NZ718073A - Substituted nicotinimide inhibitors of btk and their preparation and use in the treatment of cancer, inflammation and autoimmune disease - Google Patents

Abstract

Disclosed are substituted nicotinamide derivatives as inhibitors of Bruton’s Tyrosine Kinase (BTK) and are useful in treating associated diseases including cancer, inflammation, and autoimmune diseases.

Description

TUTED NICOTINIMIDE INHIBITORS OF BTK AND THEIR PREPARATION AND USE IN THE TREATMENT OF CANCER, INFLAMMATION AND AUTOIMMUNE DISEASE CROSS-REFERENCE TO RELATED APPLICATIONS This ation claims priority under 35 U.S.C. 119(e) to US. ional Patent Application No. 61/884,958, filed on September 30, 2013 and entitled "Kinase Inhibiting Compounds," and under 35 U.S.C. 1 19(a) to Chinese Patent ation No. 2013104850481, filed on October 16, 2013 and entitled "Aromatic Amide Derivative, Method of its Preparation, and its Application on Medicine." The entire ts of each of the above-referenced applications are incorporated herein by reference.

FIELD AND BACKGROUND The present invention s to chemical compounds, ceutical compositions including these compounds, and their use in treatment of disease. In particular, the present ion relates to the use of substituted nicotinimides as irreversible inhibitors of tyrosine kinases useful in the treatment of diseases mediated by Bruton’s Tyrosine Kinase (BTK) including cancer, inflammation and autoimmune disease.

BTK is a Tec family non-receptor protein kinase which plays a role in le signal- transduction pathways regulating survival, activation, proliferation, and differentiation of B- e lymphoid cells. BTK is overexpressed and active in several B-lineage lymphoid malignancies. BTK is expressed in malignant cells in humans with B-Cell Precursor (BCP)— Acute Lymphoblastic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL), and Non- Hodgkin’s Lymphoma (NHL). BTK is an upstream activator of poptotic signaling les and networks, including: Signal Transducer and Activator of Transcription 5 (STAT5) protein, Phosphatidylinositol (PI), 3-kinase/AKT/Mammalian Target of Rapamycin (mTOR) pathway, and Nuclear Factor kappa B (NF-KB). D’Cruz, Osmond J., OncoTargets and Therapy 2013:6,161-176. to De Man et al. describes that BTK is expressed in B cells and d cells, and is a terminal enzyme in the B-Cell antigen Receptor (BCR) signaling pathway. Mutations in human BTK leads to X-Linked Agammaglobulinemia (XLA), an immunodeficiency disease related to a failure to generate mature B cells leading to reduced immunoglobulin in serum. BTK is therefore implicated in regulation of the production of auto-antibodies in autoimmune diseases. Furthermore, BTK may play a role in ent of autoimmune diseases characterized by production of pro-inflammatory cytokines and chemokines by B cells due to BTK's position in the BCR pathway. BTK inhibitors may be used for treatment of B cell lymphomas due to BTK' s involvement in the regulation of proliferation and apoptosis of B cells. tion of BTK is relevant in particular for B cell lymphomas due to chronic active BCR signaling. Davis et al., Nature, 463 (2010), 88-94.

Adaptive immune responses may involve B lymphocyte activation and absence of B lymphocyte activation is an indication of autoimmune disease. Treatment of autoimmune disease, such as toid Arthritis (RA), with Rituximab, an anti-CD20 therapy, demonstrates that B cell therapies are effective. Additionally, treatment with mab has been shown to improve disease symptoms in Relapsing Remitting Multiple Sclerosis (RRMS) and Systemic Lupus Erythematosus (SLE) ts. ingly, targeting B cell immunity is effective for treatment of autoimmune diseases.

SUMMARY The t invention includes certain tuted compounds described herein, their pharmaceutically able salts, solvates and hydrates, preparation of the compounds, intermediates, pharmaceutical compositions and formulations thereof, and methods of treating disease including cancers, inflammation, and autoimmune diseases therewith.

It is an object of the present invention to overcome or ameliorate at least one of the antages of the prior art, or to provide a useful alternative.

The present invention includes compounds of Formula I and pharmaceutically acceptable salts thereof as provided below and further defined herein: In some aspects, compounds of the invention are rsible inhibitors of kinases, ing Bruton’s Tyrosine Kinase (BTK). In some aspects, nds ofthe ion are selective inhibitors of BTK.

In some aspects, the invention includes methods of treating proliferative disease, particularly cancers, ions causing inflammation, and autoimmune diseases mediated at least in part by BTK, alone or in combination regimens with other therapies.

Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful as inhibitors of protein kinases. In some embodiments, the compounds are effective as inhibitors of Bruton’s Tyrosine Kinase (BTK). In some aspects, the invention includes pharmaceutically acceptable salts of the compounds of Formula I: wherein: A is selected from C3_12cycloalkyl, C3_12heterocycloalkyl, C3_12aryl, or C3_12heteroaryl, any of which is optionally substituted with G1 substituents; B1 is selected from C3_12cycloalkyl—C0_1zalky1—, C34gheterocycloalkyl—C0_12alkyl—, aryl— lkyl—, aryl—C3_12cycloalkyl—, aryl—C3_lzheterocycloalkyl—, heteroaryl—C0_12alkyl—, heteroaryl—C3_12cycloalkyl—, or heteroaryl—C3_1zheterocycloalky1—, any ofwhich is optionally substituted with G2 substituents; B2 is selected from C0_12alkyl, C3-12cycloalkyl—Co_12alkyl—, eterocycloalkyl—Co_ l—, aryl—C0_12alkyl—, aryl—C3_12cycloalkyl—, aryl—C3_12heterocycloalkyl—, heteroaryl—C0_ 12alkyl—, heteroaryl—C3_12cycloalkyl—, or heteroaryl—C3_lzheterocycloalkyl—, any of which is optionally tuted with G3 substituents; L1 is ed from —C0_2alkyl—, —CR5R6—, —C0_3alkyl(R5)(OH)—, —C(O)—, —CH20—, — OCH2—, —CF2—, 6—, —CR5R6S—, —N(R5)—, —N(R5)C(O)—, —C(O)N(R5)—, — N(R5)C(0)N(R")—, —0—, —S—, —S(0)mi—, —N(R5)S(O)mi—, or —S(0)miN(R5)—; L2 is selected from —C0_4alkyl—, —C(O)—, —, —N(R7)C(O)—, or —N(R7)S(O)m2—; X is selected from C342cycloalkyl—C0_12alkyl—, C34gheterocycloalkyl—Cdlzalkyl—, aryl— C0_12alkyl—, aryl—C3_12cycloalkyl—, aryl—C3_lgheterocycloalkyl—, heteroaryl—C0_12alkyl—, heteroaryl—C3_12cycloalkyl—, or heteroaryl—C3_1gheterocycloalkyl—, any ofwhich is optionally substituted with G4 substituents; Y is selected from —C(O)—, —N(R8)—, —N(R8)C(O)—, —S(O)mg—, or —N(R8)S(O)m3—; R1 is selected from 9,—C(O)NR9R1°,—C(O)OR9, C14alkynyl, 0R9, S(O)m4R9R10, or —CN; R2, R3, and R4 are each independently selected from C0_12alkyl, —CN, halo, C3- 12cycloalkyl—C0_1zalkyl—, C3-1gheterocycloalkyl—C0_12alkyl—, aryl—C0_12alkyl—, aryl—C3_ lzcycloalkyl—, 3_1gheterocycloalkyl—, heteroaryl—C0_12alkyl—, heteroaryl—C3_lzcycloalkyl—, or aryl—C3_lzheterocycloalkyl—, any ofwhich is optionally substituted with G5 substituents; R5, R6, R7, R8, R9, and R10 are each independently selected from Co_12alkyl, C3- 12cycloalkyl—C0_1zalkyl—, C3_1gheterocycloalkyl—C0_12alkyl—, aryl—C0_12alkyl—, aryl—C3_ 12cycloalkyl—, aryl—C3_1zheterocycloalkyl—, heteroaryl—C0_12alkyl—, heteroaryl—C3_1chcloalkyl—, or heteroaryl—C3_lzheterocycloalkyl—, any of which is optionally substituted with G6 substituents; G1, G2, G3, G4, G5, and G6 are each ndently selected from one or more of C0. lzalkyl, —C2_12alkenyl, —C2_12alkynyl, D, —CD3, —OCD3, halo, CN, OX0 , CF3, OCFg, OCHFz, —N02, —B(OH)2, —1>(0)c0_3 alkyl, —PO(OR")2, —PO(OR")R12, C3_12cycloalkyl—C0_ lgalkyl—, C34gheterocycloalkyl—C0_1zalkyl—, aryl—Co_12alkyl—, aryl—C3_12cycloalkyl—, aryl—C3_ lzheterocycloalkyl—, heteroaryl—C0_12alkyl—, aryl—C3_12cycloalkyl—, heteroaryl—C3_ lzheterocycloalkyl—, lkleR11,—OC(O)NR"R12, R",—C(O)NR"R12,—C(O)R", — NRUR", O)R12, —NR13C(0)NR"R", —S(O)m5R", and —NR"S(O)m5R12, any ofwhich is optionally substituted with Q1 substituents; Q1 is selected from one or more of C0_1zalkyl—, —C2_12alkenyl, —C2_12alkynyl, D, halo, — CN, —CD3, —OCD3, —oxo—, —CF3, —OCF3, —OCHF2, —N02, —B(OH)2, —PO(OR14)2, — PO(OR14)R15,NR14R15, —C(O)NR14OH, —C0_6alkleR14, aryl—C0_12alkyl—, heteroaryl—C0_12alkyl— , C34gcycloalkyl—C0_12alkyl—, C3-12heterocycloalkyl—Co_12alkyl—, aryl—C0_1gcycloalkyl—, heteroaryl—C3_12cycloalkyl—, C34gheterocycloalkyl—C3_12cycloalkyl—, C3_12cycloalkyl—C3_ 12cycloalkyl—, C3.12heterocycloalkyl—C3_12heterocycloalkyl—, aryl—C3_1gheterocycloalkyl—, aryl—C3_12heterocycloalkyl—, —C(O)-C(O)NR14R15, C(O)OR14, —OC(O)R14, — NR14C(O)R15, —NR14S(O)m6R15, —(CR15R16)n1C(O)R14, —(CR15R16)n1C(O)OR14, — (CR15R16)H1C(O)NR14R17, —(CR15R16)H1S(O)m6NR14R17, —(CR15R16)H1NR14R17, —(CR15R16)H10R14, R16)H18(O)m6R14, —NR16C(O)NR14R15, and —NR16S(O)m6NR14R15, any of which is optionally substituted with ndently selected E1 substituents; E1 is selected from one or more of C0_12alkyl—, —C2_12alkenyl, —C2_12alkynyl, D, halo, — CN, —oxo—, —CD3, —OCD3, —CF3, —OCF3, —OCHF2, —N02, —B(OH)2, —PO(OR18)2, — PO(OR18)R19, —C(O)NR180H, R18R19, —C0_12alkleR18, 0_12alkyl—, heteroaryl—C0_ lzalkyl—, C34gcycloalkyl—C0_12alkyl—, C3-1gheterocycloalkyl—Cmgalkyl—, aryl—C0_12cycloalkyl—, aryl—C3_12cycloalkyl—, C34gheterocycloalkyl—C3_12cycloalkyl—, C3_12cycloalkyl—C3_ lzcycloalkyl—, C34zheterocycloalkyl—C3_1zheterocycloalkyl—, aryl—C3_1gheterocycloalkyl—, heteroaryl—C3_12heterocycloalkyl—, —C(O)-C(O)NR18R19, —C0_12alkle(O)OR18, —C(O)- 18, —OC(O)R18, —NR18C(O)R19, —NR18C(O)OR19, —NR188(O)m7R19, — (CR19R2°)n2C(O)R18, —(CR19R20)n2C(O)OR18,—(CR19R2°)n2C(O)NR18R21, — (CR19R20)HZS(O)m7NR18R21, —(CR19R20)n2NR18R21, —(CR19R20)HZOR18, —(CR19R20)HZS(O)m7R18’ _ NR2°C(O)NR18R19, and —NR2°S(O)m7NR18R19 substituents; R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, and R21 are each independently selected from H, C1_5alkyl—, C3_gcycloalkyl—C0_6alkyl—, C3_gheterocycloalkyl—C0_6alkyl—, aryl—Co_5alkyl—, aryl—C3_gcycloalkyl—, 3_gheterocycloalkyl—, heteroaryl—C1_6alkyl—, heteroaryl—C3_ 8cycloalkyl—, or heteroaryl—C3-8heterocycloalkyl—g R3 and R4 are taken together with the carbon atoms to which they are attached to form a 3-12 membered partially saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms ed from O, N, or S(O)m8; ml, m2, m3, m4, m5, m6, m7, m8, nl, and n2 are each independently selected from 0, l, or 2; or a pharmaceutically acceptable salt, solvate or a prodrug thereof.

In some aspects of Formula 1, compounds of the present invention are a subgenus of Formula I, having the Formula Ia: wherein: B1 is selected from C3-12cycloalkyl—C0_1zalky1—, eterocycloalkyl—C0_12alkyl—, aryl— lkyl—, 3_12cycloalkyl—, aryl—C3_lgheterocycloalkyl—, heteroaryl—C0_12alkyl—, heteroaryl—C3_12cycloalkyl—, or heteroaryl—C3_1zheterocycloalkyl—, any ofwhich is optionally substituted with G2 substituents; B2 is selected from C0_12alkyl, C3-1zcycloalkyl—C0_12alkyl—, C3_12heterocycloalkyl—C0_ 12alkyl—, aryl—C0_12alkyl—, aryl—C3_12cycloalkyl—, aryl—C3_lzheterocycloalkyl—, heteroaryl—C0_ 12alkyl—, heteroaryl—C3_12cycloalkyl—, or heteroaryl—C3.12heterocycloalkyl—, any of which is optionally substituted with G3 substituents; L1 is selected from —C0_2alkyl—, —CR5R6—, —C0_3alkyl(R5)(OH)—, —C(O)—, —CH20—, — OCH2—, —CF2—, —SCR5R6—, —CR5R6S—, —N(R5)—, —N(R5)C(O)—, —C(O)N(R5)—, — N(R5)C(O)N(R6)—i -O—i —S-i _S(O)m1_a S(O)m1_a 0r —S(O)m1N(R5)-; L2 is selected from —C0_4alkyl—, , —N(R7)—, —N(R7)C(O)—, or —N(R7)S(O)m2—; X is selected from C3_12cycloalkyl—C0_12alkyl—, C34gheterocycloalkyl—Cdlzalkyl—, aryl— C0_12alkyl—, aryl—C3_12cycloalkyl—, aryl—C3_lgheterocycloalkyl—, heteroaryl—C0_12alkyl—, heteroaryl—C3_12cycloalkyl—, or heteroal'yl—C3_1gheterocycloalkyl—, any ofwhich is optionally substituted with G4 substituents; Y is selected from , —N(R8)—, —N(R8)C(O)—, —S(O)m3—, or —N(R8)S(O)m3—; Z1 is -1; Z2 is selected from CRb, NRb, O, or S; Z3 is selected from C or N; Z4 is selected from CRC, NR°, O, or S; R1 is selected from —C(O)R9,—C(O)NR9R10,—C(O)OR9, C1_4alkynyl, 0R9, S(O)m4R9R1°, or —CN; R2, R3, R4, Ra, Rb, and R0 are each independently selected from C0_12alkyl, —CN, halo, C3- 12cycloalkyl—C0_1zalkyl—, C3_1gheterocycloalkyl—C0_12alkyl—, 0_12alkyl—, aryl—C3_ 12cycloalkyl—, aryl—C3_1gheterocycloalkyl—, heteroaryl—Co_12all(0)c0_3 alkyl, —PO(OR")2, —PO(OR")R12, C3_12cycloalkyl—C0_ lzalkyl—, C3_1gheterocycloalkyl—C0_lzalky1—, aryl—C0_12alkyl—, aryl—C3_12cycloalky1—, aryl—C3_ 12heterocycloalkyl—, heteroaryl—C0_12alkyl—, heteroaryl—C3_1zcycloalkyl—, heteroaryl—C3_ lzheterocycloalkyl—, —C0_6a1kyIOR11,—OC(O)NR"R12, R", —C(O)NR"R12, —C(O)R", — NRUR", —NR"C(O)R12, —NR"C(0)NR"R", —S(O)m5R", and —NR"S(O)m5R12, any ofwhich is ally substituted with independently selected Q1 substituents; Q1 is selected from one or more of C0_12alky1—, —C2_12alkenyl, —C2_12alkyny1, D, halo, — CN, —CD3, —OCD3, —oxo—, —CF3, —OCF3, —OCHF2, —N02, —B(OH)2, —PO(OR14)2, — PO(OR14)R15,NR14R15, —C(O)NR14OH, —C0_6alky10R14, aryl—Co_12alkyl—, heteroaryl—C0_12alkyl— , C3-1zcycloalkyl—C0_12alkyl—, eterocycloalkyl—C0_12alkyl—, aryl—C0_1zcycloalkyl—, heteroaryl—C3_12cycloalky1—, C34zheterocycloalkyl—C3_12cycloalkyl—, C3_12cycloalkyl—C3_ 12cycloalkyl—, C34gheterocycloalkyl—C3_12heterocycloalkyl—, 3_1gheterocycloalkyl—, heteroaryl—C3_lzheterocycloalkyl: —C(O)-C(O)NR14R15, —C(O)-C(O)OR14, —OC(O)R14, — NR14C(O)R15, —NR14S(O)m6R15, —(CR15R16)H1C(O)R14, —(CR15R16)H1C(O)OR14, — (CR15R16)H1C(O)NR14R17, —(CR15R16)H1S(O)m6NR14R17, R16)n1NR14R17, —(CR15R16)H10R14, R16)HIS(O)m6R14, —NR16C(O)NR14R15, and —NR16S(O)m6NR14R15, any of which is optionally substituted with independently selected El substituents; E1 is selected from one or more of C0_12alky1—, alkenyl, —C2_12alkynyl, D, halo, — CN, —oxo—, —CD3, —OCD3, —CF3, —OCF3, —OCHF2, —N02, —B(OH)2, —PO(OR18)2, — PO(OR18)R19, —C(O)NR180H, —C(O)NR18R19, —C0_12alkleR18, aryl—C0_12alkyl—, heteroaryl—C0_ lzalkyl—, C342cycloalkyl—C0_12alkyl—, C34zheterocycloalkyl—C0_1zalkyl—, aryl—C0_1zcycloalkyl—, heteroaryl—C3_ucycloalkyl—, C3.12heterocycloalkyl—C3_12cycloalkyl—, C3_12cycloalkyl—C3_ 12cycloalkyl—, C34gheterocycloalkyl—C3_12heterocycloalkyl—, aryl—C3_1gheterocycloalkyl—, heteroaryl—C3_lzheterocycloalkyl—, —C(O)—C(O)NR18R19, alkle(O)OR18, —C(O)- 18, —OC(O)R18, —NR18C(O)R19, —NR18C(O)OR19, (O)m7R19, — (CR19R2°)n2C(O)R18, R20)n2C(O)OR18,—(CR19R2°)n2C(O)NR18R21, — (CR19R20)H28(O)m7NR18R21, —(CR19R20)n2NR18R21, —(CR19R20)HZOR18, —(CR19R20)HZS(O)m7R18, _ NR20C(O)NR18R19, and —NRZOS(O)m7NR18R19 substituents; R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, and R21 are each independently selected from H, C1_6alkyl—, C3_gcycloalkyl—C0_6alkyl—, C3_gheterocycloalkyl—C0_6alkyl—, aryl—C0_6alkyl—, aryl—C3_gcycloalkyl—, aryl—C3_gheterocycloalkyl—, heteroaryl—C1_5alkyl—, heteroaryl—C3_ gcycloalkyl—, or aryl—C3_gheterocycloalkyl—; R3 and R4 are taken together with the carbon atoms to which they are attached to form a 3-12 membered partially saturated or unsaturated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(O)mg; ml, m2, m3, m4, m5, m6, m7, m8, n1, and n2 are each ndently ed from 0, l, or 2; or a pharmaceutically acceptable salt, solvate or a prodrug thereof.

In some aspects of Formula 1, compounds of the present invention are a subgenus of Formula I selected from one of Formulas Ib-Ii: R4 o \ leB2 R3\H\ / L2 A\ / Y/ \X N R2 and R4 N \ L1\B2 1 / R3 L2 / Y/ \x 0 wherein: B1 is selected from C3-12cycloalkyl—C0_1zalky1—, C3_12heterocycloalkyl—C0_12alkyl—, aryl— C0_lzalkyl—, aryl—C3_12cycloalkyl—, aryl—C3_lzheterocycloalkyl—, heteroaryl—C0_12alkyl—, heteroaryl—C3_12cycloalkyl—, or heteroaryl—C3_1gheterocycloalkyl—, any ofwhich is optionally substituted with G2 substituents; B2 is ed from C0_12alkyl, C3-12cycloalkyl—C0_12alkyl—, C3-12heterocycloalkyl—C0_ 12alkyl—, aryl—C0_12alkyl—, aryl—C3_12cycloalkyl—, aryl—C3_lzheterocycloalkyl—, heteroaryl—C0_ 12alkyl—, heteroaryl—C3_12cycloalkyl—, or heteroaryl—C3_12heterocycloalkyl—, any of which is optionally substituted with G3 substituents; L1 is selected from —C0_2alkyl—, —CR5R6—, lkyl(R5)(OH)—, —C(O)—, —CHzO—, — OCH2—, —CF2—, —SCR5R6—, —CR5R6S—, —N(R5)—, —N(R5)C(O)—, (R5)—, — (0)N(R6)-a , -S-» -S(0)m1-, -N(R5)S(O)m1-, 0r -S(0)m1N(R5)-; L2 is selected from —C0_4alkyl—, —C(O)—, —, —N(R7)C(O)—, or —N(R7)S(O)m2—; X is selected from C3_1zcycloalkyl—C0_12alkyl—, C34gheterocycloalkyl—C0_lzalkyl—, aryl— C0_12alkyl—, aryl—C3_12cycloalkyl—, aryl—C3_lgheterocycloalkyl—, heteroaryl—C0_12alkyl—, heteroaryl—C3_12cycloalkyl—, or heteroaryl—C3_1zheterocycloalkyl—, any ofwhich is optionally tuted with G4 substituents; Y is ed from —C(O)—, —N(R8)—, —N(R8)C(O)—, —S(O)m3—, or —N(R8)S(O)m3—; R1 is selected from —C(O)R9,—C(O)NR9R10,—C(O)OR9, CMalkynyl, 0R9, S(O)m4R9R1°, or —CN; R2, R3, and R4 are each independently selected from C0_12alkyl, —CN, halo, C3- 12cycloalkyl—C0_1zalkyl—, C34gheterocycloalkyl—C0_12alkyl—, aryl—C0_12alkyl—, aryl—C3_ 12cycloalkyl—, aryl—C3_1gheterocycloalkyl—, heteroaryl—C0_12alkyl—, heteroaryl—C3_lgcycloalkyl—, or heteroaryl—C3_12heterocycloalkyl—, any of which is optionally substituted with G5 substituents; R5, R6, R7, R8, R9, and R10 are each independently ed from C0_12alkyl, C3- 12cycloalkyl—C0_1galkyl—, C3.1gheterocycloalkyl—Co_1zalky1—, aryl—C0_12alkyl—, aryl—C3_ 12cycloalkyl—, aryl—C3_1gheterocycloalkyl—, aryl—C0_12alkyl—, heteroaryl—C3_lzcycloalkyl—, or heteroaryl—C3_1zheterocycloalkyl—, any of which is optionally tuted with G6 substituents; G1, G2, G3, G4, G5, and G6 are each independently selected from one or more of C0- 12alkyl, —C2_12alkenyl, —C2_12alkynyl, D, —CD3, —OCD3, halo, CN, OX0 , CF3, OCFg, OCHFZ, —N02, —B(OH)2, —1>(0)c0_3 alkyl, —PO(OR")2, —PO(OR")R12, C3_12cycloalkyl—C0_ lzalkyl—, C34gheterocycloalkyl—C0_1Zalkyl—, aryl—C0_12alkyl—, aryl—C3_12cycloalkyl—, aryl—C3_ 12heterocycloalkyl—, heteroaryl—C0_12alkyl—, heteroaryl—C3_12cycloalkyl—, heteroaryl—C3_ 12heterocycloalkyl—, —C0_6alkleR11,—OC(O)NR"R12, —C(O)OR", —C(O)NR"R12, —C(O)R", — NRllRlz, —NR"C(O)R12, —NR"C(0)NR"R", —S(O)m5R", and —NR"S(O)m5R12, any ofwhich is optionally tuted with independently selected Q1 substituents; Q1 is selected from one or more of Co_1zalkyl—, —C2_12alkenyl, —C2_12alkynyl, D, halo, — CN, —CD3, —OCD3, —oxo—, —CF3, —OCF3, —OCHF2, —N02, —B(OH)2, 14)2, — PO(OR14)R15,NR14R15, —C(O)NR14OH, —C0_6alkleR14, aryl—C0_12alkyl—, heteroaryl—C0_12alkyl— , C3_12cycloalkyl—C0_12alkyl—, C3-12heterocycloalkyl—C0_lzalkyl—, aryl—C0_12cycloalkyl—, heteroaryl—C3_12cycloalkyl—, C34gheterocycloalkyl—C3_12cycloalkyl—, C3_1zcycloalkyl—C3_ oalkyl—, C34gheterocycloalkyl—C3_12heterocycloalkyl—, aryl—C3_1gheterocycloalkyl—, heteroaryl—C3_12heterocycloalkyl—, —C(O)-C(O)NR14R15, —C(O)-C(O)OR14, —OC(O)R14, — NR14C(O)R15, (O)m6R15, R16)H1C(O)R14, —(CR15R16)n1C(O)OR14, — (CR15R16)H1C(O)NR14R17, —(CR15R16)H1S(O)m6NR14R17, —(CR15R16)H1NR14R17, —(CR15R16)n10R14, —(CR15R16)nlS(O)m6R14, —NR16C(O)NR14R15, —NR16S(O)m6NR14R15, any h is optionally tuted with independently selected E1 substituents; E1 is selected from one or more of C0_12alkyl—, —C2_12alkenyl, —C2_12alkynyl, D, halo, — CN, —oxo—, —CD3, —OCD3, —CF3, —OCF3, —OCHF2, —N02, —B(OH)2, —PO(OR18)2, — PO(OR18)R19, —C(O)NR180H, —C(O)NR18R19, —C0_12alkleR18, aryl—C0_12alkyl—, heteroaryl—C0_ 12alkyl—, C3_1gcycloalkyl—C0_1zalkyl—, C34gheterocycloalkyl—Cmzalkyl—, aryl—C0_12cycloalkyl—, heteroaryl—C3_12cycloalkyl—, C34gheterocycloalkyl—C3_12cycloalkyl—, C3_1zcycloalkyl—C3_ 12cycloalkyl—, C34gheterocycloalkyl—C3_12heterocycloalkyl—, aryl—C3_1gheterocycloalkyl—, heteroaryl—C3_12heterocycloalkyl—, —C(O)-C(O)NR18R19, alkle(O)OR18, —C(O)- C(O)OR18, —OC(O)R18, —NR18C(O)R19, —NR18C(O)OR19, —NR18S(0)m7R19, — (CR19R2°)n2C(O)R18, —(CR19R20)HZC(O)OR18, —(CR19R20)n2C(O)NR18R21, — )HZS(O)m7NR18R21, —(CR19R20)n2NR18R21, —(CR19R20)HZOR18, —(CR19R20)HZS(O)m7R18, _ NR20C(O)NR18R19, and —NRZOS(O)m7NR18R19 tuents; R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, and R21 are each independently selected from H, C1_6alkyl—, C3_gcycloalkyl—C0_6alkyl—, C3_gheterocycloalkyl—C0_6alkyl—, aryl—C0_6alkyl—, aryl—C3_gcycloalkyl—, 3_8heterocycloalkyl—, heteroaryl—C1_6alkyl—, heteroaryl—C3_ gcycloalkyl—, or heteroaryl—C3_gheterocycloalkyl—; R3 and R4 are taken together with the carbon atoms to which they are attached to form a 3-12 membered partially saturated or rated ring, wherein said ring optionally includes one or more additional heteroatoms selected from O, N, or S(O)mg; ml, m2, m3, m4, m5, m6, m7, m8, n1, and n2 are each independently ed from 0, 1, or 2; or a pharmaceutically acceptable salt, solvate or a prodrug thereof.

In some embodiments of as I, and Ia-Ii, B1 is selected from C4_gcycloalkyl—C0_ 12alkyl—, terocycloalkyl—C0_12alkyl—, C4_garyl—C0_12alkyl—, or C4_gheteroaryl—C0_12alkyl—, any of which is optionally substituted with G2 substituents.

In some embodiments of Formulas I, and Ia-Ii, B2 is selected from C4_gcycloalkyl—Co_ 12alkyl—, C4_gheterocycloalkyl—C0_12alkyl—, C4_garyl—C0_12alkyl—, or C4_gheteroaryl—C0_12alkyl—, any of which is optionally substituted with G3 substituents.

In some embodiments of Formulas I, and Ia-Ii, L1 is selected from —C0_2alkyl—, —CR5R6—, —C0_3alkyl(R5)(OH) , C(O) , CHZO , OCH2 , CF2 , N(R5) , N(R5)C(O)—, —C(O)N(R5)—, —O—, or —S(O)m1—.

In some embodiments of Formulas I, and Ia-Ii, L1 is selected from —C0_2alkyl—, —CR5R6—, —C1_2alkyl(R5)(OH)—, , —CF2—, —N(R5)—, —N(R5)C(O)—, —C(O)N(R5)—, —o—, or 1—.

In some ments of Formulas I, and Ia-Ii, L2 is selected from —C0_2alkyl—, —C(O)—, or —N(R7)—.

In some embodiments of Formulas I, and Ia-Ii, X is selected from C4_8cycloalkyl—C0_ l—, terocycloalkyl—C0_12alkyl—, C4_garyl—C0_12alkyl—, or C4_gheteroaryl—C0_12alkyl—.

In some embodiments of Formulas I, and Ia-Ii, Y is selected from —C(O)—, —N(R8)—, — N(R8)C(O)—, or —S(O)m3—.

In some embodiments of Formulas I, and Ia—Ii, R1 is selected from —C(O)R9, — C(O)NR9R10, —C(O)OR9, C1_4alkynyl, or —CN.

In some ments of Formulas I, and Ia-Ii, R2, R3, and R4 are each independently selected from C0_12alkyl, —CN, halo, cloalkyl—C0_12alkyl—, C3_6heterocycloalkyl—C0_1galkyl— of which is optionally substituted with G5 substituents. , any In some embodiments of Formulas I, and Ia-Ii, G1, G2, G3, G4, G5, and G6 are each independently selected from one to three of C0_12alkyl, —C2_12alkenyl, —C2_12alkynyl, D, —CD3, — OCD3, halo, CN, oxo , CF3, OCF3, OCHFZ, —N02, —B(OH)2, —P(O)C0_3 alkyl, — PO(OR")2, —PO(OR")R12, C34zcycloalkyl—C0_12alkyl—, C3-12heterocycloalkyl—C0_12alkyl—,aryl— C0_12alkyl—, aryl—C3_1zcycloalkyl—, aryl—C3_12heterocycloalkyl—, heteroaryl—C0_12alkyl—, heteroaryl—C3_12cycloalkyl—, heteroaryl—C3-12heterocycloalkyl—, —C0_6all In some embodiments of Formulas I, and Ia-Ii, G1, G2, G3, G4, G5, and G6 are each ndently selected from one to two of C0_12alkyl, —C2_12alkenyl, —C2_12alkynyl, D, —CD3, — OCD3, halo, CN, oxo , CF3, OCF3, OCHFZ, —N02, —B(OH)2, —P(O)C0_3 alkyl, — PO(OR")2, —PO(OR")R12, C34zcycloalkyl—C0_12alkyl—, C3_12heterocycloalkyl—C0_12alkyl—,aryl— C0_12alkyl—, aryl—C3_1zcycloalkyl—, aryl—C3_12heterocycloalkyl—, heteroaryl—C0_12alkyl—, heteroaryl—C3_12cycloalkyl—, heteroaryl—C3_12heterocycloalkyl—, —C0_6all In some aspects, the present invention includes a compound ed from the group consisting of: 6-(3-acrylamidophenyl)(4-phenoxyphenyl)nicotinamide; cryloylpiperidinyl)(4-phenoxyphenyl)nicotinamide; 6-(4-acryloylpiperazinyl)(4-phenoxyphenyl)nicotinamide; N N 6-(1-acryloylpyrrolidinyl)(4-phenoxyphenyl)nicotinamide; N N 6-(4-acrylamidophenyl)(4-phenoxyphenyl)nicotinamide; O N N O 6-(1-acryloylpiperidinyl)(4-phenoxyphenyl)nicotinamide; O NH2 N N crylamidopiperidinyl)(4-phenoxyphenyl)nicotinamide; O N N N O 6-(3-acrylamidopyrrolidinyl)(4-phenoxyphenyl)nicotinamide; HN N N 1-(1-acryloylpyrrolidinyl)(4-phenoxyphenyl)-1H-pyrazolecarboxamide; O N N O 1-(1-acryloylazetidinyl)(4-phenoxyphenyl)-1H-pyrazolecarboxamide; N O 1-(4-acrylamidophenyl)(4-phenoxyphenyl)-1H-pyrazolecarboxamide; N O 1-(3-acrylamidophenyl)(4-phenoxyphenyl)-1H-pyrazolecarboxamide; N N N O (S)(1-acryloylpyrrolidinyl)(4-phenoxyphenyl)-1H-pyrazolecarboxamide; O N O N N (1-acryloylpyrrolidinyl)(4-phenoxyphenyl)-1H-pyrazolecarboxamide; O N N O 2-(1-acryloylpyrrolidinyl)(4-phenoxyphenyl)pyrimidinecarboxamide; N NH2 N N (4-(4-(dimethylamino)butenoyl)piperazinyl)(4- phenoxyphenyl)nicotinamide; N N N O 6-(4-acryloylpiperazinyl)(4-(cyclohexyloxy)phenyl)nicotinamide; N N 6-(4-acryloylpiperazinyl)(3-methoxymethylphenyl)nicotinamide; N N 6-(4-acryloylpiperazinyl)-6'-phenoxy-2,3'-bipyridinecarboxamide; N N N O 6-(4-acryloylpiperazinyl)(4-(pyridinyloxy)phenyl)nicotinamide; N N O N 4-(dimethylamino)butenoyl)pyrrolidinyl)(4-phenoxyphenyl)-1H-pyrazole- 4-carboxamide; O N N O 6-(4-acryloylpiperazinyl)(4-(3-fluorophenoxy)phenyl)nicotinamide; N N O F 6-(4-acryloylpiperazinyl)(3-fluorophenoxyphenyl)nicotinamide; N N 6-(4-acryloylpiperazinyl)(4-(4-fluorophenoxy)phenyl)nicotinamide; N N 6-(4-acryloylpiperazinyl)(4-(2-fluorophenoxy)phenyl)nicotinamide; N N 6-(4-acryloylpiperazinyl)(2-fluorophenoxyphenyl)nicotinamide; N N F O 2-(1-acryloylpiperidinyl)(4-phenoxyphenyl)thiazolecarboxamide; O S N N 2-(1-acryloylpyrrolidinyl)(4-phenoxyphenyl)thiazolecarboxamide; N N O 2-(1-acryloylpiperidinyl)(4-phenoxyphenyl)oxazolecarboxamide; O O N N O 2-(1-acryloylpyrrolidinyl)(4-phenoxyphenyl)oxazolecarboxamide; N N cryloylpyrrolidinyl)(4-phenoxyphenyl)thiazolecarboxamide; N S 2-(1-acryloylpiperidinyl)(4-phenoxyphenyl)thiazolecarboxamide; O N N S O cryloylpiperidinyl)(4-phenoxyphenyl)oxazolecarboxamide; N O 2-(1-acryloylpyrrolidinyl)(4-phenoxyphenyl)oxazolecarboxamide; O O 2-(1-acryloylpiperidinyl)(4-phenoxyphenyl)thiazolecarboxamide; S O 2-(1-acryloylpiperidinyl)(4-phenoxyphenyl)thiazolecarboxamide; N O 2-(1-acryloylpiperidinyl)(4-phenoxyphenyl)oxazolecarboxamide; O N N O O -(1-acryloylpiperidinyl)-4'-phenoxybiphenylcarboxamide; -(4-acryloylpiperazinyl)-4'-phenoxybiphenylcarboxamide; 6-(1-acryloylpiperidinyl)(4-(hydroxy(phenyl)methyl)phenyl)nicotinamide; O OH (E)(1-(2-cyanobutenoyl)azetidinyl)(4-phenoxyphenyl)-1H-pyrazole amide; N O 6-(4-acryloylpiperazinyl)(4-((4,4-difluorocyclohexyl)oxy)phenyl)nicotinamide; N N F cryloylpiperidinyl)(4-(phenylcarbamoyl)phenyl)nicotinamide; N N O O 2-(4-phenoxyphenyl)(4-(vinylsulfonyl)piperazinyl)nicotinamide; N N S O 2-(4-phenoxyphenyl)(1-(vinylsulfonyl)piperidinyl)nicotinamide; S O or a pharmaceutically acceptable salt thereof.

In some aspects, the present invention includes a compound selected from the group consisting of: 2-(4-phenoxyphenyl)(piperidinyl)nicotinamide; 2-(4-phenoxyphenyl)(piperazinyl)nicotinamide; N N tidinyl)(4-phenoxyphenyl)-1H-pyrazolecarboxamide; N O 1-(3-aminophenyl)(4-phenoxyphenyl)-1H-pyrazolecarboxamide; H2N N O 6-(1-acryloylpiperidinyl)(4-phenoxyphenyl)pyridinecarbonitrile; 6-(4-acryloylpiperazinyl)(4-phenoxyphenyl)pyridinecarboxylic acid; N N 2-(4-acryloylpiperazinyl)-N-methyl(4-phenoxyphenyl)thiazolecarboxamide; N O O .

In some aspects, the present invention includes a compound having a a IId, or a pharmaceutically acceptable salt or solvate f: R3 X Z R2 O O Formula IId N N N N wherein X is , , , or ; Z is C or N; G1, G2, and G3 are selected from the group consisting of one or more H, D (deuterium), C1-12 alkyl, n, and CF3; R2 and R3 are each independently selected from the group consisting of H, D, C1-12 alkyl, halogen, CN, and CF3, wherein C1-12 alkyl is optionally substituted with NR11R12; R4 is selected from the group consisting of H, D, C1-12 alkyl, halogen, CN, and CF3; and R11 and R12 are independently H or C1-6 alkyl.

In some s, the present invention includes a pharmaceutical composition for treating a disease mediated by Bruton’s tyrosine Kinase (BTK), comprising a compound of Formula I or a compound of Formula IId described herein, and a pharmaceutically acceptable salt thereof.

In some aspects, the present invention includes a use of a compound bed herein in the manufacture of a medicament for treating of at least one of cancer, chronic inflammation, and autoimmune disease ed at least in part by BTK.

In some aspects, the present invention includes a pharmaceutical ition including the compound or salt of any one of the compounds of Formula I, formulated with or without one or more pharmaceutical carriers.

In some aspects, the present invention es a method for the treatment of at least one of cancer, chronic inflammation, and autoimmune disease mediated at least in part by BTK including administering to a subject in need f a therapeutically effective amount of a compound or salt of the compound of Formula I.

In some aspects, the present invention includes a method of treating cancer, chronic inflammation, or autoimmune disease in a mammal including administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, to the mammal in need thereof.

In some aspects, the present ion includes a method of irreversibly ting tyrosine kinases, the method including administering to a patient a therapeutically effective amount of a tyrosine kinase inhibitor including a compound of Formula I.

In some aspects, the present invention includes a method of irreversibly inhibiting BTK, the method including administering to a patient a therapeutically effective amount of a BTK inhibitor including a nd ing to Formula I.

The methods described herein include administering to a subject in need a composition containing a therapeutically effective amount of one or more BTK tor compounds described herein. Without being bound by theory, the diverse roles played by BTK signaling in various poietic cell functions, e.g., B-cell receptor activation, suggests that small molecule BTK inhibitors are useful for reducing the risk of or treating a variety of diseases affected by or affecting many cell types of the hematopoetic lineage including, e.g., autoimmune diseases, immune ions or diseases, inflammatory diseases, cancer ( e.g., B-cell erative disorders), and thromboembolic disorders. Further, the BTK inhibitor compounds described herein can be used to t a small subset of other tyrosine kinases that share homology with BTK by having a cysteine residue (including a Cys 481 e) that can form a [Followed by page 15]. covalent bond with the inhibitor. Thus, a subset of tyrosine kinases other than BTK may be usefiil as therapeutic targets in a number of health conditions.

The s described herein can be used to treat an autoimmune disease, which includes, but is not limited to, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, lupus, diabetes (type I and type II), enia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease Sjogren's me, multiple sclerosis, Guillain- Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, onus- myoclonus me, sing spondylitisis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, coeliac disease, Goodpasture's me, idiopathic ocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, su's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener‘s granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, and vulvodynia.

The methods described herein can be used to treat immune conditions or diseases, which include, but are not limited to graft versus host disease, transplantation, transfusion, anaphylaxis, allergies (e. g., allergies to plant s, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx), type I hypersensitivity, ic conjunctivitis, allergic rhinitis, allergic asthma, and atopic dermatitis.

The methods described herein can be used to treat an inflammatory disease, which includes, but is not limited to , inflammatory bowel disease, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, ctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, ymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, enitis suppurativa, laryngitis, mastitis, itis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, gitis, pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, and vulVitis.

The methods described herein can be used to treat a cancer, e. g., B-cell proliferative disorders, which include, but are not d to diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, splenic marginal zone ma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal al zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, burkitt lymphoma/leukemia, and lymphomatoid granulomatosis.

The s described herein can be used to treat thromboembolic disorders, which include, but are not limited to myocardial infarct, angina pectoris (including unstable angina), reocclusions or restenoses after lasty or aortocoronary bypass, stroke, transitory ischemia, peripheral arterial occlusive disorders, ary embolisms, and deep venous thromboses.

Disclosed herein is a method for treating a hematological malignancy in an individual in need thereof, comprising: administering to the individual a composition containing a eutic amount of at least one compound having the structure of Formulas I, Ia-Ii or IIa-IId.

The hematological malignancy is a chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, or a non-CLL/SLL lymphoma. In some embodiments, the hematological malignancy is follicular lymphoma, diffuse large B-cell ma (DLBCL), mantle cell lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, marginal zone lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, or extranodal marginal zone B cell ma. In some embodiments, the logical malignancy is acute or chronic myelogenous (or myeloid) leukemia, myelodysplastic syndrome, or acute lymphoblastic leukemia. In some ments, the hematological malignancy is relapsed or refractory diffuse large B-cell lymphoma (DLBCL), relapsed or refractory mantle cell lymphoma, relapsed or refractory follicular lymphoma, relapsed or refractory CLL; relapsed or refractory SLL; relapsed or refractory multiple myeloma.

In some embodiments, the hematological malignancy is a hematological malignancy that is fied as high-risk. In some ments, the hematological malignancy is high risk CLL or high risk SLL.

B-cell lymphoproliferative disorders (BCLDs) are neoplasms of the blood and encompass, inter alia, non-Hodgkin ma, multiple myeloma, and leukemia. BCLDs can originate either in the lymphatic tissues (as in the case of lymphoma) or in the bone marrow (as in the case of leukemia and a), and they all are involved with the uncontrolled growth of lymphocytes or white blood cells. There are many es of BCLD, e.g., chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). The disease course and treatment of BCLD is dependent on the BCLD subtype; however, even within each subtype the clinical tation, morphologic appearance, and response to therapy is heterogeneous.

