hz, 1H), 7.29 - 7.23 (m, 1H), 6.60 (ddd, J = 0.97, 10.52, 16.83 Hz, 1H), 6.35 (ddd, J = 0.87, 1 .65, 16.76 Hz, 1H), 5.77 (ddd, J = 0.99, 1.87, 10.48 Hz, 1H), 5.36 (s, 1H), 3.75 (d, J = 49.75 Hz, 4H), 3.53 (dd, J = 3.84, 6.35 Hz, 4H), 1.42 (d, J = 1.08 Hz, 6H). 4 oh oh У° °? Yield: 32.3%; HPLC: 98.0%; LCMS: m/z = 408.2;[M+H] ⁺ ; ^1H NMR (400 MHz, CDCh) δ 7.50 (d, J = 1.91 Hz, 1H), 7.37 (d, J = 8.30 Hz, 1H), 7.28 - 7.20 ( m, 1H), 6.55 (dd, J = 10.49, 16.79 Hz, 1H), 6.34 (dd, J = 1.87, 16.74 Hz, 1H), 5.75 (dd , J = 1.86, 10.49 Hz, 1H), 4.79 (dd, J =

-56045414

5.45, 8.32 Hz, 1H), 4.66 (d, 4= 8.35 Hz, 1H), 3.57 (dd, J= 47.14, 85.68 Hz, 8H), 2, 00 (dkv, J = 6.12, 6.60, 13.11 Hz, 1H), 1.04 (dd, J = 2.22, 6.68 Hz, 6H). 5 1 o c, ΥΤ O Yield: 25.10%; HPLC: 98.81%; LCMS: m/z 364.0 [M+H] ⁺ ; ^1H NMR (400 MHz, CDCI ₃ ) δ 7.45 (dd, J = 2.08, 7.00 Hz, 1H), 7.31 - 7.20 (m, 1H), 7.05 (t, J= 8.69 Hz, 1H), 6.54 (dd, J = 10.50, 16.78 Hz, 1H), 6.32 (dd, J = 1.89, 16.79 Hz, 1H), 5.73 (dd, J = 1.88, 10.47 Hz, 1H), 4.92 (p, J = 7.07 Hz, 1H), 4.63 (d, J = 7.88 Hz, 1H ), 3.80 - 3.28 (m, 8H), 1.48 (d, 4 = 6.85 Hz, ZN). 6 “o r O IZ >° □° Yield: 22.27%; HPLC: 99.58%; LCMS: m/z = 414.0 [M+H]+; ^1H NMR (400 MHz, CDCI3) δ 7.59 (d, J = 8.17 Hz, 1H), 7.52 (d, J = 1.29 Hz, 1H), 7.36 (ddd, J = 0.88, 1.62, 8.01 Hz, 1H), 6.54 (dd, J = 10.49, 16.79 Hz, 1H), 6.32 (dd, J = 1.86, 16, 79 Hz, 1H), 5.73 (dd, J = 1.83, 10.48 Hz, 1H), 4.96 (p, J = 7.09 Hz, 1H), 4.65 (d, J= 7.99 Hz, 1H), 3.81 3.32 (m, 8H), 1.50 (d, J = 6.89 Hz, ZN). 7 10 s, Η ι ι // ' NzS'^''^ O Yield: 28.5%; HPLC: 98.08%; LCMS: m/z = 360.2 [M+H]+; ^1H NMR (400 MHz, CDCb) δ 7.40 (d, J = 1.54 Hz, 1H), 7.22 - 7.12 (m, 2H), 6.56 (dd, J = 10.50 , 16.79 Hz, 1H), 6.34 (dd, J = 1.88, 16.79 Hz, 1H),

- 57 045414

5.75 (dd, J = 1.86, 10.54 Hz, 1H), 4.95 (p, J = 7.01 Hz, 1H), 4.66 (d, J = 7.83 Hz, 1H ), 3.79 - 3.32 (m, 8H), 2.36 (s, ZN), 1.50 (d, J = 6.83 Hz, ZN). 8 O o ν) y-I ΰ Yield: 40%; HPLC: 94.26%; LCMS: m/z =436.3[M+H] ⁺ ; ^1H NMR (400 MHz, flMCOde) δ 8.31 (s, 1H), 7.70 - 7.59 (m, 1H), 7.38 (dd, J = 1.98, 8.35 Hz, 1H ), 6.97 (d, J = 8.04 Hz, 1H), 6.29 (dd, J = 10.28, 17.00 Hz, 1H), 6.09 (dd, 7 = 2.28, 17.01 Hz, 1H), 5.66 (dd, J = 2.27, 10.27 Hz, 1H), 4.76 (p, J = 7.27 Hz, 1H), 4.22 (t, J = 8.07 Hz, 1H), 4.03 (dd, J = 4.91, 8.86 Hz, 1H), 3.92 (dd, J = 7.28, 10.30 Hz, 1H), 3.73 (dt, J = 5.02, 10.24 Hz, 1H), 3.40-3.10 (m, 5H), 2.38 - 2.15 (m, 4H), 1.38 ( d, J= 7.00 Hz, ZN) 9 1 0 OU ⁿ Yield: 3.0%; HPLC: 95.68%; LCMS: m/z =362.1 [M+H] ⁺ , ¹ H NMR (400 MHz, CDCI ₃ ): 6 7.95 (d, J = 1.47 Hz, 1H), 7.87 - 7, 71 (m, ZN), 7.54 7.41 (m, ZN), 6.56 (dd, J = 10.48, 16.81 Hz, 1H), 6.34 (dd, J = 1.85 , 16.79 Hz, 1H), 5.75 (dd, J = 1.86, 10.48 Hz, 1H), 5.02 (p, J = 6.87 Hz, 1H), 4.73 (d , J = 7.87 Hz, 1H), 3.753.42 (m.8H), 1.56 (d, J = 5.91 Hz, ZN).

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10 I o ^H %' ⁿ y^ H Yield: 17%; HPLC: 93.84%; LCMS: m/z = 352.1[M+H]+; ¹ H NMR (400 MHz, DMSOSO): δ 13.23 (s, 1H), 8.07 (t, 4= 1.28 Hz, 1H), 7.85 (d, J = 1.29 Hz, 1H ), 7.52 (dt, J = 0.90, 8.53 Hz, 1H), 7.33 (dd, J = 1.50, 8.59 Hz, 1H), 7.07 (d, J = 8.08 Hz, 1H), 6.83 (dd, J= 10.43, 16.65 Hz, 1H), 6.13 (dd, 4=2.42, 16.66 Hz, 1H), 5, 81 - 5.58 (m, 1H), 4.87 - 4.67 (m, 1H), 3.63 - 3.34 (m, 8H), 1.42 (d, 4 = 6.94 Hz, ZN). eleven -O ^4 i __ O Yield: 21%; HPLC: 94.79%; LCMS: m/z =366.1 [M+H] ⁺ ; ¹ NMR (400 MHz, DMSObb): δ 8.08 - 8.00 (m, 1H), 7.67 (d, 4 = 8.29 Hz, 1H), 7.38 (ddd, 4 = 0.91 , 7.06, 8.27 Hz, 1H), 7.19 (d, 4 = 7.12 Hz, 1H), 7.12 (d, 4 = 8.11 Hz, 1H), 6.89 - 6 .76 (m, 1H), 6.19 - 6.06 (m, 1H), 5.70 (ddd, 4 = 0.93, 2.55, 10.53 Hz, 1H), 4.92 4, 80 (m, 1H), 4.06 (s, ZN), 3.54 (d, 4 = 16.61 Hz, 4H), 3.34-3.29 (m, 4H), 1.47 (d , 4 = 6.95 Hz, ZN). 12 O O O IZ >° 0 0 Yield: 39%; HPLC: 96.86%; LCMS: m/z =394.2 [M+H]+; ¹ NMR (400 MHz, DMSO-de): δ 8.04 (d, 4 = 7.69 Hz, 1H), 7.71 - 7.59 (m, 1H), 7.38 (dd, 4 = 1 .94, 8.34 Hz, 1H), 6.95 (d, 4 = 8.02 Hz, 1H), 6.25 - 6.01 (m, 2H), 5.58 (dd, 4 = 2, 44, 9.93 Hz, 1H), 4.77 (p, 4= 7.15 Hz, 1H), 3.97-3.71 (m, ZN), 3.34 (s, 1H), 2, 90 - 2.74 (m, 2H), 1.72 (d, 4= 12.40 Hz, 2H), 1.39

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(d, J= 6.98 Hz, ZN), 1.34-1.14 (m, 2H). 13 ο Ω Α_ ΙΖ >° /—ζ ζ—' ο=/ ΛΑ Yield: 12%; HPLC: 96.5%; LCMS: m/z =456.2 [M]+; ¹ NMR (400 MHz, CDCI3): δ 7.72 (d, J = 15.33 Hz, 1H), 7.58 - 7.48 (m, 2H), 7.38 (td, J = 2.78 , 5.06 Hz, 4H), 7.26 -7.22 (m, 2H), 6.86 (d, J = 15.38 Hz, 1H), 6.73 (s, 1H), 5.05 - 4.89 (m, 1H), 3.63 (dd, J= 36.00, 104.04 Hz, 8H), 1.68-1.46 (m, ZN), 14 I 0 _Cl Η I Ν ΥΥ 0 Yield: 32%; HPLC: 98.3%; LCMS: m/z = 394.2 [M] ⁺ ; ¹ NMR (400 MHz, CDCh): δ 7.51 (d, J = 1.91 Hz, 1H), 7.37 (d, J = 8.32 Hz, 1H), 7.27 (s, ZH) , 7.23 (dd, J = 1.93, 8.30 Hz, 1H), 6.92 (dkv, J = 6.84, 14.81 Hz, 1H), 6.25 (dkv, J = 1 .65, 14.98 Hz, 1H), 4.95 (p, J = 7.04 Hz, 1H), 4.66 (d, J = 7.85 Hz, 1H), 3.55 (dd, J = 42.76, 85.91 Hz, 8H), 1.51 (d, J = 6.86 Hz, ZN). 15 ci ^Cl \x^x^ Η ι I ΥΎ ^ ^Ν γγ Cl'^^ 0 ¹ Yield: 34.5%; HPLC: 96.07%; LCMS: m/z = 408.2[M]+; ^1H NMR (400 MHz, CDCh): δ 7.51 (d, J = 1.91 Hz, 1H), 7.37 (d, J = 8.29 Hz, 1H), 7.28-7.19 (m, 1H), 5.78 (p, J = 1.40 Hz, 1H), 4.95 (p, J = 7.10 Hz, 1H), 4.65 (d, J = 7.88 Hz , 1H), 3.74 3.33 (m, 8H), 1.89 (dd, J = 1.36, 22.06 Hz, 6H), 1.51 (d, J = 6.87 Hz, ZN ).