Malignant lymphomas are neoplastic transformations of cells that reside predominantly within lymphoid tissues. Two groups of malignant lymphomas are Hodgkin's lymphoma and non-Hodgkin's lymphoma (NHL). Both types of lymphomas infiltrate reticuloendothelial s.

However, they differ in the neoplastic cell of origin, site of disease, presence of systemic symptoms, and response to treatment (Freedman et al., "Non—Hodgkin's Lymphomas" Chapter 134, Cancer Medicine, (an approved ation of the American Cancer Society, B.C. Decker Inc., Hamilton, Ontario, 2003).

Disclosed herein is a method for treating a dgkin's lymphoma in an individual in need thereof, comprising: administering to the individual a composition containing a therapeutic amount of at least one compound having the structure of Formulas I, Ia-Ii or Ila-11d.

Further disclosed herein, is a method for ng relapsed or refractory non-Hodgkin's lymphoma in an dual in need thereof, comprising: administering to the individual a composition containing a therapeutic amount of at least one compound having the structure of Formulas I, Ia—Ii or Ila-11d. In some embodiments, the non-Hodgkin's lymphoma is relapsed or refractory diffuse large B-cell ma (DLBCL), ed or refractory mantle cell lymphoma, or relapsed or refractory follicular lymphoma.

Non-Hodgkin lymphomas (NHL) are a diverse group of malignancies that are predominately of B-cell origin. NHL may develop in any organs associated with lymphatic system such as spleen, lymph nodes or tonsils and can occur at any age. NHL is often marked by enlarged lymph nodes, fever, and weight loss. NHL is fied as either B-cell or T-cell NHL.

Lymphomas related to proliferative disorders following bone marrow or stem cell transplantation are usually B-cell NHL. In the Working Formulation classification scheme, NHL has been divided into low-, intermediate-, and high-grade categories by virtue of their natural histories (see "The dgkin's Lymphoma Pathologic Classification Project," Cancer 49 (1982):2112—2135). The ade lymphomas are indolent, with a median survival of 5 to 10 years (Homing and erg (1984) N. Engl. J. Med. 71-1475). Although herapy can induce remissions in the majority of indolent lymphomas, cures are rare and most patients eventually e, requiring further therapy. The intermediate- and high-grade lymphomas are more aggressive , but they have a greater chance for cure with chemotherapy. However, a significant proportion of these ts will relapse and require further treatment.

A non-limiting list of the B-cell NHL includes Burkitt's lymphoma (e.g., Endemic Burkitt's ma and Sporadic Burkitt's Lymphoma), ous B-Cell Lymphoma, Cutaneous Marginal Zone Lymphoma (MZL), Diffiise Large Cell ma (DLBCL), Diffuse Mixed Small and Large Cell Lympoma, Diffuse Small Cleaved Cell, Diffuse Small Lymphocytic Lymphoma, Extranodal Marginal Zone B-cell lymphoma, follicular lymphoma, Follicular Small Cleaved Cell (Grade 1), Follicular Mixed Small d and Large Cell (Grade 2), Follicular Large Cell (Grade 3), ascular Large B—Cell Lymphoma, Intravascular Lymphomatosis, Large Cell blastic Lymphoma, Large Cell Lymphoma (LCL), Lymphoblastic Lymphoma, MALT Lymphoma, Mantle Cell Lymphoma (MCL), immunoblastic large cell lymphoma, precursor B—lymphoblastic lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), extranodal marginal zone B-cell ma-mucosa-associated lymphoid tissue (MALT) ma, tinal Large B-Cell Lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, primary mediastinal B-cell lymphoma, lymphoplasmocytic lymphoma, hairy cell leukemia, Waldenstrom's lobulinemia, and primary central nervous system (CNS) lymphoma.

Additional non-Hodgkin's lymphomas are contemplated within the scope of the present invention and nt to those of ry skill in the art.

Disclosed herein is a method for treating a DLCBL in an individual in need thereof, comprising: administering to the individual a composition containing a therapeutic amount of at least one compound having the structure of Formulas I, Ia-Ii or Ila-11d.

As used herein, the term "Diffuse large B-cell lymphoma (DLBCL)" refers to a neoplasm of the germinal center B lymphocytes with a diffuse growth pattern and a high-intermediate proliferation index. DLBCLs represent approximately 30% of all mas and may present with several morphological variants including the centroblastic, immunoblastic, T-cell/histiocyte rich, anaplastic and plasmoblastic subtypes. Genetic tests have shown that there are different subtypes of DLBCL. These subtypes seem to have different outlooks (prognoses) and responses to treatment. DLBCL can affect any age group but occurs mostly in older people (the average age is mid-60$).

Disclosed herein is a method for treating diffuse large B-cell lymphoma, activated B cell- like subtype (ABC-DLBCL), in an individual in need thereof, comprising: administering to the individual an rsible BTK inhibitor in an amount from 300 mg/day up to, and ing, 1000 mg/day. The ABC e of diffuse large B-cell lymphoma (ABC-DLBCL) is thought to arise from post germinal center B cells that are arrested during plasmatic differentiation. The ABC subtype of DLBCL (ABC-DLBCL) accounts for imately 30% total DLBCL diagnoses. It is considered the least curable of the DLBCL lar subtypes and, as such, patients diagnosed with the ABC-DLBCL typically display significantly reduced survival rates compared with individuals with other types of DLCBL. ABC-DLBCL is most commonly associated with chromosomal translocations deregulating the germinal center master regulator BCL6 and with mutations inactivating the PRDMl gene, which encodes a transcriptional repressor required for plasma cell differentiation.

A particularly relevant signaling pathway in the pathogenesis ofABC-DLBCL is the one mediated by the nuclear factor (NF)-1 The dependence ofABC DLBCLs on NF-KB s on a signaling pathway upstream of IkB kinase comprised of CARDl l, BCLlO and MALTl (the CBM complex). Interference with the CBM pathway extinguishes NF-KB signaling in ABC DLBCL cells and s apoptosis. The molecular basis for constitutive activity of the NF-KB pathway is a subject of current investigation but some somatic alterations to the genome ofABC DLBCLs clearly invoke this pathway. For example, somatic mutations of the —coil domain of CARDll in DLBCL render this signaling scaffold protein able to spontaneously nucleate protein-protein interaction with MALTl and BCL10, causing IKK activity and NF-KB activation. Constitutive activity of the B cell receptor signaling pathway has been implicated in the tion ofNF-KB in ABC DLBCLs with wild type CARDl l, and this is associated with mutations within the cytoplasmic tails of the B cell receptor subunits CD79A and CD79B. Oncogenic activating mutations in the signaling r MYD88 activate NF-KB and synergize with B cell receptor signaling in sustaining the survival ofABC DLBCL cells. In addition, inactivating mutations in a negative regulator of the NF-KB pathway, A20, occur almost exclusively in ABC DLBCL.

Indeed, genetic alterations affecting multiple ents of the NF-KB signaling y have been ly identified in more than 50% ofABC-DLBCL patients, where these lesions promote constitutive NF-1 An even larger fraction of cases (30%) carry biallelic genetic s inactivating the negative NF-KB regulator A20. Further, high levels of expression ofNF-KB target genes have been observed in ABC-DLBCL tumor samples. See, e.g., U. Klein et al., (2008), Nature Reviews Immunology 8:22-23; R. E. Davis et al., (2001), Journal of Experimental Medicine 194:1861- 1874; G. Lentz et al., (2008), Science 319:1676-1679; M. Compagno et al., (2009), Nature 459:712-721; and L. Srinivasan et al., (2009), Cell 139:573—586).

Disclosed herein is a method for treating a follicular lymphoma in an individual in need thereof, comprising: administering to the individual a composition ning a therapeutic amount of at least one nd having the ure of Formulas I, Ia-Ii or IIa-IId.

As used herein, the term "follicular lymphoma" refers to any of several types of non- Hodgkin's lymphoma in which the matous cells are clustered into nodules or les.

The term follicular is used because the cells tend to grow in a circular, or nodular, pattern in lymph nodes. The average age for people with this lymphoma is about 60.

Disclosed herein is a method for treating a CLL or SLL in an individual in need f, comprising: stering to the individual a composition containing a therapeutic amount of at least one compound having the structure of Formulas I, Ia-Ii or IIa-IId. c lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL) are commonly thought as the same disease with slightly different manifestations. Where the cancerous cells gather determines whether it is called CLL or SLL. When the cancer cells are primarily found in the lymph nodes, lima bean shaped structures of the lymphatic system (a system primarily of tiny vessels found in the body), it is called SLL. SLL accounts for about 5% to 10% of all lymphomas. When most of the cancer cells are in the tream and the bone marrow, it is called CLL.

Both CLL and SLL are slow-growing diseases, although CLL, which is much more , tends to grow slower. CLL and SLL are treated the same way. They are usually not ered curable with standard ents, but depending on the stage and growth rate of the disease, most patients live longer than 10 years. Occasionally over time, these slow—growing mas may transform into a more aggressive type of lymphoma.

Chronic lymphoid leukemia (CLL) is the most common type of leukemia. It is estimated that 100,760 people in the United States are living with or are in remission from CLL. Most (>75%) people newly diagnosed with CLL are over the age of 50. Currently CLL treatment s on lling the disease and its symptoms rather than on an outright cure. CLL is treated by chemotherapy, radiation therapy, biological therapy, or bone marrow transplantation.

Symptoms are sometimes treated surgically (splenectomy removal of enlarged spleen) or by radiation therapy ("de-bulking" swollen lymph nodes). Though CLL sses slowly in most cases, it is considered generally incurable. Certain CLLs are classified as high-risk. As used herein, "high risk CLL" means CLL terized by at least one of the following 1) 17p13-; 2) 11q22—; 3) unmutated IgVH together with ZAP-70+ and/or CD3 8+; or 4) y 12.

CLL treatment is typically administered when the patient's clinical symptoms or blood counts indicate that the disease has progressed to a point where it may affect the patient's quality of life.

Small lymphocytic leukemia (SLL) is very similar to CLL described supra, and is also a cancer of B-cells. In SLL the abnormal lymphocytes mainly affect the lymph nodes. However, in CLL the abnormal cells mainly affect the blood and the bone marrow. The spleen may be affected in both conditions. SLL accounts for about 1 in 25 of all cases of non-Hodgkin lymphoma. It can occur at any time from young adulthood to old age, but is rare under the age of 50. SLL is considered an indolent lymphoma. This means that the disease progresses very slowly, and ts tend to live many years after diagnosis. However, most patients are diagnosed with advanced disease, and although SLL responds well to a variety of chemotherapy drugs, it is generally ered to be incurable. Although some cancers tend to occur more often in one gender or the other, cases and deaths due to SLL are evenly split between men and women. The average age at the time of diagnosis is 60 years.

Although SLL is indolent, it is persistently progressive. The usual pattern of this disease is one of high response rates to radiation y and/or chemotherapy, with a period of disease remission. This is followed months or years later by an able relapse. Re-treatment leads to a response again, but again the disease will relapse. This means that although the short-term prognosis of SLL is quite good, over time, many patients develop fatal complications of recurrent disease. Considering the age of the individuals lly diagnosed with CLL and SLL, there is a need in the art for a simple and effective treatment of the disease with minimum side- effects that do not impede on the patient's quality of life. The t invention fulfills this long ng need in the art.

Disclosed herein is a method for treating a Mantle cell lymphoma in an individual in need thereof, comprising: administering to the individual a composition containing a therapeutic amount of at least one compound having the structure of Formulas I, Ia-Ii or IIa-IId.

As used herein, the term, "Mantle cell lymphoma" refers to a subtype of B-cell lymphoma, due to CD5 positive antigen-naive pregerminal center B-cell within the mantle zone that surrounds normal germinal center les. MCL cells generally over-express cyclin D1 due to a t(l l;l4) chromosomal translocation in the DNA. More specifically, the ocation is at t(l l;l4)(ql3;q32). Only about 5% of lymphomas are of this type. The cells are small to medium in size. Men are affected most often. The average age of patients is in the early 605. The lymphoma is usually widespread when it is diagnosed, involving lymph nodes, bone , and, very often, the spleen. Mantle cell lymphoma is not a very fast growing lymphoma, but is difficult to treat.

Disclosed , in certain embodiments, is a method for treating a marginal zone B-cell lymphoma in an individual in need thereof, comprising: administering to the individual a composition containing a therapeutic amount of at least one nd having the structure of as I, Ia—Ii or Ila-11d.

As used herein, the term "marginal zone B-cell ma" refers to a group of related B- cell neoplasms that involve the lymphoid tissues in the marginal zone, the patchy area outside the follicular mantle zone. Marginal zone lymphomas account for about 5% to 10% of lymphomas.

The cells in these lymphomas look small under the microscope. There are 3 main types of marginal zone lymphomas including extranodal al zone B-cell lymphomas, nodal marginal zone B-cell lymphoma, and splenic marginal zone lymphoma. sed herein, in certain embodiments, is a method for ng a MALT in an individual in need thereof, comprising: stering to the individual a composition containing a therapeutic amount of at least one compound having the ure of Formulas I, Ia—Ii or IIa—IId.

The term "mucosa-associated lymphoid tissue (MALT) lymphoma", as used herein, refers to extranodal manifestations of marginal-zone lymphomas. Most MALT lymphoma are a low grade, although a minority either manifest initially as intermediate-grade non-Hodgkin lymphoma (NHL) or evolve from the low-grade form. Most of the MALT lymphoma occur in the stomach, and roughly 70% of gastric MALT lymphoma are associated with Helicobacter pylori infection. Several cytogenetic abnormalities have been identified, the most common being trisomy 3 or t(l l;18). Many of these other MALT lymphoma have also been linked to infections with bacteria or viruses. The average age of patients with MALT lymphoma is about 60.

Disclosed herein, in certain embodiments, is a method for treating a nodal al zone B-cell lymphoma in an individual in need thereof, comprising: administering to the individual a composition containing a therapeutic amount of at least one compound having the structure of Formulas I, Ia—Ii or Ila-11d.

The term "nodal al zone B-cell lymphoma" refers to an indolent B-cell lymphoma that is found mostly in the lymph nodes. The disease is rare and only accounts for 1% of all Non- Hodgkin's Lymphomas (NHL). It is most commonly diagnosed in older ts, with women more susceptible than men. The disease is classified as a marginal zone lymphoma because the mutation occurs in the marginal zone of the B-cells. Due to its confinement in the lymph nodes, this e is also classified as nodal.

Disclosed herein, in certain embodiments, is a method for treating a splenic marginal zone B-cell lymphoma in an individual in need thereof, comprising: administering to the individual a composition containing a eutic amount of at least one nd having the structure of Formulas I, Ia-Ii or Ila-11d.

The term "splenic marginal zone B-cell lymphoma" refers to specific low-grade small B- cell lymphoma that is incorporated in the World Health Organization classification.

Characteristic features are splenomegaly, moderate lymphocytosis with villous morphology, intrasinusoidal pattern of ement of s organs, especially bone marrow, and relative indolent course. Tumor progression with increase of c forms and aggressive behavior are observed in a minority of patients. Molecular and cytogenetic studies have shown heterogeneous s probably because of the lack of standardized diagnostic criteria.

Disclosed herein, in certain embodiments, is a method for treating a Burkitt ma in an individual in need thereof, comprising: administering to the individual a composition containing a therapeutic amount of at least one compound having the structure of as I, Ia- Ii or IIa-Hd.

The term "Burkitt ma" refers to a type ofNon-Hodgkin Lymphoma (NHL) that commonly affects children. It is a highly aggressive type of B-cell lymphoma that often starts and involves body parts other than lymph nodes. In spite of its fast—growing , Burkitt's lymphoma is often curable with modern intensive therapies. There are two broad types of Burkitt's lymphoma—the sporadic and the endemic varieties: Endemic Burkitt's lymphoma and Sporadic t's lymphoma.

Endemic Burkitt's lymphoma involves children much more than adults, and is related to Epstein Barr Virus (EBV) ion in 95% cases. It occurs primarily in equatorial Africa, where about half of all childhood cancers are Burkitt's lymphoma. It characteristically has a high chance of involving the jawbone, a rather distinctive feature that is rare in sporadic Burkitt's. It also commonly involves the abdomen.

Sporadic Burkitt's lymphoma is a type of Burkitt's lymphoma that affects the rest of the world, including Europe and the Americas. Here too, it's mainly a e in children. The link between Epstein Barr Virus (EBV) is not as strong as with the endemic variety, though direct evidence of EBV infection is present in one out of five patients. More than the involvement of lymph nodes, it is the abdomen that is notably affected in more than 90% of the children. Bone marrow involvement is more common than in the ic variety.

Disclosed herein, in certain embodiments, is a method for ng a strom lobulinemia in an individual in need thereof, comprising: administering to the individual a composition containing a therapeutic amount of at least one compound having the structure of Formulas I, Ia—Ii or Ila-11d.

The term "Waldenstrom macroglobulinemia", also known as lymphoplasmacytic lymphoma, is cancer involving a subtype of white blood cells called lymphocytes. It is characterized by an uncontrolled clonal proliferation of terminally entiated B cytes.

It is also characterized by the lymphoma cells making an antibody called immunoglobulin M (IgM). The IgM antibodies ate in the blood in large amounts, and cause the liquid part of the blood to thicken, like syrup. This can lead to decreased blood flow to many organs, which can cause problems with Vision (because of poor circulation in blood vessels in the back of the eyes) and neurological problems (such as headache, dizziness, and ion) caused by poor blood flow within the brain. Other symptoms can include g tired and weak, and a tendency to bleed easily. The underlying etiology is not fully understood but a number of risk factors have been identified, including the locus 6p21.3 on chromosome 6. There is a 2- to 3-fold risk increase of developing WM in people with a personal history of autoimmune diseases with autoantibodies and particularly elevated risks associated with hepatitis, human immunodeficiency Virus, and rickettsiosis.

Disclosed herein, in certain embodiments, is a method for treating a myeloma in an individual in need thereof, comprising: administering to the individual a composition containing a therapeutic amount of at least one compound having the structure of Formulas I, Ia-Ii or IIa-IId. le myeloma, also known as MM, myeloma, plasma cell myeloma, or as Kahler's disease (after Otto Kahler) is a cancer of the white blood cells known as plasma cells. A type of B cell, plasma cells are a crucial part of the immune system responsible for the production of antibodies in humans and other vertebrates. They are produced in the bone marrow and are transported through the lymphatic .

Disclosed herein, in n embodiments, is a method for treating a leukemia in an individual in need thereof, comprising: stering to the individual a composition containing a therapeutic amount of at least one compound having the structure of Formulas I, Ia—Ii or IIa—IId.

Leukemia is a cancer of the blood or bone marrow characterized by an abnormal increase of blood cells, usually ytes (white blood cells). Leukemia is a broad term covering a spectrum of diseases. The first division is between its acute and chronic forms: (i) acute leukemia is characterized by the rapid increase of immature blood cells. This crowding makes the bone marrow unable to produce y blood cells. Immediate treatment is required in acute ia due to the rapid progression and accumulation of the malignant cells, which then spill over into the bloodstream and spread to other organs of the body. Acute forms of leukemia are the most common forms of ia in children; (ii) c leukemia is distinguished by the excessive build up of relatively mature, but still abnormal, white blood cells. Typically taking months or years to progress, the cells are produced at a much higher rate than normal cells, resulting in many abnormal white blood cells in the blood. Chronic leukemia mostly occurs in older people, but can theoretically occur in any age group. Additionally, the diseases are subdivided according to which kind of blood cell is affected. This split divides leukemias into blastic or lymphocytic leukemias and myeloid or myelogenous leukemias: (i) in lymphoblastic or lymphocytic leukemias, the cancerous change takes place in a type of marrow cell that normally goes on to form lymphocytes, which are infection-fighting immune system cells; (ii) in myeloid or myelogenous leukemias, the cancerous change takes place in a type of marrow cell that normally goes on to form red blood cells, some other types of white cells, and platelets.

Within these main categories, there are several egories including, but not limited to, Acute lymphoblastic leukemia (ALL), Acute myelogenous leukemia (AML), Chronic myelogenous ia (CML), and Hairy cell leukemia (HCL). ms, diagnostic tests, and stic tests for each of the above—mentioned conditions are known in the art. See, e. g., Harrison's Principles of Internal ne®," 16th ed., 2004, The McGraw-Hill Companies, Inc. Dey et a1. (2006), Cytojournal 3(24), and the "Revised European American ma" (REAL) classification system (see, e.g., the website maintained by the National Cancer Institute).

A number of animal models are useful for establishing a range of therapeutically ive doses of BTK inhibitor compounds for treating any of the foregoing diseases.

For example, dosing of BTK inhibitor compounds for treating an autoimmune disease can be assessed in a mouse model ofrheumatoid arthitis. In this model, arthritis is induced in Balb/c mice by administering anti-collagen antibodies and lipopolysaccharide. See Nandakumar et al. (2003), Am. J. Pathol 163:1827-1837.

In another example, dosing of BTK inhibitors for the treatment of B-cell erative disorders can be ed in, e.g., a human-to-mouse xenograft model in which human B-cell lymphoma cells (e. g. Ramos cells) are implanted into immunodefficient mice (e.g., "nude" mice) as described in, e.g., Pagel et al. (2005), Clin Cancer Res ll(l3):4857-4866.

Animal models for treatment of thromboembolic disorders are also known.

The therapeutic efficacy of the compound for one of the foregoing diseases can be optimized during a course of treatment. For example, a subject being treated can undergo a diagnostic evaluation to correlate the relief of disease ms or ogies to inhibition of in vivo BTK activity achieved by administering a given dose of a BTK inhibitor. Cellular assays known in the art can be used to determine in vivo activity ofBTK in the ce or absence of an BTK inhibitor. For example, since activated BTK is phosphorylated at tyrosine 223 (Y223) and tyrosine 551 (Y551), phospho-specific immunocytochemical staining of P—Y223 or P-Y551- positive cells can be used to detect or quantify tion of BTK in a population of cells (e.g., by FACS analysis of stained vs unstained cells). See, e.g., Nisitani et al. (1999), Proc. Natl. Acad.

Sci, USA 96:2221-2226. Thus, the amount of the BTK inhibitor compound that is administered to a subject can be increased or decreased as needed so as to maintain a level of BTK inhibition optimal for treating the subject's e state.

Compounds disclosed herein rsibly inhibit BTK and may be used to treat s suffering from Bruton's tyrosine kinase-dependent or Bruton‘s tyrosine kinase mediated conditions or diseases, ing, but not limited to, cancer, autoimmune and other inflammatory diseases. Compounds disclosed herein have shown cy in a wide variety of diseases and conditions that are described herein.

A further aspect resides in the use of compounds of Formulas I, Ia-Ii or IIa-IId or a pharmaceutically acceptable salt thereof for the manufacture of a medicament to be used for the ent of chronic B cell disorders in which T cells play a prominent role.

In yet another aspect, the compounds of Formulas I, Ia-Ii or IIa-IId are used for the manufacture of a medicament to be used for the treatment of BTK-mediated diseases or conditions. These include, but are not d to, the treatment of B cell lymphomas resulting from c active B cell or signaling.

BTK mediated disorders or BTK mediated conditions as used herein, mean any disease state or other deleterious condition in which B cells, mast cells, myeloid cells or osteoclasts play a central role. These diseases include but are not limited to, immune, mune and inflammatory diseases, allergies, infectious diseases, bone resorption disorders and proliferative diseases.

Immune, autoimmune and inflammatory diseases that can be treated or prevented with the compounds of Formulas I, Ia-Ii or Ila-11d further e rheumatic diseases (e.g. infectious arthritis, progressive chronic arthritis, deforming arthritis, traumatic tis, gouty arthritis, osteoporosis, Reiter's syndrome, polychondritis, acute synovitis and spondylitis), glomerulonephritis (with or without nephrotic syndrome), mune hematologic disorders (e.g. hemolytic anemia, aplasic anemia, thic thrombocytopenia, and neutropenia), and autoimmune inflammatory bowel diseases (e.g. ulcerative colitis and Crohn's disease), host versus graft disease, allograft rejection, chronic thyroiditis, oderma, primary billiary cirrhosis, systemic lupus erythematosis, contact dermatitis, , skin sunbums, chronic renal insufficiency, Stevens-Johnson syndrome, inflammatory pain, idiopathic sprue, ia, sarcoidosis, kerato conjunctivitis, otitis media, ontal disease, pulmonary interstitial fibrosis, pneumoconiosis, ary insufficiency syndrome, ary emphysema, pulmonary fibrosis, silicosis, chronic inflammatory pulmonary disease (e.g. chronic obstructive ary disease) and other inflammatory or obstructive e on s. ies that can be treated or prevented include, among others, allergies to foods, food additives, insect poisons, dust mites, pollen, animal materials and contact allergans, type I hypersensitivity allergic asthma, allergic conjunctivitis.

Infectious diseases that can be treated or prevented include, among others, sepsis, septic shock, endotoxic shock, sepsis by Gram-negative bacteria, shigellosis, meningitis, cerebral malaria, pneumonia, tuberculosis, viral myocarditis, viral hepatitis (hepatitis A, hepatitis B and tis C), HIV infection, retinitis caused by cytomegalovirus, influenza, herpes, treatment of ions associated with severe burns, myalgias caused by infections, cachexia secondary to infections, and veterinary viral infections such as lentivirus, caprine arthritic virus, maedi virus, feline immunodeficiency virus, bovine immunodeficiency virus or canine deficiency virus.

In some embodiments of Formula I, compounds are present as a material in substantially pure form.

In some embodiments of Formula 1, compounds are selected from any one of the Examples herein or a pharmaceutically acceptable salt thereof.

Each variable definition above includes any subset thereof and the compounds of Formula I include any combination of such variables or variable subsets.

The t invention includes the compounds and salts thereof, their physical forms, preparation of the compounds, useful intermediates, and pharmaceutical compositions and formulations thereof.

The compounds of the present invention and the term "compound" in the claims include any pharmaceutically acceptable salts or solvates, and any amorphous or crystal forms, or tautomers, r or not specifically recited in context.

The present invention includes all isomers of the compounds. Compounds may have one or more asymmetric carbon atoms and can exist as two or more stereoisomers. Where a compound of the invention contains an alkenyl or lene group, geometric cis/trans (or Z/E) isomers are possible. Where the compound ns, for example, a keto or oxime group or an ic moiety, tautomeric isomerism ('tautomerism') can occur. A single compound may exhibit more than one type of isomerism.

The t invention includes any stereoisomers, even if not specifically shown, dually as well as mixtures, geometric isomers, and pharmaceutically acceptable salts thereof, including nds exhibiting more than one type of isomerism,. Where a compound or stereocenter is described or shown without definitive stereochemistry, it is to be taken to embrace all possible dual isomers, configurations, and mixtures thereof. Thus, a material sample containing a mixture of stereoisomers would be embraced by a recitation of either of the stereoisomers or a recitation without ive stereochemistry. Also contemplated are any cis/trans isomers or tautomers of the compounds described. When a tautomer of the compound of Formula I exists, the compound of Formula I of the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically stated otherwise.

DETAILED DESCRIPTION OF THE INVENTION Described herein are compounds of Formula I, which include compounds of Formulas Ia- Ii and IIa-IId, and compositions and formulations containing such compounds, and methods of using and making such compounds. These compounds are useful in treating diseases or conditions modulated at least in part by BTK.

In an embodiment, a compound ing to Formula I and above embodiments is ed, wherein the compound of Formula I is ented by the compound of Formula 11a: /21 R1 | 62 x/ \24 R3 L2 wherein, Rl-R4, G2, G3, L1, L2, X, Y, and 21-24, are as previously described for a compound of Formula I and B1 and B2 are independently selected from C6cycloalkyl, C6heterocycloalkyl, C6aryl, or C6heteroaryl.

In an ment, a compound according to Formula I and above embodiments is provided, wherein the compound of Formula I is represented by the compound of Formula 11b: 2/21 R1 23 L1 R2 n 26/ \24 31/ \82 R3 Y\L2/Z wherein, Rl-R4, B1, B2, L1, L2, Y, and 21-24, are as previously described for a compound of Formula I, Z5 and Z6 are each independently ed from C(Ra) or N, where Ra is alkyl or H, and n and m are each independently selected from 0, l, or 2.

In an embodiment, a compound according to Formula I and above embodiments is provided, wherein the compound of a I is ented by the compound of Formula IIc: /z1 R1 22 I (P9326 z3 L1 / \Z4 / Bl \BZ wherein, Rl-R4, B1, B2, L1, L2, and 21-24, are as previously described for a compound of Formula I, Z5 and Z6 are each independently selected from C or N, and n and m are each ndently selected from 0, l, or 2.

In an embodiment, a compound according to a I and above embodiments is provided, wherein the compound of Formula I is represented by the compound of Formula 11d: | 62 G3 R2 0 (W326 \Z4 \ Z5 R3 L2 L1 wherein, Rl-R4, L1, L2, G2, G3, and Zl—Z4, are as previously described for a compound of Formula I, Z5 and Z6 are each independently ed from C or N, B1 and B2 are independently selected from C6cycloalkyl, C6heterocycloalkyl, C6aryl, or C6heteroaryl, and n and m are each independently selected from 0, l, or 2.

The present invention includes the compounds, intermediates, examples and synthetic methods described herein. nds of Formula I are prepared according to reaction schemes described herein. Unless otherwise indicated, the substituents in the schemes are defined as above.

Synthetic Methods: Compounds of the present invention include the intermediates, examples, and synthetic methods described herein. Synthetic methods provided herein are lly preceded by their respective synthetic schemes. Where a ure for an intermediate or example refers to an analogous procedure for an analogous ediate or example, such reference includes the procedure for that analogous intermediate or example, the associated synthetic scheme as well as the procedures and schemes utilized for the synthesis of the analogous intermediate or example.

The compounds of Formulas I, Ia-Ii and IIa-d may be prepared by the methods described below, together with synthetic methods known in the art of organic chemistry, or modifications and tizations that are familiar to those of ordinary skill in the art. The starting materials used herein are commercially available or may be prepared by routine methods known in the art [such as those methods sed in standard reference books such as the Compendium of c Synthetic Methods, Vol. I-VI -Interscience); or the Comprehensive Organic Transformations, by RC. Larock -Interscience)]. Preferred methods include, but are not limited to, those described below.

During any of the following synthetic sequences it may be ary and/or desirable to protect sensitive or reactive groups on any of the molecules ned. This can be achieved by means of conventional protecting groups, such as those described in T. W. Greene, tive Groups in Organic Chemistry, John Wiley & Sons, 1981; T. W. Greene and P. G. M. Wuts, Protective Groups in c Chemistry, John Wiley & Sons, 1991, and T. W. Greene and P. G.

M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999, which are hereby incorporated by reference.

Compounds of as I, Ia—Ii and Ila-d, or their pharmaceutically acceptable salts, can be prepared according to the reaction schemes discussed hereinbelow and utilizing ordinary skill in the art. Unless otherwise indicated, the substituents in the schemes are defined as above.

Isolation and purification of the products is accomplished by standard procedures, which are known to a t of ordinary skill.

When a general or ary synthetic procedure is referred to, one skilled in the art can readily ine the appropriate reagents, if not indicated, extrapolating from the general or exemplary procedures. Some of the general procedures are given as examples for general preparation of compounds. One skilled in the art can readily adapt such ures to the synthesis of other specific compounds. Representation of an tituted position in structures shown or referred to in the general procedures is for convenience and does not preclude substitution as described elsewhere herein. For specific groups that can be present, either as groups in the general procedures or as optional substituents not shown, refer to the descriptions in the remainder of this document, including the claims and detailed description.

A general procedure for the synthesis of compounds of as I, Ia-Ii and Ila-d is shown in the General Scheme, below.

General Scheme: CN 02NXB/ —B\L’I_B2 NH2 o N /L CouplingSuzuki OZNX/ 2 \X/ SuzukiCoupling B1 \Bz 2)acetaldoxime CuCI2 MKKUN'G (c) R2 O o o )LNHZ R3 \ 2LNH2 Pd/C, H2 R4 R4 —> 1 —>RWMXH 1 B1’L\B2 3 /L H2N\X/ Base '31 \32 LG = Leaving Group R2 0 (d) (e) Where A, B1, B2, L1, X, R2, R3, and R4 are as defined previously for a compound of Formulas I, Ia-Ii and IIa-d and LG is equal to a suitable g group such as triflate, te, te, HATU, Cl, Br or I.

In a typical preparation of a nd of Formulas I, Ia-Ii and Ila-d, a compound of Formula (a) was reacted under Suzuki coupling conditions with a suitable boronic acid. Suitable conditions include, but are not limited to, ng compounds of Formula (a) with a suitable base, such as CszC03 or K2C03, and a suitable palladium catalyst, such as Pd(dppf)C12'DCM.

Suitable solvents for use in the above synthesis include 1,4-dioxane, water, DME and mixtures thereof. The mixture was degassed with nitrogen six times and refluxed for about 16 h under nitrogen atmosphere to afford the compound of Formula (b). The above process was carried out at temperatures between about 50° C and about 150° C. Preferably, the reaction was carried out at about 100° C. The above process was preferably carried out at or about atmospheric pressure although higher or lower pressures may be used if desired. Substantially equimolar amounts of reactants were preferably used although higher or lower amounts may be used if desired.

The compound of Formula (b) was reacted with a suitable c acid under Suzuki coupling conditions. Suitable conditions include, but are not limited to, treating compounds of Formula (b) with a suitable base, such as Cs2C03 or K2C03, and a suitable palladium catalyst, such as Pd(dppt)C12‘DCM or Pd(PPh3)4. Suitable solvents for use in the above synthesis include 1,4-dioxane, water, DME and mixtures thereof. The mixture was degassed with nitrogen six times and refluxed for about 5 h under en here to afford the compound of Formula (c). The above process was carried out at atures between about 40° C and about 120° C.

Preferably, the reaction was carried out at about 900 C. The above process was preferably carried out at or about atmospheric pressure although higher or lower res may be used if desired.

Substantially lar amounts of reactants were preferably used although higher or lower amounts may be used if desired.

The compound of Formula (c) was reacted under hydrogen atmosphere with palladium on carbon, preferably degassing the mixture with hydrogen about 6 times. Suitable solvents for use in the above synthesis include ethyl acetate and methanol. The above process was carried out at temperatures between about 10° C and about 60° C, or preferably at ambient temperature, to afford the compound of Formula (d).The above process was ably carried out at or about atmospheric pressure although higher or lower pressures may be used if desired. Substantially equimolar amounts tants were ably used although higher or lower amounts may be used if desired.

The compound of Formula (d) was reacted with a suitable acryloyl chloride with a suitable base. Suitable bases include organic bases such as TEA or DIPEA. The above process was d out at temperatures between about -10° C and about ambient temperature, or ably at 0° C, to afford the compound of Formula (d). The above process was preferably carried out at or about atmospheric pressure although higher or lower pressures may be used if desired. Substantially lar amounts of reactants were preferably used although higher or lower amounts may be used if desired.

Examples: Preparations and Intermediates Scheme 1 08,0H 0 (m \ \ 2 l l/ NH2 CNPdd / \ (PP)fCl2 C$2CO i 3 N Cl doxime, CuCl2 N CI —> —'> CI N CI 14-gioxane/H20 THF/H20,11O°C 110 0.161121% No2 16h, 84% N02 1 3 4 Pd2(dba)3 5C32003 £20—>©Pd/C H2 | : NH2 14-dioxane/HZO EA, r..t, 16h O N 0 110°C 16h 60% TEA, DCM 61):) 0°C 10min Example1 2-chlor0(3-nitr0phenyl)nicotinonitrile (3). To a solution of 3-nitrophenylboronic acid 2 (5.19 g, 30 mmol), CSQCOg (19.56 g, 60 mmol) and 2,6-dichloronicotinonitrile 1 (5.51 g, 33 mmol) in dry 1,4-dioxane (100 mL) was added Pd(dppf)Clg’DCM (2.4 g, 3.0 mmol) under nitrogen atmosphere, and the mixture was degassed with nitrogen 6 times, then d for 16 h under nitrogen atmosphere. After cooling to room temperature, the solvent was evaporated and the residue was d by flash chromatography, eluting with 20:1 to 3:1 PE/EA to afford the title compound as a yellow solid (1.6 g, 21%). 2-chlor0(3-nitr0phenyl)nic0tinamide (4). To a solution of 2-chloro(3- nitrophenyl)nicotinonitrile 3 (259 mg, 1.0 mmol) and acetaldoxirne (88 mg, 1.5 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was added CuClz (15 mg, 0.1 mmol) under nitrogen atmosphere, and the mixture was degassed with nitrogen 6 times, then heated to 90°C and d for 16 h under nitrogen atmosphere. After cooling to room temperature, the solvent was evaporated and the crude product was purified by flash chromatography, g with 20:1 DCM/MeOH to afford the title compound as a yellow solid (240 mg, 84%). MS (ESI): m/Z =277.9 [M+H]+. 6-(3-nitrophenyl)(4-phenoxyphenyl)nic0tinamide (6). To a solution of 2-chloro—6-(3- nitrophenyl)nicotinamide 4 (240 mg, 0.87 mmol), Cs2C03 (567 mg, 1.74 mmol) and biphenyl ylboronic acid 5 (203 mg, 0.95 mmol) in 1,4—dioxane (10 mL) and water (2.5 mL) was added Pd2(dba)3 (80 mg, 0.09 mmol) under nitrogen atmosphere, and the mixture was degassed with nitrogen 6 times, then refluxed for 16 h under nitrogen atmosphere. After cooling to room temperature, the t was evaporated and the crude product was purified by flash tography eluting with 150:1 DCM/MeOH to afford the title compound as a yellow solid (110 mg, crude). 6-(3-aminophenyl)—2—(4-phen0xyphenyl)nicotinamide (7). To a solution of 6-(3-nitrophenyl)- 2-(4-phenoxyphenyl)nicotinamide 6 (110 mg, 0.27 mmol) in ethyl acetate (5 mL) was added Pd/C (10 mg) under hydrogen atmosphere, and the mixture was degassed with hydrogen 6 times, then stirred for 16 h at ambient temperature under hydrogen here. The on was filtered and the filtrate was evaporated to the crude product as red oil (61 mg, 60%). MS (ESI): m/z = 382.1 [M+H]+.

Example 1 6-(3-acrylamidophenyl)(4-phen0xyphenyl)nicotinamide 2| : HN\n/\ To a solution of 6-(3—aminophenyl)—2-(4-phenoxyphenyl)nicotinamide 7 (38 mg, 0.1 mmol) in DCM (5 mL) was added TEA (0.05 mL, 0.4 mmol) and yl chloride 8 (9 mg, 0.1 mmol) at 0 oC. The mixture was stirred at 0 0C for 10 minutes. The solvent was d and the residue was purified by Prep-TLC eluting with 25 :1 DCM/MeOH to afford the title compound (30 mg, 71%) as white solid. 1H NMR (400 MHz, DMSO) 8 10.36 (s, 1H), 8.43 (s, 1H), 7.72—7.97 (m, 7H), 7.49 (s, 1H), 7.33—7.52(m, 3H), 7.24(t, J: 6.9 Hz, 1H), 6.9—7.13(m, 4H), 6.45 (dd, J: 16.9, 10.0 Hz, 1H), 6.30 (d, J: 16.9 Hz, 1H), 5.79 (d, J: 10.5 Hz, 1H), MS (ESI, method A): m/Z = 436.0 [M + H]+, tR=1.553 min., HPLC: 97.5% (214nm), 98.0% (254nm).

Scheme 2 (1 or"O O N(H2304concszo \ \ N...2 Pd(dppf)Clz 052003 I ""2 —> | —> / 90°C 1h 73% N/ 1,4-dioxane/HZO Cl N CI Cl 110°C, 16h, 53% o0 1 2 4 Dc ,0 I PM: H2 Pd(PPh3)4, ch03 N/ DME/HZO EA rt 16h BOC/ 90°C, 5h 84% O O VLCI \ \ NH2 I TFA, DCM, | 9 N r1, 1h, 71% TEA DCM HN NHZOQ O 0°C,10min 44% Example3 2,6-dichloronicotinamide (2). To 2,6-dichloronicotinonitrile 1 (l .73 g, 10 mmol) was added conc H2804 (10 mL) and water (2 mL). The e was heated to 90°C and stirred for l h.

After cooling to room temperature, the solution was poured into ice—cold water, then adjusted to PH = 8 with ammonia water. The precipitate was filtered, washed with water (20 mL) and dried under vacuum to afford the title compound as an brown solid (1.4 g, 73%). MS (ESI): m/z = 191.1 [M+H]+. 6-chlor0(4-phenoxyphenyl)nicotinamide (4). To a solution of chloronicotinamide 2 (668 mg, 3.5 mmol), C82C03 (1.14 g, 7 mmol) and 4—phenoxyphenylboronic acid 3 (749 mg, 3.5 mmol) in oxane (30 mL) was added Pd(dppf)C12‘DCM (285 mg, 0.35 mmol) under nitrogen atmosphere, and the mixture was degassed with nitrogen 6 times, then refluxed for 16 h under nitrogen atmosphere. After cooling to room temperature, the solvent was evaporated and the residue was purified by flash chromatography, eluting with 20:] to 3:1 petroleum ethyl acetate (PE/EA) to afford the title compound as a yellow solid (611 mg, 53%). MS (ESI): m/Z = 325.0 [M+H]*. tert-butyl(5-carbamoyl(4-phenoxyphenyl)pyridinyl)—5,6—dihydropyridine—1(2H)— ylate (6). To a solution of 4-(4,4,5,5—tetramethyl-1,3,2-dioxaborolanyl)-1 ,2,3,6- tetrahydropyridine 5 (232 mg, 0.75 mmol), K2C03 (207 mg, 1.50 mmol) and 6-chloro—2-(4— phenoxyphenyl)nicotinamide 4 (162 mg, 0.50 mmol) in 1,2-dimethoxyethane (5 mL) and water (1 mL) was added Pd(PPh3)4 (115 mg, 0.10 mmol) under nitrogen atmosphere, and the mixture was degassed with nitrogen 6 times, then heated to 90°C and stirred for 5 h under nitrogen atmosphere. After cooling to room temperature, the solvent was evaporated and the crude product was purified by flash chromatography, eluting with 70:1 DCM/MeOH to afford the title compound as a white solid (232 mg, crude). tert-butyl 4-(5-carbamoyl—6—(4-phenoxyphenyl)pyridinyl)piperidine—l-carboxylate (7).

To a solution of 4-(5 -carbamoyl(4-phenoxyphenyl)pyridinyl)—5,6-dihydropyridine-1(2H)- carboxylate 6 (232 mg, 0.75 mmol) in ethyl acetate (5 mL) was added Pd/C (10 mg) under hydrogen atmosphere, and the mixture was degassed with hydrogen 6 times, then stirred for 16 h at ambient temperature under hydrogen atmosphere. The solution was filtered and the filtrate was evaporated to the crude product as brown solid (215 mg, 60% for two steps). MS (ESI): m/z = 474.1 . 2-(4-phenoxyphenyl)(piperidinyl)nicotinamide (Example 2) (8). To a solution of tert- butyl 4-(5 moyl(4-phenoxyphenyl)pyridinyl)piperidine— 1 -carboxylate 7 (215 mg, 0.45 mmol) in dry romethane (6 mL) was added TFA (2 mL), and the resulting mixture was stirred for 1 h at ambient temperature. The solvent was removed and the residue was partitioned between saturated aqueous sodium bicarbonate (30 mL) and ethyl acetate (20 mL).

The c phase was separated, dried over ous sodium e, filtered and concentrated.

The crude residue was purified by flash chromatography, eluting with 5 :1 DCM/MeOH to afford the title compound as a white solid (120 mg, 71%). MS (ESI): m/z = 374.2 [M+H]+.