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16 I o I x On 1 cr 0 Yield: 52%; HPLC: 95.7%; LCMS: m/z =418.2 [M+2]+; ¹ NMR (400 MHz, CDCh): δ 7.51 (d, J = 1.91 Hz, 1 Η), 7.37 (d, J = 8.30 Hz, 1 Η), 7.23 (dd, J = 1.93, 8.34 Hz, 1 Η), 5.06 - 4.87 (m, 1 Η), 4.56 (kv, J = 6.51 Hz, 1 Η), 3.90 ( dt, J = 5.85, 8.27 Hz, 1 Η), 3.82 - 3.56 (m, 2Η), 3.50 (td, J = 5.79, 9.40, 11.78 Hz , 4H), 3.33 (td, J = 5.53, 9.43 Hz, 1H), 1.69 (d, J = 6.54 Hz, ZN), 1.51 (d, J = 6, 90 Hz, ZN). 17 1 0 aZ ^H <Aa. I C Cl Yield: 45.5%; HPLC: 94.98%; LCMS: m/z = 351.7 [M+H]+; ^1H NMR (400 MHz, CDCh): δ 6.95 (d, J= 3.93 Hz, 1H), 6.84 (d, J= 3.94 Hz, 1H), 6.58 (dd, J = 10.53, 16.81 Hz, 1H), 6.32 (dd, J = 1.89, 16.85 Hz, 1H), 5.73 (dd, J = 1.88, 10.49 Hz, 1H), 5.33-5.29 (m, 1H), 4.11 (kvd, J = 3.30, 6.73 Hz, 1H), 3.67 (d, J = 52.61 Hz, 4H ), 3.45 (t, J = 5.22 Hz, 4H), 1.27 (d, J = 7.47 Hz, ZN). 18 5 0 M ZI A Yield: 12.0%; HPLC: 95.1%; LCMS: m/z = 452.1[M+H] ⁺ ; ¹ NMR (400 MHz, CDCh): δ 7.45 - 7.30 (m, 6H), 7.26 (d, J = 0.49 Hz, 1H), 6.87 (d, J = 8.48 Hz, 1H), 6.56 (dd, J = 10.47, 16.77 Hz, 1H), 6.33 (dd, J = 1.90, 16.80 Hz, 1H), 5.74 (dd , J = 1.87, 10.52 Hz, 1H), 5.16 (s, 2H), 5.00 - 4.89 (m, 1H), 4.64 (d, J = 7.74 Hz, 1H), 3.72 - 3.40 (m, 8H), 1.49 (d, J = 6.90 Hz, ZN)

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19 I 0 s, /Y Yr ^Η s i ₀ Yield: 52%; HPLC: 99.36%; LCMS: m/z = 404.2 [M+2]+; Ή NMR (400 MHz, CDCh): δ 7.51 (d, J = 1.86 Hz, 1 Η), 7.38 (d, J = 8.33 Hz, 1H), 7.23 (dd, J = 1.91, 8.29 Hz, 1H), 4.95 (kv, J = 7.15 Hz, 1H), 4.65 (d, J = 7.66 Hz, 1H), 4.09 (s , 2H), 3.68 (t, J = 5.44 Hz, 2H), 3.57 (s, 4H), 3.41 (t, J = 5.26 Hz, 2H), 1.51 (d , 4 = 6.82 Hz, ZN). 20 I o IT ^H r^ _Br Output: crude; LCMS: m/z = 474.1 [M+1] ⁺ ; 21 1 ⁰ >? Yj ^Xz ^ ^J Yield:25.3%; HPLC: 98.8%; LCMS: m/z 382.1 [M]+; ^1H NMR (400 MHz, CDCI3) δ 7.50 (d, J = 1.74 Hz, 1H), 7.39 - 7.33 (m, 1H), 7.25 7.20 (m, 1H) , 5.13 - 4.85 (m, 1H), 4.63 (d, J = 7.79 Hz, 1H), 3.59 - 3.30 (m, 4H), 3.27 - 2.99 (m, 1H), 2.96 2.73 (m, 2H), 2.73 - 2.41 (m, 5H), 2.25 (dd, J = 7.05, 13.36 Hz, 1H) , 1.62 (s, 2H), 1.62-1.48 (m, ZN). 22 Cl h i 1 YY- 0 Yield: 20%; HPLC: 95.6%; LCMS: m/z = 364.3 [M+H]+; ^1H NMR (400 MHz, CDCI ₃ ) δ 7.31 (t, J = 7.93 Hz, 1H), 7.26 (s, 1H), 7.18 (dd, J = 1.82, 9, 63 Hz, 1H), 6.55 (dd, J = 10.48, 16.78 Hz, 1H), 6.33 (dd, J = 1.87, 16.75 Hz, 1H), 5.75 ( dd, J = 1.85, 10.51 Hz, 1H), 5.02 - 4.84 (m, 1H), 3.87 - 3.25 (m, 8H), 1.65 (s, 2H) , 1.50 (d, 4=6.87 Hz, ZN).

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23 V7 ⁰ TV ''Cl'^^ 0 Yield: 16.9%; HPLC: 97.7%; LCMS: m/z=392.3 [M+H]+; ^1H NMR (400 MHz, CDCI ₃ ): 6 7.47 (d, J= 1.91 Hz, 1H), 7.32 (d, J = 8.33 Hz, 1H), 7.26 (s, 2H), 7.20 (dd, J = 1.92, 8.28 Hz, 1H), 6.55 (dd, J = 10.50, 16.79 Hz, 1H), 6.33 (dd, J = 1.90, 16.80 Hz, 1H), 5.74 (dd, J = 1.86, 10.49 Hz, 1H), 3.81-3.24 (m, 8H), 1.44- 1.07 (m, 4H). 24 /\0 c, ΎΎ - CI^^V 0 Yield: 26.3%; HPLC: 98.3%; LCMS: m/z =420.3; ¹ NMR (400 MHz, CDCb) δ 7.50 (d, J = 1.96 Hz, 1H), 7.33 (d, J = 8.28 Hz, 1H), 7.22 (ddd, J = 0 .75, 1.89, 8.33 Hz, 1H), 6.56 (dd, J = 10.45, 16.76 Hz, 1H), 6.33 (dd, J = 1.84, 16.84 Hz, 1H), 5.80 - 5.69 (m, 1H), 4.64 (s, 1H), 3.55 (dd, J = 50.76, 94.30 Hz, 8H), 2.35 - 2.03 (m, 4H), 1.83 (tdd, J = 6.78, 11.23, 15.75 Hz, 4H). 25 1 0 _c| /A h 1 1 TV . ⁿ .. 0 ό Yield: 78%; HPLC: 97.9%; LCMS: m/z =438.05 [M+H]+; ^1H NMR (400 MHz, CDCI3) δ 7.52 (d, J = 2.03 Hz, 1H), 7.40 - 7.31 (m, 2H), 7.26 (s, 1H), 7. 19 - 7.09 (m, 1H), 7.02 - 6.94 (m, 2H), 6.85 (d, J = 8.49 Hz, 1H), 6.56 (dd, J = 10, 48, 16.78 Hz, 1H), 6.34 (dd, J= 1.85, 16.75 Hz, 1H), 5.75 (dd, J = 1.86, 10.50 Hz, 1H), 4.95 (p, J = 6.99 Hz, 1H), 4.66 (d, J = 7.94 Hz, 1H), 3.84 - 3.29 (m, 8H), 1.54 (d , J = 24.85 Hz, ZN).

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26 0 △/ ld ⁿ 0 Yield: 31.8%; HPLC: 98.7%; LCMS: m/z=412.2 [M+H]+; ¹ H NMR (400 MHz, CDCI3) δ 7.39 (d, J= 2.03 Hz, 1H), 7.20 (d, J = 8.29 Hz, 1H), 7.14 (dd, 4= 2.03, 8.23 Hz, 1H), 6.55 (dd, J = 10.53, 16.78 Hz, 1H), 6.33 (dd, J = 1.84, 16.79 Hz, 1H ), 5.74 (dd, J = 1.85, 10.50 Hz, 1H), 5.14 (s, 1H), 3.54 (dd, J = 53.25, 90.26 Hz, 8H) , 1.38 - 1.32 (m, 2H), 1.30 (s, ZN), 1.21 - 1.13 (m, 2H), 0.82-0.70 (m, 4H). 27 o XP ^H ^ ^N v o Yield: 8.3%; HPLC: 97.7%; LCMS: m/z =467.4 [M+H]+; ^1H NMR (400 MHz, CDCI3) δ 7.39 (d, J= 2.02 Hz, 1H), 7.19 (s, 1H), 7.14 (dd, J = 2.03, 8.25 Hz, 1H), 6.33 (dd, J = 1.86, 17.00 Hz, 1H), 6.18 (dd, J = 10.30, 16.97 Hz, 1H), 5.67 (dd , J = 1.88, 10.29 Hz, 1H), 5.10 (s, 1H), 4.33 - 3.84 (m, 4H), 3.42 (dddd, J = 5.99, 13 ,37, 16.66, 29.80 Hz, 4H), 3.19 (ddd, J = 5.35, 7.27, 12.40 Hz, 1H), 2.36 (kV, J = 5.25 Hz, 4H), 1.46 - 1.09 (m, 7H), 0.99 - 0.59 (m, 4H). 28 1 ⁰ Г> N^nA II ^H 0 Yield: 14.5%; HPLC: 94.4%; LCMS: m/z =400.3 [M+H]+; ^1H NMR (400 MHz, CDCI3): δ 7.41 (d, J = 2.12 Hz, 1H), 7.28 - 7.19 (m, 1H), 7.17 (dd, 4=2, 08, 8.21 Hz, 1H), 6.56 (dd, 4 = 10.43, 16.80 Hz, 1H), 6.33 (dd, 4 = 1.84, 16.84 Hz, 1H), 5.75 (dd, 4 = 1.83, 10.48 Hz, 1H), 4.95 (p, 4 = 6.97 Hz, 1H), 4.67 (d, 4 = 7.88

- 64 045414

Hz, 1 Η), 3.87 - 3.19 (μ, 8Η), 1.70 1.41 (μ, 3Η), 1.26 (d, J = 44.64 Hz, ZN), 0.97 -0.54 (m, 4Η). 29 I o U /Ах Cl-Άί^ '-' ^Ν γ ^χ 4. O Yield: 17%; HPLC: 90.7%; LCMS: m/z =455.4 [M+H]+; ^1H NMR (400 MHz, CDCI3) δ 7.40 (d, J=2.05 Hz, 1H), 7.26 (s, 1H), 7.18 (d, J=2.08 Hz, 1H) , 6.33 (dd, J = 1.86, 17.02 Hz, 1H), 6.18 (dd, J = 10.29, 16.97 Hz, 1H), 5.68 (dd, J = 1 .85, 10.28 Hz, 1H), 4.94 (p, J = 6.89 Hz, 1H), 4.64 (d, 2 = 7.80 Hz, 1H), 4.343.86 (m, 4H ), 3.57 - 3.31 (m 4H), 3.20 (tm, 2 = 5.18, 7.30 Hz, 1H), 2.38 (kv, 2 = 4.74, 5.25 Hz , 4H), 1.49 (d, 2 = 6.87 Hz, ZN), 1.32 (s, ZN), 0.83 0.68 (m, 4H). thirty I o ϊ Υ-Λγ Ag ⁿ 0 Yield: 40%; HPLC: 98.4%; LCMS: m/z = 379.8 [M+H]+; ^1H NMR (400 MHz, CDCI3): δ 7.40 (d, 2 = 2.08 Hz, 1H), 7.37 (d, 2 = 8.35 Hz, 1H), 7.19 (dd, 2 = 2.08, 8.36 Hz, 1H), 6.55 (dd, 2 = 10.51, 16.78 Hz, 1H), 6.33 (dd, 2 = 1.90, 16.80 Hz, 1H), 5.75 (dd, 2 = 1.85, 10.50 Hz, 1H), 5.16-4.79 (m, 1H), 4.71 (d, 2 = 7.82 Hz, 1H ), 3.56 (dd, 2 = 46.85, 84.86 Hz, 8H), 1.74-1.30 (m, ZN). 31 I 0 ^CI \zAxY ^Η I Ji Ij АуЧ ^χΧ Αι ^χ ^ ^χ ^ ο Yield: 57%; HPLC: 95%; LCMS: m/z = 417.3 [M+H]+; ^1H NMR (300 MHz, CDCI3): δ 7.42 (d, 2 = 1.97 Hz, 1H), 7.33 - 7.17 (m, 1H), 6.95 (d, 2 = 8, 40 Hz, 1H), 6.56 (dd, 2 = 10.44, 16.77 Hz, 1H), 6.33 (dd, 2 =

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1.97, 16.78 Hz, 1H), 5.74 (dd, J= 1.97, 10.41 Hz, 1 Η), 4.94 (π, 4=6.98 Hz, 1 Η), 3.56 (dd, J = 34.77, 64.76 Hz, 8H), 3.14 (kv, J = 7.05 Hz, 6H), 1.49 (d, J = 6.82 Hz, ZN ), 1.03 (t, J = 7.05 Hz, 4H). 32 1 o n ι 1 Yj Yield: 30%; HPLC: 95.2%; LCMS: m/z = 417.4 [M+H]+; ^1H NMR (300 MHz, CDCI3): δ 7.42 (d, J=1.97 Hz, 1H), 7.33-7.17 (m, 1H), 6.95 (d, J=8, 40 Hz, 1H), 6.56 (dd, J= 10.44, 16.77 Hz, 1H), 6.33 (dd, J= 1.97, 16.78 Hz, 1H), 5.74 ( dd, J= 1.97, 10.41 Hz, 1H), 4.94 (p, J = 6.98 Hz, 1H), 3.56 (dd, J = 34.77, 64.76 Hz, 8H ), 3.14 (kv, J = 7.05 Hz, 6H), 1.49 (d, J = 6.82 Hz, ZN), 1.03 (t, J = 7.05 Hz, 4H). 33 A IZ Υ ZI M ZI λα o o Yield: 82%; HPLC: 96.8%; LCMS: m/z = 408.2[M+H]+; ^1H NMR (400 MHz, flMCOde): δ 8.01 - 7.88 (m, 1H), 7.72 - 7.57 (m, 2H), 7.38 (dt, J = 1.67, 8 .33 Hz, 1H), 6.36 6.19 (m, 2H), 6.06 (dt, J = 1.87, 17.10 Hz, 1H), 5.87 (d, J = 7.10 Hz, 1H), 5.55 (dt, J = 1.81, 10.17 Hz, 1H), 4.78 - 4.60 (m, 1H), 3.61 (d, J = 56.26 Hz , 2H), 1.50 (d, 4= 31.22 Hz, 8H), 1.35 (dd, 4= 1.40, 7.01 Hz, ZN). 34 / o ΛΑ O An IZ >° X Yield: 10%; HPLC: 96.87%; LCMS: m/z = 404.6 (M+H]; 1H NMR (400 MHz, chloroform-d) δ 7.81 (d, J = 1.9 Hz, 1H), 7.69 (t, J = 8.7 Hz, 2H), 7.49 (dd, J = 8.4, 1.8 Hz, 1H),

- 66 045414

7.15 (dd, J = 8.9, 2.5 Hz, 1H), 7.08 (d, J = 2.6 Hz, 1H), 6.33 (dd, J = 16.8, 10, 3 Hz, 1H), 6.20 (dd, J = 16.8, 2.1 Hz, 1H), 5.83 (s, 1H), 5.65 (dd, J = 10.3, 2.1 Hz, 1H), 3.89 (s, ZN), 3.08 (d, J = 35.4 Hz, 4H), 2.78 (s, 2H), 2.47 (s, 2H), 1.05- 1.02 (m, 2H), 1.00 (dd, J = 3.2, 1.8 Hz, 2H). 35 V7 ⁰ A n ι ι ΎΎ 0 Yield: 9.5%; LCMS: m/z = 374 [M]+; HPLC: 92.65%; 1H NMR (400 MHz, chloroform-d) δ 8.31 8.26 (m, 1H), 7.83 - 7.75 (m, 2H), 7.62 (dd, J = 7.2, 1, 2 Hz, 1H), 7.57 -7.45 (m, 2H), 7.37 (dd, J = 8.3, 7.2 Hz, 1H), 6.55 (dd, J = 16.8 , 10.5 Hz, 1H), 6.33 (dd, J = 16.8, 1.9 Hz, 1H), 5.74 (dd, J = 10.5, 1.9 Hz, 1H), 5 .24 (s, 1H), 3.74 (s, 2H), 3.60 (s, 2H), 3.53 (s, 2H), 3.40 (s, 2H), 1.48 - 1, 44 (m, 2H), 1.29 - 1.24 (m, 2H). 36 ο Tj ^Η Yield: 28%; HPLC: 95.14%; LCMS: m/z = 382.3[M+H] ⁺ ; ^1H NMR (400 MHz, chloroform-d) δ 7.55 (t, J = 1.2 Hz, 1H), 7.29 (d, J = 1.0 Hz, 2H), 6.55 (dd, J = 16.8, 10.5 Hz, 1H), 6.33 (dd, J = 16.8, 1.9 Hz, 1H), 5.76-5.72 (m, 1H), 5.13 (s, 1H), 3.72 (s, 2H), 3.60 (s, 2H), 3.50 (s, 2H), 3.35 (s, ZN), 1.37-1.32 ( m, 2H), 1.21 - 1.16 (m, 2H). 37 5 ,—ζ ζ^ °χ Λ ^ζτ \ν \Ί Ρ\ ο Yield: 3.6%; HPLC: 97.8%; LCMS: m/z = 442.3[M+H] ⁺ ; ^1H NMR (400 MHz, chloroform-d) δ 7.36 (s, 1H), 6.78 (s, 1H), 6.59 - 6.50 (m,

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2H), 6.36 - 6.29 (m, 1H), 5.76 - 5.71 (m, 1H), 5.18 (s, 1H), 3.80 (s, ZN), 3.53 - 3.46 (m, 2H), 3.71 (s, 2H), 3.58 (s, 2H), 3.36 (s, 2H), 1.41 - 1.35 (m, 2H), 1.27 (s, ZN), 1.22 - 1.16 (m, 2H), 0.78-0.66 (m, 4H).

Yield: 6.5%; HPLC: 99%; LCMS: m/z = 442.3[M+H] ⁺ ; ^1H NMR (400 MHz, chloroform-d) δ 7.36 (s, 1H), 6.78 (s, 1H), 6.59 - 6.50 (m, 2H), 6.36 - 6.29 (m, 1H), 5.76 - 5.71 (m, 1H), 5.18 (s, 1H), 3.80 (s, ZN), 3.53 - 3.46 (m, 2H), 3.71 (s, 2H), 3.58 (s, 2H), 3.36 (s, 2H), 1.41 - 1.35 (m, 2H), 1.27 (s, ZN), 1 .22 - 1.16 (m, 2H), 0.78-0.66 (m, 4H).

Example 39: 4-Acryloyl-^(1-((4-chloro-5-hydroxy-2-(1-methylcyclopropyl)phenyl)ethynyl)cyclopropyl)piperazine-1-carboxamide

With stirring, to a solution of Example 38 (0.050 g, 1.133 mmol) in DCM (20 ml) was added norbornadiene (2 drops) and BBr ₃ (0.1 ml, 1.13 mmol) at -78°C. The reaction mixture was stirred at this temperature for 2 hours and then at 0°C for 30 minutes. The reaction mixture was poured into ice and extracted with DCM. The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude product was purified by preparative TLC (dichloromethane/methanol=95/5) to give the title compound (0.005 g, 10%). HPLC: 85.84%; LCMS: m/z=427.9 [M] ⁺ .

^1H NMR (300 MHz, chloroform-d) δ 7.26 (s, 1H), 7.14 (s, 1H), 7.03-7.00 (m, 1H), 6.58-6.49 (m, 1H), 6.36-6.30 (m, 1H), 5.75 (d, J=10.5 Hz, 1H), 5.48 (s, 1H), 3.73-3, 42 (m, 8H), 1.62-1.18 (m, 5H), 0.72 (d, J=4.8 Hz, 2H), 0.57 (kv, J=4.4 Hz, 2H).

Example 40: N-(4-(3-acetamido-4-chlorophenyl)-but-3-yn-2-yl)-4-acryloylpiperazine-1-carboxamide (±)

The title compound was synthesized from intermediate 17ae as described in Example 1 to provide the crude compound, which was purified by preparative HPLC to provide the title compound. (Yield: 83.3%). HPLC: 96.9%; LCMS: m/z=403 [M+H]+;

1H NMR (400 MHz, CDCl ₃ ): δ 8.46 (s, 1H), 7.55 (d, J=25.46 Hz, 1H), 7.35-7.21 (m, 1H), 7 .08 (dd, J=1.92, 8.28 Hz, 1H), 6.72 (s, 1H), 6.56 (dd, J=10.51, 16.82 Hz, 1H), 6, 33 (dd, J=1.83, 16.76 Hz, 1H), 5.74 (dd, J=1.87, 10.55 Hz, 1H), 5.07-4.82 (m, 1H) , 3.85 - 3.28 (m, 8H), 2.25 (s, 3H), 1.49 (d, J=6.81 Hz, 3H).

41:

Example

4-acryloyl-^(4-(4-chloro-3-(cyclopropanecarboxamido)phenyl)-but-3-yn-2 yl)piperazine-1-carboxamide (±).

The title compound was synthesized from intermediate 17af as described in Example 1 to provide the crude compound, which was purified by preparative HPLC to provide the title compound. Yield: 75.5%; HPLC: 99.25%; LCMS: m/z=429.3 [M+H]+;

^1H NMR (400 MHz, CDCl ₃ ): δ 8.49 (s, 1H), 7.82 (s, 1H), 7.26 (s, 1H), 7.06 (dd, J=2.00 , 8.33 Hz, 1H), 6.56

- 68 045414 (dd, J=10.49, 16.78 Hz, 1H), 6.33 (dd, J=1.88, 16.76 Hz, 1H), 5.74 (dd, J=1, 86, 10.50 Hz, 1H), 4.92 (p, J=6.90

Hz, 1H), 4.72 (d, J=7.82 Hz, 1H), 3.85-3.32 (m, 8H), 1.47 (d, J=6.81 Hz, 3H), 1.38-1.18 (m, 1H), 1.18-0.81 (m,

4H).

Example 42: (E)-N-(4-(3,4-dichlorophenyl)-but-3-yn-2-yl)-4-(4,4,4-trifluorobut-2-enoyl)piperazine-1carboxamide ( ±)

With stirring, to a solution of intermediate 17 (0.150 g, 0.41 mmol) and (E)-4,4,4trifluorobut-2-enoic acid (0.086 g, 0.624 mmol) in DMF (30 ml) was added (0.095 g, 0.496 mmol), HOBT (0.084 g, 0.629 mmol) and DIPEA (0.160 g, 1.24 mmol) at 10°C and stirred for 16 h at RT. After completion of the reaction, the reaction mixture was poured into ice water and extracted with EtOAc. The EtOAc layer was dried over Na ₂ SO ₄ , evaporated under reduced pressure and concentrated to give the crude product, which was purified by preparative TLC (hexane/EtOAc=50/50) to give the title compound (0.050 g, 27%). HPLC: 99.26%; LCMS: m/z=448.3 [M] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.50 (d, J=1.89 Hz, 1H), 7.37 (d, J=8.33 Hz, 1H), 7.22 (dd, J=1.96, 8.32 Hz, 1H), 6.95 (dkv, J=1.96, 15.39 Hz, 1H), 6.82-6.70 (m, 1H), 5.02 -4.83 (m, 1H), 4.67 (d, J=7.80 Hz, 1H), 3.82-3.31 (m, 8H), 1.50 (d, J=6.86 Hz, 3H).

The resulting racemic compound was separated into two isomers (41a and 41b) using preparative chiral HPLC.

Column: lux amylose-2 (21.1 mmx250 mm), 5.0 µm, hexane and IPA:McOH (80:20); flow rate: 20 ml/min, isocratic mode (85:15).

Example 42a: (E)-N-(4-(3,4-dichlorophenyl)-but-3-yn-2-yl)-4-(4,4,4-trifluorobut-2-enoyl)piperazine-1carboxamide ( isomer-1).

Yield=0.005 g, (33.3%). LCMS: m/z=449.2 [M+H] ⁺ ; HPLC: 99.1%; chiral HPLC: 95.2% (retention time=5.067 min).

Example 42b: (E)-N-(4-(3,4-dichlorophenyl)-but-3-yn-2-yl)-4-(4,4,4-trifluorobut-2-enoyl)piperazine-1carboxamide ( isomer-2).

Yield: 0.005 g, (33.3%). LCMS: m/z=449.2 [M+H] ⁺ ; HPLC: 95.7%; chiral HPLC: 97.8% (retention time=5.138 min).