Example 3 6-(1-acryloylpiperidinyl)—2-(4-phenoxyphenyl)nic0tinamide To a solution of 2-(4-phenoxyphenyl)—6-(piperidin-4—yl)nicotinamide 8 (26 mg, 0.07 mmol) in DCM (5 mL) was added TEA (0.05 mL, 0.4 mmol) and acryloyl chloride 9 (7 mg, 0.07 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 s. The solvent was removed and the residue was purified by Prep-TLC eluting with 25 :1 DCM/MeOH to afford the title compound (13 mg, 44%) as white solid. 1H NMR (400 MHz, CDC13) 8 7.90 (d, J= 8.0 Hz, 1H), 7.71—7.62 (m, 2H), 7.42—7.31 (m, 2H), 7.21—7.11 (m, 2H), 7.10— 7.01 (m, 4H), 6.60 (dd, J: 16.8, 10.5 Hz, 1H), 6.26 (dd, J: 16.8, 2.0 Hz, 1H), 5.84 (s, 1H), 5.68 (dd, J: 10.5, 2.0 Hz, 1H), 5.54 (s, 1H), 4.79 (d, J: 13.3 Hz, 1H), 4.13 (d,J= 12.8 Hz, 1H), 3.17 (t, J: 12.3 Hz, 1H), 3.39 (t, J: 11.7 Hz, 1H), 2.76 (t, J: 11.7 Hz, 1H), 2.03 (br, 2H), 1.80 (ddd, J: 25.5, 12.5, 4.2 Hz, 2H). MS (ESI, method A): m/z = 428.0 [M + H]+, tR=1.480 min. HPLC: 96.7% (214nm), 99.3% (254nm).

Scheme 3 [f] 0 \ \ I NQI H2804((conc)/H20 | NHz Cl N/ CI K2CO3, ethanol 9,o°c 1h, 94% (\N N Cl reflux 4h, 62% BOG/N HNd 1 3 4 (1 03""O O \ NH2 Pd(dppf)C| 2! Cs co2 3 IN/ | . HQN N/ TEA DCM, (\N 1,4-dloxane/H20 110°C, 16h, 58% N\2 6 0°C,10min N O Example 4 Example 5 tert-butyl 4-(6-ch10rocyan0pyridiny])piperazine-l-carboxylate (3). To a solution of 2,6- dichloronicotinonitrile 1 (519 mg, 3.0 mmol) and tert—butyl piperazine-l-carboxylate 2 (558 mg, 3.0 mmol) in ethanol (15 mL) was added K2C03 (636 mg, 6.0 mmol), and the resulting solution was refluxed for 4 h. After g to room ature, the solvent was evaporated and the crude product was purified by flash chromatography, eluting with 5:1 to 2:1 PE/EA to afford the title nd as a white solid (600 mg, 62%). MS (ESI): m/z = 345.1 [M + Na]+. r0(4—phen0xyphenyl)nicotinamide (4). To tert-butyl-(6-chloro-5—cyanopyridin y1)piper azine—l-carboxylate 3(600 mg, 10 mmol) was added H2S04 (60716., 5 mL) and water (1 mL). The mixture was heated to 90°C and stirred for 1 h. After cooling to room temperature, the solution was poured into ice—cold water, then adjusted to PH = 8 with ammonia water. The precipitate was filtered, washed with water (20 mL) and dried under vacuum to afford the title compound as an off-white solid (420mg, 94%). MS (ESI): m/z = 241.0 [M + H]+. 2-(4-phenoxyphenyl)(piperazinyl)nicotinamide le 4) (6). To a on of 6— chloro(4-phenoxyphenyl)nicotinamide 4 (420 mg, 1.75 mmol), K2C03 (483 mg, 3.5 mmol) and 4-phenoxyphenylboronic acid 5 (374 mg, 1.75 mmol) in oxane (15 mL) and water (3 mL) was added Pd(PPh3)4 (231 mg, 0.20 mmol) under nitrogen atmosphere, and the mixture was degassed with nitrogen 6 times, then heated to 90°C and stirred for 5 h under nitrogen atmosphere. After cooling to room temperature, the solvent was evaporated and the crude product was purified by flash chromatography eluting with 70:1 DCM/MeOH to afford the title compound as a white solid (260 mg, 58%). MS (ESI): m/z = 375.0 [M + H]+.

Example 5 cryloylpiperazin-l-y])—2-(4-phenoxyphenyl)nicotinamide Nominee|\/ NH2 To a solution of 2-(4-phenoxyphenyl)—6-(piperazin-1—yl)nicotinamide 6 (59 mg, 0.16 mmol) in DCM (5 mL) was added TEA (0.05 mL, 0.4 mmol) and acryloyl chloride 7 (14 mg, 0.16 mmol) at 0°C. The mixture was stirred at 0°C for 10 minutes. The solvent was removed and the residue was d by Prep-TLC eluting with 25 :1 DCM/MeOH to afford the title compound (27 mg, 40%) as light yellow solid. 1H NMR (400 MHz, CDClg) 8 8.04 (d, J: 8.7 Hz, 1H), 7.64 (d, J= 8.2 Hz, 2H), 7.40 (t, J: 7.6 Hz, 2H), 7.18 (t, J: 7.3 Hz, 1H), 7.08 (dd, J: 12.0, 8.4 Hz, 4H), 6.66 (d, J= 8.5 Hz, 1H), 6.64—6.56 (m, 1H), 6.37 (d, J= 16.7 Hz, 1H), 5.77 (d, J= 10.6 Hz, 1H), .57 (s, 1H), 5.33 (s, 1H), 3.81 (s, 4H), 3.73 (s, 4H).MS (ESI, method A): m/z = 429.2 [M + H]+, tR=1.454 min., HPLC: 97.5% (214nm), 98.0% (254nm).

Scheme 4 Z\/ NH2 HCIIEtOH CIJK/ Example 6 6-chlor0(4-phenoxyphenyl)nic0tinamide (1). 6-chloro(4-phenoxyphenyl)nicotinamide 1 was synthesized by using the same procedure above providing a yellow solid (611 mg, 53%).

MS (ESI): m/z = 325.0 [M+H]+. tert-butyl(5-carbamoyl(4-phenoxyphenyl)pyridinyl)—2,S-dihydro-lH-pyrrole-l- carboxylate (3). The title compound was synthesized using a procedure analogous to the procedure described in tert-butyl 4-(5-carbamoyl-6—(4-phenoxypheny1)pyridin-2—y1)-5,6— dihydropyridine-1(2H)- carboxylate provided as white solid (300 mg, crude). MS (ESI): m/z = 458.2 [M+H]+. tert-butyl(5-carbam0yl—6-(4-phenoxyphenyl)pyridin-2—yl)pyrrolidine-l-carboxylate (4).

The title compound was synthesized using a procedure analogous to the procedure described in tert-butyl 4-(5—carbamoyl(4—phenoxyphenyl)pyridinyl)piperidinecarboxylate provided as white solid (240 mg, 45% for two steps). MS (ESI): m/z = 460.1 [M+H]+. 2-(4-phenoxyphenyl)(pyrrolidinyl)nic0tinamide(5). The title nd was synthesized using a procedure analogous to the ure bed in 2-(4-phenoxyphenyl)—6-(piperidin yl)nicotinamide as white solid (190 mg, crude). MS (ESI): m/z = 360.1 [M+H]+.

Example 6 6-(1-acryloylpyrrolidinyl)(4-phenoxyphenyl)nic0tinamide N K) The title compound was synthesized using a procedure analogous to the procedure described in Example 3 as a white solid (18 mg, 29%). 1H NMR (300 MHZ, CD30D) 8 7.85 (d, J: 7.9 Hz, 1H), 7.72 (d, J: 8.8 Hz, 2H), 7.37 (m, 3H), 7.15 (t, J: 7.4 Hz, 1H), 7.02 (m, 4H), 6.65 (dd, J: 16.7, 10.6 Hz, 1H), 6.28 (m, 1H), 5.74 (dd, J: 9.5, 7.4 Hz, 1H), 3.98 (m, 2H), 3.69 (m, 3H), 2.34 (dtd, J: 30.9, 12.6, 8.0 Hz, 2H). MS (ESI, method A): m/z = 414.2 [M + H]+, tR=1.421 min.

HPLC: 100% ), 100% (254nm).

Scheme 5 03‘OH |\ NHZ / / N WOO—*0 O N O O Pd(dppf)C]2, 032003 OZN o 1, 4--dioxane/HZO 110°C, 16h 58% O O VLCI Pd/C H2 5 EA, r..,t 90%H16h,ZINON\4020 TEA, DCM, OHINO:02 0):) °OC, 10min Example? tert-butyl 4-(6-chlorocyanopyridin-Z-priperazine-l-carboxylate (3). To a solution of 6- (4-phenoxyphenyl)nicotinamide 1 (130 mg, 0.4 mmol) and 4-nitrophenylboronic acid 2 (67 mg, 0.4 mmol) in DME (10 mL) /water (3 mL), was added K2C03 (110 mg, 0.8 mmol) and Pd(dppf)Clz (33 mg, 0.04 mmol) under nitrogen atmosphere, and the mixture was degassed with en 6 times, then heated to 90°C and stirred for 5 h under nitrogen atmosphere. After g to room temperature, the solvent was evaporated and the crude product was purified by flash chromatography eluting with 70:1 DCM/MeOH to afford the title compound as a white solid (60 mg, crude). MS (ESI): m/z = 412.1 [M+H]+. 6-(4-aminophenyl)(4-phenoxyphenyl)nic0tinamide (4). To a solution of tert-butyl 4-(6— chlorocyanopyridinyl)piperazinecarboxylate 3 (60 mg, 0.15 mmol) in ethyl e (5 mL) was added Pd/C (6 mg) under hydrogen atmosphere, and the mixture was degassed with hydrogen 6 times, then stirred for 16 h at ambient temperature under hydrogen atmosphere. The solution was filtered and the filtrate was evaporated to the crude product as brown solid (42 mg, 90%). MS (ESI): m/Z = 382.0 [M+H]+.

Example 7 6-(4-acrylamidophenyl)(4-phen0xyphenyl)nicotinamide | \/ NH2 0 O N O Q leu 0 To a solution of 6-(4-aminophenyl)—2-(4-phenoxyphenyl)nicotinamide 4 (42 mg, 0.11 mmol) in DCM (5 mL) was added TEA (0.05 mL, 0.4 mmol) and yl chloride 5 (10 mg, 0.11 mmol) at 0 oC. The mixture was stirred at 0 0C for 10 minutes. The solvent was removed and the residue was purified by Prep-TLC eluting with 25 :1 OH to afford the title compound (2.5 mg, %) as white solid. 1H NMR (300 MHz, CD3OD) 8 8.17—8.11 (m, 1H), 7.98—7.92 (m, 1H), 7.90—7.84 (m, 1H), 7.81 (s, 3H), 7.69— 7.60 (m, 2H), 7.58—7.52 (m, 1H), 7.42—7.34 (m, 2H), .12 (m, 1H), 7.10—7.00 (m, 3H), 6.47— 6.38 (m, 2H), 5.82—5.76 (m, 1H). MS (ESI, method A): m/z = 435.9 [M + H]+, tR=1.540 min., HPLC: 97.5% (214nm), 98.7% (254nm).

Scheme 6 fo ,Tf <3 i?"3:3? ‘9? (To LDA B\o THF -78°C-rt (JCT Pd(dppf)C[2 KOAC1 4-dioxane Boc 6h, 85% B06 85°C 16h, 54% Bee 1 5 \ \ | NHZ Boc I I CI N/ N 0Pd/C H2 N Pd(dPPf)012 052003 O EA r.t. 16h 14--dioxaneIH20 Bee Bee 7 6 90°C, 16h, 71% 8 \ NH2 I TFA | / 1—> N TEA DCM DCM 0°C 1h , , N 0 0 0 10mino 41% H 9 34% Example 8 tert-butyl 5-(trifluoromethylsulfonyloxy)—3,4-dihydr0pyridine-1(2H)—carb0xylate (3). To a solution of tert-butyl 3-oxopiperidine-l-carboxylate l (495 mg, 5.0 mmol) in tetrahydrofuran (10 mL) in a three-necked flask was added lithium diisopropylamide (2.0M, 2.5 mL, 5.0 mmol) at - 78 °C. After stirring for 2 h at -78 °C, a solution of trifluoro—N-phenyl-N— (trifluoromethylsulfonyl)methanesulfonamide 2 (1.8 g, 5.0 mmol) in tetrahydrofuran (5 mL) was added, and the solution was stirred for another 30 min at this temperature, then warmed to room temperature and stirred for 3 h. Water (30 mL) was added to quench the reaction, and the on was extracted with ethyl acetate (3 X 30 mL). The organic layers were combined, dried over anhydrous sodium e, filtered and trated. The residue was purified by silica gel column tography eluting with petroleum ether to afford the title compound as brown oil (1.4 g, 85%). tert-butyl-S-(4,4,5,5-tetramethyl—1,3,2-dioxab0rolanyl)-3,4-dihydr0pyridine-1(2H)- carboxylate (5). To a solution of 4,4,4',4',5,5,5',5'—octamethyl-2,2'—bi(1,3,2—dioxaborolane) 4 (559 mg, 2.2 mmol), KOAc (588 mg, 6.0 mmol) and tert-butyl 5-(trifluoromethylsulfonyloxy)— 3,4-dihydropyridine-1(2H)-carboxylate 3 (662 mg, 2.0 mmol) in dry l,4-dioxane (10 mL) was added f)Clz'DCM (326 mg, 0.4 mmol) under nitrogen atmosphere, and the mixture was degassed with en 6 times, then heated to 85°C and stirred overnight under nitrogen atmosphere. After cooling to room temperature, the solvent was evaporated and the crude product was purified by silica gel column chromatography, eluting with 100:1 to 20:1 PE/EA to afford the title compound as brown oil (336 mg, 54%). tert-butyl(5-carbamoyl-6—(4-phenoxyphenyl)pyridin-2—yl)—3,4—dihydr0pyridine-1(2H)— carboxylate (7). To a solution of tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl) -3,4- dihydropyridine-1(2H)- carboxylate 5 (260 mg, 0.84 mmol), C82CO3 (456 mg, 1.4 mmol) and 6- chloro(4-phenoxyphenyl)nicotinamide 6 (227 mg, 0.7 mmol) in 1,4-dioxane (10 mL) was added Pd(dppf)Clz'DCM (57 mg, 0.07 mmol) under nitrogen atmosphere, and the mixture was degassed with nitrogen 6 times, then heated to 90°C and stirred ght under nitrogen atmosphere. After cooling to room ature, the solvent was evaporated and the crude product was d by silica gel column chromatography eluting with 100:1 to 20:1 DCM/MeOH to afford the title compound as white solid (240 mg, 71%). MS (ESI): m/Z = 472.2 [M + Hr. tert-butyl 3-(5-carbam0yl—6—(4-phenoxyphenyl)pyridinyl)piperidine-l-carboxylate (8).

To a solution of tert-butyl 5-(5 -carbamoyl(4-phenoxyphenyl)pyridinyl)-3,4- dihydropyridine-1(2H)- carboxylate 7 (240 mg, 0.5 mmol) in ethyl e (5 mL) was added Pd/C (24 mg) under hydrogen atmosphere, and the mixture was degassed with en 6 times, then stirred for 16 h at ambient temperature under hydrogen atmosphere. The solution was filtered and the filtrate was evaporated to the crude product as brown solid (230 mg, crude). MS (ESI): m/Z = 474.2 [M + Hr. 2-(4-phenoxyphenyl)(piperidinyl)nicotinamide (9). To a solution of tert—butyl 3-(5- carbamoyl(4-phenoxyphenyl)pyridinyl)piperidinecarboxylate 8 (150 mg, 0.32 mmol) in dry dichloromethane (6 mL) was added TFA (2 mL), and the resulting e was stirred for 1 h at ambient temperature. The solvent was removed and the residue was partitioned between saturated s sodium bicarbonate (30 mL) and ethyl acetate (20 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel column chromatography eluting with 5:1 DCM/MeOH to afford the title nd as a white solid (77 mg, 71%). MS (ESI): m/z =374.2 [M + H]+.

Example 8 cryloylpiperidinyl)—2-(4-phenoxyphenyl)nicotinamide To a solution of 2-(4-phenoxyphenyl)—6-(piperidin-3—yl)nicotinamide 9 (19 mg, 0.05 mmol) in DCM (5 mL) was added TEA (0.05 mL, 0.4 mmol) and acryloyl chloride 10 (5 mg, 0.05 mmol) at 0°C. The mixture was stirred at 0°C for 10 minutes. The solvent was removed and the residue was purified by Prep-TLC eluting with 25 :1 DCM/MeOH to afford the title nd (7 mg, 34%) as white solid. 1H NMR (300 MHZ, CDClg) 8 7.97 (d, J: 8.9 Hz, 1H), 7.69 (d, J: 8.1 Hz, 2H), 7.38 (t, J: 7.8 Hz, 2H), 7.24—7.15 (m, 2H), 7.12—7.01 (m, 4H), 6.62 (dd, J: 16.6, 10.6 Hz, 1H), 6.28 (d, J= 16.4 Hz, 1H), 5.75—5.60 (m, 2H), 5.46 (s, 1H), 4.89—4.55 (m, 1H), 4.30—3.90 (m, 1H), 3.50 (t, J: 12.2 Hz, 0.5H), 3.24—3.06 (m, 1H), 2.99 (d, J: 10.7 Hz, 1H), 2.80 (t, J: 12.2 Hz, 0.5H), 2.13 (s, 1H), 1.87 (d, J: 13.4 Hz, 2H), 1.64 (s, 1H). MS (ESI, method A): m/z = 428.0 [M + H]+, tR=1.526 min., HPLC: 93.3% (214nm), 99.8% (254nm).

Scheme 7 H3°C 0 elm?" K200: ethanol \ NH2 N N/ conc)/H20 CI l —’ / 90°C, 1h. 96% DN N Cl reflux 6h 70% HN Boc HZN 3 4 E103:" O Pd(dppf)C|2, 052003 1 ,4—dioxane/HZO GIN: Who—,0 \jLNO": H2N TEA, DCM, NHZOQ 110°C, 1611, 31% 0°C,10min Example9 tert-butyl 1-(6-chlorocyanopyridiny])piperidin-4—ylcarbamate (3). To a solution of 2,6- dichloronicotinonitrile 1 (346 mg, 2.0 mmol) in ethanol (10 mL) was added tert-butyl piperidin- 4-ylcarbamate 2 (400 mg, 2.0 mmol) and K2C03 (552 mg, 4.0 mmol). The mixture was heated to reflux stirred for 4 h. After g to room temperature, the solvent was evaporated and the crude product was purified by silica gel column chromatography eluting with 20:1 to 5 :1 PE/EA to afford the title nd as a white solid (470 mg, 70%). MS (ESI, method A): m/Z = 337.2 [M + H].+ 6-(4-aminopiperidinyl)chloronicotinamide (4). To tert—butyl 1-(6-chlorocyanopyridin- 2-yl) piperidinylcarbamate 3 (470 mg, 1.4 mmol) was added H2804 (conc., 5 mL) and water (1 mL). The mixture was heated to 90°C and stirred for 1 h. After cooling to room ature, the on was poured into ice-cold water, then adjusted to PH = 8 with ammonia water. The precipitate was filtered, washed with water (10 mL) and dried under vacuum to afford the title compound as a white solid (340 mg, 96%). MS (ESI): m/z = 255.0 [M + H]+. 6-(4-amin0piperidinyl)—2—(4-phenoxyphenyl)nicotinamide (6). To a solution of 6-(4- aminopiperidinyl)—2-chloronicotinamide 4 (51 mg, 0.2 mmol), K2C03 (55 mg, 0.4 mmol) and 4-phenoxyphenylboronic acid 5 (43 mg, 0.2 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was added Pd(dppf)Clz (18 mg, 0.02 mmol) under nitrogen atmosphere, and the mixture was degassed with nitrogen 6 times, then heated to 90°C and stirred for 5 h under nitrogen atmosphere. After cooling to room temperature, the solvent was evaporated and the crude product was purified by silica gel column chromatography eluting with 70:1 DCM/MeOH to afford the title compound as a white solid (24 mg, 31%). MS (ESI): m/Z = 389.2 [M + H]+.

Example 9 6-(4-acrylamid0piperidinyl)(4-phenoxyphenyl)nic0tinamide VLN ONO/ D To a solution of 6-(4—aminopiperidin—1-yl)(4-phenoxyphenyl)nicotinamide 6 (62 mg, 0.16 mmol) in DCM (5 mL) was added TEA (0.05 mL, 0.4 mmol) and yl chloride 7 (15 mg, 0.16 mmol) at 0°C. The mixture was stirred at 0°C for 10 minutes. The solvent was d and the e was purified by Prep-TLC eluting with 25 :1 DCM/MeOH to afford the title compound (14 mg, 20%) as white solid. 1H NMR (300 MHz, CDC13) 8 7.98 (d, J = 8.8 Hz, 1H), 7.62 (d, J: 8.5 Hz, 2H), 7.38 (t, J: 7.8 Hz, 2H), 7.16 (t, J: 7.4 Hz, 1H), 7.12—7.00 (m, 4H), 6.65 (d, J: 8.9 Hz, 1H), 6.31 (d, J: 16.9 Hz, 1H), 6.07 (dd, J=16.9, 10.2 Hz, 1H), 5.66 (d, J: .2 Hz, 1H), 5.52—5.48 (m, 1H), 5.28 (s, 1H), 4.44 (d, J= 13.4 Hz, 2H), 4.24—4.08 (m, 1H), 3.08 (t, J: 11.9 Hz, 2H), 2.08 (d, J: 10.7 Hz, 2H), 1.62 (s, 1H), 1.47 (dt, .1: 11.3, 6.1 Hz, 2H).

MS (ESI, method A): m/z = 443.2 [M + H]+, tR=1.434 min., HPLC: 99.1% (214nm), 99.3% (254nm).

HNQ/ ‘Boc 0 2 \ \ NH2 \ | 1 K2003, ethanol / C0nC)/H20 / | N N Clo—o> N N CI CI N CI 9091111964 reflux, 6h, 70% Boc—‘NH H2N 1 4 CL 0°" 0 |\ NH2 Pd(dPPf)C|2.Cszcos N N —> NHo/Q oxane/H20 H N O0;»—»H%:lN\TEA, DCM 110°C, 16h, 31% 5 0°C 10min % \0 Example 10 tert-butyl 1-(6-chlor0cyanopyridin-Z-yl)pyrrolidinylcarbamate (3). To a on of 2, 6-dichloronicotinonitrile 1 (346 mg, 2.0 mmol) in ethanol (10 mL) was added tert-butyl piperidinylcarbamate 2 (372 mg, 2.0 mmol) and K2C03 (552 mg, 4.0 mmol). The mixture was heated to reflux and stirred for 4 h. After cooling to room temperature, the solvent was evaporated and the crude product was purified by silica gel column chromatography eluting with :1 to 5:1 PE/EA to afford the title compound as a white solid (365 mg, 57%). MS (ESI, method A): m/Z = 345.1 [M + Nar. 6-(4-amin0piperidinyl)—2—chloronicotinamide (4). To tert-butyl l-(6-chlorocyanopyridin- 2-yl) pyrrolidiny1carbamate 3 (357 mg, 1.1 mmol) was added H2804 (00:10., 5 mL) and water (1 mL). The mixture was heated to 90°C and stirred for 1 h. After cooling to room temperature, the solution was poured into ice-cold water, then adjusted to PH = 8 with ammonia water. The precipitate was d, washed with water (10 mL) and dried under vacuum to afford the title compound as brown solid (192 mg, 72%). MS (ESI, method A): m/z = 241.0 [M + H]+. 6-(3-aminopyrrolidinyl)(4-phenoxyphenyl)nic0tinamide (6). To a solution of 6-(4- aminopiperidin-l-yl)—2-chloronicotinamide 4 (192 mg, 0.79 mmol), K2C03 (220 mg, 1.6 mmol) and 4-phenoxyphenylboronic acid 5 (171 mg, 0.8 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was added Pd(dppf)Clz (69 mg, 0.08 mmol) under nitrogen atmosphere, and the mixture was degassed with nitrogen 6 times, then heated to 90°C and stirred for 5 h under en atmosphere. After cooling to room temperature, the solvent was evaporated and the crude product was purified by flash chromatography eluting with 70:1 DCM/MeOH to afford the title compound as a white solid (92 mg, 31%). MS (ESI): m/z = 375.2 [M + H]+.

Example 10 6-(3-acrylamid0pyrrolidinyl)(4-phen0xyphenyl)nicotinamide l NH2 Q N Oo To a solution of 6-(3—aminopyrrolidin-l-yl)(4-phenoxyphenyl)nicotinamide 6 (92 mg, 0.25 mmol) in DCM (5 mL) was added TEA (0.14 mL, 1.0 mmol) and acryloyl chloride 7 (23 mg, 0.25 mmol) at 0 oC. The e was stirred at 0 0C for 10 minutes. The solvent was removed and the residue was purified by Prep—TLC eluting with 25 :1 OH to afford the title compound (58 mg, 54%) as white solid. 1H NMR (300 MHz, CDCl3) 8 7.95 (d, J = 8.7 Hz, 1H), 7.62 (d, J= 8.5 Hz, 2H), 7.38 (t, J= 7.8 Hz, 2H), 7.16 (t, J= 7.4 Hz, 1H), 7.05 (dd, J= 12.6, 8.3 Hz, 4H), 6.40—625 (m, 1H), 6.10 (dd, J: 16.8, 10.2 Hz, 2H), 5.67 (d, J: 10.2 Hz, 1H), 5.48 (s, 1H), 5.31 (s, 1H), 4.71 (d, J: 4.4 Hz, 1H), 3.85 (dd, J: 11.2, 6.0 Hz, 1H), 3.75—340 (m, 4H), 2.40—2.25 (m, 1H), 2.10—1.90 (m, 1H). MS (ESI, method A): m/z = 429.0 [M + H]+, tR=l.443 min., HPLC: 100% (214nm), 100% (254nm).

Example 1 1 cryloylpiperidinyl)(4-phenoxyphenyl)—1H-pyrazole-4—carb0xamide PhO0"):o ""2 Refer to Example 34 schemes and associated experimental procedures and data described below.

Example 12 1-(1-acryloylpiperidinyl)—3-(4-phen0xyphenyl)-1H-pyrazole-4—carboxamide PhDM0 "HZ Refer to Example 34 schemes and associated experimental procedures and data described below. e 13 1-(1-acryloylpyrrolidinyl)—3-(4-phenoxyphenyl)—1H-pyrazolecarb0xamide PhD 0 ""2 Refer to Example 34 schemes and associated experimental ures and data described below.

Example 14 1-(azetidinyl)—3-(4—phenoxyphenyl)—1H-pyrazolecarb0xamide PhOMo NH2 Refer to Example 34 scheme and associated experimental procedures and data described below.

Scheme 9 N'NH HO TsC|,Pyridine Tso d C 3"0 b— 3 OE. G LiOH/EtOH , ‘NQN’BOC N D —.N . overni9 ht .

BOG BOG 052003 DMF o 100°C; 3h NH4CLHATU O HC|,DCM,rt ‘N’CN’BOC —— 7 e 15 tert-butyl 3-(tosyloxy)azetidine—l-carboxylate (2). To a on of tert-butyl 3- hydroxyazetidinecarboxylate 1 (2.0 g, 11.5 mmol) in pyridine (25 mL) was added TsCl (2.64 g, 13.8 mmol), and the ing solution was stirred for 16 h at rt. The solvent was evaporated and the crude residue was purified by silica gel column, eluting with 5 :1 petroleum ether/ethyl acetate to afford the title compound (3.2 g, 85%) as colorless oil. MS (ESI): m/z = 350.0 [M+Na]+.

Ethyl(1-(tert-butoxycarbonyl)azetidin-3—yl)—3-(4-phenoxyphenyl)—1H—pyrazole carboxylate (4). To a solution of tert—butyl 3-(tosyloxy)azetidine-l-carboxylate 2 (1.3 g, 3.88 mmol) and CsC03 (2.12 g, 6.48 mmol) in DMF (25 mL) was added ethyl 3-(4-phenoxyphenyl)- 1H-pyrazolecarboxylate 3 (1.0 g, 3.24 mmol), and the resulting solution was stirred for 16 h at 100°C. The solvent was evaporated and the crude residue was d by silica gel column eluting with 3:1 petroleum ether/ethyl acetate to afford the title compound (1.39 g, 93%) as white solid. MS (ESI): m/Z = 464.0 [M+H]+. 1-(1-(tert—butoxycarbonyl)azetidinyl)—3-(4-phenoxyphenyl)—1H-pyrazole—4-carboxylic acid (5). To a solution of ethyl 1-(1-(tert-butoxycarbonyl)azetidinyl)—3-(4-phenoxyphenyl)- lH—pyrazole-4—carboxylate 4 (1.39 g, 3.0 mmol) in EtOH (20 mL) and water (2 mL) was added LiOH (630 mg, 15.0 mmol), and the resulting solution was stirred for 16 h at rt. The solvent was evaporated, and the e was dissolved in water (5 mL) and the ing solution was acidified with 2 N hydrochloric acid to pH = 6. The precipitate was d, washed with water (15 mL) and dried under vacuum to afford the title compound (1.2 g, 92%) as a white solid. MS (ESI): m/Z = 436.0 [M+H]+. tert-butyl(4-carbamoyl(4-phenoxyphenyl)—1H-pyrazol—1-yl)azetidine—l-carboxylate (6). To a solution of 1-(1-(tert-butoxycarbonyl)azetidinyl)(4-phenoxyphenyl)-1H-pyrazole- 4-carboxylic acid 5 (800 mg, 1.84 mmol), NH4C1 (120 mg, 2.21 mmol) and HATU (1.04 mg, 2.76 mmol) in dry DMF (10 mL) was added DIPEA (957 mg, 7.36 mmol), and the resulting solution was stirred overnight at rt. After the reaction was completed, the solution was concentrated, diluted with ethyl acetate (30 mL) and washed with water (2 X 20 mL) and brine (2 X 20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated.

The residue was purified by silica gel column eluting with 40:1 DCM/MeOH to afford the title compound (700 mg, 82%) as white solid. MS (ESI): m/z = 435.0 [M+H]+. 1-(azetidinyl)(4-phen0xyphenyl)-1H-pyrazolecarb0xamide (7). To a solution of 3-(4- carbamoyl(4-phenoxyphenyl)-1H-pyrazol—1-yl)azetidinecarboxylate 6 (700 mg, 1.61 mmol) in DCM (20 mL) was added conc. HCl (5 mL) and the reaction e was stirred at rt for 1 h. After the reaction was completed, the solution was concentrated to afford the title compound (600 mg, 100%) as white solid. MS (ESI): m/z = 335.0 [M + H]+.

Example 15 cryloylazetidinyl)—3-(4-phen0xyphenyl)—1H-pyrazole—4-carb0xamide /N\N’CN/<; To a solution of 1-(azetidinyl)—3-(4-phenoxyphenyl)—1H—pyrazolecarboxamide 7 (300 mg, 0.81 mmol) in dry DCM (15 mL) were added DIEA (316 mg, 2.43 mmol) and acryloyl chloride (88 mg, 0.97 mmol) at 0°C, and the resulting on was stirred at 0°C for 10 min. Water (10 mL) was added to quench the reaction. The mixture was diluted with DCM (20 mL), and washed with water (2 X 20 mL) and brine (2 X 20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was d by Prep—HPLC (ACN-HzO = -70, 0.1%FA) to afford the title compound (160 mg, 51%) as a white solid. 1H NMR (400 MHz, DMSO) 5 8.38 (s, 1H), 7.81 (d, J: 8.7 Hz, 2H), 7.47—7.38 (m, 3H), 7.20—7.14 (m, 1H), 7.11—6.99 (m, 5H), 6.43—6.34 (m, 1H), 6.20—6.12(m, 1H), 5.76—5.70 (m, 1H), 5.38—5.29 (m, 1H), 4.78—4.68 (m, 1H), 4.59—4.49 (m, 1H), 4.48—4.40 (m, 1H), 4.32—4.22 (m, 1H). MS (ESI, Method A): m/Z = 389.1 [M + H]+, tR = 1.374 min. HPLC: 99.7% (214nm), 99.7% ).

Example 16 1-(4-acrylamid0phenyl)—3-(4-phenoxyphenyl)—1H—pyrazolecarb0xamide HN’<§ PhOMo NH2 Refer to Example 34 schemes and associated experimental procedures and data described below. e 17 1-(3-aminophenyl)—3-(4-phen0xyphenyl)—1H-pyrazolecarboxamide PhDMo ""2 Refer to Example 34 schemes and associated experimental procedures and data described below.

Example 18 1-(3-acrylamid0phenyl)(4-phen0xyphenyl)-1H-pyrazolecarb0xamide Refer to Example 34 schemes and associated experimental procedures and data described below.

Example 19 (S)(1-acryloylpyrrolidinyl)—3-(4-phenoxyphenyl)—1H-pyrazolecarboxamide Refer to Example 34 schemes and associated experimental procedures and data bed below.

Example 20 (R)(1-acryloylpyrrolidinyl)(4-phen0xyphenyl)—1H-pyrazole—4-carboxamide N’ [\I PhDMo ""2 Refer to Example 34 schemes and associated experimental procedures and data described below.

Scheme 10 0 OH O C] gOH "Hz 3H PCI5, POC13 g NH3 in dioxane gm CL 0‘OH 0 N?" N/N —’ 115 °C, overnight Y 0 °c to ,1 NYN Pd(dppf)C[2, K2003, OH Cl C] dioxane—HZO (8/1 V) 60 O 1 2 c, 3 h it Pd(PPh3)4,K2003 N \ 0 c1 N —» I DME-HZO (8/1 V) N I 85 °C, overnIght Boc Boc’N OO NI \ 0 Pd/C, H2 CF3COOH —> 000 EtOAc, rt, overnight N Boc’ O)\N/ DCM, It 2 h \JLCI DCM 0 °C 1 h q©fi$oQ Example 21 2,4-dichloropyrimidine—S-carbonyl chloride (2). To a solution of 2,4-dihydroxypyrimidine carboxylic acid (5.0 g, 32.0 mmol) in POC13 (50 mL) was added PC15 (23.9 g, 115.2 mmol), and the resulting solution was heated to 115 °C and stirred for 12 h. The solvent was evaporated and the crude e was diluted with ethyl e (100 mL). The solid was filtered and the filtrate was trated to give the title compound as brown oil (6.2 g, 92%). 2,4-dichloropyrimidine-S-carboxamide (3). To a solution of 2,4-dichloropyrimidine carbonyl chloride (6.2 g, 29.3 mmol) in oxane (50 mL) was added ammonia (1.0 g, 58.3 mmol) in 1,4-dioxane (50 mL) dropwise at 0 0C, and the resulting solution was stirred for 12 h at ambient temperature. The mixture was diluted with ethyl acetate (50 mL), and washed with water (2 X 80 mL) and brine (2 X 80 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound as a white solid (4.5 g, 80%). MS (ESI): m/Z = 191.8 [M + Hr. 2-chloro(4—phenoxyphenyl)pyrimidine—S-carboxamide (4). To a on of 4- phenoxyphenylboronic acid (1.0 g, 4.7 mmol), K2C03 (1.4 g, 10.4 mmol) and 2,4- dichloropyrimidine-5—carboxamide (1.0 g, 5.2 mmol) in 1,4—dioxane (24 mL) and water (3 mL) was added Pd(dppf)C12 (380 mg, 0.52 mmol) under en atmosphere, and the mixture was degassed with nitrogen 6 times, then heated to 60 °C and stirred for 3 h under nitrogen atmosphere. After cooling to room temperature, the solution was poured into water (50 mL), and then extracted with ethyl acetate (3 X 40 mL). The combined c layers were dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography, eluting with 100 : l dichloromethane/methanol to afford the title compound as a brown solid (410 mg, 24%). MS (ESI): m/Z = 325.9 [M + H]+. tert-butyl 4-(5-carbamoyl-4—(4-phenoxyphenyl)pyrimidinyl)—5,6-dihydr0pyridine—1(2H)- carboxylate (6). To a solution of 2-chloro-4—(4-phenoxyphenyl)pyrimidine—5-carboxamide 4 (410 mg, 1.26 mmol), K2C03 (521.6 mg, 3.78 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl —1,3,2- dioxaborolan—2—yl)-5,6—dihydropyridine-1(2H)—carboxylate 5 (583 mg, 1.89 mmol) in DME (30 mL) and water (5 mL) was added Pd(PPh3)4 (146 mg, 0.126 mmol) under en atmosphere, and the e was degassed with nitrogen 6 times, and then heated to 85 °C and stirred for 12 h under nitrogen atmosphere. After cooling to room temperature, the solvent was evaporated and the crude product was purified by flash chromatography g with 80 : 1 DCM/MeOH to afford the title compound as a brown solid (420 mg, 71%). MS (ESI): m/Z = 472.8 [M + H]+. tert-butyl 4-(5-carbam0yl—4—(4-phenoxyphenyl)pyrimidinyl)piperidine—l-carboxylate (7).

To a solution of tert—butyl 4-(5-carbamoyl-4—(4-phenoxyphenyl)pyrimidin-2—yl)—5,6— dihydropyridine-1(2H)- carboxylate 6 (100 mg, 0.212 mmol) in ethyl e (5 mL) was added Pd/C (20 mg) under hydrogen atmosphere, and the mixture was degassed with hydrogen 6 times, then stirred for 16 h at ambient temperature under hydrogen atmosphere. The solution was d and the filtrate was evaporated to the crude product as brown solid (96 mg). MS (ESI): m/Z = 474.8 [M+H]+. 4-(4-phen0xyphenyl)(piperidinyl)pyrimidinecarb0xamide (8). To a solution of tert- butyl 4-(5-carbamoyl—4-(4-phenoxyphenyl)pyrimidinyl) piperidine-l-carboxylate 7 (96 mg, crude) in dry romethane (2 mL) was added TFA (2 mL), and the resulting mixture was stirred for 1 h at ambient temperature. The t was removed and the residue was partitioned between saturated aqueous sodium bicarbonate (30 mL) and ethyl acetate (20 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The crude residue was d by flash chromatography, g with 5 : l DCM/MeOH to afford the title compound as a white solid (70 mg, 88% for two steps). MS (ESI): m/z = 374.9 [M+H]+.

Example 21 2-(1-acryloylpiperidinyl)—4-(4-phenoxyphenyl)pyrimidinecarb0xamide N \ O O"I / W" O To a solution of 4-(4-phenoxyphenyl)(piperidin-4—yl)pyrimidinecarboxamide 8 (70 mg, 0.187 mmol) in DCM (3 mL) was added TEA (56.7 mg, 0.56 mmol) and acryloyl chloride (25.3 mg, 0.28 mmol) at 0°C. The mixture was stirred at 0°C for 10 min. The solvent was removed and the residue was purified by Prep-TLC eluting with 25 : 1 DCM/MeOH to afford the title compound (50 mg, 63%) as light yellow solid. 1H NMR (400 MHz, CDCl3) 5 8.95 (s, 1H), 7.82 (d, J= 8.8 Hz, 2H), 7.49—7.36 (m, 2H), 7.27—7.17 (m, 1H), 7.16—7.04 (m, 4H), 6.64 (dd, J: 16.8, 10.6 Hz, 1H), 6.29 = 16.8, 1.9 Hz, 1H), 5.94 (s, 1H), 5.77 (s, 1H), 5.71 (dd,.]= 10.6, 1.9 Hz, 1H), 4.76 (d, J: 12.5 Hz, 1H), 4.14 (d, J: 14.1 Hz, 1H), 3.37—3.19 (m, 2H), 2.89 (t, J: 11.5 Hz, 1H), 2.16 (d, J= 11.0 Hz, 2H), 1.97 (d, J= 9.9 Hz, 2H). MS (ESI, method F): m/z = 428.8 [M + H]+, tR=1.407 min., HPLC: 99.8% (214nm), 99.6% (254nm).

Scheme 11 OTf 0335:? 3% NH2 fig PhN(CF3802)2 / >§(N:I)NI\N,O N| \ NH2 CF3COOH CI OXN/ N 0 DCMrch Niko—HODCMO°C1h\O [’3/ o 7 Example 22 1-(tert-but0xycarbonyl)—2,5-dihydro-1H-pyrrol—3-yl trifluoromethanesulfonate (2). To a solution of tert—butyl 3-oxopyrrolidinecarboxylate 1 (5.0 g, 27.0 mmol) in tetrahydrofuran (130 mL) in a three-necked flask was added m diisopropylamide (2.0M, 16.2 mL, 32.4 mmol) at -78 °C. After stirring for 2 h at -78 °C, a solution of trifluoro-N-phenyl-N— (trifluoromethylsulfonyl) methanesulfonamide (10.1 g, 28.4 mmol) in ydrofiiran (20 mL) was added, and the solution was stirred for another 30 min at this temperature, then warmed to room temperature and stirred for 3 h. Water (30 mL) was added to quench the reaction, and the solution was extracted with ethyl acetate (3 X 200 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography, eluting with petroleum ether to afford the title compound as a brown oil (4.2 g, 49%).MS (ESI): m/z = 318.1 [M + H]+. tert-butyl-(4,4,5,5-tetramethyl—1,3,2-dioxabor01anyl)-2H-pyrrole-1(5H)-carb0xylate (3).

To a solution of nacolato)diborone (4.0 g, 15.9 mmol), KOAc (2.59 g, 26.4 mmol) and 1- (tert—butoxycarbonyl)—2,5-dihydro-1H—pyrrolyl trifluoromethanesulfonate 2 (4.2 g, 13.2 mmol) in dry oxane (10 mL) was added Pd(dppf)C12 (965 mg, 1.32 mmol) under en atmosphere, and the mixture was degassed with nitrogen 6 times, then heated to 85 OC and stirred ght under nitrogen here. After cooling to room temperature, the solvent was evaporated and the crude product was purified by silica gel column chromatography, eluting from 100 : 1 to 20 : 1 petroleum ether/ethyl acetate to afford the title compound as brown oil (1.2 g, 31%). MS (ESI): m/Z = 296.1 [M + H. tert-butyl(5-carbamoyl-4—(4-phenoxyphenyl)pyrimidinyl)-2H-pyrrole—1(5H)— carboxylate (5). To a solution of tert—butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)—2H— pyrrole-1(5H)- carboxylate 3 (136 mg, 0.46 mmol), K2C03 (127 mg, 0.92 mmol) and 2-chloro (4-phenoxyphenyl)pyrimidinecarboxamide 4 (100 mg, 0.31 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was added 3)4 (35.5 mg, 0.031 mmol) under nitrogen here. The mixture was degassed with en 6 times, then heated to 90 CC and stirred for 12 h under en atmosphere. After cooling to room temperature, the solvent was evaporated and the crude product was purified by flash chromatography eluting with 70 : 1 DCM/MeOH to afford the title nd as a white solid (90 mg, 64%). MS (ESI): m/Z = 458.8 [M + H]+. tert-butyl(5-carbamoyl-4—(4-phenoxyphenyl)pyrimidinyl)pyrrolidine—l-carboxylate (6). To a solution of tert-butyl 3-(5-carbamoyl(4-phenoxyphenyl)pyrimidinyl)-2H-pyrrole- 1(5H) -carboxy1ate 5 (90 mg, 0.20 mmol) in ethyl acetate (3 mL) and MeOH (3 mL) was added Pd/C (20 mg) under hydrogen here, and the e was degassed with hydrogen 6 times, then stirred for 16 h at ambient temperature under hydrogen atmosphere. The solution was filtered and the filtrate was evaporated to the crude product as brown solid (80 mg, 88%). MS (ESI): m/Z = 461.1 [M+H]+. 4-(4-phenoxyphenyl)—2-(pyrrolidinyl)pyrimidine—S-carboxamide (7). To a solution of tert- butyl 3-(5 -carbamoyl(4-phenoxyphenyl)pyrimidinyl)pyrrolidine-l- carboxylate 6 (80 mg, 0.174 mmol) in dry dichloromethane (2 mL) was added TFA (2 mL), and the resulting mixture was stirred for 1 h at ambient temperature. The solvent was removed and the residue was partitioned between saturated aqueous sodium bicarbonate (30 mL) and ethyl acetate (20 mL).