Example 43: N-(4-(3,4-dichlorophenyl)-but-3-yn-2-yl)-4-methacryloylpiperazine-1-carboxamide (±)

With stirring, EDCI (0.080 g, 0.414 mmol), HOBT (0.055 g, 0.414 mmol) was added to a suspension of intermediate 17 (0.150 g, 0.414 mmol) and methacrylic acid (42 μL, 59.832 mmol) in DCM (4.0 mL). and triethylamine (0.23 ml, 1.654 mmol) at 0°C and stirred at RT for 12 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted with EtOAc. The combined EtOAc layers were washed with water and brine, dried over Na ₂ SO ₄ and evaporated under reduced pressure. The resulting residue was purified by preparative TLC (DCM/McOH=97/3) to obtain the title compound (0.072 g, 44.17%) as a solid. HPLC: 97.47%; LCMS:m/z=394.30 [M] ⁺¹ .

1H NMR (400 MHz, CDCf): δ 7.53 (d, J=1.84 Hz, 1H), 7.39 (d, J=8.24 Hz, 1H), 7.32-7.20 ( m, 1H), 5.26 (kv, J=1.54 Hz, 1H), 5.08 (p, J=0.89 Hz, 1H), 4.97 (p, J=7.08 Hz, 1H), 4.69 (d, J=7.78 Hz, 1H), 3.65-3.45 (m, 8H), 1.99 (kv, J=1.01 Hz, 3H), 1, 53 (d, J=6.88 Hz, 3H).

Example 44: 4-(1-cyanocyclopropane-1-carbonyl)-N-(4-(3,4-dichlorophenyl)-but-3-yn-2-yl)piperazine 1-carboxamide (±).

The title compound was synthesized from intermediate 17 and 1-cyanocyclopropane-1carboxylic acid as described in Example 43. Yield: 25.8%; HPLC: 92.02%; LCMS: m/z=419.2 [M] ⁺ ;

1H NMR (400 MHz, CDCl ₃ ): δ 7.52 (d, J=1.91 Hz, 1H), 7.38 (d, J=8.28 Hz, 1H), 7.24 (dd, J =1.95, 8.31 Hz, 1H), 5.06-4.84 (m, 1H), 4.68 (d, J=7.91 Hz, 1H), 3.88-3.48 ( m, J=37.50 Hz, 8H), 2.18 (s, 2H), 1.52 (d, J=6.87 Hz, 3H), 1.33-1.19 (m, 2H).

Example 45: (E)-4-(2-cyano-4-methiopent-2-enoyl)-N-(1-((3,4-dichlorophenyl)ethynyl)cyclopropyl)-69 045414 piperazine-1-carboxamide

Step 1: 4-(2-cyanoacetyl)-N-(1-((3,4-dichlorophenyl)ethynyl)cyclopropyl)piperazine-1carboxamide.

The title compound was synthesized from intermediate 17o and 2-cyanoacetic acid as described in Example 43 or Example 44. Yield: 77.6%; LCMS: m/z=405.2 [M+H]+.

Step 2: (E)-4-(2-cyano-4-methylpent-2-enoyl)-N-(1-((3,4-dichlorophenyl)ethynyl)cyclopropyl)piperazine-1-carboxamide.

While stirring, isobutylaldehyde ( 0.022 g, 0.313 mmol) and piperidine acetate (0.007 g, 0.049 mmol) at room temperature. After stirring at room temperature for 5 s, the reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative TLC (dichloromethane/methanol: 98/2) in two cycles to give the title compound (0.020 g, 22.1%). HPLC: 96.8%; LCMS: m/z=459.3 [M] ⁺ .

^1H NMR (300 MHz, chloroform-d): δ 7.47 (d, J=1.9 Hz, 1H), 7.35-7.30 (m, 1H), 7.23-7.17 ( m, 1H), 6.99 (d, J=10.5 Hz, 1H), 5.13 (s, 1H), 3.64 (dd, J=6.5, 4.0 Hz, 4H), 3.47 (s, 4H), 1.39 - 1.31 (m, 1H), 1.23-1.17 (m, 2H), 1.15 (d, J=6.7 Hz, 6H) , 1.07 (d, J=6.7 Hz, 2H).

Example 46: (E)-4-(2-cyano-3-cyclopropylacryloyl)-N-(1-((3,4-dichlorophenyl)ethynyl)cyclopropyl)piperazine-1-carboxamide

The title compound was synthesized from the intermediate of Step 1 of Example 45 and cyclopropanecarbaldehyde as described in Step 2 of Example 45. Yield: 25.85%; LCMS: m/z=457.4 [M] ⁺ ; HPLC: 97.45%;

¹ H NMR (400 MHz, chloroform-d) δ 7.47 (d, J=1.8 Hz, 1H), 7.33 (d, J=8.3 Hz, 1H), 7.20 (dd, J=8.3, 1.9 Hz, 1H), 6.65 (d, J=11.3 Hz, 1H), 5.14 (s, 1H), 3.67 (s, 4H), 3, 51-3.43 (m, 4H), 3.10-3.06 (m, 1H), 1.37-1.32 (m, 2H), 1.31-1.24 (m, 2H), 1.21-1.14 (m, 2H), 0.95-0.88 (m, 2H).

Example 47: (E)-N-(4-(3,4-dichlorophenyl)-but-3-yn-2-yl)-4-(4-(dimethylamino)-but-2enoyl)piperazine-1-carboxamide ( ±).

With stirring, to a solution of Example 20 (0.3 g, 0.709 mmol) in acetonitrile (25 ml) was added dimethylamine (2.0 M solution in THF) (3.5 ml, 7.09 mmol) at room temperature. After stirring at room temperature for 16 hours, the reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the title compound (0.050 g, 54%). HPLC: 99.3%; LCMS: m/z=437.4 [M] ⁺ ;

1H NMR (400 MHz, DMSO-dg) δ 7.66 (d, J=1.96 Hz, 1H), 7.37 (dd, J=1.98, 8.37 Hz, 1H), 7.04 (d, J=7.94 Hz, 1H), 6.60 (d, J=2.32 Hz, 2H), 4.77 (p, J=7.13 Hz, 1H), 3.55 - 3 .45 (m, 8H), 3.32 (s, 1H), 3.12 - 2.93 (m, 2H), 2.13 (s, 6H), 1.39 (d, J=6.99 Hz, 3H).

Example 48a: trans-N-((1S,2S)-2-(3-(4-(3,4-dichlorophenyl)-but-3-yn-2-yl)-1-methylureido)cyclohexyl)-N- methylacrylamide (±) (isomer-1).

With stirring, to a suspension of 3-(4-(3,4-dichlorophenyl)-but-3-yn-2-yl)-1-methyl-1-(2(methylamino)cyclohexyl)urea (intermediate 17ag) (0.060 g , 0.157 mmol) triethylamine (65 μL, 0.470 mmol) and acryloyl chloride (14 μL, 0.172 mmol) were added to DCM (5 ml) at 0°C. The reaction mixture was allowed to warm to RT for 2 hours. The reaction mixture was extracted with DCM, the combined DCM layers were washed with water and brine, dried over Na ₂ SO ₄ and evaporated under reduced pressure. The resulting crude product (mixture of isomers by TLC) was purified by preparative TLC (dichloromethane/methanol=99/1) to give individual isomers 48a and 48b.

- 70 045414

Example 48b: trans-N-((1S,2S)-2-(3-(4-(3,4-dichlorophenyl)-but-3-yn-2-yl)-1-methylureido)cyclohexyl)-N- methylacrylamide (±) (isomer-2).

Example 48a: yield: 0.010 g, 14.70%; HPLC: 97.47%; chiral HPLC: 4.36 peak 1, 7.74 peak 2; LCMS: m/z=436.4 [M+H]+;

1H NMR (300 MHz, CDCl ₃ ): δ 7.47 (d, J=1.92 Hz, 1H), 7.37 (d, J=8.31 Hz, 1H), 7.26-7.21 (m, 1H), 6.45 (dd, J=10.44, 16.82 Hz, 1H), 6.20 (dd, J=2.12, 16.91 Hz, 1H), 5.59- 5.46 (m, 1H), 4.86 (p, J=7.12 Hz, 1H), 4.674.42 (m, 2H), 2.88 (d, J=10.39 Hz, 3H), 2.69 (s, 3H), 1.79 (d, J=9.66 Hz, 4H), 1.59-1.35 (m, 7H).

Example 48b: yield: 0.008 g, 11.76%; HPLC 96.80%; chiral HPLC: 5.90 peak 1, 8.57 peak 2; LCMS: m/z=436.4 [M+H] ⁺¹ ;

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.49 (d, J=1.95 Hz, 1H), 7.36 (d, J=8.34 Hz, 1H), 7.26-7, 20 (m, 1H), 6.54 (dd, J=10.38, 16.80 Hz, 1H), 6.25 (dd, J=2.11, 16.79 Hz, 1H), 5.66 (d, J=10.40 Hz, 1H), 4.96-4.78 (m, 1H), 4.704.31 (m, 2H), 2.88 (d, J=17.49 Hz, 3H) , 2.70 (s, 3H), 1.79 (d, J=8.71 Hz, 4H), 1.58-1.24 (m, 7H).

Example 49: X-(4-(3,4-dichlorophenyl)-but-3-yn-2-yl)-4-(vinylsulfonamido)-piperidine-1carboxamide (±).

With stirring, chloroethylsulfonyl chloride (0.03 mL, 0.292 mmol) and triethylamine (0.111 mL, 0.807 mmol) were added to a solution of intermediate 17k (0.1 g, 0.269 mmol) in dichloromethane (5 mL) at 10 °C. After stirring for 1 hour at room temperature, the reaction mixture was washed with saturated sodium bicarbonate solution. The dichloromethane layer was dried and concentrated. The crude compound was purified by preparative HPLC to give the title compound (0.020 g, 17%).

Method: Column: Xbridqe-C-18 (19x150) mm; water:acetonitrile; flow rate 15 ml/min. HPLC: 98.27%, LCMS: m/z=429.9 [M+H] ⁺ .

1H NMR (400 MHz, DMSO- _d6 ): δ 7.75-7.49 (m, 2H), 7.47-7.29 (m, 2H), 6.93 (d, J=8.18 Hz, 1H), 6.76 (ddd, J=0.86, 9.94, 16.52 Hz, 1H), 6.11-5.86 (m, 2H), 4.75 (p, J= 7.13 Hz, 1H), 3.94-3.72 (m, 2H), 3.17 (tdd, J=4.73, 7.05, 8.84, 10.58 Hz, 2H), 2 .78 (ddt, J=5.89, 11.88, 15.23 Hz, 2H), 1.74 (d, J=12.57 Hz, 2H), 1.34-1.22 (m, 3H ).

Example 50: N-((1s,4s)-4-(3-(4-(3,4-dichlorophenyl)-but-3-yn-2-yl)ureido)cyclohexyl)ethensulfonamide (±).

The target compound was synthesized from intermediate 17y as described in example 49. Yield: 27%, LCMS: m/z=444.2 [M+H] ⁺ ; HPLC=98.84%.

1H NMR (400 MHz, DMSO- _d6 ): δ 7.71-7.58 (m, 2H), 7.38 (dd, J=1.99, 8.35 Hz, 1H), 7.27 ( d, J=5.96 Hz,

1H), 6.70 (dd, J=9.91, 16.52 Hz, 1H), 6.26 (d, J=8.25 Hz, 1H), 6.07-5.90 (m, 2H ), 5.85 (d, J=7.40 Hz, 1H), 4.744.57 (m, 1H), 3.49 (s, 1H), 3.18-2.99 (m, 1H), 1 .50 (s, 8H), 1.34 (d, J=6.90 Hz, 3H).

Example 51: X-(1-((3,4-dichlorophenyl)ethynyl)cyclopropyl)-4-(vinylsulfonyl)piperazine-1carboxamide

The title compound was synthesized from intermediate 17o as described in Example 49.