The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound as a white solid (70 mg, . MS (ESI): m/z = 360.8 [M+H]+.

Example 22 2-(1-acryloylpyrrolidinyl)(4-phenoxyphenyl)pyrimidine—5-carb0xamide To a solution of 4-(4-phenoxyphenyl)(pyrrolidinyl)pyrimidinecarboxamide 7 (70 mg, crude) in DCM (5 mL) was added TBA (59 mg, 0.58 mmol) and acryloyl chloride (26 mg, 0.29 mmol) at 0°C. The mixture was stirred at 0°C for 10 min. The solvent was removed and the residue was purified by Prep-TLC eluting with 25 : 1 DCM/MeOH to afford the title compound (20 mg, 25%) as a white solid. 1H NMR (400 MHZ, CDClg) 5 8.95 (d, J: 6.2 Hz, 1H), 7.82 (d, J = 6.6 Hz, 2H), 7.42 (t, J: 7.8 Hz, 2H), 7.22 (t, J: 7.4 Hz, 1H), 7.10 (t, J: 7.9 Hz, 4H), 6.55— 6.47 (m, 1H), 6.39 (d,J= 16.8, Hz, 1H), 5.84 (s, 2H), 5.71 (d, J: 10.1 Hz, 1H), 4.14—3.96 (m, 2H), 3.94—3.78 (m, 2H), .62 (m, 1H), .36 (m, 2H). MS (ESI, method F): m/z = 414.8 [M + H]+, tR=1.382 min, HPLC: 99.0% (214nm), 98.4% (254nm).

Scheme 12 3’0 Pd(PPh3)4. \ 0 | K2003 / —> + / CI N N Q DME-HZO (8/1 V) \ 85 Oc, 16 h Boo o 1 2 \ NH \ ""2 2 Pd/C, H2 | CFscOOH I —> N —> N tOAc. rt, overnight DCM, rt, 2 h HN 0 N O , 0 4 5 d \ NH2 CI l —’ N DCM,O°C, 10 min N O / 0 Example 23 tert-butyl—3-(5-carbamoyl(4-phen0xyphenyl)pyridinyl)—2H—pyrrole-1(5H)-carb0xylate (3). To a solution of tert—butyl 3—(4,4,5,5-tetramethyl—1,3,2-dioxaborolanyl)—2H—pyrrole- 1(5H)—carboxylate 1 (136 mg, 0.0.46 mmol), K2C03 (127.5 mg, 0.92 mmol) and 6-chloro(4- phenoxyphenyl) nicotinamide 2 (100 mg, 0.31 mmol) in 1,2-dimethoxyethane (5 mL) and water (1 mL) was added Pd(PPh3)4 (35.6 mg, 0.031 mmol) under nitrogen here, and the mixture was degassed with nitrogen 6 times, then heated to 85 °C and stirred for 12 h under nitrogen atmosphere. After g to room temperature, the solvent was evaporated and the crude product was purified by flash chromatography, eluting with 50 : 1 DCM/MeOH to afford the title compound as a white solid (84 mg, 60%). MS (ESI): m/z = 458.1 [M+H]+. tert-butyl 3-(5-carbamoyl(4-phenoxyphenyl)pyridin-Z-yl)pyrrolidine-l-carboxylate (4).

To a solution of tert—butyl 3-(5-carbamoyl(4-phenoxyphenyl)pyridinyl)—2H—pyrrole-1(5H)- carboxylate 3 (84 mg, 0.18 mmol) in ethyl acetate (5 mL) and MeOH (5 mL) was added Pd/C (40 mg) under en atmosphere, and the mixture was ed with hydrogen 6 times, then stirred for 12 h at ambient temperature under hydrogen atmosphere. The solution was filtered and the filtrate was evaporated to the crude product as brown solid (80 mg, 95%). MS (ESI): m/z = 459.8 [M+H]+. 2-(4-phenoxyphenyl)—6-(pyrrolidinyl)pyridinecarb0xamide (5). To a on of tert- butyl 3-(5 -carbamoyl(4-phenoxyphenyl)pyridinyl)pyrrolidinecarboxylate 4 (80 mg, 0.17 mmol) in dry dichloromethane (2 mL) was added TFA (2 mL), and the resulting e was stirred for 1 h at ambient temperature. The solvent was removed and the residue was partitioned between saturated aqueous sodium bicarbonate (30 mL) and ethyl acetate (20 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound as a white solid (70 mg, crude). MS (ESI): m/z = 359.9 [M+H]+.

Example 23 6-(1-acryloylpyrrolidinyl)—2-(4-phenoxyphenyl)pyridine—3-carboxamide To a solution of 2-(4-phenoxyphenyl)(pyrrolidinyl)pyridine-3—carboxamide 5 (70 mg, crude) in DCM (5 mL) was added TBA (59 mg, 0.58 mmol) and acryloyl chloride (26.4 mg, 0.29 mmol) at 0 OC. The e was stirred at 0 °C for 10 min. The solvent was removed and the residue was d by Prep-TLC eluting with 25 : l DCM/MeOH to afford the title compound (18 mg, 25% for two steps) as white solid. 1H NMR (400 MHz, CDC13) 8 8.06 (s, 1H), 7.72 (s, 2H), 7.41 (t, J: 7.8 Hz, 2H), 7.28—7.24 (m, 1H), 7.19 (t, J: 7.4 Hz, 1H), 7.11—7.09 (m, 4H), 6.55—6.47 (m, 1H), 6.41 (d,J= 16.8, Hz, 1H), 5.71 (d,J= 10.1 Hz, 1H), 5.65 (br, 1H), 5.45 (br, 1H), 4.14—3.96 (m, 1H), .78 (m, 2H), 3.76—3.62 (m, 2H), 2.55—2.36 (m, 2H). MS (ESI, method F): m/z = 413.8 [M + H]+, tR=1.393 min, HPLC: 97.3% (214nm), 99.5% (254nm).

Scheme 13 0% O \ o CN ' Va" Boc’N 100 0C’ 3 h o HN o/O DCM, 0 DC, 10 min 1 2 Ar"%l/" 0Q Example 24 2-(4-phen0xyphenyl)—6-(piperidinyl)pyridinecarbonitrile (2). A solution of tert—butyl 4- (5 -carbamoyl(4-phenoxyphenyl)pyrimidinyl)piperidinecarboxylate (100 mg, 0.21 mmol) in POCl3 (3 mL) was heated to 100 °C and stirred for 3 h. After cooling to room temperature, the reaction mixture was poured into water (3 mL), and basified by saturate aqueous NaHC03 to PH=10. Then the on was extracted with ethyl acetate (3 X 60 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude residue was purified by preparative TLC eluting with 8 : 1 DCM/MeOH to afford the title compound as brown oil (10 mg, 13%). MS (ESI): m/z = 356.1 [M + H]+.

Example 24 6-(1-acryloylpiperidinyl)—2-(4-phen0xyphenyl)pyridinecarb0nitrile Ar"0%l/N 0 To a solution of 2-(4-phenoxyphenyl)(piperidinyl)pyridinecarbonitrile 2 (10 mg, 0.028 mmol) in DCM (2 mL) was added TEA (8.5 mg, 0.084 mmol) and acryloyl chloride (3.8 mg, 0.042 mmol) at 0 oC. The mixture was stirred at 0 0C for 10 min. The solvent was removed and the e was purified by Prep-TLC eluting with 25 : 1 OH to afford the title compound (13 mg, 44%) as white solid. 1H NMR (400 MHz, CDCl3) 5 8.01 (d, J = 8.1 Hz, 1H), 7.97 (dd, J: 92,23 Hz, 2H), 7.41 (t, J: 7.9 Hz, 2H), 7.24—7.17 (m, 2H), 7.16—7.09 (m, 4H), 6.64 (dd, .1: 16.8, 10.6 Hz, 1H), 6.32 (dd, .1: 16.8, 1.8 Hz, 1H), 5.73 (dd, J: 10.6, 1.9 Hz, 1H), 4.85—4.79 (m, lH),4.21—4.16(m, 1H),3.25—4.18(m, 1H), 3.12 (tt,J= 12.0, 3.8 Hz, 1H), 2.84— 2.78 (m, 1H), 2.09—2.06 (m, 2H), 1.93—1.82 (m, 2H). MS (ESI, method F): m/Z = 409.8 [M + Hr, tR=1.669 min, HPLC: 98.7% ), 98.8% (254nm).

Scheme 14 WE] \ H? K2003 | "Hz / 20 |\ —> N N CI / N N CI CI , p EtOH reflux 3h Boo/Nd 90°C,40mm HNQ 2 3 4 ' F’d2(dba)3, 05003 I +11 <1B\0H 1 OH HATU DIPEA 1,4-dioxaneIH20 "NJ o0+w —. o Hg 0 DMF,rt.12h 90°C, 16h | : NH2 " O Example 25 tert-butyl 4-(6-chloro—S-cyanopyridinyl)piperazine-l-carboxylate (3). To a solution of 2,6- ronicotinonitrile 1 (1.0 g, 5.78 mmol) and tert—butyl piperazine-l-carboxylate 2 (1.08 g, .78 mmol) in ethanol (20 mL) was added K2C03 (636 mg, 6.0 mmol). The resulting solution was d for 3 h. After cooling to room temperature, the solvent was evaporated and the crude product was purified by flash chromatography eluting from 5:1 to 2:1 PE/EA to afford the title compound as a white solid (800 mg, 43%). MS (ESI): m/z = 345.1 [M + Na]+. 6-chlor0(4—phenoxyphenyl)nicotinamide (4). To tert—butyl-(6-chlorocyanopyridin yl)piper azine-l-carboxylate 3(800 mg, 2.5 mmol) was added conc. H2S04 (5 mL) and water (1 mL). The mixture was heated to 90°C and stirred for 40 min. After cooling to room temperature, the on was poured into ice-cold water, then adjusted to PH = 8 by ammonia water. The precipitate was filtered, washed with water (20 mL) and dried under vacuum to afford the title compound as an off-white solid (580 mg, 96%). MS (ESI): m/z = 241.1 [M + H]+. 2-(4-phen0xyphenyl)—6-(piperazinyl)nic0tinamide (6). To a solution of 6-chloro(4- phenoxyphenyl)nicotinamide 4 (580 mg, 2.41 mmol), Cs2C03 (2.35 g, 7.23 mmol) and 4— phenoxyphenylboronic acid 5 (619 mg, 2.89 mmol) in l,4-dioxane (15 mL) and water (3 mL) was added Pd2(dba)3 (220 mg, 0.24 mmol) under nitrogen atmosphere, and the mixture was degassed with en 6 times, then heated to 90 °C and stirred for 12 h under nitrogen atmosphere. After g to room temperature, the solvent was ated and the crude product was purified by flash chromatography eluting with 10:1 DCM/MeOH to afford the title compound as a white solid (480 mg, 52%). MS (ESI): m/z = 375.1 [M + H]+.

Example 25 (E)—6-(4-(4-(dimethylamino)but—2-enoyl)piperazinyl)(4-phen0xyphenyl)nic0tinamide \NWO%O©| : NH2 A mixture of 2-(4-phenoxyphenyl)(piperazinyl)nicotinamide 6 (100 mg, 0.27 mmol), (E)- 4-(dimethylamino)but—2-enoic acid hydrochloride 7 (53 mg, 0.32 mmol), HATU (152 mg, 0.4 mmol), and DIPEA (172.5 mg, 1.34 mmol) in DMF (10 mL) was stirred at rt for 12 h. The solution was poured into water (50 mL), and then extracted with ethyl acetate (3 X 50 mL). The combined organic layers were dried over anhydrous sodium e, filtered and concentrated.

The residue was purified by Prep-TLC eluting with 10:1 DCM/MeOH to afford the title compound (30 mg, 23%) as a white solid. 1H NMR (400 MHz, MeOD) 8 7.78 (d, J = 8.7 Hz, 1H), 7.69 (d, J: 8.6 Hz, 2H), 7.40 (t, J: 7.9 Hz, 2H), 7.17 (d, J: 7.4 Hz, 1H), 7.04 (dd, J: .3, 8.3 Hz, 4H), 6.93 (d, J: 15.3 Hz, 1H), 6.82 (d, J: 8.7 Hz, 1H), 6.77 (m, 1H), 3.89—3.68 (m, 10H), 2.76 (s, 6H). MS (ESI, method F): m/z = 485.9 [M + H]+, tR=1.249 min, HPLC: 93.3% (214nm), 93.0% (254nm).

Scheme 15 \ EHH Pd(dppf)C|2 K2003 (\N N Cl 1 4--dioxane/HZO Boc’N Boc’N 110°C 12h con.HC|, sealed tube IN/ EtN, CH Cl 5h HNQ OHOQ 3 2 2’ min HCI 4 Example 26 2-(4-phen0xyphenyl)—6-(piperazinyl)nic0tinamide (3). To a solution of tert—butyl 4-(6— chlorocyanopyridinyl)piperazinecarboxylate 1 (300 mg, 0.93 mmol), K2C03 (385 mg, 2.79 mmol) and 4-phenoxyphenylboronic acid 2 (297 mg, 1.39 mmol) in oxane (12 mL) and water (2 mL) was added Pd(dppf)Clz (68 mg, 0.093 mmol) under nitrogen atmosphere. The mixture was degassed with nitrogen 6 times, then heated to 90 CC and stirred for 12 h under nitrogen atmosphere. After cooling to room temperature, the solvent was evaporated and the crude product was purified by flash chromatography eluting with 20:1 OH to afford the title compound as a white solid (260 mg, 58%). MS (ESI): m/z = 457.1 [M + H]+. 2-(4-phenoxyphenyl)—6-(piperazin-l-yl)nicotinic acid hydrochloride (4). In a 20 mL sealed tube, was placed a solution of henoxyphenyl)(piperazinyl)nicotinamide 3 (140 mg, 0.31 mmol) in come. HCl (5 mL). The mixture was heated to 115 °C and stirred for 4 h. After cooling to room temperature, the solution was concentrated under vacuum to afford the title compound as an off—white solid (120 mg, 95%). MS (ESI): m/z = 376.1 [M + H]+.

Example 26 6-(4-acryloylpiperazinyl)(4-phenoxyphenyl)pyridine—3-carb0xylic acid To a solution of 2-(4—phenoxyphenyl)(piperazinyl)nicotinic acid hydrochloride 4 (120 mg, 0.32 mmol) in DCM (5 mL) was added TEA (162 mg, 1.6 mmol) and acryloyl chloride (35 mg, 0.38 mmol) at 0°C. The mixture was d at 0 0C for 10 minutes. The solvent was removed and the residue was purified by Prep-TLC eluting with 20:1 DCM/MeOH to afford the title compound (15 mg, 11%) as a white solid. 1H NMR (400 MHz, CDClg) 8 8.17 (d, J= 8.9 Hz, 1H), 7.55 (d, J: 8.3 Hz, 2H), 7.38 (t, J: 7.7 Hz, 2H), 7.16 (t, J: 7.4 Hz, 1H), 7.11 (d, J: 8.0 Hz, 2H), 7.03 (d, J: 8.3 Hz, 2H), 6.65—6.55(m, 2H), 6.38 (d, J: 16.7 Hz, 1H), 5.78 (d, J: 10.6 Hz, 1H), 3.86—375 (m, 8H). MS (ESI, method F): m/z = 429.8 [M + H]+, tR=1.477 min., HPLC: 93.5% (214nm), 93.0% (254nm).

Scheme 16 OH H o K2003 DMF f)C|2 KOAc + 1150c:N/O:OBDMFreflux ,o 1 2 4 O O \ NH2 \ | | NH2 Pd2(dba)3, CSZCO3 N N/ pN N/ dioxane/HZO, 120°C p Et3N CHZCIQO0°C HN O N 06% /\n,01 /j (\N N’ 01 HNd 5 Example 27 4-(4-bromophenoxy)benzonitrile (3). The mixture of 4-bromophenol 1 (0.50 g, 2.9 mmol), 4- fluorobenzonitrile 2 (0.28 g, 2.31 mmol), K2C03 (0.80 g, 5.8 mmol) and DMF (4 mL) was d at 115 °C for 16 h. After cooled to It, the mixture was concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 100:] petroleum ether/EtOAc to afford the title compound (0.59 g, 74%) as white solid. 1H NMR (400 MHZ, DMSO-d6) 8 7.86 (d, J = 8.7 Hz, 2H), 7.64 (d, J: 6.0 Hz, 2H), 7.13 (dd, J: 5.1, 4.7 Hz, 4H). 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenoxy)benzonitrile (4). The mixture of romophenoxy)benzonitrile 3 (0.59 g, 2.15 mmol), bispinacolato diboron (1.09 g, 4.3 mmol), KOAc (0.63 g, 6.45 mmol), Pd(dppf)Clz (0.157 g, 0.215 mmol) and DMF (3.5 mL) was ed with N2 6 times and then stirred under reflux for 16 h. After cooled to rt, the mixture was concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 50:1 petroleum ether/EtOAc to afford the title compound (0.55 g, 79%) as white solid. 2-(4-(4-cyan0phenoxy)phenyl)—6-(piperazinyl)nic0tinamide (6). The title compound was obtained using a procedure analogous to the procedure described in 2-(4- (hydroxy(phenyl)methyl)phenyl)(piperidin—4-yl)nicotinamide (see Scheme 48) as yellow solid (0.15 g, 37%). MS (ESI): m/z = 400.1 [M + H.

Example 27 6-(4-acryloylpiperazinyl)—2-(4-(4-cyanophenoxy)phenyl)nicotinamide The title compound was obtained using a procedure analogous to the procedure described in Example 1 as white solid (40 mg, 23%). 1H NMR (400 MHz, DMSO—d6) 8 7.88 (d, J = 8.7 Hz, 2H), 7.73 (d, J: 8.6 Hz, 2H), 7.68 (d, J: 8.7 Hz, 1H), 7.59 (s, 1H), 7.26 (s, 1H), 7.21—7.14 (m, 4H), 6.86 (dd, J= 17.8, 9.3 Hz, 2H), 6.16 (dd, J= 16.7, 2.2 Hz, 1H), 5.73 (dd, J= 10.4, 2.2 Hz, 1H), 3.66—3.67 (m, 8H). MS (ESI, method A): m/z = 454.1 [M + H]+, tR=1.685 (min). HPLC: 97.1% (214nm), 99.7% (254nm).

Scheme 17 I O OH 10-phenanthroline Pd(dppf)C[2 KOAc ngco3 toluene 1200c DMF reflux + 8’0 1 2 4 O O \ \ Ed2(dba)3,ngcog I NH2 I NH2 E N CH Cl 000 / dloxane/H20,120 0C (\N N t3, 2 2. (\N N 0 HNd O O Nd rr" Arc} 0 0 / (‘N N’c 6 e 28 1-br0mo(cyclohexyloxy)benzene (3). The mixture of 1-bromo-4—iodobenzene l (2.83 g, 10 mmol), cyclohexanol 2 (5.0 g, 50 mmol), CuI (0.381 g, 2.0 mmol), 1,10-phenanthroline (0.793 g, 4.0 mmol), CS2C03 (8.15 g, 25 mmol) and toluene (5 mL) was stirred at 120 °C in a sealed tube under N2 for 16 h. After cooled to rt, the mixture was filtered over celite. The filtrate was dried over NazSO4, concentrated in vacuo and purified by silica gel chromatography eluting with 20:1 petroleum ether/EtOAc to afford the title compound (1.17 g, 46%) as colorless oil. 1H NMR (400 MHz, CDC13) 5 7.40—7.33 (m, 2H), 6.83—6.77 (m, 2H), 4.26—4.16 (m, 1H), .92 (m, 2H), .75 (m, 2H), 1.65—1.47 (m, 3H), 1.45—1.25 (m, 3H). 2-(4-(cyclohexyloxy)phenyl)—4,4,5,5—tetramethyl-1,3,2-di0xab0rolane (4). The title compound was obtained using a procedure ous to the procedure described in 4-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)phenoxy)benzonitrile (see Scheme 16) as brown oil (1.04 g, 75%). 1H NMR (400 MHz, CDClg) 6 7.75 (d, J: 8.5 Hz, 2H), 6.91 (d, J: 8.5 Hz, 2H), 4.40— 4.25 (m, 1H), 2.09—1.94 (m, 2H), 1.89—1.76 (m, 2H), 1.66—1.49 (m, 4H), 1.48—1.23 (m, 14H). cyclohexyloxy)phenyl)(piperazinyl)nicotinamide (6). The title compound was obtained using a procedure analogous to the procedure described in 6-(3 -nitrophenyl)(4- phenoxyphenyl)nicotinamide (see Scheme 1) as brown gum (0.157 g, 41%). MS (ESI): m/z = 381.1 [M + H.

Example 28 6-(4-acryloylpiperazinyl)(4-(cyclohexyloxy)phenyl)nicotinamide The title compound was obtained using a procedure analogous to the procedure described in e 1 as white solid (61 mg, 34%). 1H NMR(400 MHZ, CD30D) 5 7.76 (d, J = 8.7 HZ, 1H), 7.63 (d, J= 8.7 Hz, 2H), 6.96 (d, J: 8.7 Hz, 2H), 6.87—6.76 (m, 2H), 6.27 (dd, J: 16.8, 1.8 Hz, 1H), 5.80 (dd, J: 10.6, 1.8 Hz, 1H), 4.43—4.35 (m, 1H), 3.79—3.75 (m, 8H), 2.07—1.96 (m, 2H), 1.89—1.78 (m, 2H), .34 (m, 6H). MS (ESI, method A): m/z = 435.2 [M + H]+, tR=1.800 (min). HPLC: 98.2% (214nm), 98.5% (254nm).

Scheme 18 NNHZ Pd2(()3dba,C52003 ()ZHO28\©/\O\ dioxane/HZO 120°C \ NH2 + I HO / p / O N N CI \ Et3N, CHZCIZ, o 00 | / O\ MCI O O 0 Z Example 29 2-(3-methoxy—4-methylphenyl)—6-(piperazinyl)nicotinamide (3). The title compound was obtained using a ure analogous to the procedure described in 2-(4- (hydroxy(phenyl)methyl)phenyl)(piperidinyl)nicotinamide (see Scheme 48) as brown solid (0.238 g, 58%). MS (ESI): m/z = 327.1 [M + H.

Example 29 6-(4-acryloylpiperazinyl)—2-(3-meth0xy—4-methylphenyl)nicotinamide The title compound was obtained using a procedure analogous to the procedure described in e 1 as white solid (115 mg, 43%). 1H NMR (400 MHZ, CDC13) 5 7.77 (d, J: 8.7 HZ, 1H), 7.23 (s, 1H), 7.21—7.15 (m, 2H), 6.88—6.78 (m, 2H), 6.26 (dd, J: 16.8, 1.9 Hz, 1H), 5.80 (dd, J: 10.6, 1.9 Hz, 1H), 3.88 (s, 3H), 3.75—3.78 (m, 8H), 2.24 (s, 3H).MS (ESI, method A): m/z = 381.1 [M + H]+, tR=l.513 (min). HPLC: 95.9% (214nm), 98.7% (254nm).

Scheme 19 Pd2(()3dba,CSZC03 | NH2 ()2H023\©[:K dioxane/HZO 120°C \ | NH2 (\N / / O N Cl (\N N \ Example 30 u0r0methoxyphenyl)—6-(piperazinyl)nic0tinamide (3). The title compound was obtained using a ure analogous to the procedure described in 6-(3 -nitrophenyl)(4- phenoxyphenyl)nicotinamide (see Scheme 1) as brown gum (0.264 g, 72%). MS (ESI): m/z = 331.1 [M + H.

Example 30 6-(4-acryloylpiperazinyl)—2-(4-flu0rometh0xyphenyl)nicotinamide The title compound was obtained using a procedure analogous to the procedure described in Example 1 as White solid (45 mg, 15%). 1H NMR (400 MHz, CDgOD) 5 7.78 (d, J: 8.7 Hz, 1H), 7.41 (dd, J: 8.3, 2.0 Hz, 1H), 7.28—7.22 (m, 1H), 7.16—7.12(m,= 1H), 6.88—6.77 (m, 2H), 6.27 (dd, J: 16.8, 1.9 Hz, 1H), 5.80 (dd, J: 10.6, 1.9 Hz, 1H), 3.93 (s, 3H), 3.87—3.71 (m, 8H).

MS (ESI, method A): m/z = 385.1 [M + H]+, tR=1.527 (min). HPLC: 99.6% (214nm), 99.7% (254nm).

Scheme 20 0H ch03 DMF d(,dppf)C|2 KOAc \ DMF reflux + | 115°C B’0 1 2 3 4 o o \ NH \ NH Pd2(dba)3,C32003 | 2 | 2 / / dioxane/H20,120°C (\N N |\ EtsN,CHzC|2,0°C (\N N l\ o HNJ N/ 0 0 We] Nd N/ O (\N N/ 01 6 e31 -br0m0phen0xypyridine (3). The title compound was obtained using a procedure analogous to the procedure described in 4—(4-bromophenoxy)benzonitrile (see Scheme 16) as yellow solid (3.85 g, 81%). 2-phenoxy—5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-Z-yl)pyridine (4). The title compound was obtained using a procedure analogous to the procedure described in 4-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaboroIanyl)phenoxy)benzonitrile (see Scheme 16) as yellow solid (0.536 g, 90%). 6'-phen0xy-6—(piperazinyl)-2,3'-bipyridine—3-carb0xamide (6). The title compound was obtained using a procedure ous to the procedure described in 6-(3 -nitrophenyl)(4- phenoxyphenyl)nicotinamide (see Scheme 1) as brown gum (0.14 g, 55%). MS (ESI): m/z = 376.1 [M + H. e 3 1 6-(4-acryloylpiperazin-l-yl)-6'-phen0xy—2,3 '-bipyridine—3-carb0xamide (\N \ 0}" | N’ 0 / G The title compound was obtained using a ure analogous to the procedure described in Example 1 as white solid (50 mg, 31%). 1H NMR (400 MHz, CDgOD) 5 8.43 (d, J: 2.4 Hz, 1H), 8.10 (dd, J: 8.6, 2.4 Hz, 1H), 7.80 (d, J: 8.7 Hz, 1H), 7.49—7.41 (m, 2H), 7.29—7.22 (m, 1H), 7.16 (d, J: 7.9 Hz, 2H), 6.97 (d, J: 8.6 Hz, 1H), .77 (m, 2H), 6.27 (dd, J: 16.8, 1.8 Hz, 1H), 5.80 (dd, J: 10.6, 1.8 Hz, 1H), 3.87—3.69 (m, 8H). MS (ESI, method A): m/Z = 430.1 [M + H]+, tR=1.620 (min). HPLC: 95.1% (214nm), 96.2% (254nm).

Scheme 21 F K2003 DMF Pd(dppf)C|2 KOAc Pd2(dba)s.052003 115 DMF reflux dioxane/HZO, 120 °C + \N DC Br {NJ/03m11'1 0% 11 4 HO N CI | NH2 (\N N/ Et3N CHZCIZ 0°C N/ 0 To \ \ 6 Example 32 2-(4-br0mophen0xy)pyridine (3). The title compound was obtained using a procedure analogous to the procedure described in 4-(4-bromophenoxy)benzonitrile (see Scheme 16) as yellow solid (2.83 g, 57%). MS (ESI): m/z = 250.1 [M + H]+. 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxab0r0]anyl)phenoxy)pyridine (4). The title compound was obtained using a procedure analogous to the procedure described in 4—(4-(4,4,5,5- ethyl-1,3,2-dioxaborolanyl)phenoxy)benzonitrile (see Scheme 16) as brown solid (0.882 g, 74%). MS (ESI): m/z = 298.1 [M + Hr. 6-(piperazinyl)(4-(pyridin-Z-yloxy)phenyl)nic0tinamide (6). The title compound was obtained using a procedure analogous to the procedure described in 2-(4- (hydroxy(phenyl)methyl)phenyl)(piperidin—4-yl)nicotinamide (see Scheme 48) as brown gum (0.198 g, 53%). MS (ESI): m/z = 376.0 [M + Hr. e 32 6-(4-acryloylpiperazinyl)—2-(4-(pyridinyloxy)phenyl)nic0tinamide |\ NH2 N N The title compound was obtained using a procedure analogous to the procedure described in Example 1 as white solid (41 mg, 18%). 1H NMR (400 MHz, CDgOD) 5 8.18 (dd, J: 5.0, 1.4 Hz, 1H), 7.86 (ddd, J: 8.4, 7.3, 2.0 Hz, 1H), 7.82—7.74 (m, 3H), 7.20—7.14(m, 3H), 7.01 (d, J: 8.3 Hz, 1H), 6.88—6.79 (m, 2H), 6.27 (dd, J: 16.8, 1.9 Hz, 1H), 5.80 (dd, J: 10.6, 1.9 Hz, 1H), 3.86—3.71 (m, 8H). MS (ESI, method A): m/z = 430.1 [M + H]+, 60 (min). HPLC: 100% (214nm), 100% (254nm).

Scheme 22 O O Pd2(dba)3, C52C03 \ NH, (HO)2B dioxaneiH20,120°C \ | NH2 H2C'2yOOC | + —> —> (\N / / N CI CI (\N N m" HNd HNd 0 1 2 3 |\ NH2 (\N N/ Oj/N\2 CI Example33 2-(4-chlor0phenyl)(piperazinyl)nic0tinamide (3). The title compound was obtained using a procedure analogous to the procedure described in hydroxy(phenyl)methyl)phenyl)—6- (piperidinyl)nicotinamide (see Scheme 48) as brown gum (0.23 g, 72%).

Example 33 6-(4-acryloylpiperazinyl)(4-chlorophenyl)nic0tinamide Oj/Q / N N The title compound was obtained using a procedure analogous to the procedure described in Example 1 as white solid (50 mg, 18%). 1H NMR (400 MHZ, CDgOD) 5 7.78 (d, J: 8.7 Hz, 1H), 7.72—7.64 (m, 2H), 7.45—7.39 (m, 2H), .76 (m, 2H), 6.27 (dd, J: 16.8, 1.9 Hz, 1H), .80 (dd, J: 10.6, 1.9 Hz, 1H), 3.87—3.69 (m, 8H). MS (ESI, method A): m/z = 371.0 [M + H]+, tR=1.645 (min). HPLC: 95.1% (214nm), 95.3% (254nm).

Scheme 23 o o o o o 00<0E02 DMF-DMA O/\ N2H4.Et0H —> —> | —> PhO NaH, toluene PhOWOA PhO N/ 1 2 3 ,R‘ ,R‘ N’N N’N TsO-RBoc orF-RNO2 ' / ‘ / LiOH, EtOH HATU, NHs. DMF a)052003 DMF 0 OH Pho O Pho or b) 052003 NMP \\ O 4 s 7 ,R ,R ,R N/N a)HC|/EtOH DOM N—N . N—N or b) Zn NH4C| EtOH I / acwlovlchlorlde I / TEA, DCM PhD 0 "Hz PhO 0 "Hz C: 9 1o . N'w w'w (7 Q r: O O Boc 30¢ Boc l|30c (1 0:1 b c e @ 3:9 M 1'4 E: (5W NH (1,, 0 (SR) HNO f0 JO f (£0 a b c d e\ f 9 h Ethyl 3-0x0(4-phen0xyphenyl)propanoate (2). To a solution of diethyl carbonate (14 g, 120 mmol) in toluene (100 mL) was added NaH (60%, 4.7 g, 12 mmol) at 0 °C, and the resulting solution was heated to 90 CC, then a solution of l-(4—phenoxyphenyl)ethanone 1 (10 g, 47 mmol) in toluene (50 mL) was added drop-wise over 30 min, and the solution was refluxed for 20 min.

After cooling to room temperature, AcOH/HZO (55 mL/275 mL) was added. Toluene was removed under vacuum, and the crude residue was diluted with water (500 mL). Then the mixture was ted with dichloromethane (4 X 800 mL). The organic layers were combined, dried over ous sodium sulfate, filtered and concentrated. The e was purified by silica gel column chromatography g with 9:1 PE/EA to get the title compound as brown oil (11.5 g, 79%). MS (ESI): m/Z = 285.0 [M + H] i Ethyl 3-(dimethylamino)—2-(4-phenoxybenzoyl)acrylate (3). A solution of ethyl 3—oxo-3—(4- phenoxyphenyl)propanoate 2 (9.6 g, 34 mmol) in DMA-DMF (100 mL) was stirred at 100 0C for 1 h. The resulting solution was concentrated in high vacuum to get the title compound (12 g, 100%) as brown thick oil. MS (ESI): m/Z = 340.1 [M + Hr.

Ethyl 3-(4-phenoxyphenyl)—1H-pyrazole—4—carboxylate (4). To a solution of ethyl 3- (dimethylamino)(4-phenoxybenzoyl)acrylate 3 (6 g, 17 mmol) in ethanol (30 mL) was added hydrazine hydrate (875 mg, 17 mmol), and the resulting solution was heated to 85 °C and stirred for 3 h. The solvent was ated and the crude residue was purified by silica gel column chromatography eluting with 4:1 PE/EA to get the title compound as brown oil (4.3 g, 78%). MS (ESI): m/Z = 309.0 [M + H.

Ethyl(1-(tert-but0xycarb0nyl)pyrrolidinyl)(4-phen0xyphenyl)—lH-pyrazole—4- carboxylate (6c). C52C03 (1.08 g, 3.3 mmol) was added to a solution of ethyl 3-(4- phenoxyphenyl)-1H-pyrazolecarboxylate 4 (500 mg, 1.6 mmol) and tert-butyl 3— (tosyloxy)pyrrolidinecarboxylate 5c (1.1 g, 3.2 mmol) in DMF (20 mL) and the resulting mixture was stirred at 100 CC for 16 h. The reaction mixture was concentrated in high vacuum and the crude e was purified by silica gel column chromatography eluting with 20:1 DCM/EA to get the title compound (780 mg, 100%) as colorless thick oil. MS (ESI): m/z = 478.1 [M + Hr.

Similar ures were used to e the following compounds: 6a, 6b, 6d, 6g, 6h. tert-butyl(4-(ethoxycarbonyl)(4-phenoxyphenyl)—1H-pyrazolyl)piperidine—1- carboxylate (6a) = 492.1 [M + H]+. , thick colorless oil, 340 mg, 36%. MS (ESI): m/z tert-butyl(4-(ethoxycarbonyl)—3-(4-phenoxyphenyl)—1H-pyrazolyl)piperidine—1- carboxylate (6b), thick oil 557 mg, 71%. MS (ESI): m/z = 492.1 [M + H]+.

Ethyl(1-(tert-butoxycarbonyl)azetidinyl)—3-(4-phen0xyphenyl)—1H—pyrazole—4- carboxylate (6d), white solid, 1.7 g, 61%. MS (ESI): m/z = 464.1 [M + H]+. hyl(1-(tert-but0xycarb0nyl)pyrrolidinyl)—3-(4-phenoxyphenyl)—1H-pyrazole—4- carboxylate (6g), colorless oil, 1.5 g, 99%. MS (ESI): m/z = 478.1 [M + H]+.

(R)—ethyl(1-(tert-but0xycarb0nyl)pyrrolidinyl)(4—phenoxyphenyl)—1H-pyrazole—4- carboxylate (6h), yellow oil, 2 g, 100%. MS (ESI): m/z = 478.1 [M + H]+.

Ethyl 1-(4-nitrophenyl)(4-phenoxyphenyl)—1H-pyrazole—4-carboxylate (6e). To a solution of ethyl henoxyphenyl)—1H—pyrazolecarboxylate 4 (300 mg, 1.0 mmol) and 1-fluoro nitrobenzene 5e (140 mg, 1.0 mmol) in 1-methylpyrrolidone (8 mL) was added cesium carbonate (950 mg, 3.0 mmol), and the resulting solution was heated to 130 oC and stirred for 3 h. After cooling to ambient temperature, the solvent was evaporated and the crude residue was purified by silica gel column tography eluting with 4:1 PE/EA to get the title compound as a yellow solid (290 mg, 68%). MS (ESI): m/Z = 430.1 [M + H]+.

Similar ures were used to prepare compound of 6f: ethyl 1-(3-nitr0phenyl)—3-(4-phenoxyphenyl)—1H-pyrazole—4-carboxylate (61), yellow solid , 290 mg, 40%. MS (ESI): m/Z = 430.1 [M + H]+. 1-(1-(tert-but0xycarb0nyl)pyrrolidinyl)(4-phenoxyphenyl)-1H-pyrazole—4—carb0xylic acid (7c). To a solution of ethyl 1-(1—(tert—butoxycarbonyl)pyrrolidin—3-yl)—3—(4- yphenyl)—1H- pyrazolecarboxylate 6c (390 mg, 0.8 mmol) in EtOH (8 mL) was added 1N LiOH/HZO (4 mL). the reaction e was stirred at 75 °C for 1 h. Then to the solution was added 1N HCl/HgO to pH = 4—5, concentrated to give title compound (690 mg, crude) as white solid contented LiCl salt. MS (ESI): m/z = 450.1 [M + H]+. r procedures were used to prepare the following compounds: 7a, 7b, 7d, 7e, 7f, 7g, 7h. 1-(1-(tert—butoxycarb0nyl)piperidinyl)—3-(4-phen0xyphenyl)—lH—pyrazolecarb0xylic acid (7a), white solid, 310 mg, 100%. MS (ESI): m/z = 464.1 [M + H]+. 1-(1-(tert—butoxycarb0nyl)piperidinyl)—3-(4-phen0xyphenyl)—1H-pyrazolecarb0xylic acid (7b), yellow solid, 525 mg, 99%. MS (ESI): m/z = 464.1 [M + H]+. 1-(1-(tert—butoxycarbonyl)azetidinyl)—3-(4-phenoxyphenyl)—1H-pyrazole—4-carb0xylic acid (7d), yellow solid, 300 mg, 80%. MS (ESI): m/Z = 436.1 [M + Hr. 1-(4-nitr0phenyl)—3-(4-phen0xyphenyl)—1H-pyrazole—4-carb0xylic acid (7e), white solid, 280 mg, 99%. MS (ESI): m/z = 402.1 [M + Hr. 1-(3-nitr0phenyl)—3-(4-phe0nxyphenyl)—1H-pyrazole—4-carb0xylic acid (71), yellow oil, 260 mg, 100%. MS (ESI): m/Z = 402.1 [M + H]+.

(S)(1-(tert—butoxycarbonyl)pyrrolidinyl)(4-phen0xyphenyl)—lH-pyrazole carboxylic acid (7g) = 450.1 [M + H]+. , yellow foam, 1.2 g, 99%. MS (ESI): m/z (R)(1-(tert—butoxycarbonyl)pyrrolidinyl)—3-(4-phen0xyphenyl)—1H-pyrazole carboxylic acid (7h), yellow oil, 1.2 g, 99%. MS (ESI): m/z = 450.1 [M + H]+.

Tert-butyl(4-carbamoyl(4-phenoxyphenyl)—lH-pyrazolyl)pyrrolidine-l-carboxylate (80). To a solution of 1-(1-(tert-butoxycarbonyl)pyrrolidinyl)—3-(4-phenoxyphenyl)-1H- pyrazole carboxylic acid 7c (630 mg, crude, 0.67 mmol) in DMF (20 mL) was added HATU (510 mg, 1.33 mmol) and stirred at rt for 30 minutes, the ing solution was bubbled with NH3 gas for 10 minutes. After stirring at rt for 1 h, the solution was concentrated in high vacuum and the crude residue was diluted with DCM (50 mL), washed with water (3 X 20 mL), dried over , concentrated to give a residue which was purified by silica gel column chromatography eluting with 100:1 DCM/MeOH to get the title compound (120 mg, 33%) as colorless foam. MS (ESI): m/z = 471.2 [M + Na]+.

Similar procedures were used to e the following compounds: 8a, 8b, 8d, 8e, 8f, 8g, 8h tert-butyl(4-carbamoyl(4-phen0xyphenyl)-1H-pyrazol-l-yl)piperidine-l-carboxylate (83), colorless oil, 310 mg, 100%. MS (ESI): m/z = 463.1 [M + H]+. tert-butyl(4-carbamoyl(4-phen0xyphenyl)-1H-pyrazol-l-yl)piperidine-l-carboxylate (8b), yellow solid, 320 mg, 63%. MS (ESI): m/Z = 463.1 [M + Hr. tert-butyl(4-carbam0yl(4-phenoxyphenyl)—1H-pyrazolyl)azetidine-l-carboxylate (8d), yellow solid, 300 mg, 99%. MS (ESI): m/Z = 435.1 [M + H]+. 1-(4-nitrophenyl)—3-(4-phenoxyphenyl)—1H-pyrazolecarb0xamide (8e), yellow solid, 230 mg, 99%. MS (ESI): m/Z = 401.1 [M + Hr. 1-(3-nitrophenyl)—3-(4-phenoxyphenyl)—1H-pyrazolecarb0xamide (81), yellow solid, 260 mg, 100%. MS (ESI): m/Z = 401.0 [M + H]+.

(S)—tert—butyl(4-carbam0yl(4-phenoxyphenyl)—1H-pyrazolyl)pyrrolidine carboxylate (8g), white solid, 1.2 g, 100%. MS (ESI): m/z = 449.0 [M + H]+.

(R)-tert-butyl(4-carbamoyl(4-phen0xyphenyl)—lH-pyrazolyl)pyrrolidine-l- carboxylate (8h), white solid, 960 mg, 80%. MS (ESI): m/z = 449.0 [M + H]+. 3-(4-phenoxyphenyl)(pyrrolidinyl)-1H-pyrazolecarboxamide. To a on of tert- butyl 3 -(4-carbamoyl(4-phenoxyphenyl)-1H-pyrazolyl)pyrrolidinecarboxylate 80 (120 mg, 0.27 mmol) in DCM (10 mL) was added 6 N HCl/EtOH (5 mL, 30 mmol), stirred at rt for 1h, the ing solution was concentrated in high vacuum and the crude residue was purified by Prep-HPLC to give title compound (86 mg, 91%) as white solid. 1H NMR (400 MHZ, CDgOD): 5 8.20 (s, 1H), 7.75 (d, J: 8.6 Hz, 2H), 7.43—7.36 (m, 2H), 7.20—7.13 (m, 1H), 7.08—7.00 (m, 4H), .32—5.27 (m, 1H), 3.87—3.72 (m, 3H), 3.59—3.50 (m, 1H), .56 (m, 1H), 2.52—2.43 (m, 1H). MS (ESI, Method A): m/z = 349.1 [M + H]+, tR= 1.242 min. HPLC: 99.3% (214nm), 99.5% (254nm).

Similar procedures were used to prepare the following compounds: 9a, 9b, 9d, 9g, 9e, and 9f. 3-(4-phen0xyphenyl)—1-(piperidinyl)—1H—pyrazolecarboxamide (921), white solid, 240 mg, 99%. 1H NMR (400 MHz, CD30D): 8 8.23 (s, 1H), 7.73 (d, J: 8.6 Hz, 2H), 7.48—7.31 (m, 2H), 7.21—7.12 (m, 1H), 7.12—6.97 (m, 4H), .65 (m, 1H), 3.74—3.57 (m, 2H), 3.43—3.36 (m, 1H), 3.28—3.15 (m, 1H), 2.39—2.02 (m, 3H), 2.01—1.84 (m, 1H). MS (ESI, Method A): m/Z = 363.2 [M + H]+, tR= 1.255 min. HPLC: 100% (214nm), 100% (254nm). 3-(4-phen0xyphenyl)—1-(piperidin-4—yl)—1H—pyrazolecarboxamide (9b), light yellow solid, 3.1 mg, 40%. 1H NMR (300 MHz, CD30D)I 5 8.18 (s, 1H), 7.67 (d, J: 8.7 Hz, 2H), 7.43—7.31 (m, 2H), 7.19—7.09 (m, 1H), 7.07—6.95 (m, 4H), .55 (m, 1H), 3.64—3.54 (m, 2H), 3.29— 3.17(m, 2H), 2.42—2.23 (m, 4H). MS (ESI, Method A): m/z = 363.0 [M + H]+, tR= 1.288 min.