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Yield: 43.8%, LCMS: m/z=427.8 [MH] ⁺ ; HPLC=98.75%.

1H NMR (300 MHz, chloroform-d) δ 7.47 (dd, J=2.0, 1.0 Hz, 1H), 7.33 (dd, J=8.3, 1.0 Hz, 1H) , 7.22-7.17 (m, 1H), 6.41 (ddd, J=16.6, 9.6, 1.0 Hz, 1H), 6.27 (dd, J=16.6, 1.0 Hz, 1H), 6.08 (dd, J=9.7, 1.0 Hz, 1H), 5.13 (s,

1H), 3.48 (t, J=5.1 Hz, 4H), 3.16 (t, J=5.1 Hz, 4H), 1.38-1.31 (m, 2H), 1, 19-1.12 (m, 2H).

Example 52: 4-Acryloyl-N-(4-(3,4-dichlorophenyl)-but-3-yn-2-yl)-3-oxopiperazine-1-carboxamide (±).

With stirring, to a solution of intermediate 15f (0.1 g, 0.29 mmol) in THF (50 ml) was added LiCl (0.016 g, 0.382 mmol), (Et) _3N (0.05 ml, 0.382 mmol), and then acrylic anhydride (0.05 g, 0.382 mmol). The reaction mixture was stirred at room temperature for 16 hours, poured into water and extracted with EtOAc (50 ml). The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude compound was purified by preparative TLC using 2% methanol in dichloromethane as the mobile phase. 0.02 g (17%), HPLC: 93.98%; LCMS: m/z=m/z=444.2 [M+H] ⁺¹ ;

1H NMR (300 MHz, CDCl ₃ ): δ 7.50 (d, J=1.92 Hz, 1H), 7.37 (d, J=8.32 Hz, 1H), 7.23 (dd, J =1.97, 8.28 Hz, 1H), 7.19 - 7.10 (m, 1H), 6.46 (dd, J=1.68, 16.92 Hz, 1H), 5.85 ( dd, J=1.68, 10.41 Hz, 1H), 5.07 - 4.82 (m, 1H), 4.63 (d, J=7.94 Hz, 1H), 4.28 (s , 2H), 4.01 (ddd, J=1.98, 4.41, 5.29 Hz, 2H), 3.77-3.48 (m, 2H), 1.51 (d, J=6 .89 Hz, 3H).

Example 53: N-(2-(3-(4-(3,4-dichlorophenyl)-but-3-yn-2-yl)-1-methylureido)ethyl)acrylamide.

With stirring, to a suspension of N-(4-(3,4-dichlorophenyl)-but-3-yn-2-yl)-4-(hydroxymino)piperidine-1-carboxamide (intermediate 15s) (0.090 g, 0.254 mmol) triethylamine (70 µl, 0.508 mmol) and acryloyl chloride (20 µl, 0.191 mmol) were added to DCM (3 ml) at 0°C. The reaction mixture was allowed to warm to RT and stirred for 2 hours. The reaction mixture was poured into ice water, extracted with DCM, the combined DCM layers were washed with brine, water, dried over Na ₂ SO ₄ and evaporated under reduced pressure. The resulting crude compound was purified by preparative TLC (2×) (dichloromethane/methanol=95/05) to give the title compound (0.010 g, 9.70%). HPLC: 90.18%; LCMS: m/z=408.1 [M+H] ⁺ ;

1H NMR (400 MHz, CDCl ₃ ): δ 7.50 (d, J=1.87 Hz, 1H), 7.37 (d, J=8.34 Hz, 1H), 7.22 (dd, J =1.93, 8.26 Hz, 1H), 6.54 (dd, J=1.24, 17.32 Hz, 1H), 6.20 (dd, J=10.57, 17.31 Hz, 1H), 5.95 (dd, J=1.24, 10.56 Hz, 1H), 4.95 (p, J=7.00 Hz, 1H), 4.69 (d, J=7.87 Hz, 1H), 3.59 (ddt, J=6.11, 13.01, 19.09 Hz, 4H), 2.85 - 2.59 (m, 4n), 1.50 (d, J= 6.84 Hz, 3H).

Example 54: (E)-4-acryloyl-N'-cyano-N-(4-(3,4-dichlorophenyl)-but-3-yn-2-yl)piperazinecarboximidamide (±).

To a solution of intermediate 13 (0.3 g, 0.83 mmol) and 1-(piperazin-1-yl)prop-2-en-1-one (intermediate 6a) (0.275 g, 1.08 mmol) in DMSO (10 yl) was added to triethylamine (0.346 ml, 2.49 mmol) at RT and stirred for 16 h at 90°C. After completion of the reaction, the reaction mixture was poured into ice water (20 ml), the resulting solid was filtered and purified by a Combiflash® silica gel column (dichloromethane/methanol=95/5) to obtain the title compound (0.05 g, 14.7%). LCMS: m/z 404.0 [M] ⁺ ;

1H NMR (400 MHz, CDCl ₃ ): δ 7.45 (d, J=1.89 Hz, 1H), 7.34 (d, J=8.30 Hz, 1H), 7.23 - 7.16 (m, 1H), 6.48 (dd, J=10.42, 16.77 Hz, 1H), 6.30 (dd, J=1.80, 16.72 Hz, 1H), 5.73 ( dd, J=1.84, 10.44 Hz, 1H), 4.95 - 4.80 (m, 2H), 3.88 - 3.40 (m, 8H), 1.56-1.54 ( m, 3H).

The following examples were prepared essentially according to the method described in Example 54, with appropriate changes in reagents and reaction conditions.

- 72 045414

Example Structure Output and Analytics 55 10 1 x n ι/Ί n S|A>n Yield: 55%; HPLC: 97.61%; LCMS: m/z =406.2[M] ⁺ ; ^1H NMR (400 MHz, flMCOde) δ 8.36 - 8.17 (m, 1H), 7.72 7.50 (m, 2H), 7.34 (ddd, J = 1.95, 4.86 , 8.25 Hz, 1H), 6.59 (m, 1H), 6.41 - 5.92 (m, 2H), 5.53 (dt, J = 2.36, 10.10 Hz, 1H) , 4.89 - 4.62 (m, 1H), 4.24 - 3.92 (m, 2H), 3.17 - 2.92 (m, 2H), 2.65 (d, J = 8, 58 Hz, 1H), 2.12 - 1.83 (m, 1H), 1.54 (s, 2H), 1.41 -1.19 (m, 4H). 56 1 ⁰ Ho v XX '% SG ^p Yield:30%; HPLC: 95.17%; LCMS: m/z = 442.3[M] ⁺ ; ^1H NMR (400 MHz, flMCOde): δ 7.71 - 7.52 (m, 2H), 7.46 7.28 (m, 1H), 6.77 - 6.47 (m, 2H), 6 ,16 5.87 (m, 1H), 4.76 (s, 1H), 4.10 (d, J = 6.23 Hz, 1H), 3.59 - 3.11 (m, 5H), 2 .49 (dt, J = 2.01, 3.56 Hz, 2H), 2.00 - 1.93 (m, 1H), 1.54-1.46 (m, 2H), 1.36 (dd , J = 8.88, 15.19 Hz, ZN). 57 1 ⁰ 1 x O, ·Τ T 0 it ⁿ Yield:42.4%; HPLC: 98.70%; LCMS: m/z =452.2 [M+H] ⁺ ; ^1H NMR (400 MHz, DMSOc16): δ 7.66 (d, J = 1.91 Hz, 1H), 7.62 (d, J = 8.24 Hz, 1H), 7.46 (d, J = 15.39 Hz, 1H), 7.40 - 7.34 (m, 1H), 7.07 (d, J = 7.91 Hz, 1H), 6.56 (dd, J = 0.80, 15.43 Hz, 1H), 4.78 (kv, J = 7.30 Hz, 1H), 4.27 - 4.08 (m, 2H), 3.52 (dt, J = 5.21, 10 .45 Hz, 4H), 3.33 (d, J = 0.75 Hz, 4H), 1.39 (d, J = 6.96 Hz, ZN), 1.24 (td, J = 0.81 , 7.14 Hz, ZN). 58 10 X x οι^γΑ O ? XX S Yield: 15.8%; HPLC: 98.9%; LCMS: m/z =434.2[M] ⁺ ; ^1H NMR (400 MHz, CDCh): δ 7.52 (d, J=1.90 Hz, 1H), 7.39 (d, J=8.30 Hz, 1H), 7.29 - 7.23 (m, 1H), 6.51 - 6.35 (m, 2H), 5.92 - 5.77 (m, 1H), 5.71 (dd, J = 3.20, 9.27 Hz, 1H ), 5.22 (dd, J = 13.80, 20.35 Hz, 2H), 5.04 - 4.87 (m, 1H), 4.83 - 4.60 (m, 2H), 4, 18 - 3.97 (m, 2H), 3.91 (d, J = 4.31 Hz, 2H), 2.92 (t, J = 12.83 Hz, 2H), 1.84-1.69 (m, 2H), 1.69 1.56 (m, 2H), 1.51 (d, J = 6.86 Hz, ZN).

-73 045414

59 I 0 Η 1 1 Jl A U Yield: 55%; HPLC: 99.06%; LCMS: m/z =420.3[M] ⁺ ; ^1H NMR (400 MHz, DMSOc) δ 7.67 (d, J = 1.94 Hz, 1H), 7.62 (d, J = 8.35 Hz, 1H), 7.38 (dd, J = 1.97, 8.31 Hz, 1H), 6.97 (s, ZN), 4.87 - 4.68 (m, 1H), 4.16 - 3.86 (m, ZN), 2.82 - 2.61 (m, 2H), 2.08 - 1.83 (m, 2H), 1.56 (d, J = 12.78 Hz, 2H), 1.39 (d, 7 = 6.98 Hz, ZN). 60 4" ZI o o Yield: 54.54%; HPLC: 97.99%; LCMS: m/z =448.35 [M+H] ⁺ ; ^1H NMR (300 MHz, CDCb) δ 7.57 (s, 1H), 7.51 (d, J=1.76 Hz, 1H), 7.37 (d, J=8.32 Hz, 1H) , 7.30 - 7.20 (m, 1H), 4.94 (d, J = 7.05 Hz, 1H), 4.66 (s, 1H), 3.66 (dd, J = 3.73 , 6.73 Hz, 4H), 3.47 (dd, J= 3.88, 6.55 Hz, 4H), 3.36 (s, ZH), 3.19 (s, ZH), (dimethyl in another isomer), 2.66 - 2.60 (m, 6H), 1.50 (d, 7 = 6.87 Hz, ZN). 61 1 o e, Υ^Ί Ύτ ⁿ C1 0 Yield: 34.01%; HPLC: 98.34%; LCMS: m/z =393.27 [M+H] ⁺ ; ^1H NMR (400 MHz, CDCb) δ 6.95 (s, 1H), 6.836.81 (m, 1H), 6.68 - 6.66 (m, 1H), 4.414.37 (m, 1H) , 4.13-4.07 (m, 1H), 3.16 - 3.13 (m, 2H), 3.03 - 2.96 (m, 6H), 2.88 - 2.85 (m, 2H), 9.66 (d, J = 17.61 Hz, ZN). 62 1 ⁰ s, Η ι 1 JL J Yield: 32.05%; HPLC: 99.24%; LCMS: m/z = 391.30[M] ⁺ ; ¹ H NMR (400 MHz, CDCb): δ 7.70-7.55 (m, 1 H), 7.47 (d, J = 1.90 Hz, 1 H), 7.34 (d, J = 8 .28 Hz, 1H), 7.27 - 7.16 (m, 1H), 7.20 - 7.00 (m, 2H), 4.98 - 4.88 (m, 1H), 4.72 ( d, J = 7.86 Hz, 1H), 4.12 (d, J = 11.72 Hz, ZN), 2.99 2.86 (m, 2H), 2.10 (d, J = 12, 44 Hz, 2H), 1.94-1.80 (m, 2H), 1.48 (d, J = 6.86 Hz, ZN). 63 1 0 _FC ³ γγ^ ⁿ ^ Υ ⁴ Yield: 26.78%; HPLC: 98.26%; LCMS: m/z =405.2 [M+H] ⁺ . ^1H NMR (400 MHz, CDCb): δ 7.84 - 7.73 (m, 2H), 7.71 -7.64 (m, 1H), 6.55 (dd, J= 10.47, 16 .81 Hz, 1H), 6.34 (dd, J= 1.80, 16.84 Hz, 1H), 5.75 (dd, J= 1.76, 10.55 Hz, 1H), 4.99 (p, J= 7.13 Hz, 1H), 4.65 (d, 7= 7.86 Hz, 1H), 3.57 (dd, J= 48.36, 85.73 Hz, 8H), 1 .52 (d, 7=20.12 Hz, ZN). 64 1 ⁰ Gu ⁿ Yield: 50.74%; HPLC: 98.69%; LCMS: m/z =330.2 [M+H] ⁺ ; ^1H NMR (300 MHz, CDCb): δ 7.44 - 7.35 (m, 2H), 7.04 -6.94 (m, 2H), 6.56 (dd, 7= 10.43, 16 .76 Hz, 1H), 6.33 (dd, 7= 1.94, 16.79 Hz, 1H), 5.75 (dd, 7= 1.93, 10.42 Hz, 1H), 4.95 (p, 7 = 6.94 Hz, 1H), 4.68 (d, 7 = 7.80 Hz, 1H), 3.73-3.40 (m, 8H), 1.49 (d, 7= 20.12 Hz, ZN).

- 74 045414

Example 65: (E)-4-(4-amino-4-oxobut-2-enoyl)-N-(4-(3,4-dichlorophenyl)-but-3-yn-2-yl)piperazin-1carboxamide ( ±).

Step 1: synthesis of (E)-4-(4-((4-(3,4-dichlorophenyl)-but-3-yn-2-yl)carbamoyl)piperazin-1-yl)-4oxobut-2-enoic acid (±).

With stirring, LiOH.H _{2 O (0.093 g, 2.220 mmol) was added to a solution of example 57 (0.200 g, 0.440 mmol) in a mixture of THF:MeOH:H 2 O} (1:1:8) and stirred for 12 hours at RT . The reaction mixture was concentrated under reduced pressure, diluted with water (25 ml) and washed with diethyl ether (2x50 ml). The aqueous layer was separated and the pH was adjusted to slightly acidic using dil. HCl and extracted with EtOAc (50 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ ; concentrated under reduced pressure to give a cream solid (0.08 g, 42.6%). LCMS: m/z 456.2 [M+H+38] ⁺ .

Step 2: synthesis of (E)-4-(4-amino-4-oxobut-2-enoyl)-N-(4-(3,4-dichlorophenyl)-but-3-yn-2yl)piperazine-1-carboxamide (±).

The target compound was synthesized according to the procedure described in Example 42 from the intermediate from Step-1 and ammonium chloride using EDC.HCl and HOBt in the presence of Et3N in DMF. Yield: 18.7%; HPLC: 98.4%; LCMS: m/z=423.0 [M]+;

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.66 (d, J=1.96 Hz, 1H), 7.62 (d, J=8.38 Hz, 1H), 7.41-7, 35 (m, 1H), 7.25 (d, J=15.06 Hz, 1H), 6.78 (d, J=15.09 Hz, 1H), 4.77 (p, J=7.17 Hz, 1H), 3.61-3.44 (m,4H), 3.33-3.17 (m,4H), 3.18 (s, 1H), 1.24 (d, J=17.61 Hz , 3H),

Example 66: (E)-N-(1-((3,4-dichlorophenyl)ethynyl)cyclopropyl)-4-(4,4,4-trifluorobut-2enoyl)piperazine-1-carboxamide.

With stirring, to a solution of intermediate 17o (0.100 g, 0.267 mmol) in DMF (25 ml) was added DIPEA (0.103 g, 0.80 mmol), (E)-4,4,4-trifluorobut-2-enoic acid (0.056 g, 0.400 mmol) and HATU (0.152 g, 0.400 mmol) at RT and stirred for 2 h at RT. After completion of the reaction, the reaction mixture was poured into ice water and extracted with EtOAc. The EtOAc layer was dried, concentrated and purified on a Combiflash® silica gel column (DCM/MeOH=96/4) to give the title compound (0.040 g, 32.7%). LCMS: m/z=459.8 [M]+; HPLC: 99.3%;

^1H NMR (400 MHz, CDCl ₃ ): δ 7.47 (d, J=1.89 Hz, 1H), 7.37-7.30 (m, 1H), 7.23-7.17 (m , 1H), 6.95 (dkv, J=2.11, 15.38 Hz, 1H), 6.82-6.70 (m, 1H), 5.13 (s, 1H), 3.80- 3.28 (m, 8H), 1.47-1.04 (m, 4H).

Example 67: N-(1-((3,4-dichlorophenyl)ethynyl)cyclopropyl)-4-(2-fluoroacryloyl)piperazine-1 carboxamide.

With stirring, to a suspension of N-(1-((3,4-dichlorophenyl)ethynyl)cyclopropyl)piperazine-1carboxamide hydrochloride (intermediate 17o) (0.2 g, 0.534 mmol) and 2-fluoroacetic acid (0.096 g, 1.067 mmol ) HATU (0.304 g, 0.800 mmol) and DIPEA (0.28 mL, 1.601 mmol) were added to DMF (4.0 mL) at 0°C and stirred for 16 h at RT. After completion of the reaction, the reaction mixture was poured into ice water and extracted with EtOAc. The combined EtOAc layers were washed with brine and water, dried over Na2SO4 and evaporated under reduced pressure (0.220 g crude). Yield: 0.050 g (22.72%). HPLC: 98.93%; LCMS: m/z=410.0 [M+H] ⁺¹ ;

1H NMR (400 MHz, CDCl ₃ ): δ 7.47 (d, J=1.92 Hz, 1H), 7.33 (d, J=8.40 Hz, 1H), 7.20 (dd, J =1.93, 8.28 Hz, 1H), 5.38-5.12 (m, 2H), 3.65-3.42 (m, 8H), 1.39-1.30 (m, 2H ), 1.24-1.11 (m, 2H).

Example 68: 4-(1-acryloyl azetidin-3-carbonyl)-N-(1-((3,4-dichlorophenyl)ethynyl)cyclopropyl)piperazine-1-carboxamide.

Step 1: synthesis of tert-butyl-3-(4-((1-((3,4-dichlorophenyl)ethynyl)cyclopropyl)-75 045414 carbamoyl)piperazine-1-carbonyl)-azetidine-1-carboxylate.

Intermediate 17o was reacted with 1-(tert-butoxycarbonyl)-azetidine-3carboxylic acid, triethylamine, HOBT, EDCl at 0°C as described in the example synthesis procedure

25, yielding the title compound (0.455 g, crude); LCMS: m/z=421.2 [M+H-100]+.

Step 2: synthesis of 4-(azetidine-3-carbonyl)-N-(1-((3,4-dichlorophenyl)ethynyl)cyclopropyl)piperazine 1-carboxamide hydrochloride.

With stirring, a solution of tert-butyl 3-(4-((1-((3,4-dichlorophenyl)ethynyl)cyclopropyl)carbamoyl)piperazine-1-carbonyl)-azetidine-1-carboxylate (0.45 g, 0 86 mmol) in dioxane (5 ml), dioxane.HCl (10 ml) was added dropwise at RT and stirred for 2 hours at RT. The solvent was evaporated under reduced pressure to give (0.390 g, crude); LCMS: m/z=421 [M36] ⁺ .

Step 3: synthesis of 4-(1-acryloyl azetidin-3-carbonyl)-N-(1-((3,4-dichlorophenyl)ethynyl)cyclopropyl)piperazine-1-carboxamide.

With stirring to a solution of 4-(azetidine-3-carbonyl)-N-(1-((3,4-dichlorophenyl)ethynyl)cyclopropyl)piperazine-1-carboxamide hydrochloride (step 2) (0.25 g, 0.54 mmol) in DCM (10 ml), a solution of NaHCO ₃ (10 ml) and acryloyl chloride (45 μl, 0.54 mmol) was added at room temperature and stirred for 1 hour. The DCM layer was separated, washed with brine, and dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting residue was purified by preparative HPLC to give the title compound (0.080 g, 30.8%); LCMS: m/z=475.3 [M]+, HPLC: 99%,

Ή NMR (400 MHz, CDCl ₃ ): δ 7.47 (d, J=1.87 Hz, 1H), 7.33 (d, J=8.30 Hz, 1H), 7.20 (dd, J =1.90, 8.30 Hz, 1H), 6.34 (dd, J=1.82, 16.98 Hz, 1H), 6.18 (dd, J=10.25, 16.99 Hz, 1H), 5.69 (dd, J=1.84, 10.29 Hz, 1H), 5.16 (s, 1H), 4.31 (kv, J=9.20, 9.84 Hz, 2H ), 4.14 (dd, J=6.31, 9.88 Hz, 1H), 3.48 (kv, J=6.95 Hz, 4H), 3.33 (p, J=5.28 Hz , 4H), 1.42-1.31 (m, 2H), 1.31-1.12 (m, 4H).

Example 69: 4-acryloyl-N-(4-(3,4-dichlorophenyl)-but-3-yn-2-yl)piperazine-1-carbothioamide (±).

To a solution of thiophosgene (0.290 g, 2.52 mmol) in THF, a mixture of Intermediate-11 (HCl salt) (0.500 g, 2.016 mmol) and triethylamine (0.610 g, 6.04 mmol) in THF was slowly added with stirring at 0° C. After stirring at RT for 15 minutes, a mixture of Intermediate 12 (0.765 g, 4.34 mmol) and triethylamine (0.610 g, 6.04 mmol) in THF was added and the reaction mixture was stirred for 1 hour at RT. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, and the ethyl acetate layer was dried and concentrated. The crude product was purified by preparative TLC using 70% ethyl acetate in hexanes to give the title compound as a sticky solid (Yield: 0.1 g, 12.5%); HPLC: 91.1%; LCMS: m/z=396.2 [M] ⁺ ;

Ή NMR (400 MHz, CDCl3) δ 7.42 - 7.37 (m, 2H), 7.14 (dd, J=2.14, 8.41 Hz, 1H), 6.57 (dd, J= 10.50, 16.77 Hz, 1H), 6.42-6.27 (m, 2H), 5.75 (dd, J=1.83, 10.58 Hz, 1H), 5.08 (tt , J=3.72, 7.60 Hz, 1H), 3.96-3.50 (m, 8H), 1.45 (d, J=6.75 Hz, 3H).

The following examples were prepared essentially according to the procedure described for Example 1 with appropriate changes in reagents and reaction conditions.