HPLC: 100% (214nm), 100% (254nm). 1-(azetidinyl)—3-(4—phenoxyphenyl)—1H-pyrazolecarboxamide (Example 14) (9d), yellow solid, 300 mg, 100%. 1H NMR (300 MHz, CD30D)I 8 8.20—8.14 (m, 1H), 7.82—7.66 (m, 2H), 7.44—7.30 (m, 2H), .11(m, 1H), 7.07—6.96 (m, 4H), 5.52—5.40 (m, 1H), 4.64—4.55 (m, 4H). MS (ESI, Method A): m/Z = 335.1 [M + H]+, tR= l.235-l.255 min. HPLC: 100% (214nm), 100% (254nm).

(S)—3-(4-phenoxyphenyl)—1-(pyrrolidinyl)—1H-pyrazole—4-carboxamide (9g), white solid, 90 mg, 83%. 1H NMR (400 MHz, I 6 8.25 (s, 1H), 7.80—7.68 (m, 2H), 7.45—7.33 (m, 2H), 7.20—7.11 (m, 1H), 7.11—6.98 (m, 4H), 5.38—5.25 (m, 1H), 3.88—3.69 (m, 3H), 3.62—3.49 (m, 1H), 2.68—2.54 (m, 1H), 2.54—2.40 (m, 1H). MS (ESI, Method A): m/z = 349.1 [M + H]+, tR= 1.219 min. HPLC: 100% (214nm), 100% (254nm).

(R)—3-(4-phen0xyphenyl)—1-(pyrrolidinyl)-1H-pyrazole—4-carboxamide (9h), yellow oil, 100mg, 100%. MS (ESI, Method A): m/z = 349.1 [M + H]+. 1-(4-amin0phenyl)—3-(4-phen0xyphenyl)—1H-pyrazolecarboxamide (9e). To a solution of 1-(4—nitrophenyl)-3—(4-phenoxyphenyl)-1H-pyrazolecarboxamide 8e (200 mg, 0.50 mmol) in ethanol (8 mL) was added saturated aqueous NH4Cl (4 mL), followed by the addition of zinc powder (260 mg, 4.0 mmol) in portion over 5 min, then the resulting solution was stirred for 10 h at t temperature. The mixture was d and the filtrate was diluted with ethyl acetate (30 mL), and washed with water (2 X 20 mL) and brine (2 X 20 mL). The organic layer was dried over anhydrous sodium e, filtered and concentrated to give the title compound as a yellow solid (150 mg, 81%). 1H NMR (400 MHz, cogoD): 8 8.47 (s, 1H), 7.78 (d, J: 8.7 Hz, 2H), 7.51 (d, J: 8.7 Hz, 2H), 7.44—7.36 (m, 2H), 7.16 (s, 1H), 7.19—7.13 (m, 4H), 6.83 (d, J: 8.7 Hz, 2H). MS (ESI, Method A): m/z = 371.1 [M + H]+, tR= 1.468 min. HPLC: 97.8% (214nm), 98.0% (254nm).

Similar ures were used to prepare nd 8f. 1-(3-aminophenyl)—3-(4-phenoxyphenyl)—1H-pyrazole—4-carb0xamide (81), white solid, 105 mg, 47%. 1H NMR (400 MHz, CD30D)C 8 8.60 (s, 1H), 7.81 (d, J: 8.6 Hz, 2H), 7.44—7.36 (m, 2H), 7.28—7.03 (m, 8H), 6.75 (d, J: 7.9 Hz, 1H). MS (ESI, Method A): m/z = 371.1 [M + H]+, tR= 1.507 min. HPLC: 96.9% (214nm), 98.2% (254nm). 1-(1-acryloylpyrrolidinyl)—3-(4-phen0xyphenyl)-1H-pyrazolecarboxamide (Example 13) (10c). To a solution of 3-(4-phenoxyphenyl)—1-(pyrrolidinyl)—1H-pyrazole-4—carboxamide 9c (43 mg, 0.12 mmol) and TEA (50 mg, 0.5 mmol) in DCM (10 mL) was added acryloyl chloride (22 mg, 0.24 mmol) and stirred at 75 °C for 1 h, the resulting was concentrated and purified by Prep-TLC eluting with 10:1 DCM/MeOH to get the title compound (17 mg, 35%) as white solid. 1H NMR (400 MHz, CD3OD)I 8 8.18 (d, J= 8.7 Hz, 1H), 7.70 (d, J= 8.6 Hz, 2H), 7.43—7.34 (m, 2H), 7.18—7.08 (m, 1H), 7.03 (dd, J: 15.5, 8.3 Hz, 4H), 6.72—6.58 (m, 1H), 6.32 (dd, J: 15.9, 4.0 Hz, 1H), 5.83—5.73 (m, 1H), 5.18—5.04 (m, 1H), 4.21—3.65 (m, 4H), 2.63—2.45 (m, 2H). MS (ESI, Method A): m/Z = 403.1 [M + H]+, tR= 1.414 min. HPLC: 95.3% (214nm), 95.3% (254nm). r procedures were used to e the following compounds: 10a, 10b, 10d, 10e, 10f, 10g and 10h. 1-(1-acryloylpiperidiny])(4-phenoxyphenyl)—1H-pyrazole-4—carb0xamide (Example 11) . White solid, 39 mg, 23%. 1H NMR (400 MHz, CDgOD) 8 8.20 (d, J: 5.4 Hz, 1H), 7.71 (d, J: 8.3 Hz, 2H), 7.44—7.35 (m,2H),7.19—7.12(m, 1H), 7.04 (dd, J: 12.3, 8.4 Hz, 4H), 6.89—6.73 (m, 1H), 63—612 (m, 1H), 5.76 (dd, J: 25.5, 10.7 Hz, 1H), 4.71 (d, J: 11.5 Hz, 0.5 H), 4.45—4.17 (m, 2H), 4.08 (d, J: 14.3 Hz, 0.5 H), 3.85—3.73 (m, 0.5 H), 3.45—3.34 (m, 1H), 3.27—3.14 (m, 0.5 H), 2.39—2.18 (m, 2H), 2.06—1.92 (m, 1H), 1.71—1.61 (m, 1H). MS (ESI, Method A): m/z = 417.2 [M + H]+, tR= 1.468 min. HPLC: 97.7% (214nm), 98.7% (254nm). 1-(1-acryloylpiperidinyl)—3-(4-phen0xyphenyl)—1H-pyrazole-4—carb0xamide (Example 12) (10b). White solid, 4.7 mg, 20.8%. 1H NMR (400 MHz, CD30D) 8 8.19 (s, 1H), 7.69 (d, J: 8.5 Hz, 2H), 7.45—7.33 (m, 2H), 7.25—7.12 (m, 1H), 7.04 (dd, J: 12.2, 8.5 Hz, 4H), 6.84 (dd, J: 16.8, 10.7 Hz, 1H), 6.24 (dd,J= 16.8, 1.5 Hz, 1H), 5.79 (dd, J: 10.7, 1.5 Hz, 1H), 4.77—4.64 (m, 1H), 4.61—4.46 (m, 1H), 4.35—4.23 (m, 1H), 3.38 (d, J: 13.0 Hz, 1H), 3.03—2.92 (m, 1H), 2.34—2.17(m, 2H), 2.12—1.96 (m, 2H). MS (ESI, Method A): m/z = 417.1 [M + H]+, tR=1.421 min. HPLC: 97.5% (214nm), 97.8% (254nm). 1-(1-acryloylazetidinyl)—3-(4-phen0xyphenyl)—1H-pyrazole—4-carb0xamide (10d). White solid, 19 mg, 18%. 1H NMR (300 MHz, CD30D) 5 8.21 (s, 1H), 7.71 (d, J= 9.1 Hz, 2H), 7.42— 7.31 (m, 2H), 7.20—7.09 (m, 1H), 7.06—6.94 (m, 4H), 6.46—6.22 (m, 2H), 5.78 (dd, J: 9.9, 2.3 Hz, 1H), 5.33 (td, J: 8.0, 4.0 Hz, 1H), 4.83—4.65 (m, 2H), 4.62—4.41 (m, 2H). MS (ESI, Method A): m/Z = 389.1 [M + H]+, tR=1.388-1.401 min. HPLC: 95.1% (214nm), 96.1% (254nm). 1-(4-acrylamid0phenyl)—3-(4-phenoxyphenyl)—1H-pyrazolecarboxamide (Example 16) (10e). White solid, 52 mg, 46%. 1H NMR (400 MHz, CD3OD) 8 8.67 (s, 1H), 7.89—7.78 (m, 6H), 7.44—7.36 (m, 2H), 7.20—7.12 (m, 1H), 7.11—7.02 (m, 4H), 6.52—6.37 (m, 2H), 5.82 (dd, J: 9.4, 2.4 Hz, 1H). MS (ESI, Method A): m/z = 425.2 [M + H]+, tR=1.521 min. HPLC: 97.3% ), 97.0% (254nm). 1-(3-acrylamid0phenyl)—3-(4-phenoxyphenyl)—1H-pyrazolecarb0xamide le 18) (101). White solid, 24 mg, 24%. 1H NMR (400 MHz, CD30D) 8 8.70 (s, 1H), 8.35 (s, 1H), 7.84 (d, J: 8.7 Hz, 2H), 7.60 (d, J: 8.1 Hz, 2H), 7.54—7.48 (m, 1H), 7.44—7.36 (m, 2H), 7.11—7.03 (m, 1H), 7.20—7.13(m, 4H), 6.53—6.38(m, 2H), 5.83 (dd, J: 9.2, 2.6 Hz, 1H). MS (ESI, Method A): m/z = 425.1 [M + H]+, tR=1.547 (min). HPLC: 97.6% (214nm), 98.6% (254nm).

(S)(1-acryloylpyrrolidinyl)—3-(4-phenoxyphenyl)—1H-pyrazolecarboxamide (Example 20) (10g). Gray solid, 120 mg, 27%. 1H NMR (400 MHz, CD30D) : 8 8.21 (d, J = 6.6 Hz, 1H), .64 (m, 2H), 7.43—7.34 (m, 2H), 7.20—7.10 (m, 1H), 7.10—6.96 (m, 4H), 6.75— 6.55 (m, 1H), 6.32 (ddd, J: 16.8, 4.8, 1.9 Hz, 1H), 5.86—5.72 (m, 1H), 5.21—5.03 (m, 1H), 4.22— 4.07 (m, 1H), 4.05—3.67 (m, 3H), .43 (m, 2H). MS (ESI, Method A): m/z = 403.2 [M + H]+, tR= 1.421 min. HPLC: 99.0% ), 99.0% (254nm).

(R)(1-acryloylpyrrolidinyl)(4-phenoxyphenyl)—1H-pyrazole—4-carboxamide (Example 19) (10h). White solid, 20 mg, 6%. 1H NMR (300 MHz, CDgOD) : 8 8.16 (d, J: 5.9 Hz, 1H), 7.67 (d, J: 8.7 Hz, 2H), 7.42—7.30 (m, 2H), 7.17—6.92 (m, 5H), 6.71—6.56 (m, 1H), 6.34—6.25 (m, 1H), 5.80—5.72 (m, 1H), 5.18—5.02 (m, 1H), 4.20—4.05 (m, 1H), 4.02—3.65 (m, 3H), 2.62—2.45 (m, 2H). MS (ESI, Method A): m/z = 403.1 [M + H]+, tR= 1409 min. HPLC: 95.0% (214nm), 97.0% (254nm).

Scheme 24 0 I HomN\ 1 1 N‘N N—N M HATU, TEA, DMF M PhD 0 ""2 PhD o ""2 Example 34 Example 34 1-(1-(4-(dimethylamin0)but—2-enoyl)pyrrolidinyl)(4—phenoxyphenyl)—1H-pyrazole—4- carboxamide 0 | PhDMo ""2 To a solution of 4-(dimethylamino)butenoic acid 11 (22 mg, 0.17 mmol) and HATU (98 mg, 0.26 mmol) in DMF (10 mL) was added henoxyphenyl)—1-(pyrrolidinyl)-lH-pyrazole- 4-carboxamide 90 (Scheme 23) (60 mg, 0.17 mmol) and DIPEA (22 mg, 0.5 mmol). The reaction e was stirred at rt for 1 h. The solution was concentrated in high vacuum and the residue was d in DCM (10 mL), washed with water (3 X 10 mL), dried over NazSO4, concentrated to give a residue which was purified by Prep-TLC eluting with 10:1 DCM/MeOH to get the title compound (26 mg, 37%) as brown solid. 1H NMR (300 MHz, CD3OD)I 8 8.20 (d, J: 9.0 Hz, 1H), 7.73—7.56 (m, 2H), 7.41—7.27 (m, 2H), 7.11 (t, J: 7.4 Hz, 1H), 7.05—6.91 (m, 4H), 6.88—6.66 (m, 2H), 5.22—5.02 (m, 1H), 4.24—4.06 (m, 1H), 4.05—3.76 (m, 4.5H), 3.76—3.61 (m, 0.5H), 2.86 (d, J: 6.1 Hz, 6H), 2.66—2.39 (m, 2H). MS (ESI, Method A): m/z = 459.8 [M + H]+, tR= 1.244 min. HPLC: 97.5% (214nm), 98.2% (254nm).

Scheme 25 OH CU(OAC)2, Et3N Pd(dppf)Cl2, KOAc 4A MS 0 DMF, reflux cH Cl rt —> —B(L:)12_> go i‘B-B\0% O 0 Br O )‘—/\ 1 2 4 \ \ Pd2(dba)3 052003 | NH2 / / dioxane/HZO 120°C IN HNQ Et3N CHZCIZ 0°C (\N N /\n/C' Example 35 4-(4,4,5,5-tetramethyl-1,3,2-di0xab0rolany1)phenol (2). The title compound was obtained using a procedure analogous to the procedure described in 4—(4-(4,4,5,5-tetramethyl-1,3,2- oro1any1)phenoxy)benzonitri1e (see Scheme 16) as white solid (10.2 g, 80%). 2-(4-(3-flu0r0phenoxy)phenyl)-4,4,5,5-tetramethyl—1,3,2-di0xab0rolane (4). The mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol 2 (1.0g, 4.5mmol), 3-fluorophenylboronic acid 3 (0.70 g, 5.0 mmol), Cu(OAc)2 (1.0 g, 5.0 mmol), Eth (2.75 g, 27.3 mmol), 4A molecular sieves (1 g) and CHzClz (15 mL) was stirred at rt for 16 h. Then the mixture was trated in vacuo and the residue was purified by silica gel chromatography eluting with 20:1 eum ether/EtOAc to afford the title compound (0.45 g, 32%) as white solid. 2-(4-(3-fluor0phen0xy)phenyl)—6-(piperazinyl)nicotinamide (6). The title compound was obtained using a procedure analogous to the procedure described in 6-(3 -nitropheny1)(4- phenoxyphenyl)nicotinamide (see Scheme 1) as white solid (0.15 g, 41%). MS (ESI): m/z = 393.1 [M + H. e 35 6-(4-acryloylpiperaziny])—2-(4-(3-flu0rophenoxy)phenyl)nicotinamide (\N N/ o Nd j 0 The title compound was obtained using a procedure analogous to the procedure described in e 1 as white solid (50 mg, 27%). 1H NMR (400 MHz, CDgOD) 5 7.79 (d, J = 8.7 Hz, 1H), 7.77—7.70 (m, 2H), .33 (m, 1H), 7.13—7.06 (m, 2H), 6.93—6.75 (m, 5H), 6.27 (dd, J: 16.8, 1.9 Hz, 1H), 5.80 (dd, J: 10.6, 1.9 Hz, 1H), 3.84 —3.72 (m, 8H). MS (ESI, method A): m/z = 447.1 [M + H]+, tR=1.746 (min). HPLC: 95.9% (214nm), 96.4% (254nm).

Scheme 26 OH )2, Et3N B(OH)2 4A Ms Pd(dppf)C[2 KOAc Pd2(dba)3 052003 dioxane/HZO 120°C + 1 o Br \ClIN 1 2 CH2C12,rt©/E|3r—>]©\DMF reflux 5 HNJ0N O O \ \ NH2 (\N N/ Et3N,CH2CI2,o°C (\N N/ HN\/‘ ON F6 2,Cl j FE) Example 36 4-brom0flu0ro-l-phenoxybenzene (3). The title compound was obtained using a procedure analogous to the procedure described in 2-(4-(3-fluorophenoxy)phenyl)—4,4,5,5-tetramethyl— 1,3,2-dioxaborolane (see Scheme 25) as yellow oil (1.5 g, 21%). MS (ESI): m/z = 267.1 [M + u0r0phenoxyphenyl)—4,4,5,5-tetramethyl—1,3,2-di0xaborolane (5). The title compound was obtained using a procedure analogous to the procedure described in 4-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolanyl)phenoxy)benzonitrile (see Scheme 16) as yellow oil (1.04 g, 73%). 2-(3-fluor0phen0xyphenyl)—6-(piperazinyl)nic0tinamide (7). The title compound was obtained using a procedure analogous to the procedure described in 6-(3 -nitrophenyl)(4- phenoxyphenyl)nicotinamide (see Scheme 1) as brown gum (0.194 g, 49%). MS (ESI): m/z = 393.1 [M + H.

Example 36 6-(4-acryloylpiperaziny])—2-(3-flu0r0phenoxyphenyl)nic0tinamide The title nd was obtained using a procedure analogous to the procedure bed in Example 1 as white solid (38 mg, 17%). 1H NMR (400 MHZ, 6) 8 (m, 2H), 7.59 (d, J = 11.4 Hz, 1H), 7.48 (d, J: 8.2 Hz, 1H), 7.42 (t, J: 7.7 Hz, 2H), 7.35—7.28 (m, 1H), 7.24—7.15 (m, 2H), 7.04 (d, J: 7.9 Hz, 2H), 6.95—6.81 (m, 2H), 6.16 (d, J: 16.6 Hz, 1H), 5.73 (d, J: 10.2 Hz, 1H), 3.79—3.50 (m, 8H). MS (ESI, method A): m/z = 447.1 [M + H]+, tR=1.753 (min).

HPLC: 98.6% (214nm), 98.4% (254nm).

Scheme 27 F Cuu(OAc)2, £th 4A MS Pd2(dba)s 082C03 N/ dioxane/HZO 120°C + CH2C|2,rt 474 B(0H)2 <10; Ad\IN 1 2 3 5 Eth, CHZCIZ, 0 00 e 37 2-(4-(4-flu0r0phen0xy)phenyl)-4,4,5,5-tetramethyl—1,3,2-di0xab0rolane (3). The title compound was obtained using a procedure analogous to the procedure described in 2—(4-(3— fluorophenoxy)phenyl)-4,4,5,5-tetramethy1—1,3,2-dioxaborolane (see Scheme 25) as White solid (0.45 g, 32%). 2-(4-(4-fluorophenoxy)phenyl)—6-(piperazinyl)nic0tinamide (5). The title compound was obtained using a procedure analogous to the procedure described in 6-(3 -nitrophenyl)(4- phenoxypheny1)nicotinamide (see Scheme 1) as brown gum (0.18 g, 41%).

Example 37 6-(4-acryloylpiperazinyl)(4-(4-flu0rophenoxy)phenyl)nic0tinamide \ NH2 ‘/\N N/ The title compound was obtained using a procedure analogous to the procedure described in Example 1 as white solid (80 mg, 44%). 1H NMR (400 MHZ, CD30D) 5 7.77 (d, J = 8.7 Hz, 1H), 7.69 (d, J: 8.7 Hz, 2H), 7.17—7.05 (m, 4H), 7.00 (d, J: 8.7 Hz, 2H), 6.87—6.76 (m, 2H), 6.26 (dd, J: 16.8, 1.8 Hz, 1H), 5.80 (dd, J: 10.6, 1.8 Hz, 1H), 3.87—3.71 (m, 8H). MS (ESI, method A): m/z = 447.0 [M + H]+, tR=1.739 (min). HPLC: 99.8% ), 100% (254nm).

Scheme 28 052003, DMF Fe NH4C| CHZIZ, amyl nitrite OM32 + CE: —’E:E: 120 °c ONOZ EtOH 70°C a:ONHZ CHgCN 75°C F OH 1 2 Pd2(dban 052co Pd(dppf)C|2 KOAc | 0 o / . 03 DMF reflux dioxane/HZO, 120 C ‘/\N N Wit-1m".OB‘o O HNd F I o HN\) Pg Et3N, CHZCIZ, 0 °C KN e 38 0(4-nitr0phen0xy)benzene (3). The mixture of 1-fluoronitrobenzene 1 (10.0 g, 70.8 mmol), 2-fluorophenol 2 (9.54 g, 85.0 mmol), CS2C03 (34.6 g, 106 mrnol) and DMF (80 mL) was heated to 120 °C and stirred for 2 h. After being cooled to rt, the mixture was diluted with water (150 mL) and extracted with EtOAc (200 mL X 2). The combined organic phase was washed with brine (100 mL X 3), dried over Na2S04 and filtered. The filtrate was concentrated in vacuo. The residue was recrystallized from MeOH (20 mL X 2) to afford the title compound as light yellow solid (14.6 g, 88%). 4-(2-fluorophenoxy)benzenamine (4). To the mixture of 1-fluoro-2—(4-nitrophenoxy)benzene 3 (16.2 g, 69.3 mmol), saturated aqueous NH4Cl solution (30 mL) and EtOH (150 mL) was added iron powder (19.4 g, 347 mmol) slowly and then the resulting mixture was heated to 70 CC for 3.5 h. After being cooled to rt, the mixture was filtered. The filtrate was concentrated in vacuo.

The residue was dissolved in EtOAc (160 mL) and washed successively with water (100 mL X 2) and brine (100 mL X 2). The organic phase was dried over Na2S04, filtered and concentrated in vacuo to afford the title compound (13.6 g, 96%) as yellow solid. 1H NMR (400 MHz, DMSO- d6) 8 7.35—7.28 (m, 1H), .00 (m, 2H), 6.93—6.85 (m, 1H), 6.80—6.73 (m, 2H), 6.64—6.56 (m, 2H), 4.99 (brs, 2H). 1-flu0r0(4-iodophenoxy)benzene (5). The mixture of 4-(2—fluorophenoxy)benzenamine 4 (7.94 g, 39.1 mmol), CHZIZ (29.0 g, 136.8 mmol) and CH3CN (120 mL) was heated to 55 °C and then amyl nitrite (11.6 g, 97.7 mmol) was added. The resulting mixture was heated to 75 °C for 3.5 h. After being cooled to rt, the mixture was d with EtOAc and then washed successively with 10% g and brine. The organic phase was dried over Na2S04, filtered, concentrated in vacuo and purified by silica gel chromatography eluting with petroleum ether to afford the title compound (4.12 g, 51%) as light yellow oil. 1H NMR (400 MHZ, DMSO) 8 7.78— 7.63 (m, 2H), 7.44—7.37 (m, 1H), 7.34—7.14 (m, 3H), 6.87—6.74 (m, 2H). 2-(4-(2-flu0r0phenoxy)phenyl)-4,4,5,5-tetramethyl—1,3,2-di0xab0rolane (7). The title compound was obtained using a procedure analogous to the procedure described in 4-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolanyl)phenoxy)benzonitrile (see Scheme 16) as yellow oil (0.40 g, 13%). 2-(4-(2-fluorophenoxy)phenyl)—6-(piperazinyl)nic0tinamide (9). The title compound was ed using a procedure ous to the procedure bed in 6-(3 -nitrophenyl)(4- phenoxyphenyl)nicotinamide (see Scheme 1) as white solid (0.16 g, 31%). MS (ESI): m/z = 393.1 [M + Hr.

Example 38 cryloylpiperaziny])(4-(2-flu0rophenoxy)phenyl)nicotinamide O / N The title compound was obtained using a procedure ous to the procedure described in Example 1 as white solid (28 mg, 24%). 1H NMR (400 MHZ, CDgOD) 5 7.77 (d, J = 8.7 Hz, 1H), 7.71—7.68 (m, 2H), 7.34—7.13 (m, 4H), 6.99 (d, J: 8.7 Hz, 2H), 6.88—6.79 (m, 2H), 6.26 (dd, J: 16.8, 1.9 Hz, 1H), 5.80 (dd, J: 10.6, 1.9 Hz, 1H), 3.89—3.71 (m, 8H). MS (ESI, method A): m/z = 447.1 [M + H]+, tR=1.723 (min). HPLC: 98.6% (214nm), 98.8% ).

Scheme 29 Cu(OAc)2, Et3N Pd(dppf)C|2 KOAc 4A MS Pd2(dba)3, 052003 DMF reflux ,1 dioxane/HZO, 120°C —>F CHZCIZ , , é <1 115 5 55 M 1:5 o . 511* |/\N N/ CI 1 2 4 I Et N CH3 2CI 1 21 0°C 6N N/ HN¢F 0qu O/NdFj o 11 <5 Example 39 3-fluor0(4,4,5,5-tetramethyl-1,3,2-di0xab0r01anyl)phenol (2). The title compound was obtained using a procedure analogous to the procedure described in 4-(4,4,5,5-tetramethy1—1,3,2- dioxaborolan-2—y1)phenol (see Scheme 25) as white solid (4.1 g, 66%). MS (ESI): m/z = 239.2 [M + Hr. 2-(2-fluoro-4—phenoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxab0rolane (4). The title compound was obtained using a procedure analogous to the procedure described in 2-(4-(3- fluorophenoxy)phenyl)-4,4,5,5-tetrarnethyl-1,3,2-dioxaborolane (see Scheme 25) as white solid ( g9 ) 2-(2-fluoro-4—phenoxyphenyl)—6-(piperazinyl)nicotinamide (6). The title nd was obtained using a procedure ous to the procedure described in 6-(3 -nitropheny1)(4- phenoxyphenyl)nicotinamide (see Scheme 1) as brown solid (0.105 g, 21%). MS (ESI): m/z = 393.1 [M + Hr.

Example 39 6-(4-acryloylpiperazinyl)—2-(2-flu0r0phenoxyphenyl)nic0tinamide / ZIN Oj/O N F o / i) The title nd was obtained using a ure analogous to the procedure described in Example 1 as white solid (78 mg, 65%). 1H NMR(400 MHz, MeOD) 5 7.78 (d, J = 8.7 Hz, 1H), 7.59 (dd, J: 11.8, 2.0 Hz, 1H), 7.48 (d, J: 9.2 Hz, 1H), 7.44—7.33 (m, 2H), 7.17—7.06 (m, 2H), 7.05—6.99 (m, 2H), 6.90—6.79 (m, 2H), 6.27 (dd, J= 16.8, 1.8 Hz, 1H), 5.80 (dd, J: 10.6, 1.8 Hz, 1H), 3.86—3.70 (m, 8H). MS (ESI, method A): m/z = 447.0 [M + H]+, tR=1.770 (min).

HPLC: 96.5% (214nm), 96.9% (254nm).

Scheme 30 o O o s o CAOH )L CI 0«I/ O O NH2 Lawesson reagent 0%.

NH; "4 1NB°° —> NB°° THF/TEA/NH3‘HZO toluene "3°C EtOHl60°C COOH COOEt BocN BocN«3,8,3 LiOH 00—»THFH20 DMF/DIPEA CONH CONHZ 2 BOON0*? ofl’g W (DD—*09 \CONHz Example 40 tert-butyl amoylpiperidine—l-carboxylate (2). To a solution of 1-(tert— butoxycarbonyl)piperidinecarboxylic acid 1 (5.0 g, 21.8 mmol) in dry THF (100 mL) was added TEA (3.30 g, 32.7 mmol), isobutyl carbonochloridate (3.27 g, 23.99 mmol) at 0°C and the resulting solution was stirred for 20 min. NH3-H20 was added and stirred at rt for 2 h. The mixture was diluted with ethyl acetate (30 mL), and washed with sat. aq. N32C03 (2 X 20 mL) and sat. aq. citric acid (2 X 20 mL). The c layer was dried over anhydrous sodium sulfate, filtered and trated to give crude product (3.6 g, 72%) as white solid. MS (ESI): m/z = 173.0 [M — 551+. tert-butyl 2-carbamothioylpiperidinecarb0xylate (3). To a solution of tert—butyl 2- carbamoylpiperidine-l-carboxylate 2 (2.0 g, 8.77 mmol) in dry toluene (20 mL) was added Lawesson’s reagent (2.13 g, 5.26 mmol) at N2 atmosphere. The resulting solution was d at 80°C for 16 h. The mixture was diluted with ethyl acetate (30 mL), and washed with saturated aqueous (sat. aq.) N32C03 (2 X 20 mL) and brine (2 X 20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give crude product which was purified by silica gel column chromatography eluting with 4 : 1 PE/EA to get the title compound (330 mg, %) as white solid. MS (ESI): m/Z = 245.2 [M + H. ethyl(1-(tert-butoxycarbonyl)piperidinyl)(4-phen0xyphenyl)thiazole-5—carboxylate (5). A solution of tert-butyl 2-carbamothioylpiperidinecarboxylate 3 (60 mg, 0.239 mmol) and ethyl 2-bromooxo(4-phenoxyphenyl)propanoate 4 (250 mg, 0.7 mmol) in EtOH (10 mL) was stirred for 2 h at 60°C. The mixture was diluted with ethyl acetate (30 mL), and washed with water (2 X 20 mL) and brine (2 X 20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with 40 : 1 PE/EA to get the title nd (120 mg, 34%) as colorless oil. MS (ESI): m/Z = 509.3[M + HT. 2-(1-(tert-butoxycarbonyl)piperidinyl)(4-phenoxyphenyl)thiazolecarboxylic acid (6). A on of ethyl 2-(1-(tert-butoxycarbonyl)piperidin-3 -yl)(4-phenoxyphenyl)thiazole- -carboxylate 5 (120 mg, 0.263 mmol ) in THF-HZO (1/1, 20 mL) and added LiOH (30 mg, 0.71 mmol) was stirred at rt for 13 h. The mixture was evaporated and diluted with water (5 mL), and the solution was acidified with 2 N hydrochloric acid to pH = 4. The residue was extracted with Ethyl Acetate (EA) (3 X 30 mL). Dried and trated to get crude nd (110 mg, 100%) as light red liquid. MS (ESI): m/Z = 481.0 [M + H]+. tert-butyl 3-(5-carbamoyl(4-phenoxyphenyl)thiazolyl)piperidine—l-carboxylate (7).

The mixture of 2-(1-(tert-butoxycarbonyl)piperidinyl)(4-phenoxyphenyl)thiazole-S- carboxylic acid 6 (110 mg, 0.229 mmol), HATU (113 mg, 0.297 mmol), DIPEA (88 mg, 0.687 mmol) and dry DMF (10 mL) was bubbled with NH3 for 20 min, and the resulting solution was stirred for 3 h at ambient ature. The mixture was diluted with ethyl acetate (30 mL), and washed with water (2 X 20 mL) and brine (2 X 20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Prep-TLC with 3 : 2 PE/EA to get the title compound (100 mg, 75%) as colorless oil. MS (ESI): m/z = 480.1 [M + H]+. 4-(4-phenoxyphenyl)(piperidinyl)thiazole—5-carb0xamide (8). To a solution of tert—butyl 3-(5-carbamoyl(4—phenoxyphenyl)thiazolyl)piperidine- l -carboxylate 7 (100 mg, 0.21 mmol) in DCM (5 mL) was added TFA (2.5 mL) at t temperature. The mixture was stirred for 3 h. The mixture was diluted with water (2 X 150 mL) and extracted with ethyl acetate (2 X 20 mL) and washed with brine (2 X 150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (60 mg, 76%) as brown oil.

MS (ESI): m/Z = 380.0 [M + H.

Example 40 2-(1-acryloylpiperidinyl)(4-phen0xyphenyl)thiazolecarb0xamide .1] CONH2 M1606.

To a solution of 4-(4-phenoxyphenyl)(piperidinyl)thiazole-5—carboxamide 8 (60 mg, 0.155 mmol) in dry dichloromethane (10 mL) were added TEA (19 mg, 0.21 mmol) and acryloyl de 9 (32 mg, 0.316 mmol), and the resulting solution was stirred at rt for l h. Water (10 mL) was added to quench the reaction. The mixture was diluted with ethyl acetate (30 mL), washed with brine (2 X 20 mL). The organic layer was dried over NazSO4, filtered and concentrated to get the residue which was purified by Prep-TLC with 17:1 DCM/MeOH to get the title nd (33 mg, 50%) as a white solid. 1H NMR (400 MHz, DMSO) 8 7.76 (d, J = 8.5 Hz, 2H), 7.76 (brs, 70 (brs, 1H), 7.44 (t, J= 8.0 Hz, 2H), 7.19 (t, J: 7.4 Hz, 1H), 7.08 (t, J = 8.6 Hz, 4H), 6.92—6.82 (m, 1H), 6.14—6.04 (m, 1H), 5.73—5.64 (m, 1H), 4.65—4.62 (m, 0.5H), 4.15—4.04 (m, 0.5H), 4.02—4.00 (m, 1H), 3.59—3.56 (m, 0.5H), 3.26—3.14 (m, 15H), 3.09—2.98 (m, 1H), 2.22—2.16 (m, 1H), 1.90—1.74 (m, 2H), 1.58—1.48 (m, 1H). MS (ESI, method A): m/z = 433.8 [M + H]+, tR=l.488 min. HPLC: 99.1% (214 nm), 99.2% (254 nm).

Scheme 31 Omoo 0 S \/ 0A CIOO/Y Lawessons reagent 0 0 NHZ NH2 BOON BOCN THF/TEAINH3-H20 toluene BocN 1 EtOH/60°C COO" COOEt (>4: —> BocN(>4: BocN 00 THEH20 00—,DMFIDIPEA CONH2 CONH2 CONH2 O’Qil —>BOCNO’<:\THF (Vim? BocN OHCQI tert-butlyl 3-carbam0ylpyrrolidine—l-carboxylate (2). To a solution of 1-(tert-Example 41 butoxycarbonyl)pyrrolidinecarboxylic acid 1 (5 g, 23.23 mmol) in dry THF (100 mL) was added TEA (4.69 6 mmol), isobutyl carbonochloridate (3.8 g, 27.87 mmol) at 0°C and the resulting solution was stirred for 20 min. 0 added and stirred at rt for 2 h. The mixture was diluted with ethyl acetate (30 mL), and washed with saturated (sat) Na2C03 (2 X 20 mL) and sat. citric acid (2 X 20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give crude product (2.39 g, 49%) as yellow solid. MS (ESI): m/z = 159.0 [M + H. tert-butyl 3-carbamothioylpyrrolidine—l-carboxylate (3). To a solution of tert-butyl 3- carbamoylpyrrolidine—1-carboxylate 2 (0.76 g, 3.55 mmol) in dry toluene (20 mL) was added Lawesson’s regent (0.71 g, 1.77 mmol) at N; atmosphere . The resulting solution was stirred at 80°C for 16 h.The mixture was diluted with ethyl acetate (30 mL), and washed with sat. Na2C03 (2 X 20 mL) and brine (2 X 20 mL). The organic layer was dried over anhydrous sodium e, filtered and concentrated to give crude product which was purified by silica gel column chromatography eluting with 6 : 1 PE/EA to get the title compound (230 mg, 28%) as brown oil.

MS (ESI): m/Z = 175.2 [M + Hr. ethyl 2-(1-(tert-butoxycarbonyl)pyrrolidinyl)-4—(4-phenoxyphenyl)thiazole—S-carboxylate (5). A solution of tert—butyl 3-carbamothioylpyrrolidinecarboxylate 3 (360 mg, 0.1 mmol) and ethyl 2—bromo—3-oxo—3-(4-phenoxyphenyl)propanoate 4 (230 mg, 0.1 mmol) in EtOH (10 mL) was d for 2 h at 60°C. The mixture was diluted with ethyl acetate (30 mL), and washed with water (2 X 20 mL) and brine (2 X 20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and trated. The residue was purified by silica gel column chromatography eluting with 30 : 1 PE/EA to get the title compound (100 mg, 20%) as colorless oil. MS (ESI): m/Z = 495.3[M + H. 2-(1-(tert-butoxycarbonyl)pyrrolidiny])(4-phenoxyphenyl)thiazole—S-carboxylic acid (6). A solution of ethyl 2-(1-(tert-butoxycarbonyl)pyrrolidin-3 -yl)(4-phenoxyphenyl)thiazole- - carboxylate 5 (100 mg, 0.2 mmol ) in THF-HZO (1/ 1, 20 mL) and added LiOH (84 mg, 2 mmol) was stirred at rt for 13 h. The mixture was evaporated and diluted with water (5 mL), and the solution was acidified with 2 N hydrochloric acid to pH = 4. The residue was extracted with EA (3 X 30 mL). Dried and evaporated to get crude compound (95 mg, 100%) as red oil. MS (ESI): m/Z = 411.0 [M + Hr. tert-butyl 3-(5-carbamoyl-4—(4-phenoxyphenyl)thiazol-Z-yl)pyrrolidine—l-carboxylate (7).

The e of 2-(1-(tert-butoxycarbonyl)pyrrolidinyl)(4-phenoxyphenyl)thiazole carboxylic acid 6 (950 mg, 0.2 mmol), HATU (116 mg, 0.3 mmol), DIPEA (103 mg, 0.8 mmol) and dry DMF (10 mL) was bubbled with NH3 for 20 min, and the resulting solution was stirred for 3 h at ambient temperature. The mixture was diluted with ethyl acetate (30 mL), and washed with water (2 X 20 mL) and brine (2 X 20 mL). The c layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was d by Prep-TLC with 2 : l PE/EA to get the title compound (70 mg, 75%) as colorless oil. MS (ESI): m/z = 466.1 [M + H]+. tert-butyl 3-(5-carbamoyl-4—(4-phenoxyphenyl)thiazol-Z-yl)pyrrolidine-l-carboxylate (8).

To a on of tert-butyl 3-(5-carbamoyl(4-phenoxyphenyl)thiazolyl)pyrrolidine carboxylate 7 (70 mg, 0.15 mmol) in DCM (5 mL) was added TFA (2.5 mL) at ambient temperature. The mixture was stirred for 3 h. The e was diluted with water (2 X 150 mL) and ted with ethyl acetate (2 X 20 mL) and washed with brine (2 X 150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (65 mg, 100%) as brown oil. MS (ESI): m/z = 366.1 [M + H]+.

Example 41 2-(1-acryloylpyrrolidiny])(4-phenoxyphenyl)thiazolecarboxamide f CONH2 O "in To a tert-butyl 3-(5-carbamoyl(4-phenoxyphenyl)thiazol—2-y1)pyrrolidine—1-carboxylate 8 (65 mg, 0.15 mmol) in dry dichloromethane (10 mL) were added TBA (50 mg, 0.45 mmol) and acryloyl chloride 9 (20.4 mg, 0.225 mmol), and the resulting solution was stirred at It for 1 h.

Water (10 mL) was added to quench the reaction. The mixture was diluted with ethyl acetate (30 mL), washed with brine (2 X 20 mL). The organic layer was dried over Na2S04, filtered and concentrated to get the residue which was d by Prep-TLC with 1 : 1 PE/EA to get the title compound (22 mg, 35%) as a white solid. 1H NMR (400 MHz, DMSO) 8 7.76 (d, J = 8.0 Hz, 2H), 7.76 (brs, 1H),7.70 (brs, 1H), 7.44 (t, J: 8.0 Hz, 2H), 7.19 (t, J: 7.4 Hz, 1H), 7.07 (t, J: 8.6 Hz, 4H), 6.65—6.59 (m, 1H), 6.19—6.15 (m, 1H), 5.72—5.68 (m, 1H), 4.11—4.07 (m, 0.5H), 3.99—3.95 (m, 0.5H), 3.91—3.78 (m, 2H), 3.70—3.62 (m, 1.5H), 3.50—3.47 (m, 0.5H), 2.44—2.36 (m, 1H), 2.28—2.25 (m, 0.5H), 2.18—2.13 (m, 0.5H). MS (ESI, method A): m/z = 419.8 [M + H]+, tR=1.429 min. HPLC: 97.2% (214 nm), 97.5% (254 nm).

Scheme 32 AJ°L J 0 0 , dioxane o°c~n 2h—>©\o NaH, toluene. reflux, 40 min 0 DIPEA, CH3CN rt o Q EtO AcONH4, AcOH, reflulx ° NaOH. MeOH, H20 Boc20, Nazco3 0 —> —> / —> Eto / Eto THF/HZO N ° ° 0 /\g’/ 0 HATU, NH3, DMF HCI/EtOH HO / —>H2N —> / HZN / H2N / o / o /N DCM o /N o ’N "‘30:: N~Boc NH N 8 9 Example 42 ethyl 3-0x0(4-phenoxyphenyl)propanoate (2). To a mixture of l carbonate (14 g, 120 mmol) and NaH (4.8 g, 120 mmol) in toluene (100 mL) was added 1-(4- phenoxyphenyl)ethanone 1 (10 g, 47 mmol) dropwise for 20 min. The ing mixture was refluxed for 40 min. When it cooled to rt, which was quenched with AcOH/HZO (6 mL/30 mL), then diluted with EA (100 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and trated. The residue was applied onto silica gel column g with 20:1 PE/EA to get the title compound (7.5 g, 56%) as yellow oil. MS (ESI): m/z = 285.1 [M + H]+. ethyl 2-br0m00x0(4-phen0xyphenyl)pr0panoate (3). To a mixture of ethyl 3-oxo(4- phenoxyphenyl)propanoate 2 (6.55 g, 23.1 mmol) in dioxane (100 mL) was added Brz (3.69 g, 23.1 mmol) dropwise at 0 °C under N2. The resulting e was stirred at rt for 3 h. The volatile phase was removed under reduced pressure. This resulted in crude title compound (9.5 g, overweight) as yellow oil. MS (ESI): m/Z = 3630/3650 [M + Hr. 1-tert—buty] 3-(l-ethoxy-1,3-dioxo(4-phenoxyphenyl)propanyl) piperidine-1,3- dicarboxylate (4). To a mixture of ethyl 2-bromo-3—oxo(4-phenoxyphenyl)propanoate 3 (1.0 g, 2.75 mmol) in CH3CN (20 mL) was added DIEA (0.39 g, 3.0 mmol) dropwise. The resulting mixture was stirred at rt overnight. The volatile phase was removed under reduced pressure. The residue was applied onto silica gel column eluting with 3 :1 PE/EA to get the title compound (1.15 g, 82%) as yellow oil. MS (ESI): m/Z = 412.1 [M + H — Boer. ethyl 4-(4-phen0xyphenyl)(piperidinyl)oxazole-S-carboxylate (5). A mixture of 1-tert- butyl 3—(1-ethoxy-1,3—dioxo-3—(4-phenoxyphenyl)propanyl) piperidine-l ,3-dicarboxylate 4 (1.15 g, 2.25 mmol) and AcONH4 (0.86 g, 11.23 mmol) in AcOH (20 mL) was stirred at 120 CC for 2 h. The volatile phase was d under reduced pressure. The residue was dissolved in EA (50 mL), which was washed with sat. NaHCOg, brine, dried over sodium sulfate, filtered and concentrated. This resulted in crude title nd (0.85 g, crude) as yellow oil. MS (ESI): m/z = 393.1 [M + H.