- 76 045414

Yield and analytical data Yield: 57%; HPLC: 99.03%; LCMS: m/z =379.2 [M+H]+; ¹ NMR (400 MHz, DMSOс): δ 8.40 (d, J = 7.80 Hz, 1H), 7.70 - 7.54 (m,2H), 7.35 (d, J = 8.27 Hz, 1H), 6.76 (dd, J = 10.45, 16.70 Hz, 1H), 6.12 - 5.97 (m, 1H), 5.68 - 5.56 (m, 1H) , 4.79 (p, J = 7.24 Hz, 1H), 4.35 (d, J = 12.83 Hz, 1H), 4.02 (d, J = 13.40 Hz, 1H), 3 .01 (t, J = 12.89 Hz, 1H), 2.61 (d, J = 14.82 Hz, 1H), 2.37 (td, J = 4.82, 9.91, 11.52 Hz, 1H), 1.69 (d J = 12.62 Hz, 2H), 1.39 9 (ush s, 1H), 1.32 d, J = 7.00 Hz, ZN). Yield: 15%; HPLC: 92.13%; LCMS: m/z =364.9 [M] ⁺ ; ¹ H NMR (400 MHz, flMCOde): δ 8.65 - 8.53 (m, 1Η), 7.66 (d, J = 1.95 Hz, 1Η), 7.61 (d, J = 8, 35 Hz, 1H), 7.36 (dd, J = 1.97, 8.34 Hz, 1H), 6.53 (ddd, J = 2.17, 10.29, 16.78 Hz, 1H), 6.08 (ddd, J = 1.28, 2.36, 16.68 Hz, 1H), 5.62 (ddd, J = 1.38, 2.49, 10.33 Hz, 1H), 4, 81 (p, J = 7.13 Hz, 1H), 3.77-3.37 (m, ZN), 2.94 (dp, J = 7.52, 39.79 Hz, 2H), 2.13 1.80 (m, 2H), 1.35 (d, J = 6.94 Hz, ZN). Yield: 28%: HPLC: 98.58%; LCMS: m/z =365.0 [M+H] ⁺ ; ¹ NMR (400 MHz, flMCOd ₆ ): δ 8.65 - 8.53 (m, 1H), 7.66 (d, J = 1.95 Hz, 1H), 7.61 (d, J = 8, 35 Hz, 1H), 7.36 (dd, J = 1.97, 8.34 Hz, 1H), 6.53 (ddd, J = 2.17, 10.29, 16.78 Hz, 1H), 6.08 (ddd, J = 1.28, 2.36, 16.68 Hz, 1H), 5.62 (ddd, J = 1.38, 2.49, 10.33 Hz, 1H), 4, 81 (p, J = 7.13 Hz, 1H), 3.77 - 3.37 (m, ZN),

- 77 045414

2.94 (dp, J = 7.52, 39.79 Hz, 2H), 2.13 - 1.80 (m, 2H), 1.35 (d, J = 6.94 Hz, ZN).

Yield: 33%; HPLC: 94.8%; LCMS: m/z =393.2 [M+H] ⁺ ; ¹ NMR (400 MHz, flMCOde) δ 8.31 (d, J = 7.94 Hz, 1H), 7.96 (d, J = 7.87 Hz, 1H), 7.80 - 7.54 (m , 2H), 7.38 (dd, J = 1.98, 8.28 Hz, 1H), 6.17 (dd, 4 = 9.95, 17.10 Hz, 1H), 6.05 (dd, J= 2.46, 17.07 Hz, 1H), 5.55 (dd, J= 2.49, 9.90 Hz, 1H), 4.83 (kV, J = 7.09 2.20 12, 05, 10.05,

11.09, 12.51 Hz, 2H).

Hz, 1H), 3.64 - 3.43 (m, 1H), 1.99 (m, 1H), 1.80 (dd, J= 38.80 Hz, 4H), 1.38 (dd, J= 24.97 Hz, 5H), 1.17 (p, J=

Yield: 29%; HPLC: 95.48%; LCMS: m/z =381.2 [M+2]+; ^1H NMR (400 MHz, CDCI ₃ ) δ 7.49 (d, J = 1.92 Hz, 2H), 7.35 (d, J = 8.27 Hz, 1H), 7.21 (dd, J = 1.94, 8.33 Hz, 1H), 6.32 (dd, J = 1.32, 16.86 Hz, 1H), 6.11 (dd, J = 10.25, 16.87 Hz, 1H), 5.74 - 5.69(m, 2H), 5.05 - 4.84 (m, 1H), 2.38 - 2.31 (m, 2H), 2.04 (td, J = 6.27, 13.71 Hz, 2H), 1.87 - 1.70 (m, 4H), 1.46 (d, J = 6.90 Hz, ZN).

Example 75: (1r,4r)-N-(4-(3,4-dichlorophenyl)-but-3-yn-2-yl)-4-(vinylsulfonamido)cyclohexane-1carboxamide (±)

The target compound was obtained according to the procedure described in the synthesis of Example-1. Yield: 20%, LCMS: m/z=431.1 [M+H]+; HPLC: 95.5%,

Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.29 (d, J=7.92 Hz, 1H), 7.70 - 7.55 (m, 2H), 7.37 (dd, J=1 .95, 8.39 Hz, 1H), 7.26 (d, J=7.36 Hz, 1H), 6.73 (dd, J=9.96, 16.49 Hz, 1H), 6.08 -5.84 (m, 2H), 4.80 (t, J=7.32 Hz, 1H), 2.90 (dt, J=4.00, 7.48 Hz, 1H), 2.00 ( m, 1H) 1.88 - 1.93 (m, 4H), 1.44 - 1.28 (m, 4H), 1.28-1.03 (m, 3H).

Example 76: 4-Acrylamido-N-(4-(3,4-dichlorophenyl)-but-3-yn-2-yl)benzamide (±).

Step 1: synthesis of 4-acrylamido-N-(but-3-yn-2-yl)benzamide (±).

But-3-yn-2-ylmethanesulfonate (±) (1.0 g, 6.75 mmol) was stirred in aq. NH3 (10 ml) at RT for 16 h. The reaction mixture was extracted with DCM (25 ml). The DCM layer was dried over Na ₂ SO ₄ and filtered. To the resulting solution was added a DCM solution of 4-acrylamidobenzoic acid (prepared according to the procedure described in US2008/300268 A1) (0.990 g, 5.19 mmol, 1.0 eq), DIPEA (3.58 ml, 20.22 mmol) and HATU (3.86 g, 10.12 mmol, 1.5 eq) at RT and the resulting reaction mixture was stirred for 16 h at RT. The reaction mixture was washed with water (20 ml) and then with brine

- 78 045414 (20 ml). The DCM layer was dried and concentrated to give the crude compound. The resulting residue was purified on a Combiflash® silica gel column (hexane/ethyl acetate=60/40) to give the title compound (0.650 g, 40%) LCMS: m/z=243.4 [M+H]+.

Step 2: synthesis of 4-acrylamido-M-(4-(3,4-dichlorophenyl)-but-3-yn-2-yl)benzamide (±).

4-Acrylamido-M-(but-3-yn-2-yl)benzamide (±) (0.65 g, 2.68 mmol) was treated with 1,2-dichloro-4iodobenzene (0.487 g, 1.79 mmol), as described in the procedure for the synthesis of Intermediate 8, giving the title compound (Yield: 0.12 g, 11.5%) LCMS: m/z=387.0 [M+H]+. HPLC: 95.13%;

1H NMR (400 MHz, DMSO- _d6 ): δ 10.39 (s, 1H), 8.87 (d, J=7.89 Hz, 1H), 7.93-7.85 (m, 2H) , 7.77-7.69 (m, 3H), 7.64 (d, J=8.38 Hz, 1H), 7.42 (dd, J=1.99, 8.32 Hz, 1H), 6.45 (dd, J=10.04, 16.96 Hz, 1H), 6.29 (dd, J=2.04, 16.90 Hz, 1H), 5.80 (dd, J=2, 06, 10.05 Hz, 1H), 5.11 (p, J=7.04 Hz, 1H), 1.50 (d, J=6.97 Hz, 3H).

Example 77: 4-(3-bromo-4,5-dihydroisoxazole-5-carbonyl)-A4-(3,4-dichlorophenyl)-but-3-yn-2yl)piperazine-1-carboxamide (±)

Step 1: tert-butyl 4-(3-bromo-4,5-dihydroisoxazole-5-carbonyl)piperazine-1-carboxylate.

While stirring, hydroxycarbonimide dibromide (0.253 g, 1.248 mmol) and aq. KHCO3 (0.250 g, 2.496 mmol, 1.2 ml) at 0°C. After stirring at room temperature for 14 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The resulting crude product was purified by a Combiflash® silica gel column (hexane/ethyl acetate=99.9/0.1) to obtain the title compound (0.160 g, 53.15%) as a liquid. LCMS: m/z=448.35 [M+H]+.

Step 2: (3-bromo-4,5-dihydroisoxazol-5-yl)(piperazin-1-yl)-methanone trifluoromethyl carbonate (±).

While stirring, TFA (0.552 mmol) in dichloromethane (5.0 ml) was added to a suspension of tert-butyl 4-(3-bromo-4,5-dihydroisoxazole-5carbonyl)piperazine-1-carboxylate (0.20 g, 0.552 mmol) in dichloromethane (5.0 ml). 20 ml, 2.612 mmol) at RT and stirred for 14 hours. The reaction mixture was evaporated under reduced pressure and the resulting residue was triturated with diethyl ether to give the title compound (0.199 g crude). LCMS: m/z=262.11 [M] ⁺ .

Step 3: 4-(3-bromo-4,5-dihydroisoxazole-5-carbonyl)-A4-(3,4-dichlorophenyl)-but-3-yn-2yl)piperazine-1-carboxamide(±)

The target compound was obtained according to the method described in example 54. Yield: 53.15%; HPLC: 99.7%; LCMS: m/z=448.35 [M+H]+.

^1H NMR (400 MHz, CDCl3) δ 7.52-7.46 (m, 1H), 7.34 (d, J=8.31 Hz, 1H), 7.23-7.18 (m, 1H ), 5.28 (dd, J=7.62, 11.27 Hz, 1H), 5.00-4.84 (m, 1H), 4.61 (d, J=7.87 Hz, 1H) , 3.89-3.76 (m, 2H), 3.66-3.38 (m, 6H), 3.25 (dd, J=11.29, 17.52 Hz, 2H), 1.46 (d, J=6.87 Hz, 3H).

Example 78: Determination of antiproliferative activity in NCI-H1792 cells using the XTT test:

NCI-H1792 cells (ATCC CRL-5895) were seeded at 2000 cells/well in clear-bottom 96-well plates (Corning, Cat. No. 3596) using complete RPMI medium. After 24 hours, the compounds of the present invention were added as 20 mM stock solutions in DMSO (Sigma Cat no. D2650). Each concentration of compounds was tested in triplicate, with the final concentration of DMSO in the cells not exceeding 0.3 percent. After 72 h of incubation in a CO2 incubator, XTT (Invitrogen, Cat.no X6493) was added to the wells. XTT was dissolved in serum-free medium at a concentration of 1 mg/ml and absorbance was recorded on a spectrophotometer at a wavelength of 465 nm. Data were analyzed using graph pad prism software. Positive control (100% survival=cells in complete medium with 0.3% DMSO; negative control/blank (0% survival)=medium containing 0.3% DMSO only.

The compounds of the present invention were tested in the above test, and the results obtained are shown in the table below. The IC ₅₀ values of the compounds are listed below, with A referring to an IC ₅₀ value of less than 10 μM, B referring to an IC ₅₀ value in the range of 10.01 μM to 25 μM, and C referring to an IC ₅₀ value greater than 25 μM.

- 79 045414

IC ₅ q and % survival values for selected compounds of the present invention

Example H1792 cell line Example H1792 cell line 1C ₅₀ (µM) % survival (at 30 µM) 1C ₅₀ (µM) % survival (at 30 µM) 1 A 40 16 IN 3 1a A 45 19 A BUT 1b IN 37 33 BUT 54 2 A 22 47 A 26 2a WITH 56 49 IN 35 2b IN 57 50 A 17 3 A 3 54 A 22 4 IN 15 55 WITH 100 5 A 57 56 IN 39 6 IN 19 57 A 17 7 IN 33 58 WITH BUT 8 A 35 65 WITH 73 9 WITH 47 69 IN 18 10 WITH 89 70 A 33 eleven WITH 91 71 IN 26 12 WITH 83 72 IN 27 13 WITH BUT 73 WITH 64 14 WITH BUT 75 A 10 15 WITH 90 76 A 26

N/A=not defined.

Example 79: Determination of antiproliferative activity in NCI-H2122 cells using the XTT test.

NCI-H2122 ATCC CRL-5985 cells were seeded at 2000 cells/well in clear-bottom 96-well plates (Corning, Cat. No. 3596) using RPMI-1640 complete medium. After 24 hours, the compounds of the present invention were added as 10 mM stock solutions in DMSO (Sigma Cat no. D2650). Each concentration of compounds was tested in triplicate, with the final concentration of DMSO in the cells not exceeding 0.3 percent. Complete RPMI-1640 medium was replaced on day 3 (72 hours) and day 6 (144 hours) along with the compounds of the present invention. After 8 days (192 hours) of incubation, the test was stopped with 50 μl of XTT reagent (Invitrogen, Cat. no. X6493). The XTT reagent was prepared by dissolving 1 mg/ml XTT in a serum-free medium with the addition of 25 μM phenazine methosulfate (sigma Cat. no. P9625). Absorbance was recorded on a spectrophotometer at a wavelength of 465 nm. Data were analyzed using graph pad prism software. Positive control (100% survival)=cells in complete medium with 0.3% DMSO; negative control/blank (0% survival)=medium containing 0.3% DMSO only.

The compounds of the present invention were tested in the above test, and the results obtained are shown in the table below. The 1C ₅ o values of the compounds are indicated below, with A referring to an 1C ₅ o value of less than 10 μM, B referring to an 1C ₅ o value in the range of 10.01 μM to 25 μM, and C referring to an 1C ₅ o value greater than 25 μM.

-80045414

IC ₅₀ and % Survival Values for Selected Compounds of the Present Invention

Example H2122 cell line 1С ₅ о (µM) % survival (at 30 µM) 1a BUT 26 17 IN 19 18 A 1 21 IN 31 26 IN BUT 27 A BUT 28 IN BUT 29 A BUT thirty IN 19 31 IN 19 32 IN 15 33 WITH BUT 40 IN BUT 41 IN BUT 42 A 0 42a A BUT 42b A BUT 43 WITH 78 44 WITH 99 48a WITH BUT

N/A=not defined.

Example 80: Determination of antiproliferative activity in OCI-Ly10 cells.

OCI-Ly10 cells (UHN Canada) were seeded at 7500 cells/well in 96-well flat-bottom plates (Corning, Cat.No CLS3904) using complete Iscove's modified Dulbecco's medium (IMDM). After 6 hours, the compounds of the present invention were added as 10 mM stock solutions in DMSO (Sigma, Cat. No. D2650). Each concentration of compounds was tested in triplicate, with the final concentration of DMSO in the cells not exceeding 0.1 percent. After 72 hours of incubation in a _CO2 incubator, CTG (Promega, Cat.No G7572) was added to the wells and the luminescence was read on a plate reader. The percentage of proliferation inhibition was calculated using Microsoft Excel software. Positive control (100% survival) = cells in complete medium with 0.1% DMSO; negative control/blank (0% survival)=medium containing 0.1% DMSO only.

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Claims (28)

Percent inhibition for selected compounds of the present invention. Example % inhibition (for 1 µM) % inhibition (for 10 µM) 3 12 92 5 43 77 23 48 67 24 35 68 25 3 72 29 42 90 35 24 67 36 39 65 41 0 36 42 81 62 45 0 44 50 32 48 51 3 52 52 3 82 54 37 56 59 25 100 63 49 79 66 75 73 71 9 62 72 4 55 CLAIM 1. Compound of formula (I) or a pharmaceutically acceptable salt of said compound; Where A is (C ₆ -C ₁₄ )aryl or 5-10 membered heteroaryl containing from 1 to 4 heteroatoms selected from N, O and S; X is N-Ry or absent; Y is O, S or NCN; B is (C ₆ -C ₁₄ )aryl, (C ₃ -C ₁₀ )cycloalkyl or 3-15 membered heterocycloalkyl containing at least one heteroatom selected from O, N and S; wherein aryl, cycloalkyl or heterocycloalkyl are unsubstituted or substituted with one or more groups selected from (C ₁ -C ₆ )alkyl, halogen and oxo; R1 represents unsubstituted (C ₁ -C ₆ )alkyl; R2 represents hydrogen or unsubstituted (C ₁ -C ₆ )alkyl; or R1 and R2 together with the carbon atoms to which they are attached form a 3-5 membered cycloalkyl ring; R3 represents -C(O)R _a , -S(O)2R _a , -NHS(O)2R _a , -NR _b C(O)R _a , =NOR _a , 5-10 membered heteroaryl containing from 1 to 4 heteroatoms selected from N, O and S, 3-15 membered heterocycloalkyl containing at least one heteroatom selected from O, N and S, or (3-15 membered heterocycloalkyl containing at least one heteroatom , selected from O, N and S)-(C ₁ -C ₆ )alkyl; wherein heteroaryl and heterocycloalkyl are unsubstituted or substituted with one or more groups selected from (C ₁ -C ₆ )alkyl, halogen, oxo and -C(O)R _x ; R4 is (C ₁ -C ₆ )alkyl, halogen, halogen(C ₁ -C ₆ )alkyl, cyano, (C ₁ -C ₆ )alkoxy, (C ₆ C ₁₄ )aryloxy, (C ₁ -C ₆ ) alkoxy(C ₆ -C ₁₄ )aryl, hydroxy(C ₁ -C ₆ )alkyl, acetylene, acyl, hydroxy, (C3C ₁₀ )cycloalkyl or -N(R _x ) ₂ ; wherein the cycloalkyl is unsubstituted or substituted with (C ₁ -C ₆ )alkyl; Ra is (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, halogen(C ₁ -C ₆ )alkyl, (C ₃ -C ₁₀ )cycloalkyl or 3-15 membered heterocycloalkyl containing at least at least one heteroatom selected from O, N and S; - 82 045414 wherein (C1-C6)alkyl, (C2-C6)alkenyl, halogen(C1-C6)alkyl, (C3- _C10 )cycloalkyl and heterocycloalkyl are unsubstituted or substituted by one or more groups selected from (C1-C6 )alkyl, halogen, (C ₆ -C ₁₄ )aryl, (C ₃ -C ₁₀ )cycloalkyl, halogen(C ₁ -C ₆ )alkyl, amino, amido, (C ₁ -C ₆ )alkylamino, amino(C ₁ -C ₆ )alkyl, hydroxyl, cyano, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkoxy(C ₆ -C ₁₄ )aryl, (C ₆ -C ₁₄ )aryloxy, hydroxy(C ₁ - C ₆ )alkyl, carboxyl group, -C(O)OR11, -C(O)SR11, -SC(O)R11, oxo group (=O) and -C(O)R _X ; R _x represents hydrogen, (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, acyl or -C(O)-(C ₃ -C ₁₀ )cycloalkyl; R _y represents hydrogen or (C ₁ -C ₆ )alkyl; R _b represents hydrogen, (C ₁ -C ₆ )alkyl or (C ₂ -C ₆ )alkenyl; R11 represents (C ₁ -C ₆ )alkyl; m represents 0, 1, 2 or 3. 2. A compound according to claim 1, characterized in that B is a 3-15 membered heterocycloalkyl containing at least one heteroatom selected from O, N and S. 3. A compound according to claim 1, characterized in that B is 4. The compound according to claim 1, characterized in that R1 represents unsubstituted (C ₁ -C ₆ )alkyl; and R2 is hydrogen. 5. A compound according to claim 1, characterized in that R ₁ and R ₂ together with the carbon atoms to which they are attached form a cyclopropyl or cyclopentyl ring. 6. A compound according to any one of claims 1 to 5, characterized in that A is (C ₆ -C ₁₄ )aryl. 7. A compound according to claim 1, represented by a compound of formula (IA) or a pharmaceutically acceptable salt of said compound. 8. A compound according to claim 7, characterized in that B is a 5- or 6-membered cycloalkyl. 9. A compound according to claim 7, characterized in that B is a 5- or 6-membered heterocycloalkyl containing at least one heteroatom selected from O, N and S. 10. A compound according to any one of claims 7 to 9, characterized in that A is (C ₆ -C ₁₄ )aryl. 11. A compound according to any one of claims 7 to 10, characterized in that R3 is -NHS(O) ₂ R _a or -NR _b C(O)R _a . 12. A compound according to claim 1, represented by a compound of formula (IB) ^R 1 ^R 2 Q e) or a pharmaceutically acceptable salt of the said compound. 13. The compound according to claim 12, characterized in that B is a 3-15 membered heterocycloalkyl containing at least one heteroatom selected from O, N and S, unsubstituted or substituted by one or more groups selected from (C ₁ -C ₆ )alkyl, halogen or oxo group. 14. The compound according to claim 12, characterized in that B is a 5- or 6-membered heterocycloalkyl containing at least one heteroatom selected from O, N and S. 15. A compound according to claim 1, represented by a compound of formula (IC) or a pharmaceutically acceptable salt of said compound. 16. The compound according to claim 15, characterized in that R1 represents unsubstituted (C ₁ -C ₆ )alkyl; R2 represents hydrogen or unsubstituted (C ₁ -C ₆ )alkyl. - 83 045414 17. The compound according to claim 15, characterized in that R1 and R2, together with the carbon atoms to which they are attached, form a cyclopropyl or cyclopentyl ring. 18. A compound according to any one of claims 15-17, characterized in that R3 is a 3-15 membered heterocycloalkyl containing at least one heteroatom selected from O, N and S, unsubstituted or substituted by a -C(O) group Rx. 19. A compound according to any one of claims 15-18, characterized in that R ₄ represents (C ₁ -C ₆ )alkyl, halogen, halogen(C ₁ -C ₆ )alkyl or (C ₃ -C ₁₀ )cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with _{( CrC6} )alkyl. 20. A compound according to claim 1, represented by a compound of formula (ID) or a pharmaceutically acceptable salt of said compound. 21. The compound according to claim 20, characterized in that R _a represents (C ₂ -C ₆ )alkenyl, (C3C ₁₀ )cycloalkyl or 3-15-membered heterocycloalkyl containing at least one heteroatom selected from O, N and S, wherein alkenyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with one or more groups selected from halogen, (C ₆ -C ₁₄ )aryl or halo(C1C ₆ )alkyl. 22. The compound according to claim 21, characterized in that R _a represents (C ₂ -C ₆ )alkenyl substituted with (C1-C6)alkyl or halogen(C ₁ -C ₆ )alkyl. 23. A compound according to claim 1, represented by a compound of formula (IE) or a pharmaceutically acceptable salt of said compound. 24. A compound according to claim 1, represented by a compound of formula (IF) or a pharmaceutically acceptable salt of said compound. 25. Connection selected from: - 84 045414 - 85 045414 - 86 045414 - 87 045414 - 88 045414 - 89 045414 - 90 045414 - 91 045414 - 92 045414 or a pharmaceutically acceptable salt of said compound. 26. A method of treating cancer or a proliferative disorder, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 25. 27. The method according to claim 26, characterized in that the cancer or proliferative disorder is selected from solid tumor, benign or malignant tumor, brain, kidney, liver, stomach, vaginal, ovarian, stomach, breast, bladder, colon colon, prostate, pancreas, lung, cervix, testicle, skin, bone or thyroid, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer - 93 045414 tract, head and neck tumors, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasia, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphomas, Hodgkin and non-Hodgkin, breast carcinoma, foul licular carcinoma, papillary Carcinomas, seminomas, melanomas, hematological malignant formations selected from leukemia, diffuse large-cell bckeletal lymphoma (DLBCl), DLBCl of activated B cells, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary epofusion lymphoma, Lee Lee, Lee Lee Mfoma/leukemia of Berkitt, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, small cell lymphocytic lymphoma, lymphoplasmacytic lymphoma, Waldenström macroglobulinemia (WM), splenic marginal zone lymphoma, intravascular large B-cell lymphoma, plasmacytoma and multiple myeloma. 28. The method of claim 26, wherein the cancer or proliferative disorder is selected from lymphoma, leukemia, breast cancer, lung cancer (non-small cell lung cancer), colon cancer, colorectal cancer, brain cancer (glioma, medulloblastoma and ependymoma ), familial adenomatous polyposis (FAP) and Barrett's esophagus. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2