Ethyl(1-(tert-butoxycarbonyl)piperidinyl)—4—(4-phenoxyphenyl)oxazole-S-carboxylate (6). The title compound was obtained using a procedure analogous to the procedure described in ethyl tert-butoxycarbonyl)piperazinyl)(4-phenoxyphenyl)thiazole-5 -carboxylate (see Scheme 37) as pale yellow oil (0.35 g, 33%, two steps). MS (ESI): m/z = 437.0 [M + H - 56]+. 2-(1-(tert—butoxycarb0nyl)piperidinyl)(4-phen0xyphenyl)0xazole-5—carboxylic acid (7). The title compound was obtained using a ure ous to the procedure described in -(1-(tert-butoxycarbony1)piperidin-4—y1)-4'-phenoxybiphenylcarboxylic acid (see Scheme 45) as yellow oil (350 mg, overweight). MS (ESI): m/z = 465.1 [M + H]+. tert-butyl 3-(5-carbamoyl(4-phenoxyphenyl)0xazolyl)piperidine-l-carboxylate (8).

The title compound was obtained using a procedure analogous to the procedure described in tert- butyl-3 -(4-carbamoyl—3-(4-phenoxyphenyl)—lH-pyrazolyl)pyrrolidine—1—carboxylate (see Scheme 23) as pale yellow solid (250 mg, overweight). MS (ESI): m/z = 408.0 [M + H - 56]+. 4-(4-phenoxyphenyl)(piperidinyl)0xazole-S-carboxamide hydrochloride (9). The title compound was obtained using a procedure analogous to the ure bed in 1-(4- phenoxyphenyl)(piperidinyl)-1H-pyrazolecarboxamide hydrochloride (see Scheme 46) as white solid (150 mg, overweight). MS (ESI): m/z = 364.1 [M + H]+.

Example 42 cryloylpiperidinyl)(4-phenoxyphenyDoxazole—S-carboxamide The title compound was obtained using a procedure analogous to the procedure described below in Example 43 as white solid (60 mg, 45%, four . 1H NMR (300 MHz, DMSO) 8 8.26 (d, J: 9.0 Hz, 2H), 7.92 (s, 1H), 7.67 (s, 1H), 7.53—7.29 (m, 2H), 7.25—7.13 (m, 1H), 7.11—6.99 (m, 4H), 6.85 (dd, J: 16.7, 10.5 Hz, 1H), 6.11 (dd, J: 16.7, 2.4 Hz, 1H), 5.68 (dd, J: 10.4, 2.4 Hz, 1H), 4.39—4.31 (m, 1H), 4.12—4.04 (m, 1H),3.33—3.14(m,2H),3.02—2.89(m, 1H), 2.14—2.06 (m, 2H), 1.90—1.65 (m, 2H). MS (ESI, method A): m/z = 418.1 [M + H]+, tR=1.488 min. HPLC: 97% (214nm), 97% (254nm).

Scheme 33 OQ o@ o@ O/Q HO N.Bon: 0 O 0 02—0 510 ,AcOH,reflulx Etc, / 3092010132903 5,0 / NaOH,Me0H,Hzo —> 0 —> ' ’ O N N 0 ° / THFIH o / 0 2 0 DIPEA, CH3CN, rt NH N\ N Boc 1 3 4 0 0 0 Cl / / HO / HATU. NHa. DMF OH HzN / q: H2" N HZN / N N —> —> —> ’ O / o I N ° o / DIPEA,DCM z) N N E NH HCI ‘Boc N‘ A Bee 0 6 7 Example 43 1-tert—butyl 3-(1-eth0xy-1,3-di0X0(4-phenoxyphenyl)propanyl) pyrrolidine-1,3- dicarboxylate (2). The title compound was obtained using a ure analogous to the procedure described in 1-tert—buty1 3—( 1 -ethoxy- 1 ,3 -dioxo(4-phenoxypheny1)propanyl) piperidine-l,3-dicarboxy1ate (see Scheme 32) as pale yellow oil (1.1 g, 80%). MS (ESI): m/z = 441.8 [M + H - 561+. ethyl 4-(4-phenoxyphenyl)(pyrrolidinyl)oxazole-S-carboxylate (3). The title compound was obtained using a procedure analogous to the procedure described in ethyl 4-(4- phenoxyphenyl)(piperidin—3-y1)oxazole-5—carboxy1ate (see Scheme 32) as yellow oil (0.80 g, crude). MS (ESI): m/Z = 420.1 [M + H + 411*. ethyl 2-(1-(tert-butoxycarbonyl)pyrrolidinyl)(4-phenoxyphenyl)oxazole—S-carboxylate (4). The title compound was obtained using a procedure analogous to the procedure bed in ethyl 2—(4-(tert—butoxycarbonyl)piperazinyl)(4—phenoxyphenyl)thiazole—5-carboxy1ate (see Scheme 37) as pale yellow oil (0.35 g, 33%, two steps). MS (ESI): m/z = 423.1 [M + H - 56]+. 2-(1-(tert-butoxycarbonyl)pyrrolidinyl)(4-phenoxyphenyl)oxazole-S-carboxylic acid (5). The title compound was obtained using a procedure analogous to the procedure described in -(1-(tert-butoxycarbony1)piperidinyl)-4'-phenoxybiphenylcarboxylic acid (see Scheme 45) as yellow oil (350 mg, overweight). MS (ESI): m/z = 395.0 [M + H — 56]+. tert-butyl 3-(5-carbam0yl—4—(4-phenoxyphenyl)oxazol-Z-yl)pyrrolidine-l-carboxylate (6).

The title compound was obtained using a procedure analogous to the procedure described in tert- butyl-3 —(4-carbamoyl—3-(4-phenoxyphenyl)-lH-pyrazolyl)pyrrolidine-1 -carboxylate (see Scheme 23) as pale yellow solid (250 mg, overweight). MS (ESI): m/z = 394.1 [M + H - 56]+. 4-(4-phenoxyphenyl)—2-(pyrrolidinyl)oxazole-S-carboxamide hydrochloride (7). The title compound was obtained using a procedure analogous to the procedure described in 1-(4- phenoxyphenyl)(piperidinyl)—lH-pyrazole-3—carboxamide hydrochloride (see Scheme 46) as white solid (150 mg, overweight). MS (ESI): m/z = 350.1 [M + H]+.

Example 43 2-(1-acryloylpyrrolidinyl)—4-(4—phenoxyphenyDoxazole-S-carboxamide The title compound was obtained using a procedure ous to the procedure described in Example 15 as white solid (45 mg, 34%, four . 1H NMR (400 MHZ, DMSO) 5 8.27 (d, J = 8.8 Hz, 2H), 7.94 (d, J: 8.0 Hz, 1H), 7.70 (d, J: 8.0 Hz, 1H), 7.43 (t, J: 7.9 Hz, 2H), 7.19 (t, J = 7.9 Hz, 1H), 7.11—7.02 (m, 4H), 6.69—6.55 (m, 1H), 6.19 (d, J: 18.0 Hz, 1H), 5.70 (d, J: .4 Hz, 1H), 4.08—3.96 (m, 1H), 3.90—3.65 (m, 3H), 3.64—3.55 (m, 0.5H), .45 (m, 0.5H), 2.45—2.37 (m, 1H), 2.36—2.27 (m, 1H). MS (ESI, method A): m/z = 404.1 [M + H]+, tR=1.542 min. HPLC: 98% (214nm), 98% (254nm).

Scheme 34 O O NBoc O 0 . OEt 1, oxalyl chloride Iawesson s reagent, OEt—>pho HN o S —> \ 2, TEA, DCM \ NH THF 2 HC' COOEt NBoc PhD 1 2 3 NBoc 8PNBOC LiOH H20 NH3, HATU \\N —> 3.9 THF/MeOH/HZO DIPEA! DMF COOH PhO o NH2 \ TEA,DCM HCI ’ HCI/EtOH N \ s PhD 0 NHz PhD 0 NH2 tert-butyl 3-(1-eth0xy—1,3-di0x0(4-phenoxyphenyl)propan-Z-ylcarbamoyl)pyrrolidine carboxylate (2). The title compound was obtained using a procedure analogous to the procedure bed in tert-butyl 3-(1-ethoxy-l,3-dioxo(4-phenoxyphenyl)propan ylcarbamoyl)piperidine-l-carboxylate (see Scheme 35) as yellow oil (0.35 g, 30%). MS (ESI): m/Z = 440.7 [M — 551+. ethyl 2-(1-(tert-butoxycarbonyl)pyrrolidinyl)(4-phenoxyphenyl)thiazole—4—carb0xylate (3). The title compound was obtained using a ure analogous to the procedure described in ethyl 2-(1 -(tert-butoxycarbonyl)piperidin-3 -yl)—5 -(4-phenoxyphenyl)thiazolecarboxylate (see Scheme 35) as yellow oil (0.12 g, 61%). MS (ESI): m/z = 494.7 [M + H]+. 2-(1-(tert—butoxycarb0nyl)pyrrolidinyl)(4-phenoxyphenyl)thiazolecarboxylic acid (4). The title compound was ed using a procedure analogous to the procedure described in -(l -(tert-butoxycarbonyl)piperidinyl)- l -(4-phenoxyphenyl)- l H-pyrazole-3 -carboxylic acid (see Scheme 46) as colorless oil (110 mg, 97%). MS (ESI): m/z = 488.7 [M + Na]+. tert-butyl 3-(4-carbamoyl-S—(4-phenoxyphenyl)thiazol-Z-yl)pyrrolidine-l-carb0xylate (5).

The title compound was obtained using a procedure analogous to the procedure bed in tert- butyl4-carbamoylpiperidinecarboxylate (see Scheme 42) as colorless oil (95 mg, 87%). MS (ESI): m/Z = 487.7 [M + Na]+. -(4-phenoxyphenyl)(pyrrolidinyl)thiazole-4—carboxamide hydrochloride (6). The title nd was obtained using a procedure analogous to the procedure described in 1-(4- phenoxyphenyl)—5-(piperidinyl)-1H—pyrazolecarboxamide hydrochloride (see Scheme 46) as colorless oil (90 mg, 100%). MS (ESI): m/z = 365.8 [M + H]+.

Example 44 2-(1-acryloylpyrrolidinyl)—5-(4-phenoxyphenyl)thiazole—4-carboxamide N .0 The title compound was obtained using a procedure analogous to the procedure described in e 3 as a White solid (30 mg, 30%). 1H NMR (300 MHZ, CD30D) 5 7.52 (d, J = 9.0 Hz, 2H), 7.37 (d, J = 9.0 Hz, 2H), 7.15 (t, J = 7.4 Hz, 1H), 7.06—7.02 (m, 2H), 6.99—6.94 (m, 2H), 6.64 (ddd, J = 16.9, 10.4, 7.2 Hz, 1H), 6.29 (dt, J =16.8, 1.9 Hz, 1H), 5.76 (dt, J = 10.4, 1.7 Hz, 1H), 4.19—4.05 (m, 0.5H), 4.03—3.82 (m, 3H), 3.83—3.71 (m, 1H), 3.65—3.55 (m, 0.5H), 2.61— 2.23 (m, 2H). MS (ESI, method F): m/z = 419.7 [M + H]+, tR=1.487 min. HPLC: 99.3% (214nm), 98.7% (254nm).

Scheme 35 NaNOQ, ACOH Pd/C HCl/EtOH OEt H—O> 0 O O 0 1, oxalyl chloride GE 00 OEt —> Iawesson's reagent H" O 2, TEA, DCM —> S NH2 HCl Pho \ PhO THF mN COOEt NBoc PhO 4 5 NBoc NBoc HCl/EtOH LiOH H20 NH3, HATU S 8 , —> \N —> \ N THF THF/MeOH/HZO m DIPEA, DMF COOH PhO O NH2 6 7 NH N‘<— S TEA, DCM \ HCl S PhD 0 NH2 PhD 0 NH2 3 Example 45 (E)—ethyl 2-(hydr0xyimin0)—3-0x0(4-phen0xyphenyl)pr0panoate (2). To a solution of ethyl 3-oxo(4-phenoxyphenyl)propanoate 1 (1 g, 3.52 mmol) in AcOH (15 mL) was added a solution ofNaNOz (0.364 g, 5.28 mmol) in water (10 mL) at 0 oC. The mixture was stirred at t temperature for 15 h. After finished, the e was extracted with ethyl acetate (2 X 20 mL). The organic layers were washed with water (2 X 10 mL) and brine (2 X 10 mL). The c layer was dried over NaZSO4, filtered and concentrated to give the title compound (1.1 g, 100%) as a yellow solid. MS (ESI): m/z = 313.8 [M + H]+. ethyl 2-amin00x0(4-phen0xyphenyl)pr0pan0ate hydrochloride (3). To the solution of (E)-ethyl 2-(hydroxyimino)—3—oxo(4—phenoxyphenyl)propanoate 2 (6 g, 19.15 mmol) in MeOH (50 mL) was added Pd/C (10%, 500 mg) and HCl/EtOH (33%, 20 mL) under en atmosphere, and the resulting solution was stirred for 24 h at ambient temperature, then filtered and the filtrate was concentrated. The crude product was purified by Prep-HPLC g with CH3CN/H20 (containing 0.5% TFA) from 10:90 to 60:40 to get the title compound (3.5 g, 61%) as yellow oil. MS (ESI): m/Z = 299.9 [M + Hr. tert-butyl 3-(1-eth0xy-1,3-di0xo(4-phenoxyphenyl)pr0panylcarbamoyl)piperidine—1- carboxylate (4). To the solution of l-(tert-butoxycarbonyl)piperidinecarboxylic acid (0.5 g, 2.18 mmol) in DCM (10 mL) was added oxalyl chloride (0.415 g, 3.27 mmol) and 5 drops of DMF. The mixture was stirred at rt for 2 h, concentrated to give the crude mixture. To the solution of ethyl 2—aminooxo-3—(4-phenoxyphenyl)propanoate hydrochloride 3 (0.73 g, 2.18 mmol) in DCM (20 mL) was added TEA (0.66 g, 6.54 mmol) and a solution of above mixture in DCM (10 mL). The resulting solution was stirred at rt for 2 h. The on mixture was washed with brine (2 X 10 mL), dried over NaZSO4, filtered and concentrated to get a residue which was purified by silica gel column chromatography eluting with 1:1 PE/EA to get the title compound (0.16 g, 14%) as a yellow oil. MS (ESI): m/z = 454.7 [M — 55]+. ethyl 2-(1-(tert—butoxycarbonyl)piperidinyl)(4-phenoxyphenyl)thiazole—4-carboxylate (5). To a solution of tert-butyl 3-(1-ethoxy-1,3-dioxo(4-phenoxyphenyl)propan ylcarbamoyl)piperidine-l-carboxylate 4 (0.16 g, 0.31 mmol) in THF (20 mL) was added lawesson’s t (0.127 g, 0.31 mmol). The mixture was degassed with N; for 3 times, then heated to reflux and stirred for 2 h. When finished, the mixture was extracted with ethyl acetate (2 X 20 mL). The c layers were washed with sat. NaHC03 (2 X 20 mL) and brine (2 X 20 mL). The organic layer was dried over Na2S04, filtered and concentrated to get a residue which was purified by silica gel column chromatography eluting with 2:1 PE/EA to get the title compound (90 mg, 57%) as a yellow oil. MS (ESI): m/z = 508.8 [M + H]+. 2-(1-(tert-but0xycarb0nyl)piperidinyl)(4-phenoxyphenyl)thiazolecarboxylic acid (6). The title compound was obtained using a procedure analogous to the procedure described in -(l -(tert-butoxycarbonyl)piperidinyl)- l -(4-phenoxyphenyl)— l H-pyrazole-3 xylic acid (see Scheme 46) as a white solid (80 mg, 94%). MS (ESI): m/z = 480.8 [M + H]+. tert-butyl 3-(4-carbamoyl(4-phenoxyphenyl)thiazolyl)piperidine—l-carboxylate (7).

The title compound was obtained using a procedure analogous to the procedure described in tert- butyl 4-carbamoylpiperidine-l-carboxylate (see Scheme 42) as ess oil as colorless oil (40 mg, 50%). MS (ESI): m/Z = 479.7[M + Hr. henoxyphenyl)—2-(piperidinyl)thiazolecarboxamide hydrochloride (8). The title nd was obtained using a procedure analogous to the procedure bed in 1-(4- phenoxyphenyl)—5-(piperidinyl)-1H—pyrazolecarboxamide hydrochloride (see Scheme 46) as yellow oil (35 mg, 100%). MS (ESI): m/z = 379.8[M + H]+.

Example 45 2-(1-acryloylpiperidinyl)—5-(4-phenoxyphenyl)thiazolecarboxamide (fifioQ The title compound was obtained using a procedure ous to the procedure described in Example 3 as a white solid (10 mg, 27%). 1H NMR (300 MHz, CD30D) 5 .48 (m, 2H), 7.44—7.32 (m, 2H), 7.15 (t, J: 7.4 Hz, 1H), 7.03 (d, J: 0.9 Hz, 2H), 6.99—6.94 (m, 2H), 6.84 (ddd,J= 23.2, 16.7, 10.6 Hz, 1H), 6.21 (dd,J= 16.8, 1.9 Hz, 1H), 5.75 (d,J= 10.7 Hz, 1H), 4.62 (d, J: 11.6 Hz, 0.5H), 4.27 (d, J: 13.2 Hz, 0.5H), 4.15 (d, J: 12.8 Hz, 0.5H), 4.00 (d, J: 13.6 Hz, 0.5H), 3.72 (dd, J= 13.5, 8.9 Hz, 0.5H), 3.42—3.33 (m, 1H), 3.29—3.15 (m, 15H), 2.35— 2.23 (m, 1H), 2.08—1.85 (m, 2H), 1.75—1.55 (m, 1H). MS (ESI, method F): m/z = 433.8 [M + H]: tR=1.557 min. HPLC: 96.7% (214nm), 98.0% (254nm).

Scheme 36 QC? 0@ 0 g o AcONH4,AcOH,reflulx EtO / Boc2O,Na2603 OC 0 —> —> N ° ) Etc O / THFIHZO DIPEA, CchN, rt 0 N N Boc H 1 2 3 o@ o@ °Q 0 0 EtO / NaOH, MEOH, H20 HATU, NHg, DMF H2N / / HCl/EtOH IN —> HO —> 03> /N —> O IN 0 Bee N Eoc o Wm / o o H2N —> o / "'2N / DIPEA,DCM Bee \ e 46 -butyl 4-(l-ethoxy-1,3-di0X0(4-phenoxyphenyl)pr0panyl) piperidine—1,4- dicarboxylate (2). The title compound was obtained using a procedure analogous to the procedure described in l -tert—butyl 3-( l -ethoxy- l ,3 -dioxo(4-phenoxyphenyl)propanyl) piperidine-l,3-dicarboxylate (see Scheme 32) as pale yellow oil (0.85 g, 60%). MS (ESI): m/z = 456.1 [M + H — 561+. ethyl 4-(4-phenoxyphenyl)(piperidinyl)oxazole—S-carboxylate (3). The title compound was obtained using a procedure analogous to the procedure described in ethyl 4-(4- phenoxyphenyl)(piperidinyl)oxazolecarboxylate (see Scheme 32) as yellow oil (0.80 g, crude). MS (ESI): m/Z = 393.2 [M + H.

Ethyl(1-(tert-butoxycarbonyl)piperidinyl)—4—(4-phenoxyphenyl)oxazole-S-carboxylate (4). The title nd was obtained using a procedure analogous to the procedure described in ethyl 2—(4-(tert—butoxycarbonyl)piperazinyl)(4—phenoxyphenyl)thiazole—5 -carboxylate (see Scheme 37) as pale yellow oil (0.85 g, 68%, two steps). MS (ESI): m/z = 437.2 [M + H - 56]+. 2-(1-(tert—butoxycarbonyl)piperidinyl)(4-phenoxyphenyl)0xazole-5—carboxylic acid (5). The title compound was obtained using a procedure analogous to the procedure described in -(1—(tert-butoxycarbonyl)piperidin—4-yl)-4'-phenoxybipheny1—2-carboxylic acid (see Scheme 45) as yellow oil (0.8 g, 99%). MS (ESI): m/Z = 409.1 [M + H — 561+. tert-butyl 4-(5-carbamoyl-4—(4-phenoxyphenyl)0xazolyl)piperidine-l-carboxylate (6).

The title nd was obtained using a procedure analogous to the procedure described in tert- butyl-3 -(4-carbamoyl(4-phenoxyphenyl)—1H-pyrazolyl)pyrrolidine-1—carboxylate (see Scheme 23) as pale yellow solid (390 mg, overweight). MS (ESI): m/z = 408.0 [M + H - 56]+. 4-(4-phenoxyphenyl)(piperidinyl)oxazole-S-carboxamide hydrochloride (7). The title nd was obtained using a procedure analogous to the procedure bed in 1—(4- phenoxyphenyl)(piperidinyl)-1H-pyrazolecarboxamide hydrochloride (see Scheme 46) as white solid (400 mg, overweight). MS (ESI): m/z = 364.1 [M + H]+. e 46 2-(1-acryloylpiperidinyl)(4-phenoxyphenyl)0xazolecarboxamide The title compound was obtained using a procedure analogous to the procedure described in Example 15 as white solid (45 mg, 34%, three steps). 1H NMR (300 MHz, DMSO) 8 8.26 (d, J = 9.0 Hz, 2H), 7.92 (s, 1H), 7.674 (s, 1H), 7.53—7.29 (m, 2H), 7.25—7.13 (m, 1H), 7.11—6.99 (m, 4H), 6.85 (dd, J: 16.7, 10.5 Hz, 1H), 6.11 (dd, J: 16.7, 2.4 Hz, 1H), 5.68 (dd, J: 10.4, 2.4 Hz, 1H), 4.39—4.31 (m, 1H), 4.12—4.04 (m, 1H), 3.33—3.14(m, 2H), 3.02—2.89 (m, 1H), 2.14—2.06 (m, 2H), 1.90—1.65 (m, 2H). MS (ESI, method A): m/z = 418.1 [M + H]+, tR=1.489 min. HPLC: 97% ), 97% (254nm).

Scheme 37 GNi"D J 0"" (N’ Y""2 ODMO 0 20 STNJ [N)1. 2, THF 55°C, 1h o N 2N;3H20 ET] 0 N r..,t 3d /0 Egg/H reflux 2h TEA, THF, Boc o r.t., 2h,73% 1 3 00 00 6 OH \NH o S /—\ L'OH. |/>_N N_BOC HATU,CH3NH2 o s /—‘\ —’ N—Boc N \__/ —> | />—N THF/HZO/MeoH Q TEA, DCM, r.t., 3h,90% N 60°C, 4h, 97% 0 7 ©\0 8 1;:thr..t 1h ©\OO film—N Iii/39w TEA THF 0°C 10min Example 47 tert-butyl 4-carbamothioylpiperazine—1-carb0xylate (3). To a solution of imidazol-l- yl)methanethione 2 (2.14 g, 12 mmol) in anhydrous THF (30 mL) was added tert-butyl piperazine-l-carboxylate 1 (1.86 g, 10 mmol) at ambient temperature. The mixture was allowed to stir at ambient temperature for 2 h, then the mixture was heated at 55 °C for l h. The mixture was concentrated under vacuum to about half the volume. To the remaining reaction mixture was added 2 M solution of ammonia in methanol (20 mL) and allowed to stir at ambient temperature for 3 days. The solvent was removed and the residue was purified by chromatography eluting with 50:1 DCM/MeOH to afford the title compound (1.7 g, 69%) as white solid. MS (ESI): m/z = 246.1 [M + H]+. ethyl 4-(4-phen0xyphenyl)—2-(piperazinyl)thiazolecarboxylate (5). To a solution of ethyl 2-bromooxo(4-phenoxyphenyl)propanoate 4 (362 mg, 1 mmol) in ethanol (10 mL)was added tert-butyl 4-carbamothioylpiperazine—l-carboxylate 3 (245 mg, 1 mmol) at ambient temperature. The mixture was then heated to reflux and stirred for 2 h. After cooling to ambient temperature, the solvent was removed and the e was purified by silica gel column tography g with 40:1 to 20:1 DCM/MeOH to afford the title compound (214 mg, 52%) as brown solid. MS (ESI): m/Z = 410.1 [M + H. ethyl 2-(4-(tert-but0xycarb0nyl)piperazinyl)—4—(4-phenoxyphenyl)thiazole—5-carboxylate (6). To the compound of ethyl 4-(4-phenoxyphenyl)—2-(piperazin-1—yl)thiazolecarboxylate 5 (214 mg, 0.51 mmol) were added di-tert-butyl dicarbonate (134 mg, 0.6 mmol) and TEA (0.2 mL, 1.5 mmol) at t ature. The mixture was then stirred at ambient ature for 2 h. The solvent was removed and the residue was purified by silica gel column chromatography eluting with 50:1 DCM/MeOH to afford the title compound (190 mg, 73%) as brown solid. MS (ESI): m/Z = 510.1 [M + Hr. 2-(4-(tert-but0xycarbonyl)piperazinyl)(4-phenoxyphenyl)thiazole—5-carboxylic acid (7). To a solution of ethyl tert—butoxycarbonyl)piperazinyl)(4- yphenyl)thiazolecarboxy1ate 6 (190 mg, 0.37 mmol) in THF (50 mL)/H20 (1 mL)/MeOH (3 mL) was added lithium hydroxide (30 mg, 0.74 mmol) at ambient temperature.

The mixture was then heated to 60 °C and stirred for 2 h. After cooling to t temperature, the solvent was removed and the residue was purified by chromatography eluting with 10:1 DCM/MeOH to afford the title compound (173 mg, 97%) as white solid. MS (ESI): m/z = 482.0 [M + Hr. tert-butyl 4-(5-(methylcarbamoyl)(4—phenoxyphenyl)thiazolyl)piperazine—1- carboxylate (8). To a solution of 2-(4-(tert-butoxycarbonyl)piperaziny1)—4-(4- phenoxyphenyl)thiazole carboxylic acid 7 (124 mg, 0.26 mmol) in DCM (10 mL) was added HATU (117 mg, 0.3 mmol) and methanamine (0.26 ml, 0.26 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 3 h. The solvent was removed and the residue was purified by silica gel column chromatography eluting with 1:5 EA/PE to afford the title compound (115 mg, 90%) as ess oi1. MS (ESI): m/z = 495.2 [M + H]+.

N-methyl(4-phenoxyphenyl)(piperazinyl)thiazolecarb0xamide (9). To a solution of tert—butyl 4-(5 -(methylcarbamoy1)—4-(4-phenoxypheny1)thiazo1-2—y1)piperazineCarboxy1ate 8 (115 mg, 0.23 mmol) in DCM (5 mL) was added TFA (1 mL) at ambient temperature. The e was stirred for 1 h at ambient temperature. The solvent was removed and the residue was purified by silica gel column chromatography eluting with 10:1 DCM/MeOH to afford the title compound (117 mg, 100%) as colorless oil.

Example 47 2-(4-acryloylpiperazin-l-y])—N-methyl—4-(4—phenoxyphenyl)thiazole-S-carboxamide AWOSEQD../ To a solution of N—methyl(4-phenoxyphenyl)(piperazinyl)thiazole—5-carboxamide 9 (117 mg, 0.23 mmol) in DCM (5 mL) were added TEA (0.1 mL, 0.7 mmol) and acryloyl chloride 10 (0.21 mg, 0.23 mol) at 0 CC. The mixture was stirred at 0 CC for 10 minutes. The solvent was removed and the residue was purified by Prep-TLC eluting with 50:1 to 20:1 DCM/MeOH to afford the title compound (50 mg, 49%) as white solid. 1H NMR (400 MHz, CDCl3) 5 7.57 (d, J: 8.6 Hz, 2H), 7.40 (t, J: 7.9 Hz, 2H), 7.19 (t, J: 7.4 Hz, 1H), 7.09 (d, J: 8.4 Hz, 4H), 6.60 (dd, J: 16.8, 10.5 Hz, 1H), 6.37 (d, J: 16.7 Hz, 1H), 5.79 (d, J: 11.8 Hz, 1H), 5.59 (d, J: 4.1 Hz, 1H), 3.78 (d, J: 48.5 Hz, 4H), 3.62 (s, 4H), 2.80 (d, J: 4.8 Hz, 3H), MS (ESI, method A): m/z = 449.1 [M + H]+, tR=1.528 min. HPLC: 96.9% (214nm), 96.9% (254nm).

Scheme 38 O O NBoc NBoc O O 1, oxalyl chloride. 12, Pth LIOH H20 h0 "N o —> O O \ —> \ \ N \ N NH 2, TEA, DCM TEA, DCM THF/MeOH/HZO 2 HCI coca COOH NBOC PhO PhD 1 2 3 4 NBoc NH NH3: HATU HCI/E OHt O O \N TEA,DCM \N HCI O DIPEA‘ DMF m THF m \ N PhD 0 NH2 PhD 0 NH2 PhD 0 6 Example 48 utyl(1-eth0xy—1,3-di0x0(4-phenoxyphenyl)pr0panylcarbamoyl)pyrrolidine carboxylate (2). The title compound was ed using a procedure analogous to the procedures described in the General Scheme and Example 15 as yellow oil (0.35 g, 30%). MS (ESI): m/Z = 440.7 [M — 551+.

Ethyl-2—(1-(tert-butoxycarbonyl)pyrrolidinyl)(4-phenoxyphenyl)0xazole carboxylate (3). To a solution of Pth (159 mg, 0.604 mmol) in DCM (20 mL) was added 12 (153 mg, 0.604 mmol). The ing mixture was degassed with N2 3 times and stirred at ambient temperature for 2 h. TEA (122 mg, 1.208 mmol) was added and stirred for 10 min, then a solution of tert-butyl 3-(1-ethoxy-1,3-dioxo—3-(4-phenoxyphenyl)propan-2— ylcarbamoy1)pyrrolidinecarboxy1ate 2 (150 mg, 0.302 mmol) was added and stirred for 15 h.

The mixture was diluted with ethyl acetate (50 mL), and washed with sat. 3 (20 mL), brine (3 X 20 mL). The organic layer was dried over NazSO4, filtered and trated to get a e which was purified by silica gel column tography eluting with 1:1 PE/EA to get the title compound (0.11 g, 76%) as a colorless oil. MS (ESI): m/z = 422.8 [M — 55]+. tert—butoxycarbonyl)pyrrolidinyl)(4-phenoxyphenyl)oxazole—4-carboxylic acid (4). The title compound was obtained using a procedure analogous to the procedure described in -(1 -(tert-butoxycarbonyl)piperidinyl)(4-phenoxyphenyl)— 1 H—pyrazole-3 -carboxylic acid (see Scheme 46) as yellow oil (110 mg, 100%). MS (ESI): m/z = 394.8 [M — 55]+ tert-butyl 3-(4-carbam0yl-5—(4-phenoxyphenyl)oxazol-Z-yl)pyrrolidine-l-carboxylate (5).

The title compound was obtained using a procedure analogous to the procedure described in tert- butyl 4-carbamoylpiperidinecarboxylate (see Scheme 42) as ess oil (95 mg, 92%). MS (ESI): m/z = 393.8 [M — 551+. -(4-phenoxyphenyl)(pyrrolidinyl)0xazole—4—carb0xamide hydrochloride (6). The title compound was obtained using a procedure analogous to the procedure described in 1-(4- phenoxyphenyl)—5-(piperidinyl)-1H-pyrazolecarboxamide hydrochloride (see Scheme 46) as a white solid (75 mg, 92%). MS (ESI): m/z = 349.9 [M + H]+.

Example 48 2-(1-acryloylpyrrolidinyl)(4—phenoxyphenyl)0xazolecarboxamide The title compound was obtained using a procedure analogous to the procedure described in Example 1 as an off white solid (50 mg, 64%). 1H NMR (400 MHz, DMSO) 5 8.27—8.22 (m, 2H), 7.61 (s, 1H), 7.58 (s, 1H), 7.45 (t, J: 7.9 Hz, 2H), 7.21 (t, J: 7.3 Hz, 1H), 7.14—7.06 (m, 4H), 6.67—6.58 (m, 1H), 6.16 (d, J: 16.7 Hz, 1H), 5.70 (d, J: 10.4 Hz, 1H), 4.05—4.01 (m, 0.5H), .92 (m, 0.5H), 3.90—3.59 (m, 3.5H), 3.53—3.45 (m, 0.5H), 2.45—2.21 (m, 2H). MS (ESI, method A): m/z = 404.1 [M + H]+, tR=1.484 min. HPLC: 99.5% (214nm), 99.3% (254nm) Scheme 39 O O NBoc NBoc 1 oxalyl chloride HN O lawesson's rea ent LiOH H 0 08—»Pho —g> —2> S \ NHz HCI 2, TEA DCM PhO Tm"COOEt THF/MeOHiHZOmNCOOH N PhO 1 2 NBoc NH3. HATU HCI/EtOH TEA DCM S —> \ —> sp\ HCI '—>Pho DIPEA, DMF m" THF MHZ PhD 0 NH2 NH PhD 0 6 Example 49 utyl—4-(1-ethoxy—1,3-di0X0(4-phenoxyphenyl)propanylcarbamoyl)piperidine carboxylate (2). The title compound was obtained using a procedure analogous to the ures described in the General Scheme and Example 15 as colorless oil (0.18 g, 16%). MS (ESI): m/Z = 454.8[M — 55]+ ethyl 2-(1-(tert—butoxycarb0nyl)piperidinyl)—5-(4-phenoxyphenyl)thiazolecarboxylate (3). The title compound was obtained using a procedure analogous to the ure described in tert-butyl 2-carbamothioylpiperidinecarboxylate (see Scheme 30) as colorless oil (0.12 g, 67%). MS (EST): m/Z = 508.8 [M + H]+. 2-(1-(tert—butoxycarb0nyl)piperidinyl)(4-phenoxyphenyl)thiazolecarboxylic acid (4). The title compound was ed using a procedure analogous to the procedure described in -(1 -(tert-butoxycarbonyl)piperidin-4—yl)(4-phenoxyphenyl)— 1 zole-3 -carboxylic acid (see Scheme 46) as yellow oil (120 mg, 100%). MS (ESI): m/z = 480.8 [M + H]+. tert-butyl 4-(4-carbam0yl-5—(4-phenoxyphenyl)thiazolyl)piperidine—l-carboxylate (5).

The title compound was obtained using a procedure analogous to the procedure described in tert- butyl 3—(5-carbamoyl—4—(4-phenoxyphenyl)thiazol-2—yl)piperidine-1—carboxylate (see Scheme ) as colorless oil (100 mg, 88%). MS (ESI): m/z = 479.8[M + H]+. -(4-phenoxyphenyl)(piperidinyl)thiazole—4-carboxamide hloride (6). The title compound was obtained using a procedure analogous to the procedure described in 1-(4- phenoxyphenyl)—5-(piperidinyl)—1H-pyrazolecarboxamide hydrochloride (see Scheme 46) as a white solid (80 mg, 92%). MS (ESI): m/z = 379.8[M + H]+.

Example 49 2-(1-acryloylpiperidinyl)—5-(4-phenoxyphenyl)thiazole—4-carboxamide PhD SQ O \ / The title compound was obtained using a procedure analogous to the ure described in Example 51 as an off white solid (20 mg, 24%). 1H NMR (400 MHz, DMSO) 8 7.68 (s, 1H), 7.56 (d, J: 8.7 Hz, 2H), 7.50 (s, 1H), 7.47—7.42 (m, 2H), 7.21 (t, J: 7.4 Hz, 1H), 7.10 (d, J: 7.7 Hz, 2H), 7.00 (d, J= 8.7 Hz, 2H), 6.85 (dd, J= 16.7, 10.5 Hz, 1H), 6.12 (dd, J= 16.7, 2.4 Hz, 1H), .69 (dd, J: 10.5, 2.4 Hz, 1H), 4.49 (d, J: 12.8 Hz, 1H), 4.15 (d, J: 12.8 Hz, 1H), 3.33—3.19 (m, 2H), 2.88 (d, J: 11.5 Hz, 1H), 2.12 (d, J: 12.8 Hz, 2H), 1.73—1.55 (m, 2H). MS (ESI, method A): m/z = 434.0 [M + H]+, tR=1.606 min. HPLC: 95.0% (214nm), 96.6% (254nm) Scheme 40 OO o O "Gk/IN O O ‘N,.CNH N / ~N,CN/ Scheme 41 C D 0 0 J NH ~ ~ . SW (1 .r 0/‘0 m mB..

O SYN N \ [ 1 ' 2 THF 55°C 1h N IN (300120 ’ ‘ ’ E 4 0 o \SYN{I N 2. NH H O, r.t., 3d EtOH, reflux, 2h, face 69%3 2 '1 TEAvTHE 3°C at, 2h, 73% 1 3 00 5 QOG LiOH />_N/—\—NBoc HATU NH3 THFiHZO/MeOH TEA DCM, rt 3h 100% |:\/:/\,>—NN-Boc 60°C 4h 97% l:/—\/>—N l:/—\/>~N Ego/M rt 1h goo TEA THF 0°C 10mim Example 51 tert-butyl 4-carbamothioylpiperazine-l-carb0xylate (3). To a solution of di(1H—irnidazol yl)methanethione 2 (2.14 g, 12 mmol) in anhydrous THF (30 mL) was added tert-butyl piperazine-l—carboxylate 1 (1.86 g, 10 mmol) at ambient ature. The mixture was d to stir at ambient temperature for 2 h, and then the mixture was heated to 55 °C for 1 h. The mixture was concentrated in vacuum to about half the volume. To the remaining reaction mixture was added a 2 M ammonia in methanol (20 mL) and was allowed to stir at t temperature for 3 days. The solvent was removed and the residue was purified by silica gel column chromatography eluting with 50:1 DCM/MeOH to afford the title compound (1.7 g, 69%) as white solid. MS (ESI): m/Z = 246.1 [M + H]+. ethyl 4-(4-phen0xyphenyl)(piperazinyl)thiazolecarboxylate (5). To a solution of ethyl 2-bromooxo(4-phenoxyphenyl)propanoate 4 (362 mg, 1 mmol) in ethanol (10 l 1 1 mL)was added tert-butyl 4-carbamothioylpiperazine—1-carboxy1ate 3 (245 mg, 1 mmol) at ambient temperature. The mixture was then heated to reflux and stirred for 2 h. After cooling to ambient ature, the solvent was removed and the residue was purified by silica gel column chromatography eluting with 40:1 to 20:1 DCM/MeOH to afford the title compound (214 mg, 52%) as brown solid. MS (ESI): m/z = 410.1 [M + H]+. 2-(4-(tert-butoxycarbonyl)piperazinyl)-4—(4-phenoxyphenyl)thiazole-S-carboxylate (6). To the compound of ethyl 4-(4-phenoxyphenyl)(piperazin-1—yl)thiazolecarboxylate 5 (214 mg, 0.51 mmol) was added di-tert-butyl dicarbonate (134 mg, 0.6 mmol) and TEA (0.2 mL, 1.5 mmol) at ambient temperature. The mixture was then stirred at ambient temperature for 2 h.

The solvent was removed and the residue was d by silica gel column tography eluting with 50:1 DCM/MeOH to afford the title compound (190 mg, 73%) as brown solid. MS (ESI): m/Z = 510.1 [M + Hr. 2-(4-(tert-but0xycarb0nyl)piperazinyl)(4-phenoxyphenyl)thiazole—5-carb0xylic acid (7). To a solution of ethyl 2-(4-(tert-butoxycarbonyl)piperazinyl)(4- yphenyl)thiazolecarboxylate 6 (190 mg, 0.37 mmol) in THF (50 mL)/H20(1mL)/MeOH(3 mL) was added lithium hydroxide (30 mg, 0.74 mmol) at ambient temperature. The mixture was then heated to 60 CC and d for 2 h. After cooling to ambient temperature, the solvent was removed and the residue was purified by silica gel column chromatography eluting with 10:1 DCM/MeOH to afford the title compound (173 mg, 97%) as white solid. MS (ESI): m/Z = 482.0 [M + H]+. tert-butyl 4-(5-carbamoyl-4—(4-phenoxyphenyl)thiazol-Z-yl)piperazine—l-carboxylate (8).

To a solution of 2-(4-(tert-butoxycarbonyl)piperazinyl)(4-phenoxyphenyl)thiazole carboxylic acid 7 (173 mg, 4.6 mmol) in DCM (10 mL) was added HATU (164 mg, 0.43 mmol) at ambient temperature. The mixture was degassed three times with ammonia gas and stirred at ambient temperature under ammonia atmosphere for 6 h. The solvent was removed and the residue was purified by silica gel column chromatography eluting with 30:1 DCM/MeOH to afford the title nd (170 mg, 100%) as white solid. MS (ESI): m/z = 481.1 [M + H]+. 4-(4-phen0xypheny])—2-(piperazinyl)thiazole-S-carboxamide (9). A on of tert-butyl 4-(5-carbamoyl(4-phenoxyphenyl)thiazolyl)piperazinecarboxylate 8 (170 mg, 0.35 mmol) in DCM (5 mL) and TFA (1 mL) at ambient temperature was stirred for 1 h. The solvent was removed and the residue was purified by silica gel column chromatography eluting with :1 to 10:1 DCM/MeOH to afford the title compound (110 mg, 58%) as white solid.

Example 51 2-(4-acryloylpiperazinyl)(4-phenoxyphenyl)thiazole—5-carboxamide 0 S /—\ 0 lN/>_N\__/NJ<= To a on of 4-(4-phenoxyphenyl)—2-(piperazin-l—yl)thiazolecarboxamide 9 (110 mg, 0.22 mmol) in DCM (5 mL) was added TEA (0.1 mL, 0.66 mmol) and acryloyl chloride 10 (0.20 mg, 0.22 mmol) at 0 OC. The mixture was stirred at 0 °C for 10 minutes. The solvent was removed and the residue was d by Prep-TLC eluting with 25 :1 DCM/MeOH to afford the title compound (70 mg, 73%) as white solid. 1H NMR (400 MHz, MeOD) 8 7.66—7.61 (m, 2H), 7.37— 7.43 (m, 2H), 7.18 (t, J: 7.4 Hz, 1H), .04 (m, 4H), 6.83 (dd, J: 16.8, 10.6 Hz, 1H), 6.27 (dd,J=16.8, 1.8 Hz, 1H), 5.81 (dd,J= 10.6, 1.9 Hz, 1H), 3.87—3.78 (m, 4H), 3.69—3.61 (m, 4H). MS (ESI, method A): m/z = 435.0 [M + H]+, tR=1.539 min., HPLC: 95.5% (214nm), 96.4% (254nm).

Scheme 42 HO s 60 Q mBr 4 HATU NH3 DMF 150 Lawessons reagent 0 O OEt toluene, , 2h EtOH, reflux 2 3 o@ o@ o@ o 0 "0 / NHS’HATU'DMF EtO / EC / Boc20,NaZCO3 NaOH,MeOH,H20 N —’ —> 3% N —> s THF/H20 3% E/ N N Boc H Boc e 7 o o H2N / / N HCI/EtOH HZN "I H2N S / 3 / i S /N E DIPEA,DCM N N Example 52 tert-butyl 4-carbamoylpiperidine-l-carboxylate (2). To a mixture of l-(tert- butoxycarbonyl)piperidinecarboxylic acid 1 (2.29 g, 10 mmol), DIEA (3.87 g, 30 mmol) and HATU (4.18 g, 11 mmol) in DMF (50 mL) was added NH3 by bubbling for 20 min. The resulting mixture was stirred at rt overnight. The mixture was diluted with water (200 mL) and extracted with EA (2 X 50 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was applied onto silica gel column eluting with EA to get the title compound (1.3 g, 56%) as white solid. MS (ESI): m/Z = 173.2 [M + H — 561+. tert-butyl 4-carbamothioylpiperidinecarb0xylate (3). The title compound was obtained using a procedure analogous to the procedure described in cyclopentanecarbothioamide (see Scheme 30) as pale yellow solid (0.35 g, 29%). MS (ESI): m/z = 245.2 [M + H]+. ethyl henoxyphenyl)—2-(piperidinyl)thiazolecarb0xylate (5). The crude of the title compound was obtained using a ure analogous to the procedure described in ethyl 2- cyclopentyl-4—(4-phenoxyphenyl)thiazolecarboxylate (see Scheme A-2) as yellow oil (0.90 g, overweight). MS (ESI): m/Z = 408.8 [M + H]+. ethyl 4-(4-phenoxyphenyl)—2-(piperidinyl)thiazolecarboxylate (6). The title nd was obtained using a procedure analogous to the procedure described in ethyl 2-(4-(tert- butoxycarbony1)piperazinyl)-4—(4-phenoxyphenyl)thiazolecarboxylate (see Scheme 37) as yellow solid (0.30 g, 30%, two steps). MS (ESI): m/Z = 509.1 [M + H]+. tert-but0xycarb0nyl)piperidinyl)(4-phenoxyphenyl)thiazolecarboxylic acid (7). The title compound was obtained using a procedure analogous to the procedure described in -(1-(tert-butoxycarbonyl)piperidiny1)-4'-phenoxybiphenylcarboxylic acid (see Scheme 45) as yellow oil (250 mg, overweight). MS (ESI): m/z = 481.0 [M + H]+. tert-butyl 4-(5-carbamoyl(4-phenoxyphenyl)thiazolyl)piperidine—l-carboxylate (8).

The title compound was obtained using a procedure analogous to the procedure bed in tert- butyl-3 -(4-carbamoyl(4-phenoxyphenyl)-1H-pyrazoly1)pyrrolidinecarboxylate (see Scheme 23) as pale yellow solid (250 mg, overweight). MS (ESI): m/Z = 480.1 [M + H]+. 4-(4-phenoxyphenyl)(piperidinyl)thiazole—5-carb0xamide (9). The title compound was obtained using a procedure ous to the procedure described in 1-(4-phenoxyphenyl) (piperidinyl)—1H-pyrazolecarboxamide hydrochloride (see Scheme 46) as white solid (300 mg, overweight). MS (ESI): m/z = 380.1 [M + H]+.

Example 52 cryloylpiperidinyl)(4-phen0xyphenyl)thiazolecarb0xamide WNO"i \ o O o The title compound was obtained using a procedure analogous to the procedure described in Example 15 as white solid (50 mg, 23%, four steps). 1H NMR (300 MHz, DMSO) 8 7.76—7.69 (m, 4H), 7.42 (t, J= 7.4 Hz, 2H), 7.19 (t, J= 7.4 Hz, 1H), 7.09—7.00 (m, 4H), 6.84 (dd, J= 16.7, .4 Hz, 1H), 6.10 (dd, J: 16.7, 2.4 Hz, 1H), 5.68 (dd, J: 10.4, 2.4 Hz, 1H), 4.52—4.41 (m, 1H), 4.19—4.08 (m, 1H), 3.32—3.15 (m, 2H), 2.90—2.78 (m, 1H), .06 (m, 1.73—1.46 , 2H), (m, 2H). MS (ESI, method A): m/Z = 434.0 [M + H]+, tR=1.540 min. HPLC: 96% ), 96% (254nm) Scheme 43 w (9 o .

EtOH,70°C / Example 50 e 53 Example 53 (E)(1-(2-cyan0cyclopropylacryloyl)azetidinyl)—3-(4-phenoxyphenyl)—1H-pyrazole carboxamide OO O / ‘N/CN o / To a solution of 1-(1—(2-cyanoacetyl)azetidinyl)—3-(4-phenoxyphenyl) -1H-pyrazole carboxamide (100 mg, 0.25 mmol) and piperidine (2 drops) in EtOH (10 mL) was added cyclopropanecarbaldehyde (70 mg, 1.0 mmol). Then the solution was d at 70°C for 1 h.

After the reaction was completed, the solution was concentrated and purified by Prep—TLC with :1 DCM/MeOH to give the crude product (70 mg) and then purified by Prep-HPLC (ACN/H20 = 42%, 0.1%FA) to afford the title compound (15 mg, 13%) as a white solid. 1H NMR (400 MHZ, CDClg) 8 8.16 (s, 1H), 7.64—7.57 (m, 2H), 7.45—7.37 (m, 2H), 7.22—7.16 (m, 1H), 7.15—7.03 (m, 5H), 5.60 (s, 2H), 5.23—5.13 (m, 1H), 5.11—4.95 (m, 2H), 4.68—4.54 (m, 2H), 2.16—2.05 (m, 1H), 1.33—1.29 (m, 2H), 1.02—0.95 (m, 2H). MS (ESI, Method A): m/z = 454.1 [M + H]+, tR = 1.485 min. HPLC: 100% ), 100% (254nm).

Scheme 44 O O NBOC NBOC O O 1 ,oxayc one[ | hl 'd M03 HN o A|,PhP LiOHHO (mt—who o\ —2, o\ NHz HC] 2, TEA, DCM TEA, DCM mN THF/MeOH/HZO @N NBoc COOEt COOH PhO PhO 1 2 3 4 N_<— 0QNBOC NH3, HATU HCl/EIOH 0 TEA, DCM —, \ —> QNH\ HQ] —> \ DIPEA, DMF m" THF O/jl" PhD ml 0 NHz PhO o NHz PhO o NH2 6 Example 54 tert-butyl—3-(1-eth0xy—1,3-di0x0(4-phenoxyphenyl)propanylcarbamoyl)piperidine carboxylate (2). The title nd was obtained using a procedure analogous to the ures described in the General Scheme and Example 15 as yellow oil (0.4 g, 36%). MS (ESI): m/z = 454.8 [M —55]+.

Ethyl(1-(tert-butoxycarbonyl)piperidinyl)—5—(4-phenoxyphenyl)0xazole-4—carboxylate (3). The title compound was obtained using a procedure analogous to the procedure described in ethyl 2-(1-(tert-butoxycarbonyl)pyrrolidinyl)(4—phenoxyphenyl)oxazolecarboxylate (see Scheme 44) as yellow oil (0.25 g, 65%). MS (ESI): m/z = 492.8 [M + H]+. 2-(1-(tert—butoxycarbonyl)piperidinyl)(4-phenoxyphenyl)0xazolecarboxylic acid (4). The title compound was obtained using a procedure analogous to the procedure described in -(1 -(tert-butoxycarbonyl)piperidin-4—yl)(4—phenoxyphenyl)— 1 H-pyrazole—3 -carboxylic acid (see Scheme 46) as yellow oil (0.25 g, 100%). MS (ESI): m/z = 464.8 [M + H]+. utyl 3-(4-carbamoyl-5—(4-phenoxyphenyl)0xazolyl)piperidine-l-carboxylate (5).

The title compound was obtained using a procedure analogous to the procedure described in tert- butyl 3-(5-carbamoyl—4-(4—phenoxyphenyl)thiazol—2—yl)piperidinecarboxylate (see Scheme ) as yellow oil (0.2 g, 84%). MS (ESI): m/z = 407.8 [M — 55]+. -(4-phenoxyphenyl)(piperidinyl)oxazolecarboxamide hydrochloride (6). The title compound was obtained using a procedure analogous to the procedure bed in 1-(4- yphenyl)(piperidinyl)—1H-pyrazolecarboxamide hydrochloride (see Scheme 46) as brown oil (180 mg, 100%). MS (ESI): m/Z = 363.8[M + H]+.

Example 54 2-(1-acryloylpiperidinyl)—5-(4—phenoxyphenyl)0xazolecarboxamide The title compound was obtained using a procedure analogous to the procedure described in Example 1 as a yellow solid (70 mg, 37%). 1H NMR (400 MHz, DMSO) 8 8.24 (d, J= 7.2 Hz, 2H), 7.57 (s, 1.5H), 7.50 (s, 0.5H), 7.45 (t, J: 7.9 Hz, 2H), 7.21 (t, J: 7.4 Hz, 1H), 7.11 (d, J: 3.1 Hz, 2H), 7.08 (d,J= 4.2 Hz, 2H), 6.96—6.78 (m, 1H), 6.13 (t, J= 18 Hz, 1H), 5.75—5.57 (m, 1H), 4.51 (d, J: 11.6 Hz, 0.5H), 4.08 (d, J: 12 Hz, 0.5H), 3.93 (d, J: 13.2 Hz, 0.5H), 3.85— 3.73 (m, 0.8H), 3.34—3.20 (m, 2H), 3.10—2.97 (m, 0.7H), 2.27—2.09 (m, 1H), 2.07—1.64 (m, 2H), 1.60—1.43 (m, 1H). MS (ESI, method F): m/z = 418.1 [M + H]+, tR=1.679 (min). HPLC: 100% ), 100% ).

Scheme 45 C')H COOH COOEt Boc-N::>—Blo Cl HO‘B Cl / EtOH st04 Cl ‘o / 000 EtOOC N-Boc reflux overn'gh' Pd(dppf)ClZ, chog, Pd2(dba)3, K3PO4, dioxane H20, 80°C dioxane H20,110°C COOEt COOEt COOH O/RPd/CH2 MeOHmO/Oi‘:NaOH, MeOH THF H20 CONHz CONH2 NH3 HATU DMF HCI/THF DIEA DCM Example 55 ethyl ochlor0benzoate (2). To a mixture of 4-bromochlorobenzoic acid 1 (1.9 g, 8.1 mmol) in EtOH (50 mL) was added H2S04 (5 mL) dropwise carefully at 0 CC. The resulting mixture was refluxed overnight. The volatile phase removed under reduced pressure. The residue was diluted with EA (100 mL), which was washed with water (2 X 50 mL) and brine, dried over sodium sulfate, filtered and concentrated. This resulted in the title compound (2.0 g, 95%) as brown oil. MS (ESI): m/Z = 263.0/2650 [M + H]+. tert-butyl 4-(3-chlor0(ethoxycarb0nyl)phenyl)-5,6-dihydr0pyridine-l(2H)—carb0xylate (3). A mixture of ethyl 4-bromochlorobenzoate 2 (0.53 g, 2.0 mmol), tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)—5,6-dihydropyridine-1(2H)-carboxylate (0.74 g, 2.4 mmol), potassium carbonate (0.83 g, 6.0 mmol) and f)Cl2 (0.15 g, 0.2 mmol) in dioxane/H2O (20 mL/5 mL) was stirred at 80 °C for 4h under N2 atmosphere. The le phase was removed under reduced pressure. The residue was applied onto silica gel column eluting with 6:1 PE/EA to get the title compound (0.7 g, 96%) as yellow oil. MS (ESI): m/z = 310.1 [M + H — 56]+. tert-butyl 4-(6-(eth0xycarb0nyl)—4'-phenoxybiphenylyl)-5,6-dihydr0pyridine—1(2H)- ylate (4). A mixture of tert-butyl 4-(3—chloro—4—(ethoxycarbonyl)phenyl)-5,6— dihydropyridine- 1(2H)-carboxylate 3 (200 mg, 0.66 mmol), 4-phenoxyphenylboronic acid (172 mg, 0.80 mmol), K3PO4 (414 mg, 2.0 mmol), tricyclohexylphosphine (40 mg, 0.14 mmol) and Pd2(dba)3 (64 mg, 0.07 mmol) in dioxane/H2O (15 mL/3 mL) was d at 110 CC overnight under N2 atmosphere. The le phase was removed under reduced pressure. The residue was applied onto silica gel column eluting with 6:1 PE/EA to get the title nd (200 mg, 61%) as yellow oil. MS (ESI): m/z = 500.0 [M + H]+. tert-butyl 4-(6-(eth0xycarb0nyl)—4'-phen0xybiphenylyl)piperidine—l-carboxylate (5). A mixture of 4-(6-(ethoxycarbonyl)-4'-phenoxybiphenylyl)—5,6-dihydropyridine-1(2H)- carboxylate 4 (180 mg, 0.36 mmol) and Pd/C (wet 10%, 18 mg) in MeOH (10 mL) was stirred at rt under H2 atmosphere for 5h. The solid was filtered off and the filtrate was concentrated under reduced pressure. This resulted in the title compound (180 mg, 99%) as colorless oil, which was used directly for the next step. MS (ESI): m/z = 524.0 [M + Na]+. -(1-(tert—butoxycarbonyl)piperidinyl)—4'-phenoxybiphenyl—Z-carboxylic acid (6). A mixture of tert-butyl ethoxycarbonyl)-4'-phenoxybiphenylyl)piperidinecarboxylate 5 (180 mg, 0.36 mmol) and NaOH (72 mg, 1.8 mmol) in THF/MeOH/H2O (5 mL/5 mL/5 mL) was stirred at rt ght. The volatile phase was removed under reduced pressure. The PH of which was adjusted to 3 by HCl (1 N), which was extracted with EA (2 X 30 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. This resulted in the title compound (180 mg, overweight) in colorless oil, which was used directly for the next step. MS (ESI): m/Z = 374.1 [M + H - Boc]+. tert-butyl arbamoyl-4'-phenoxybiphenylyl)piperidine—l-carboxylate (7). The title compound was obtained using a procedure analogous to the procedure bed in utyl (4-carbamoyl(4-phenoxyphenyl)—1H-pyrazol-l-yl)pyrrolidine—1-carboxylate (see Scheme 23) as pale yellow solid (200 mg, overweight). MS (ESI): m/z = 416.8 [M + H - 56]+. tert-butyl 4-(6-carbam0yl-4'-phenoxybiphenylyl)piperidine—l-carboxylate (8). The title compound was obtained using a procedure analogous to the procedure described in 1-(4- phenoxypheny1)(piperidiny1)—1H-pyrazolecarboxamide hydrochloride (see Scheme 46) as white solid (200 mg, overweight). MS (ESI): m/z = 373.1 [M + H]+.

Example 55 -(1-acryloylpiperidiny])—4'-phenoxybiphenyl-Z-carboxamide 4009 The title compound was obtained using a procedure analogous to the procedure described in Example 61 as white solid (70 mg, 20%). 1H NMR (300 MHZ, CDClg) 5 7.75 (d, J: 7.9 Hz, 1H), 7.44—7.32 (m, 4H), 7.23—7.28 (m, 1H), 7.20—7.12 (m, 2H), 7.11—6.99 (m, 4H), 6.62 (dd, J: 16.5 Hz, 10.5 Hz, 1H), 6.31 (dd, J: 16.5 Hz, 1.8 Hz, 1H), 5.73 (brs, 1H), 5.71 (dd,J= 10.5 Hz, 1.8 Hz, 1H), 5.35 (brs, 1H), 4.99—4.74 (m, 1H), 4.24—4.03 (m, 1H), 3.30—3.05 (m, 1H), 2.97— 2.58 (m, 2H), 2.04—1.88 (m, 2H), 1.83—1.58 (m, 2H). MS (ESI, method A): m/z = 427.1 [M + H]+, tR=1.563 min. HPLC: 99% (214nm), 99% (254nm).

Scheme 46 H N o 0 N _, N\ / \. 0%N w N 0 0v \ I H \ o 0 0H 8 O 9 0 o G o NH4C| HCI-EtOH —> —> Q AvofN _> :1 ‘IN m 37" HCI HN O NH2 0 ""2 MWN‘N I 2 0 1 1 12 Example 56 (4-phenoxyphenyl)hydrazine (2). To a solution of 4—phenoxybenzenamine 1 (1.0 g, 5.4 mmol) in HCl (100 mL) was added NaNOz (700 mg, 10.1 mmol) at 0°C. Then the mixture was stirred at 0°C for 1 h. A solution of SnClz (5.0 g, 22.1 mmol) in HCl (100 mL) was added to the mixture, and the resulting mixture was stirred at rt for 3 h. Aqueous NaOH (3N) was added to adjust pH to 10, and the mixture was extracted with EA (3 X 50 mL), the combined organic phase was washed with brine (20 mL), dried over NaZSO4. The solvent was removed under reduced pressure to give a crude title compound (567 mg, 56%) as a yellow solid, which was used to next step without further purification. MS (ESI): m/z = 201.0 . ethyl 5-hydr0xy—1-(4-phen0xyphenyl)—1H-pyrazolecarb0xylate (4). To the solution of diethyl fumarate 3 (260mg, 1.5 mmol) in EtOH (25 mL) was added (4-phenoxyphenyl)hydrazine 2 (254 mg, 1.3 mmol), and the resulting solution was d overnight at 80°C. The solvent was evaporated under vacuum and the crude residue was diluted with water (30 mL). The solution was extracted with ethyl acetate (3 X 30 mL). The organic layers were ed, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column tography eluting with 20:1 DCM/MeOH to afford the title nd (174 mg, 42%) as a yellow solid. MS (ESI): m/Z = 325.1 [M+H]+. ethyl 1-(4-phenoxyphenyl)—5—(trifluoromethylsulfonyloxy)—1H-pyrazole—3-carb0xylate (6).

To a solution of ethyl oxy-l-(4-phenoxyphenyl)-1H-pyrazole—3-carboxylate 4 (170 mg, 0.5 mmol) in DCM (20 mL) was added trifluoromethanesulfonic anhydride 5 (295 mg, 1.0 mmol) and stirred for 1 h at -30°C under N2 atmosphere. The mixture was poured into water (60 mL), and the solution was extracted with ethyl acetate (3 X 30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with 5:1 PE/EA to afford the title compound (210 mg, 92%) as a yellow solid. MS (ESI): m/z = 457.0 [M+H]+. tert-butyl(3-(eth0xycarb0nyl)—1-(4-phen0xyphenyl)—1H—pyrazol-S-yl)—5,6- dihydropyridine— carb0xylate (8). To a solution of ethyl 1-(4-phenoxyphenyl) (trifluoromethylsulfonyloxy)-1H-pyrazolecarboxylate 6 (210 mg, 0.5 mmol), K2C03 (552 mg, 4.0 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl— l ioxaborolan-2—yl)-5,6—dihydropyridine— 1(2H)—carboxylate 7 (201 mg, 0.6 mmol) in dioxane/H2O (10:1, 20 mL) was added Pd(dppf)Cl2 (327 mg, 0.2 mmol) under nitrogen atmosphere, and the mixture was ed with nitrogen 6 times, then heated to 90°C and stirred overnight under nitrogen atmosphere. After cooling to room temperature, the solvent was evaporated and the crude product was purified by silica gel column chromatography eluting with 20:1 OH to afford the title compound (95 mg, 42%) as a yellow solid. MS (ESI): m/Z = 490.2[M+H]+. tert-butyl(3-(eth0xycarb0nyl)—1-(4-phen0xyphenyl)—1H—pyrazolyl)piperidine carboxylate (9). The mixture of tert—butyl 4—(3-(ethoxycarbonyl)—l—(4-phenoxyphenyl)-1H- pyrazol—5-yl)—5,6- dihydropyridine-l(2H)-carboxylate 8 (95 mg, 0.2 mmol), Pd/C (10% palladium on carbon, 56.5% water, 48 mg) and MeOH (20 mL) was ed with H2 6 times and then stirred under H2 at rt for l h. Then the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (56 mg, 58%) as colorless oil. MS (ESI): m/z = 492.2 [M + Hr. -(1-(tert-but0xycarbonyl)piperidinyl)—1-(4-phen0xyphenyl)—lH-pyrazolecarb0xylic acid (10). To the solution of tert-butyl 4-(3-(ethoxycarbonyl)(4-phenoxyphenyl)—lH-pyrazol- iperidine-l-carboxylate 9 (166mg, 0.3 mmol) in THF/MeOH/H2O (20 : 20 : 10 mL) was added LiOH (60mg, 1.4 mmol), and the resulting on was stirred for 15 h at t temperature. The mixture was concentrated, the residue was diluted with water (10 mL), and the solution was acidified with citric acid to pH = 4, extracted with ethyl acetate (3 X 20 mL), washed with brine (20 mL), dried over Na2S04, filtered and concentrated to get the title compound (120 mg, 76%) as a brown solid. MS (ESI): m/z = 464.2 [M + H]+ tert-butyl(3-carbam0y](4-phenoxyphenyl)—1H—pyrazol-S-yl)piperidine—l-carboxylate (11). To a solution of 5-(1-(tert-butoxycarbonyl)piperidinyl)-l-(4-phenoxyphenyl)-1H- pyrazole carboxylic acid 10 (250 mg, 0.59 mmol) and HATU (147 mg, 0.38 mmol) in dry N,N—dimethyl formamide (25 mL) was added DIPEA (67 mg, 0.51 mmol), and the resulting solution was stirred for 20 min at ambient ature, then NH4C1 (28 mg, 0.51 mmol) was added and stirred overnight. The mixture was diluted with ethyl acetate (50 mL), and washed with water (2 X 20 mL) and brine (2 X 20 mL). The organic layer was dried over Na2SO4, filtered and concentrated to get a residue which was purified by silica gel column chromatography g with 20:1 DCM/MeOH to afford the title compound (100 mg, 84%) as a yellow solid.

MS (ESI): m/Z = 463.2 [M+H]+. henoxyphenyl)—5-(piperidinyl)—1H-pyrazole—3-carb0xamide hydrochloride (12). To a solution of tert-butyl 4-(3 -carbamoyl(4-phenoxyphenyl)-1H-pyrazol-5 -yl)piperidine carboxylate 11 (100mg, 0.21 mmol) in EtOH (20 mL) was added HCl/EtOH (33%, 2 mL) at ambient temperature. The mixture was stirred for 12 h at room temperature. The mixture concentrated to give the title compound (70 mg, 89%) as yellow oil. MS (ESI): m/z =363.1 [M + Example 56 -(1-acryloylpiperidinyl)—1-(4-phen0xyphenyl)-lH-pyrazolecarboxamide _ <3; 7w \.~ To the solution of henoxyphenyl)—5-(piperidin—4-yl)-lH-pyrazolecarboxamide hloride 12 (110 mg, 0.3 mmol), DIPEA (117 mg, 0.9 mmol) and CH2C12 (10 mL) was added acryloyl chloride (28 mg, 0.3 mmol) dropwise and then the on mixture was stirred at 0°C for 1 h. The mixture was diluted with CHzClz (20 mL) and washed with saturated aqueous NaHC03 solution (20 mL). The aqueous phase was reextracted with EtOAc (20 mL). The combined organic phase was dried over Na2S04, concentrated in vacuo and purified by Prep- TLC developing with 20:1 CH2C12/1V1eOH to give the title compound (66 mg, 52%) as yellow oil. 1H NMR (300 MHz, CD30D) 5 7.52—7.37 (m, 4H), 7.24—7.06 (m, 5H), 6.84—6.68 (m, 2H), 6.21 (d, J= 2.0 Hz, 0.5H), 6.15 (d, J= 2.0 Hz, 0.5H), 5.73 (dd, J= 10.6, 2.0 Hz, 1H), 4.61 (d, J = 12.8 Hz, 1H), 4.15 (d, J: 14.0 Hz, 1H), 3.04 (tt, .1: 8.0, 7.5 Hz, 2H), .59 (m, 1H), 2.03—1.81 (m, 2H), 1.72—1.46 (m, 2H). MS (ESI, method A): m/z = 417.1 [M + H]+, tR=1.547 min. HPLC: 98.2% (214nm), 98.8% (254nm).

Scheme 47 0 Br 0 Br 0 Br 0 Br r"\ 3°C N\_,NH3_ SOCI2 HO NH3, HATU H2N HQ —>o —> —> MeOH K2003 DMF N/fi DIPEA,DMF N F F K/N. Boo 5km.Bee 1 2 4 ch03 Pd(dppf)C|2 HCUEtOH dioxane/HZO oc OK/NH TEA/DOM 7 ONO? e 57 methyl 2-brom0flu0r0benz0ate (2). To a mixture of 2-bromofluorobenzoic acid 1 (2.19 g, mmol) in MeOH (20 mL) was added SOC12 (0.5 mL) dropwise at rt. The resulting mixture was stirred at 60°C for 10 h. The mixture was concentrated to give the title compound (2 g, 86%) as brown oil. MS (ESI): m/Z = 232.8 [M + H]+. 2-brom0(4—(tert—butoxycarbonyl)piperazinyl)benzoic acid (4). To a solution of methyl 2-bromofluorobenzoate 2 (1.8 g, 7.72 mmol) in DMSO (30 mL) was added tert-butyl piperazine-l-carboxylate 3 (1.726 g, 9.27 mmol) and K2C03 (4.26 g, 30.9 mmol). The mixture was stirred at 120°C for 5 h. When finished, the mixture was extracted with ethyl acetate (2 X 50 mL), and washed with water (50 mL) and brine (2 X 50 mL). The organic layer was dried over Na2S04, filtered and concentrated to get a residue which was purified by silica gel column tography eluting with 10:1 PE/EA to get the title compound (1.1 g, 36%) as a yellow oil.

MS (ESI): m/Z = 328.7 [M — 551+. tert-butyl 4-(3-br0m0carbamoylphenyl)piperazine-l-carboxylate (5). The title nd was obtained using a procedure analogous to the procedure described in tert—butyl 3-(5- carbamoyl(4-phenoxyphenyl)thiazoly1)pyrrolidinecarboxylate (see Scheme 31) as a yellow solid (0.8 g, 73%). MS (ESI): m/Z = 327.7 [M — 551+. tert-butyl arbamoyl-4'-phenoxybiphenylyl)piperazine—l-carboxylate (6). To a mixture of tert-butyl 4-(3-bromocarbamoylphenyl)piperazinecarboxylate 5 (192 mg, 0.5 mmol), 4-phenoxyphenylboronic acid (102 mg, 0.5 mmol) and K2C03 (207 mg, 1.5 mmol) in dioxane/water (20/4 mL) were added Pd(dppf)2C12 (36.55 mg, 0.05 mmol). The e was degassed with N2 3 times, then heated to 100 CC and stirred for 16 h. After cooling to room temperature, the mixture was added to ethyl acetate (30 mL), washed with water (2 X 20 mL) and brine (2 X 20 mL). The organic layer was dried over NazSO4, filtered and concentrated to get a residue which was purified by silica gel column tography eluting with 30:1 DCM/MeOH to get the title nd (50 mg, 21%) as a yellow solid. MS (ESI): m/z = 473.8 [M + H]+ 4'-phenoxy-5—(piperazinyl)biphenylcarboxamide hydrochloride (7). The title compound was obtained using a procedure analogous to the procedure described in 1-(4- phenoxyphenyl)(piperidinyl)-1H-pyrazolecarboxamide hydrochloride (see Scheme 46) as a yellow solid (40 mg, 92%). MS (ESI): m/Z = 374.1[M + H.

Example 57 -(4-acryloylpiperazinyl)—4'-phenoxybiphenyl-Z-carboxamide The title compound was obtained using a procedure analogous to the procedure described in Example 1 as an off white solid (15 mg, 36%). 1H NMR (400 MHZ, DMSO) 5 .30 (m, 6H), 7.25—6.93 (m, 7H), 6.91—6.82 (m, 2H), 6.15 (d,J= 16.7 Hz, 1H), 5.73 (d, J: 9.9 Hz, 1H), 3.70 (d, J: 12.0 Hz, 4H), 3.27 (s, 4H). MS (ESI, method A): m/z =428.1 [M + H]+, tR=1.525 min. HPLC: 96.4% (214nm), 99.3% (254nm) Scheme 48 NH2 \ Pd(dppf)C12,KZCO3 0 | \ f)Clz,K2CO3 \ O + I —>CI N/ —> CI N/ CI dioxane-Hzo (6/1 V) O O '3 dioxane—HZO (6/1 V) 90°C, 12 h 300 90 00, 12h 2 o 3 [foo O Pd/C H2 MeOH n Boo/N {5 040—,DCMCF3COOHrt \ O ' | / N/ N DCM 0°C 1h HN O O —>/\|OrN Example 58 2-(4-benz0ylphenyl)—6-chloronicotinamide (2). To a on of 4-phenoxyphenylboronic acid (650 mg, 2.88 mmol), K2C03 (1.08 g, 7.86 mmol) and 2,6—dichloronicotinamide (500 mg, 2.62 mmol) in 1,4-dioxane (25 mL) and water (4 mL) was added Pd(dppf)Clg (192 mg, 0.262 mmol) under nitrogen atmosphere, and the mixture was degassed with nitrogen 6 times, then heated to 60 CC and stirred for 12 h under nitrogen atmosphere. After cooling to room temperature, the solution was poured into water (50 mL), and then ted with ethyl acetate (2 X 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated.

The crude product was purified by column chromatography, eluting with 80 : 1 romethane/methanol to afford the title compound as a brown oil (868 mg, 98%). MS (ESI): m/Z = 336.9 [M + H]+. tert-butyl 4-(6-(4-benzoylphenyl)carbamoylpyridin-Z-yl)—5,6-dihydropyridine—1(2H)— carboxylate (4). To a solution of tert—butyl 4—(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)— 5,6- dihydropyridine-1(2H)—carboxylate (1.2 g, 3.87 mmol), K2C03 (1.07 g, 7.74 mmol) and 2-(4- benzoylphenyl)—6-chloronicotinamide 2 (868 mg, 2.58 mmol) in 1,4—dioxane (24 mL) and water (3 mL) was added Pd(dppf)C12 (188 mg, 0.258 mmol) under nitrogen atmosphere, and the e was degassed with nitrogen 6 times, then heated to 90 CC and stirred for 12 h under nitrogen atmosphere. After cooling to room temperature, the solution was poured into water (50 mL), and then extracted with ethyl acetate (3 X 40 mL). The ed organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography, eluting with 80 : l dichloromethane/methanol to afford the title compound as a brown oil (800 mg, 64%). MS (ESI): m/z = 484.0 [M + H]+. tert-butyl(5-carbamoyl—6—(4-(hydr0xy(phenyl)methyl)phenyl)pyridinyl)piperidine—1- carboxylate (5). To a solution of tert—butyl 4-(6-(4-benzoylphenyl)—5-carbamoylpyridinyl) - ,6-dihydropyridine-1(2H)- ylate 4 (800 mg, 1.65 mmol) in MeOH (15 mL) was added Pd/C (150 mg) under hydrogen atmosphere, and the mixture was degassed with hydrogen 6 times, then stirred for 16 h at t temperature under hydrogen atmosphere. The solution was d and the filtrate was evaporated to provide crude product as a white solid (500 mg, 62%).

MS (ESI): m/Z = 488.1 [M+H]+. 2-(4-(hydroxy(phenyl)methyl)phenyl)(piperidinyl)nicotinamide (6). To a solution of tert—butyl 4-(5-carbamoyl(4-(hydroxy(phenyl)methyl)phenyl)pyridinyl)piperidine- l - carboxylate 5 (500 mg, 1.03 mmol) in dry dichloromethane (5 mL) was added TFA (2 mL), and the resulting mixture was stirred for 3 h at ambient temperature. The solvent was removed and the residue was partitioned between saturated aqueous sodium bicarbonate (30 mL) and ethyl acetate (20 mL). The organic phase was ted, dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound as a white solid (350 mg, 88%). MS (ESI): m/z = 388.1 [M+H]+.

Example 58 6-(1-acryloylpiperidinyl)—2-(4-(hydroxy(phenyl)methyl)phenyl)nicotinamide \ O N O 0 0 OH To a solution of hydroxy(phenyl)methyl)phenyl)-6—(piperidinyl) namide 6 (350 mg, 0.90 mmol) in DCM (10 mL) was added TEA (182 mg, 1.8 mmol) and acryloyl chloride (90 mg, 0.99 mmol) at 0 OC. The mixture was stirred at 0 °C for 10 min. The solvent was removed and the residue was purified by Prep-HPLC to afford the title compound (150 mg, 38%) as white solid. 1H NMR (300 MHz, CDClg) 8 8.03 (d, J: 7.9 Hz, 1H), 7.65 (d, J = 7.1 Hz, 2H), 7.56— 7.15 (m, 9H), 6.67—6.49 (m, 1H), 6.27 (d, J = 16.6 Hz, 1H), 5.88 (s, 1H), 5.68 (d, J: 10.1 Hz, 1H), 5.52 (d, .1: 27.1 Hz, 2H), 4.79—4.72 (m, 1H), .06 (m, 1H), 3.18—3.10 (m, 2H), 2.80— 2.74(m, 1H), 2.08—1.98(m, 2H), 1.78 (d, J: 10.5 Hz, 2H). MS (ESI, method F): m/Z = 441.8 [M + Hr, tR=1.268 min., HPLC: 100.0% (214nm), 100.0% (254nm).

Scheme 49 O0 O/\ O 0 O N N / ‘N'CN’KZN— / ‘N’CN :N \ \ o 5°C (>00 / NH2 NH2 Example 50 Example 59 Example 59 (E)(1-(2-cyanobutenoyl)azetidinyl)—3-(4-phen0xyphenyl)—lH-pyrazole carboxamide : : N / \N’CN To a solution of 1-(1-(2-cyanoacetyl)azetidinyl)—3-(4-phenoxyphenyl)-1H-pyrazole carboxamide (150 mg, 0.37 mmol) and piperidine (3 drops) in AcOH (10 mL) was added dehyde (99 mg, 0.74 mmol), then stirred at 45°C overnight. After the reaction was completed, sat. NaOH was added to the solution to pH = 6—7. Then the solution was extracted with DCM (2 X 20 mL). The organic layer was combined and concentrated under vacuum to dryness. The residue was purified by Prep-HPLC (MeOH-HzO = 60-70, 0.1%FA) to afford the title compound (40 mg, 26%) as a white solid. 1H NMR (300 MHz, CDC13) 5 8.15 (S, 1H), 7.79— 7.68 (m, 1H), 7.62—7.54 (m, 2H), .34 (m, 2H), 7.21—7.13 (m, 1H), 7.13—7.04 (m, 4H), .62 (s, 2H), 5.26—5.10(m, 1H), 5.08—4.79 (m, 2H), 4.71—451 (m,2H),3.51—3.36(m,1H), 2.26—2.16 (m, 2H). MS (ESI, Method A): m/z= 428 1 [M + H], tR= 1 4.38 min HPLC: 98.4% (214nm), 98.4% (254nm).

Scheme 50 OH Cul 1 10--phenanthroline HCI (1 N) Br\©\ Q CSzCOg toluene 120°C 000OBTHF OOQ/OB + 0 o £0 1 2 3 4 DAST Pd(dppf)C|2 KOAc _>F?©/O Pd2(dba)3, 052003 DCM, rt 5Br—>\©\1,-4dioxane 100°C F70 08/0 dioxane/H20,1ZO°C 33F?#3" | 0 e ‘55 ’11* (‘N N C] O O HNQ \ NH2 \ I | NH2 FN , / N Et3N,CH2C|2,O°C FN N HNd O —C]> / Nd O /\n/ O (I? o E j F F F F ExampleGO 8-(4-br0m0phen0xy)—1,4-di0xaspir0[4.5]decane (3). The title compound was obtained using a procedure analogous to the procedure described in l-bromo(cyclohexyloxy)benzene (see Scheme 17) as colorless oil (0.272 g, 87%). 4-(4-bromophenoxy)cyclohexanone (4). A solution of 8-(4-bromophenoxy)— 1,4- dioxaspiro[4.5]decane 3 (0.272 g, 0.87 mmol) in THF (5 mL) was treated with HCl (1 N, 5 mL) at 50 0C for l h. Then the e was neutralized with NaHCOg and extracted with EtOAc (5 mL X 3). The combined organic phase was dried over Na2S04, filtered and concentrated. The e was purified by silica gel column chromatography eluting with 5:1 petroleum ether/EtOAc to give the title nd (147 mg, 63%) as white solid. 1H NMR (400 MHz, CDC13) 8 7.46—7.37 (m, 2H), 6.91—6.83 (m, 2H), 4.68 (s, 1H), 2.75—2.64 (m, 2H), 2.43—2.25 (m, 4H), 2.15—2.08 (s, 2H). 1-brom0((4,4-diflu0r0cyclohexyl)0xy)benzene (5). To the solution of 4-(4- henoxy)cyclohexanone 4 (0.538 g, 2.0 mmol) in dry DCM (5 mL) was added a solution ofDAST (0.654 g, 4.0 mmol) in dry DCM (5 mL) at 0 CC and the resulting mixture was stirred at rt for 4 h. The reaction was quenched by ice water (5 mL), d with saturated NaHC03 to pH = 8 and extracted with EtOAc (10 mL X 3). The combined organic phase was dried over Na2S04, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with 10:1 petroleum ether/EtOAc to afford the title compound (0.547 g, 94%) as yellow oil. 2-(4-((4,4-difluorocyclohexyl)oxy)phenyl)-4,4,5,5-tetramethyl—1,3,2-di0xabor0]ane (6). The mixture of 1-bromo((4,4-difluorocyclohexyl)oxy)benzene 5 (0.328 g, 1.13 mmol), bis(pinacolato)diboron (0.429 g, 1.69 mmol), f)C12 (0.168 g, 0.23 mmol), KOAc (0.323 g, 3.29 mmol) and dry dioxane (3 mL) was stirred at 100 CC for 3 h. After cooled to rt, the mixture was poured into water (10 mL) and extracted with EtOAc (15 mL X 3). The combined organic phase was dried over Na2S04, filtered and concentrated. The e was purified by silica gel column chromatography eluting with PE to afford the title compound (0.258 g, 68%) as a white solid. 2-(4-((4,4-diflu0r0cyclohexyl)0xy)phenyl)(piperazinyl)nic0tinamide (8). The title compound was obtained using a procedure analogous to the procedure described in 6—(3- nitrophenyl)—2-(4-phenoxyphenyl)nicotinamide (see Scheme 1) as white solid (0.10 g, 31%). MS (ESI): m/Z = 417.1 [M + Hr.

Example 60 6-(4-acryloylpiperazinyl)(4-((4,4-difluorocyclohexyl)0xy)phenyl)nic0tinamide @115\ NH2 l F The title compound was obtained using a procedure analogous to the ure described in Example 1 as white solid (6 mg, 11%). 1H NMR (400 MHz, DMSO—d6) 5 7.88 (d, J: 8.7 Hz, 2H), 7.73 (d, J: 8.6 Hz, 2H), 7.68 (d, J: 8.7 Hz, 1H), 7.59 (s, 1H), 7.26 (s, 1H), 7.21—7.14 (m, 4H), 6.86 (dd, J: 17.8, 9.3 Hz, 2H), 6.16 (dd, J: 16.7, 2.2 Hz, 1H), 5.73 (dd, J: 10.4, 2.2 Hz, 1H), 3.66—3.67 (m, 8H). MS (ESI, method A): m/z = 471.2 [M + H]+, 53 (min). HPLC: 99.2% (214nm), 99.2% (254nm).

Scheme 51 cN NH2 \ H2304(conc)/H20 NNWZZES | —> —3> Cl N Cl 9000 m 73/ C, N/ [iiB-CN-Boo Cl Pd(dppf)Cl2 0520030 f)C|2 eszco3 DME/H20 90°C overnight O,DMEIH2090°C overnightB O—NHZ Pd/C/ H2/MeOH OLiOHfr—>HF/H2O ONHZQ rt. 4 days OH—>HATUDIEADMF BocN 5000 4 h BocN | NH2 TFA!DCM N/ HN NH DIEADCM o HfN e 61 2,6-dichloronicotinamide (2). The title compound was sized using a procedure analogous to the procedure described in 2,6-dichloronicotinamide (see Scheme 51) (9.5 g, 81%) as a brown solid. MS (ESI): m/z = 191.0 [M + Hr. methyl 4-(3-carbam0ylchloropyridin-Z-yl)benz0ate (4). To a solution of 2,6- dichloronicotinamide 2 (1.91 g, 10.0 mmol), 4-(methoxycarbonyl)phenylboronic acid 3 (1.8 g, .0 mmol) and Pd(dppf)Cl2 (816 mg, 1.0 mmol) in DME/H2O (20 mL/2mL) was added CS2C03 (6.5 g, 20.0 mmol). The resulting solution was ed with N2 6 times and stirred overnight at 90 0C under N2 protection. After the reaction was completed, the solution was concentrated, diluted with ethyl e (30 mL) and washed with water (2 X 20 mL) and brine (2 X 20 mL).

The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column diluted with 100:1 to 60:1 DCM/MeOH to afford the title compound (1 .95g, 67%) as a white solid. MS (ESI): m/z = 291.1 [M + H]+. tert-butyl(5-carbam0y]-6—(4-(methoxycarbonyl)phenyl)pyridinyl)-5,6- dihydropyridine— 1(2H)-carboxylate (6). To a solution of methyl 4-(3-carbamoyl chloropyridin—2-yl)benzoate 4 (170 mg, 0.59 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2— dioxaborolan—2-y1)-5,6-dihydropyridine-1(2H)- carboxylate 5 (200 mg, 0.65 mmol) and f)Cl2 (50 mg, 0.06 mmol) in DME/H2O (20 mL/2mL) was added Cs2C03 (390 mg, 1.2 mmol), the resulting solution was degassed with N2 6 times and d overnight at 90 0C under N2. After the reaction was completed, the solution was concentrated, diluted with ethyl acetate (30 mL) and washed with water (2 X 20 mL) and brine (2 X 20 mL). The organic layer was dried over anhydrous sodium e, filtered and concentrated. The residue was purified by silica gel column diluted with 50:1 to 10:1 DCM/MeOH to afford the title compound (145 mg, 56%) as brown oil. MS (ESI): m/Z = 438.2 [M + Hr. tert-butyl(5-carbam0yl—6—(4-(methoxycarbonyl)phenyl)pyridinyl)piperidine carboxylate (7). To a solution of tert-butyl 4-(5-carbamoy1(4- (methoxycarbonyl)phenyl)pyridinyl)-5,6- opyridine-1(2H)—carboxylate 6 (145 mg, 0.33 mmol) in MeOH (10 mL) was added Pd/C (15 mg) and degassed with H2 6 times and stirred ght at rt under H2. After the reaction was completed, the solution was filtered and the e was concentrated to afford the title compound (100 mg, 69%) as brown oil. MS (ESI): m/Z = 440.2 [M + H]+. 4-(6-(1-(tert-but0xycarb0nyl)piperidinyl)—3-carbamoylpyridin-Z-yl)benzoic acid (8) To a solution of tert—butyl 4—(5-carbamoyl—6—(4-(methoxycarbonyl)phenyl)pyridin—2-yl)piperidine— 1- carboxylate 7 (460 mg, 1.05 mmol) in THF/HZO (20 mL/2 mL) was added LiOH (84 mg, 2.1 mmol), the resulting solution was d ght at rt. After the reaction was complete, the on was concentrated, added water (10 mL) and acidified with HCl (00110., 1 mL) to pH = 5- 6, diluted with ethyl acetate (30 mL) and washed with water (2 X 20 mL) and brine (2 X 20 mL).

The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (390 mg, 87%) as a yellow solid. MS (ESI): m/z = 426.2 [M + H]+. utyl(5-carbamoyl(4-(phenylcarbamoyl)phenyl)pyridinyl)piperidine—1- carboxylate (9). To a solution of 4-(6-(1-(tert-butoxycarbonyl)piperidinyl)—3- carbamoylpyridin-Z-yl)benzoic acid 8 (390 mg, 0.917 mmol), aniline (102 mg, 1.101 mmol) and HATU (418 mg, 1.101 mmol) in dry DMF (10 mL) was added DIEA (355 mg, 2.751 mmol), the resulting solution was stirred overnight at rt. The mixture was diluted with ethyl acetate (30 mL), and washed with water (2 X 20 mL) and brine (2 X 20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Prep-TLC with :1 DCM/MeOH to get the title compound (120 mg, 27%) as a yellow solid. MS (ESI): m/z = 501.2 [M + Hr. 2-(4-(phenylcarbamoyl)phenyl)—6-(piperidinyl)nic0tinamide (10) To a solution of tert— butyl 4-(5 -carbamoyl(4-(phenylcarbamoyl)phenyl)pyridinyl)piperidinecarboxylate 9 (120 mg, 0.24 mmol) in dry DCM (10 mL) was added TFA (3 mL), the resulting solution was stirred overnight at rt. The mixture was washed with NaHC03/H20 (3 X 20 mL) and brine (3 X mL). The organic layer was dried over anhydrous sodium e, filtered and concentrated.

The residue was concentrated to get the title compound (100 mg, 99%) as a yellow solid. MS (ESI): m/Z = 401.2 [M + Hr.

Example 61 6-(1-acryloylpiperidinyl)—2-(4-(phenylcarbamoyl)phenyl)nicotinamide 0 HNO To a on of 2-(4-(phenylcarbamoyl)phenyl)(piperidinyl)nicotinamide 10 (100 mg, 0.24 mmol) in dry DCM (15 mL) was added DIEA (95 mg, 0.72 mmol) and acryloyl chloride (35 mg, 0.36 mmol) at 0 CC, and the ing solution was stirred at 0 CC for 10 min. Water (10 mL) was added to quench the reaction. The mixture was diluted with DCM (20 mL), and washed with water (2 X 20 mL) and brine (2 X 20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Prep-HPLC (ACN—HzO = 30-90, 0.1%FA) to afford the title compound (31 mg, 29%) as a white solid. 1H NMR (300 MHz, CDC13) 8 8.59 (s, 1H), 8.04—7.58 (m, 3H), 7.75—7.54 (m, 4H), 7.37—7.27 (m, 2H), 7.21—7.08 (m, 2H), 6.65—6.49 (m, 1H), 6.29—6.10 (m, 3H), 5.74—5.63 (m, 1H), .63 (m, 1H), 4.17—3.99 (m, 1H), 3.27—2.96 (m, 2H), 2.83—2.66 (m, 1H), 2.07—1.88 (m, 2H), 1.83—1.60 (m, 2H). MS (ESI): m/z = 455.2 [M + H]+, tR= 1.316 min. HPLC: 95.3% (214nm), 93.0% (254nm).

Scheme 52 o o | NH2 0 Et3N \ NH2 + \\ /CI | ‘/\N N/ C|/\/3\\ / HN\/l 0 CHZCIZJt, 1 h 0" NJ 0 VS\\ 0 1 2 0 e 62 Example 62 2-(4-phenoxypheny])—6-(4-(vinylsu]f0nyl)piperazinyl)nic0tinamide ' NH2 a O 0 \A’ o To a solution of henoxyphenyl)(piperazinyl)nicotinamide 1 (200 mg, 0.53 mmol) in DCM (8 mL) was added TEA (161 mg, 1.59 mmol) and 2-chloroethanesulfonyl chloride (131 mg, 0.80 mmol) at rt. The mixture was stirred at rt for 1 h. The solution was poured into water (50 mL), and then extracted with CHzClz (2 X 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by Prep- TLC eluting with 100 : 1 DCM/MeOH to afford the title compound (17 mg, 6.9%) as a white solid. 1H NMR (300 MHz, CDC13)8 8.01 (d, J: 8.8 Hz, 1H), 7.59 (d, J: 8.6 Hz, 2H), 7.43— 7.30 (m, 2H), 7.15 (t, J: 7.4 Hz, 1H), 7.09—7.01(m, 4H), 6.64 (d, J: 8.8 Hz, 1H), 6.42 (dd, J: 16.6, 9.7 Hz, 1H), 6.26 (d, J= 16.5 Hz, 1H), 6.06 (d, J: 9.7 Hz, 1H), 5.46 (br, 1H), 5.28 (br, 1H), 3.87—3.75 (m, 4H), 3.32—3.18 (m, 4H). MS (ESI, method F): m/z = 465.1.0 [M + H]+, 46 min., HPLC: 99.5% (214nm), 98.3% (254nm).

Scheme 53 I NH2 \ W200 CIA/SO / | Q, Cl Et3N N / o —>\/"3\NCHZCIZ rt1 h O 1 Example 63 Example 63 hen0xyphenyl)(1-(vinylsu]f0nyl)piperidinyl)nic0tinamide | NH2 V8" 0 To a solution of 2-(4-phenoxyphenyl)—6-(piperidin-4—yl)nicotinamide 1 (200 mg, 0.54 mmol) in DCM (8 mL) was added TEA (164 mg, 1.62 mmol) and 2-chloroethanesulfonyl chloride (131 mg, 0.80 mmol) at It. The mixture was stirred at rt for 1 h. The solution was poured into water (50 mL), and then extracted with ethyl acetate (2 X 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by Prep-HPLC to afford the title nd (40 mg, 16%) as a white solid. 1H NMR (300 MHz, CDC13) 5 8.03 (d, J= 8.0 Hz, 1H), 7.71—7.61 (m, 2H), 7.43—7.31 (m, 2H), 7.17 (dd, J= 15.6, 7.8 Hz, 2H), 7.10—7.01(m, 4H), 6.46 (dd, J: 16.6, 9.8 Hz, 1H), 6.26 (d, J: 16.6 Hz, 1H), 6.04 (d, J = 9.9 Hz, 1H), 5.60 (b, 1H), 5.41 (b, 1H), 3.94—3.82(m, 2H), 2.97—2.86(m, 1H), 2.80—2.71(m, 2H), 2.11—1.92(m, 4H). MS (ESI, method F): m/Z = 464.0 [M + H]+, tR=1.566 min, HPLC: 99.3% (214nm), 100.0% (254nm).

The following examples can be synthesized according to methods referenced below and ing ordinary skill in the art. These examples are believed to be useful as inhibitors of BTK based on the biological activities of the compounds bed above. e 64 1-(1-acryloylpiperidinyl)—3-(4-(phenylcarbamoyl)phenyl)—1H-pyrazolecarb0xamide The title compound may be obtained using a procedure ous to the procedures described in the General Scheme and Example 15.

Example 65 1-(1-acryloylpiperidinyl)—3-(4-((4-(triflu0r0methyl)pyridinyl)carbamoyl)phenyl)—1H- pyrazolecarb0xamide The title compound may be obtained using a procedure analogous to the ures bed in the General Scheme and Example 15.

Example 66 6-(4-acrylamidophenyl)—2-(4-(phenylcarbamoyl)phenyl) nicotinamide The title compound may be obtained using a procedure analogous to the procedures described in the General Scheme and Example 16.

Example 67 6-(4-acrylamid0phenyl)—2-(4-((4-(triflu0r0methyl)pyridinyl)carbamoyl)phenyl) nicotinamide The title compound may be obtained using a procedure analogous to the procedures bed in the General Scheme and Example 16.

Example 68 1-(1-acryloylpiperidinyl)(4-(hydroxy(phenyl)methyl)phenyl)—1H-pyrazole—4- carboxamide The title compound may be obtained using a procedure analogous to the ures described in the General Scheme and Examples 15 and 58.

Example 69 1-(1-acryloylpiperidinyl)(4-(methyl(phenyl)amino)phenyl)—1H—pyrazole-4— carboxamide The title compound may be obtained using a procedure ous to the procedures described in the General Scheme and Example 15.

Example 70 6-(4-acrylamidophenyl)—2-(4-(1-hydr0xyphenylethyl)phenyl)nic0tinamide \. .' The title compound may be obtained using a procedure analogous to the procedures described in the General Scheme and Examples 16 and 58.

Example 71 6-(4-acrylamidophenyl)—2-(4-(difluor0(phenyl)methyl)phenyl)nicotinamide . 1‘ 1’? l The title nd may be obtained using a procedure analogous to the procedures described in the General Scheme and Example 16.

Example 72 1-(1-acryloylpiperidinyl)(4-(phenylsulf0nyl)phenyl)—1H-pyrazolecarboxamide \\ // G o I The title compound may be obtained using a procedure analogous to the procedures described in the General Scheme and Example 15.

Example 73 6-(4-acrylamidophenyl)—2-(4-(phenylsulfonyl)phenyl) nicotinamide The title compound may be obtained using a procedure analogous to the procedures described in the General Scheme and Example 16.

Scheme A-l o o HN’N PhO N/ EtOH COOEt C52C03, DMF ' COOEt 1 2 '-'OH H20 N»N NH3, HATU H2N ' / —> THF/MeOH/HZO / DIPEA DMF EN ’ N COOH (5 Analog 1 ethyl hen0xyphenyl)-1H-pyrazolecarb0xylate (2). The title compound was obtained using a procedure analogous to the procedure described in ethyl 3-(4-phenoxyphenyl)-lH- pyrazolecarboxylate (see Scheme 23) as yellow oil (0.3 g, 97%). MS (ESI): m/z = 308.8 [M + ethyl opentyl—3-(4-phenoxyphenyl)-lH—pyrazolecarb0xylate (4). To a solution of ethyl henoxyphenyl)-lH-pyrazolecarboxylate 2 (150 mg, 0.486 mmol) in DMF (10 mL) was added bromocyclopentane 3 (87 mg, 0.584 mmol) and C82C03 (475.5 mg, 1.46 mmol). The mixture was stirred at 100 °C for 3 h. After finished, the mixture was extracted with ethyl acetate (2 X 30 mL), and washed with water (2 X 10 mL) and brine (3 X 10 mL). The organic layer was dried over NaZSO4, filtered and concentrated to give the title compound (0.13 g, 71%) as yellow oil. MS (ESI): m/Z = 376.9 [M + H]+ 1-cyclopentyl(4-phenoxyphenyl)—1H-pyrazole-4—carboxylic acid (5). The title compound was obtained using a procedure analogous to the procedure described in 5-(1-(tert- butoxycarbonyl)piperidinyl)(4-phenoxyphenyl)—lH-pyrazole—3-carboxylic acid (see Scheme 46) as yellow oil (0.12 g, 100%). MS (ESI): m/z = 348.8 [M + H]+.

Analog 1 1-cyclopentyl(4-phen0xyphenyl)—1H-pyrazole—4—carboxamide The title compound was obtained using a procedure analogous to the procedure described in tert- butyl 3-(5 -carbamoyl—4-(4-phenoxyphenyl)thiazo1-2—yl)pyrrolidine— l xylate (see Scheme 31) as an offwhite solid (70 mg, 59%). 1H NMR (300 MHz, DMSO) 5 8.23 (s, 1H), 7.79 (d, J: 8.5 Hz, 2H), 7.41 (t, J: 7.0 Hz, 3H), 7.15 (t, J: 7.1 Hz, 1H), 7.05 (d, J: 7.6 Hz, 2H), 7.00 (s, 2H), 6.98 (d, J: 1.4 Hz, 1H), .62 (m, 1H), 2.19—1.55 (m, 8H). MS (ESI, method F): m/z = 347.9 [M + H]+, tR=1.589 (min). HPLC: 97.6% (214nm), 98.0% (254nm).

Scheme A—Z HO H N 0 5O 0 HZN S JL 1) (00002 Lawesson’s reagent QC : :Br 0 0E! —> —> 2) NH4OH e, reflux, 2h EtOH, reflux 1 2 3 CG OQ oJO o O NaOH, MeOH, H20 / NH3, HATU, DMF EtO —’ / N H0 / ’ HZN N 4 5 Analog 2 cyclopentanecarboxamide (2). To a mixture of cyclopentanecarboxylic acid 1 (2.85 g, 25 mmol) and DMF (3 drops) in DCM (60 mL) was added (COCl)2 (3.2 g, 25 mmol) se carefully at 0 °C under N2. The resulting mixture was stirred at rt for 2h, then NH4OH (5 mL) was added dropwise to this mixture at 0 0C. After the on, the mixture was stirred at rt for another 1h, which was diluted with DCM (50 mL). It was washed with water (50 mL), brine, dried over sodium sulfate, filtered and concentrated. This resulted in the title compound (1.8 g, 64%) as white solid. MS (ESI): m/Z = 114.8 [M + H]+. cyclopentanecarbothioamide (3). A mixture of cyclopentanecarboxamide 2 (1.8 g, 15.9 mmol) and on’s t (3.2 g, 8.0 mmol) in toluene (40 mL) was stirred at 80 0C for 2h under N2 atmosphere. It was quenched with sat. NaHC03 (50 mL). which was extracted with EA (2 X 40 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was applied onto silica gel column eluting with 3:1 PE/EA to get the title compound (0.25 g, 12%) as yellow solid. MS (ESI): m/z = 130.1 [M + H - 56]+. ethyl 2-cyclopentyl(4-phen0xyphenyl)thiazole—5-carboxylate (4). A mixture of cyclopentanecarbothioamide 3 (150 mg, 1.16 mmol) and ethyl 2-bromooxo(4— phenoxyphenyl)propanoate (422 mg, 1.16 mmol) in EtOH (15 mL) was d for 2 h. The volatile phase was removed under reduced pressure. The residue was dissolved in EA (50 mL), which was washed with sat. NaHC03 (30 mL), brine, dried over sodium sulfate, filtered and concentrated. The residue was applied onto silica gel column eluting with 4:1 PE/EA to get the title compound (200 mg, 43%) as pale yellow oil. MS (ESI): m/z = 394.1 [M + H]+. 2-cyclopentyl(4-phenoxyphenyl)thiazole-S-carboxylic acid (5). The title compound was obtained using a procedure ous to the procedure described in 5-(1-(tert- butoxycarbonyl)piperidinyl)-4'-phenoxybipheny1carboxy1ic acid (see Scheme 45) as pale yellow solid (190 mg, 99%). MS (ESI): m/Z = 366.1 [M + H.

Analog 2 2-cyclopentyl—4-(4-phenoxyphenyl)thiazole—5-carboxamide CW 0&3 The title compound was obtained using a procedure analogous to the procedure described in tert- butyl 4-(6-carbamoyl-4'-phenoxybiphenylyl)piperidinecarboxylate (see Scheme 45) as white solid (70 mg, 38%). 1H NMR (300 MHz, CDC13) 8 7.66—7.56 (m, 2H), 7.43—7.33 (m, 2H), 7.17 (t, J: 7.4 Hz, 1H), 7.12—7.00 (m, 4H), 5.73 (brs, 2H), 3.52—3.35 (m, 1H), 2.32—2.16 (m, 2H), 1.90—1.77 (m, 4H), 1.76—1.66 (m, 2H). MS (ESI, method A): m/z = 365.1 [M + H]+, tR=1.780 min. HPLC: 97% (214nm), 96% (254nm). cal conditions Unless otherwise noted, all solvents, chemicals, and ts were obtained cially and used without purification. The lH-NMR spectra were obtained in CDClg, DMSO-d6, CD301), or acetone-d6 at 25°C at 300 MHz or 400 MHz on an OXFORD (Varian) with chemical shift (5, ppm) reported relative to TMS as an internal standard. HPLC-MS chromatograms and spectra were obtained with an Agilent 1200-6110 system. Prep-HPLC ments were Gilson GX—281 (Gilson) and P230 Preparative nt System (Gradient: 95% water, 5% acetonitrile, 30-50 min gradient to 25% water, 75% acetonitrile). The microwave instrument was a CEM Discover Biological ties: IC50 Determination OfBTK Inhibitors In o Kinase Biochemical Assay The activity of the Examples and Analogs described herein, as inhibitors of BTK are demonstrated and confirmed by pharmacological in vitro assays. Activity possessed by the compounds may be trated in vivo. Those skilled in the art will appreciate that a variety of assay formats may be used to determine the activity of the nds described herein.

Materials: ADP-GloTM Kinase Assay (cat. V9102, 10000 tests), components: 0 1><50ml ADP-GloTM Reagent, o 1><100ml Kinase ion Buffer, o 1><5ml Ultra Pure ATP, 10mM o 1><5ml ADP, 10mM Reagents and Plate: Tris.Hcl (Sigma cat. 154563), MgClz (Sigma cat.M1028), MnClz (Sigma, M3634), BSA (Sigma cat.05470), BTK Substrate lchem, P61-58), DTT (Sigma, D0632), DMSO (Sigma, S5879), BTK enzyme. (1 .5mg/ml, purity 75%, 90ng/ul, made in . 384 well assay plate (cat. 3674).

Assay ions: 0 Enzyme concentration: 8ng/5ul. 0 ATP concentration: 50uM o ate de) tration: 0.2mg/ml. 0 Reaction buffer composition: 40mM Cl pH7.5, lOmM MgClg, 2mM MnClz, 0.1mg/mL BSA, 0.05mM DTT. 0 Test compound concentration: DMSOSO.5%.

Methods: Compound Dosage Gradient Solution Preparation: A 3-fold serial dilution of test compound was made for 10 gradient points (100, 33.33, 11.11, 3.70, 1.23, 0.41, 0.14, 0.046, 0.015, 0.005uM) in 100% DMSO. The intermediate dilution was done by adding 2ul of diluted compound into 78ul of assay buffer (containing 40mM Tris.Hcl, pH 7.5 10mM MgClz, 2mM MnCl 0.05mM DTT), making the final , 0.1mg/mL BSA, compound concentration (1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, 0.05nM) and DMSO concentration 0.5% percentage.

ADP-Glo Kinase Assay Protocol For BTK Inhibitors Testing: 1x and 2x assay buffer were made at first. BTK kinase was diluted with 1x assay buffer but ate was diluted with 2x assay buffer. 1ul of diluted compound was transferred into 384- well assay plate, and then 2.0ul of enzyme solution was added, and spun at 2000rpm for 1min.

This mixture was incubated at 24°C for 30mins. 2ul of peptide substrate/ATP mixture was added into the assay plate to start the reaction. The mixture was mixed thoroughly and then the 384- well plate was spun and incubated at 24°C for 60mins. 5.0ul of ADP—Glo Reagent was added to stop the kinase activity and deplete the ATP unconsumed, and the plate was mixed thoroughly and incubated at 24°C for 40min. Then, 10.0ul of Kinase Detection reagent was added, and the plate was centrifuged and then kept at 24°C for 30min. The luminescence signal was read on Envision.

Data Analysis: % inhibition of nds at each different concentration is calculated from Equation (1): % inhibition = 100-100*(Signal-low control)/(High control—low control). . .. Equation(1) IC50 values of compounds were calculated from a 4-parameter fit using Equation (2): Y=Bottom + (TOP-Bottom)/(1+((C/X)Ahillslope)) .............. Equation (2) In Equation 2, Y represents % inhibition, X is the log value of the test compound concentration. IC50 was the concentration of nd where half of maximal inhibition was achieved.

All data was analyzed with IDBS XLfit5 re (ID Business ons Ltd., UK). The IC50 data is ized in Table 1.

Table 1: IC50 BTK Activity Values For Examples 1-63 2, 4, 14, 27, 30, 33, 50, 53, 56 9, 24, 31 1, 3, 5, 6, 7, 8,10,11,12,13,15,16,17,18,19, 20, 21, 22, 23, 25, 26, 28, 29, 32, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 51, 52, 54, 55, 57, 58, 59, 60, 61, 62, 63 Table 2 provides a ison of Examples 3 and 5 to Analogs 1 and 2 in terms of in Vitro BTK potency. es 3 and 5 demonstrate about a 100x improvement in potency over Analogs 1 and 2 when compared in head-to-head assays.

Table 2: Comparison of Examples 3 and 5 to Analogs 1 and 2 Example 3 Example 5 Analog 1 Analog 2 347.4 364.5 Examples 3 and 5 also demonstrate from 10x — 100x differences in potency between BTK and Src and are thus selective for BTK over Src.

Furthermore, selectivity of Examples 3 and 5 was determined. Table 3 provides in Vitro biochemical data demonstrating that Examples 3 and 5 are selective for BTK over Src.

Table 3: Selectivity Data for Examples 3 and 5 Target Example 3 Example 5 % Inhibition @ % Inhibition @ 1000 nM 1000 nM BT 99.35 99.7 SRC 23 33 Fold >100x >100x Difference To obtain the data provided in Table 3, kinase-tagged T7 phage s were grown in parallel in 24—well blocks in an E. coli host derived from the BL21 strain. E. coli were grown to log-phase and infected with T7 phage from a frozen stock (multiplicity of infection = 0.4) and ted with shaking at 32°C until lysis (90-150 minutes). The lysates were fuged (6,000 x g) and filtered (0.2um) to remove cell debris. The remaining kinases were produced in HEK- 293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small le ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. The ed beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1 % BSA, 0.05 % Tween 20, 1 mM DTT) to remove unbound ligand and to reduce nonspecific phage binding. Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in 1x binding buffer (20 % SeaBlock, 0.17x PBS, 0.05 % Tween 20, 6 mM DTT).

Example compounds were ed as 40x stocks in 100% DMSO and directly diluted into the assay. All reactions were performed in polypropylene 384-well plates in a final volume of 0.04 ml. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (1x PBS, 0.05 % Tween 20). The beads were then re-suspended in elution buffer (lx PBS, 0.05 % Tween 20, 0.5 uM non-biotinylated affinity ligand) and ted at room temperature with shaking for 30 minutes. The kinase concentration in the eluates was measured by qPCR.

The compound(s) were ed at 1000 nM, and results for y screen binding interactions are provided in Table 3 as "% Ctrl", where lower numbers indicate stronger hits. The % Ctrl is calculated according to Equation (1), below: Where: test compound = Example negative control = DMSO (100 % Ctrl) positive control = control compound ( 0% Ctrl) Additional biological selectivity data for Examples 3 and 5 against each member of the SRC family of protein s as well as EGFR are provided in Table 4, below. The data in Table 4 was obtained using the same proecedure as described above with respect to the data in Table 3.

Table 4: Selectivity Data for Examples 3 and 5 Example 3 Example 5 - %Inhibition @ 1000 nM % Inhibition @ 1000 nM --——_ -__— -__— Compositions: The present invention includes pharmaceutical compositions comprising a compound or pharmaceutically acceptable salt thereof of the invention, which is formulated for a desired mode of administration with or without one or more pharmaceutically acceptable and useful rs.

The compounds can also be ed in pharmaceutical compositions in combination with one or more other eutically active compounds.

The pharmaceutical compositions of the invention comprise a compound of the invention (or a pharmaceutically acceptable salt thereof) as an active ingredient, optional pharmaceutically acceptable carrier(s) and optionally other eutic ients or adjuvants. The compositions include itions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

Compounds of the invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to tional pharmaceutical compounding ques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the invention can be presented as discrete units suitable for oral administration such as capsules, cachets or s each containing a predetermined amount of the active ingredient. Further, the compositions can be ted as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound represented by Formula I, or a pharmaceutically acceptable salt thereof, can also be stered by controlled release means and/or delivery devices. The compositions can be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that tutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and tely admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the d presentation.

The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.

Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, , acacia, ium te, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

A tablet containing the composition of this invention can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be ed by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, ally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded s can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05 mg to about 5 g of the active ingredient and each cachet or capsule preferably containing from about 0.05 mg to about 5 g of the active ingredient.

A formulation intended for the oral administration to humans may contain from about 0.5 mg to about 5 g of active agent, compounded with an appropriate and convenient amount of carrier al which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms will generally contain between from about 1 mg to about 2 g of the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

Compounds of the invention can be provided for formulation at high purity, for example at least about 90%, 95%, or 98% pure by weight. ceutical compositions of the invention suitable for parenteral stration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a vative can be included to prevent the detrimental growth of microorganisms. ceutical compositions of the invention suitable for injectable use include sterile aqueous ons or sions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such e injectable solutions or sions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy ability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the invention can be in a form suitable for l use such as, for example, an aerosol, cream, ointment, lotion, dusting , or the like. r, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, ing a compound represented by Formula I of this invention, or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 5 wt % to about 10 wt % of the compound, to produce a cream or ointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first ng the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.

In on to the aforementioned r ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as ts, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient.

Compositions containing a compound described by Formula I, or pharmaceutically acceptable salts thereof, may also be ed in powder or liquid concentrate form.

Compounds of the present invention inhibit the activity of BTK in animals, including , and are useful in the treatment and/or prevention ous diseases and conditions such as cancer, inflammation, fibrotic diseases, and autoimmune disease which are caused, mediated and/or ated by BTK. In particular, compounds of the invention, and itions thereof, are inhibitors of BTK, and are useful in treating conditions modulated, at least in part, by BTK.

In some aspects, the invention includes a method of treating cancer comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or salt of the invention.

In some aspects, the ion includes a method of ng a cancer mediated at least in part by BTK comprising administering to a mammal in need thereof a therapeutically ive amount of a compound or salt of Formula I.

In some aspects, the invention includes a method of treating or a method of manufacturing a medicament for treating a cancer, such as those described herein, which is mediated at least in part by BTK, comprising administering to a mammal in need f a therapeutically effective amount of a compound or salt of the invention.

In some aspects, the invention includes a method of treating lymphocyte homing and ation mediated at least in part by BTK sing administering to a mammal in need thereof a therapeutically effective amount of a compound or salt of Formula I.

In some aspects, the invention includes a method of treating or a method of manufacturing a medicament for treating lymphocyte homing and inflammation, such as those bed herein, which is mediated at least in part by BTK, comprising stering to a mammal in need thereof a therapeutically effective amount of a compound or salt of the invention.

In some aspects, the invention includes a method of treating neuropathic pain comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or salt of the invention.

In some aspects, the invention includes a method of treating neuropathic pain mediated at least in part by BTK comprising administering to a mammal in need thereof a therapeutically effective amount of a nd or salt of Formula I.

In some aspects, the invention includes a method of treating or a method of manufacturing a medicament for treating neuropathic pain, such as those described herein, which is mediated at least in part by BTK, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or salt of the invention.

In some aspects, the invention includes a method of treating ic diseases comprising administering to a mammal in need f a therapeutically effective amount of a compound or salt of the invention.

In some aspects, the invention includes a method of treating fibrotic es mediated at least in part by BTK comprising administering to a mammal in need thereof a therapeutically effective amount of a nd or salt of Formula I.

In some aspects, the invention includes a method of treating or a method of manufacturing a medicament for treating a fibrotic e, such as those described herein, which is mediated at least in part by BTK, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or salt of the invention.

In some aspects, the invention includes a method of treating thrombosis comprising administering to a mammal in need f a therapeutically effective amount of a compound or salt of the invention.

In some aspects, the invention es a method of treating thrombosis mediated at least in part by BTK comprising stering to a mammal in need thereof a therapeutically effective amount of a compound or salt of Formula I.

In some aspects, the invention includes a method of treating or a method of manufacturing a medicament for treating thrombosis, such as those described herein, which is mediated at least in part by BTK, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or salt of the invention.

In some aspects, the invention includes a method of ng cholestatic pruritus comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or salt of the invention.

In some aspects, the invention includes a method of treating cholestatic pruritus mediated at least in part by BTK comprising administering to a mammal in need f a therapeutically ive amount of a compound or salt of Formula I.

In some aspects, the invention includes a method of ng or a method of manufacturing a medicament for cholestatic pruritus, such as those described herein, which is mediated at least in part by BTK, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or salt of the invention.

The compounds of Formula I of the invention are usefial in the treatment of a variety of cancers, including, but not limited to, solid tumors, sarcoma, fibrosarcoma, osteoma, melanoma, retinoblastoma, rhabdomyosarcoma, glioblastoma, neuroblastoma, teratocarcinoma, hematopoietic malignancy, and ant s. More specifically, the cancers include, but not limited to, lung cancer, bladder , pancreatic cancer, kidney cancer, gastric cancer, breast , colon cancer, te cancer (including bone ases), hepatocellular carcinoma, ovarian cancer, esophageal squamous cell carcinoma, melanoma, an anaplastic large cell lymphoma, an inflammatory myofibroblastic tumor, and a glioblastoma.

In some aspects, the above methods are used to treat one or more of bladder, colorectal, non-small cell lung, breast, or pancreatic cancer. In some aspects, the above s are used to treat one or more of ovarian, gastric, head and neck, prostate, hepatocellular, renal, glioma, or a cancer.

In some aspects, the invention includes a method, including the above methods, wherein the compound is used to inhibit cellular epithelial to mesenchymal transition (EMT).

In some aspects, the method r comprises stering at least on additional active agent. In some aspects, the invention includes a method of treating cancer sing administering to a mammal in need thereof a therapeutically effective amount of a compound or salt of the invention, wherein at least one additional active anti-cancer agent is used as part of the method.

In some s, the invention includes a method of treating the disease described herein ed at least in part by BTK sing administering to a mammal in need thereof a therapeutically effective regimen comprising a compound or salt of a I and at least one additional active agent. Generally, dosage levels on the order of from about 0.01 mg/kg to about 150 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day. For example, inflammation, cancer, psoriasis, allergy/asthma, disease and ions of the immune system, disease and conditions of the Central Nervous System (CNS), may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day.

It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

General Definitions and iations: Except where otherwise indicated, the following general conventions and definitions apply. Unless otherwise ted herein, language and terms are to be given their broadest reasonable interpretation as understood by the skilled artisan. Any es given are nonlimiting.

Any section headings or subheadings herein are for the reader's convenience and/or formal compliance and are non-limiting.

A recitation of a compound herein is open to and embraces any material or composition containing the d compound (e.g., a composition containing a racemic mixture, tautomers, epimers, stereoisomers, impure mixtures, etc.). In that a salt, solvate, or hydrate, polymorph, or other complex of a compound includes the compound itself, a recitation of a compound embraces materials containing such forms. ically labeled compounds are also encompassed except where specifically excluded. For example, en is not limited to hydrogen containing zero neutrons. For example, deuterium is referred to herein as "D" and means a hydrogen atom having one n.

The term "active agent" means a compound of the invention in any salt, polymorph, crystal, solvate, or hydrated form.

The term "substituted" and substitutions ned in formulas herein refer to the replacement of one or more hydrogen radicals in a given structure with a ed radical, or, if not specified, to the replacement with any chemically feasible radical. When more than one position in a given structure can be tuted with more than one substituent ed from specified groups, the substituents can be either the same or different at every position (independently selected) unless otherwise indicated. In some cases, two positions in a given structure can be substituted with one shared substituent. It is understood that chemically impossible or highly unstable configurations are not desired or intended, as the skilled artisan would appreciate.

In descriptions and claims where subject matter (e.g., substitution at a given molecular position) is recited as being selected from a group of possibilities, the tion is specifically intended to include any subset of the recited group. In the case of multiple variable positions or substituents, any combination of group or variable subsets is also plated.

Unless indicated otherwise, a substituent, diradical or other group referred to herein can be bonded through any suitable position to a referenced subject molecule. For e, the term "indolyl" includes l-indolyl, 2-indolyl, 3-indolyl, etc.

The convention for describing the carbon content of certain es is )" or "Ca- Cb" meaning that the moiety can contain any number of from "a" to "b" carbon atoms. Coalkyl means a single covalent chemical bond when it is a connecting moiety, and a hydrogen when it is a terminal moiety. Similarly, "x-y" can indicate a moiety containing from x to y atoms, e.g.,5_ 6heterocycloalkyl means a heterocycloalkyl having either five or six ring members. "CH" may be used to define number of carbons in a group. For example, "C0_1galkyl" means alkyl having 0- 12 carbons, wherein Coalkyl means a single covalent chemical bond when a linking group and means hydrogen when a terminal group. C0_12alkyl includes various alternative embodiments, including, but not 111111th to, C1_12alkyl, C2_12alkyl, C3_12alkyl, C4_12alkyl, C5_12alkyl, C6_12alkyl, C7_12alkyl, Cg_12alkyl, C9_12alkyl, C10_12alkyl, C11_12alkyl, C1_11alkyl, C1_10alkyl, C1_9alkyl, C1_ galkyl, C1_7alkyl, C1_6alkyl, C1_5alkyl, kyl, C1_3alkyl, C1_2alkyl, Clalkyl, and Coalkyl. C0_ lzalkyl further includes any combination of "a" and "b" and/or "x" and "y" number of carbon atoms including, but not limited to, C2_12alkyl, C3_11alkyl, C4_10alkyl, C5_9alkyl, C6_galkyl and C7alky1.

The term "absent," as used herein to describe a structural variable (e.g., "—R— is absent") means that diradical R has no atoms, and merely represents a bond between other adjoining atoms, unless otherwise indicated.

Unless otherwise indicated (such as by a ting "-"), the connections of compound name moieties are at the rightmost recited moiety. That is, the substituent name starts with a terminal moiety, continues with any bridging moieties, and ends with the connecting moiety. For example, "heteroarylthioC1-4alkyl" is a heteroaryl group connected through a thio sulfur to a C1- 4alkyl, which alkyl connects to the al species bearing the substituent.

The term "aliphatic" means any hydrocarbon moiety, and can contain linear, branched, and cyclic parts, and can be saturated or unsaturated.

The term "alkyl" means any saturated hydrocarbon group that is straight-chain or branched. Examples of alkyl groups include methyl, ethyl, propyl, 2—propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and the like.

The term "alkenyl" means any ethylenically unsaturated straight-chain or ed hydrocarbon group. entative examples include, but are not limited to, ethenyl, l-propenyl, 2-propenyl, l—, 2-, or nyl, and the like.

The term yl" means any enically unsaturated ht-chain or branched hydrocarbon group. Representative examples include, but are not limited to, l, l-propynyl, 2-propynyl, l—, 2-, or 3-butynyl, and the like.

The term "alkoxy" means —O-alkyl, —O-alkenyl, or —O—alkynyl. "Haloalkoxy" means an —O-(haloalkyl) group. entative examples include, but are not limited to, trifluoromethoxy, tribromomethoxy, and the like.

"Haloalkyl" means an alkyl, ably lower alkyl, that is tuted with one or more same or different halo atoms.

"Hydroxyalkyl" means an alkyl, ably lower alkyl, that is substituted with one, two, or three hydroxy groups; e.g., hydroxymethyl, l or oxyethyl, 1,2-, 1,3-, or 2,3- dihydroxypropyl, and the like.

The term "alkanoyl" means —C(O)—alkyl, —C(O)-alkenyl, or —C(O)—alkynyl.

"Alkylthio" means an —S-(alkyl) or an —S-(unsubstituted cycloalkyl) group.

Representative examples e, but are not limited to, methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.

The term "cyclic" means any ring system with or without atoms (N, O, or S(O)0_2), and which can be saturated, partially saturated, or unsaturated. Ring systems can be bridged and can include fused rings. The size of ring systems may be described using terminology such as "X- ycyclic," which means a cyclic ring system that can have from x to y ring atoms. For example, the term "9.1ocarbocyclic" means a 5,6 or 6,6 fused bicyclic carbocyclic ring system which can be saturated, unsaturated or aromatic. It also means a phenyl fused to one 5 or 6 membered saturated or unsaturated carbocyclic group. Nonlimiting examples of such groups e naphthyl, l,2,3,4 tetrahydronaphthyl, indenyl, indanyl, and the like.

The term "carbocyclic" means a cyclic ring moiety containing only carbon atoms in the ring(s) without regard to aromaticity. A 3-10 membered carbocyclic means chemically feasible clic and filSGd bicyclic carbocyclics having from 3 to 10 ring atoms. rly, a 4-6 ed carbocyclic means monocyclic carbocyclic ring moieties having 4 to 6 ring carbons, and a 9-10 membered carbocyclic means fused bicyclic carbocyclic ring moieties having 9 to 10 ring carbons.

The term "cycloalkyl" means a non-aromatic 3-12 carbon mono-cyclic, bicyclic, or polycyclic aliphatic ring moiety. lkyl can be bicycloalkyl, polycycloalkyl, bridged, or spiroalkyl. One or more of the rings may contain one or more double bonds but none of the rings has a completely conjugated pi-electron system. Examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, adamantane, eptane, cycloheptatriene, and the like.

The term "unsaturated carbocyclic" means any cycloalkyl containing at least one double or triple bond. The term "cycloalkenyl" means a cycloalkyl having at least one double bond in the ring moiety.

The terms "bicycloalkyl" and "polycycloalkyl" mean a structure consisting of two or more cycloalkyl moieties that have two or more atoms in common. If the cycloalkyl moieties have exactly two atoms in common they are said to be "fused". Examples include, but are not limited to, bicyclo[3.l .0]hexyl, perhydronaphthyl, and the like. If the lkyl moieties have more than two atoms in common they are said to be "bridged". Examples include, but are not limited to, bicyclo[2.2. l]heptyl ("norbornyl"), o[2.2.2]octyl, and the like.

The term "spiroalkyl" means a structure consisting of two cycloalkyl moieties that have exactly one atom in common. Examples include, but are not limited to, spiro[4.5]decyl, spiro[2.3]hexyl, and the like.

The term "aromatic" means a planar ring moieties containing 4n+2 pi electrons, wherein n is an integer.

The term "aryl" means aromatic moieties containing only carbon atoms in its ring system.

Non-limiting examples include phenyl, naphthyl, and anthracenyl. The terms "aryl-alkyl" or "arylalkyl" or "aralkyl" refer to any alkyl that forms a bridging portion with a terminal aryl.

"Aralkyl" means alkyl that is substituted with an aryl group as defined above; e. g., — CH2 , —(CH2)2phenyl, —(CH2)3 phenyl, CH3CH(CH3)CH2phenyl, and the like and derivatives thereof.

The term "heterocyclic" means a cyclic ring moiety containing at least one heteroatom (N, O, or S(O)0_2), ing heteroaryl, heterocycloalkyl, including unsaturated heterocyclic rings.

The term "heterocycloalkyl" means a omatic clic, bicyclic, or polycyclic heterocyclic ring moiety of 3 to 12 ring atoms containing at least one ring having one or more heteroatoms. The rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system. Examples, without limitation, of heterocycloalkyl rings include ine, oxetane, tetrahydrofiiran, tetrahydropyran, e, oxocane, thietane, lidine, oxazolidine, idine, pyrazolidine, isoxazolidine, azolidine, tetrahydrothiophene, tetrahydrothiopyran, thiepane, thiocane, azetidine, pyrrolidine, dine, N—methylpiperidine, azepane, 1,4-diazapane, azocane, [l,3]dioxane, oxazolidine, piperazine, homopiperazine, morpholine, thiomorpholine, 6-tetrahydropyridine and the like. Other examples of heterocycloalkyl rings include the oxidized forms of the sulfur—containing rings.

Thus, ydrothiophene- l -oxide, tetrahydrothiophene-l , l-dioxide, thiomorpholine- l -oxide, thiomorpholine- l , 1 -dioxide, tetrahydrothiopyranoxide, tetrahydrothiopyran-l , 1 -dioxide, thiazolidine-l-oxide, and thiazolidine- l , l -dioxide are also considered to be heterocycloalkyl rings. The term "heterocycloalkyl" also includes fused ring s and can include a yclic ring that is partially or fully unsaturated, such as a benzene ring, to form benzofused heterocycloalkyl rings. For example, 3,4-dihydro-1,4-benzodioxine, tetrahydroquinoline, tetrahydroisoquinoline and the like. The term "heterocycloalkyl" also includes heterobicycloalkyl, heteropolycycloalkyl, or spiroalkyl, which are bicycloalkyl, polycycloalkyl, or spiroalkyl, in which one or more carbon ) are replaced by one or more heteroatoms selected from O, N, and S. For example, 2-oxa-spiro[3.3]heptane, 2,7-diaza- spiro[4.5]decane, 6-oxa-2—thia—spiro[3.4]octane, octahydropyrrolo[l,2-a]pyrazine, 7—azabicyclo [2.2. l]heptane, 2-oxa-bicyclo[2.2.2]octane, and the like, are such heterocycloalkyls.

Examples of saturated heterocyclic groups include, but are not d to oxiranyl, thiaranyl, aziridinyl, oxetanyl, thiatanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, ydrothiopyranyl, piperidinyl, 1,4-dioxanyl, 1,4-oxathianyl, morpholinyl, l,4-dithianyl, piperazinyl, 1,4-azathianyl, oxepanyl, thiepanyl, azepanyl, 1,4- dioxepanyl, 1,4-oxathiepanyl, 1,4-oxaazepanyl, 1,4—dithiepanyl, 1,4-thieazepanyl, 1,4-diazepanyl Non-aryl heterocyclic groups include saturated and unsaturated systems and can include groups having only 4 atoms in their ring system. The cyclic groups include benzo-fused ring systems and ring systems substituted with one or more oxo moieties. Recitation of ring sulfur is tood to include the sulfide, sulfoxide or sulfone where feasible. The heterocyclic groups also include lly unsaturated or fully saturated 4—10 membered ring systems, e.g., single rings of 4 to 8 atoms in size and bicyclic ring systems, including aromatic 6-membered aryl or heteroaryl rings fused to a non-aromatic ring. Also ed are 4-6 ed ring systems ("4-6 membered heterocyclic"), which include 5-6 membered heteroaryls, and include groups such as azetidinyl and piperidinyl. cyclics can be heteroatom—attached where such is possible. For instance, a group derived from pyrrole can be pyrrol—l-yl (N-attached) or pyrrol- 3-yl (C-attached). Other heterocyclics include imidazo(4,5—b)pyridinyl and benzoimidazol-l- es of heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, rpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, nyl, oxazepinyl, diazepinyl, thiazepinyl, l,2,3,6-tetrahydropyridinyl, 2- pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, l,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, lidinyl, imidazolinyl, olidinyl, 3-azabicyclo[3.1.0]hexanyl, 3- azabicyclo[4.1.0]heptanyl, 3H—indolyl, quinolizinyl, and the like.

The term urated heterocyclic" means a heterocycloalkyl containing at least one unsaturated bond. The term "heterobicycloalkyl" means a bicycloalkyl structure in which at least one carbon atom is replaced with a heteroatom. The term "heterospiroalkyl" means a spiroalkyl structure in which at least one carbon atom is replaced with a heteroatom. es of partially rated heteroalicyclic groups include, but are not limited to: 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, ZH-pyranyl, l,2,3,4-tetrahydropyridinyl, and l ,2,5 ,6—tetrahydropyridinyl.

The terms oaryl" or "hetaryl" mean a monocyclic, bicyclic, or polycyclic aromatic heterocyclic ring moiety containing 5-12 atoms. Examples of such heteroaryl rings include, but are not limited to, fiiryl, thienyl, pyrrolyl, lyl, imidazolyl, oxazolyl, olyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, olyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. The terms "heteroaryl" also include heteroaryl rings with fused carbocyclic ring systems that are partially or fiJlly unsaturated, such as a benzene ring, to form a benzofused heteroaryl. For example, benzimidazole, benzoxazole, benzothiazole, benzofuran, quinoline, isoquinoline, quinoxaline, indazole, imidazo[l,2-a]pyridine, 3-methyloxo-2,3- obenzo[d]oxazol—5-yl, 2—methyl—2H-indazol-5—yl, 3-methylimidazo[l,5—a]pyridine, 2— methyl- 1 H-benzo [d]imidazole, lH-pyrrolo [2,3 -b]pyridine, 3,4-Dihydro-2H- benzo[b][1,4]oxazine, 2-oxo-2,3-dihydrobenzo[d]oxazole, 3-oxo-3,4-dihydro-2H- benzo[b] [l ,4]oxazine, 2,3-Dihydrobenzo [b] [l xine, 2-methyl-[l ,2,4]triazolo[ l ,5-a]pyridine, and the like. Furthermore, the terms "heteroaryl" e filSCd 5-6, 5-5, 6-6 ring systems, optionally possessing one nitrogen atom at a ring junction. Examples of such hetaryl rings include, but are not limited to, pyrrolopyrimidinyl, imidazo[l,2-a]pyridinyl, imidazo[2,l- b]thiazolyl, imidazo[4,5-b]pyridine, pyrrolo[2,l-f][l,2,4]triazinyl, and the like. Heteroaryl groups may be attached to other groups through their carbon atoms or the heteroatom(s), if applicable. For example, pyrrole may be connected at the nitrogen atom or at any of the carbon atoms.

Heteroaryls include, e.g., 5 and 6 membered monocyclics such as pyrazinyl and pyridinyl, and 9 and 10 membered fused bicyclic ring moieties, such as quinolinyl. Other examples of heteroaryl include quinolinyl, 7—methoxy-quinolin-4—yl, nyl, pyridin—3- yl, and pyridinyl. Other examples of heteroaryl include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, nyl, tetrazolyl, furanyl, l, isoxazolyl, lyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, fiarazanyl, benzofiarazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, and the like. Examples of 5-6 ed heteroaryls include, enyl, isoxazolyl, 1,2,3-triazolyl, 1,2,3-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-triazolyl, oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-oxadiazolyl, 1,2,5- thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4 oxadiazolyl, 1,2,5-triazinyl, 1,3,5-triazinyl, 6-oxo-l,6-dihydropyridine, and the like.

"Heteroaralkyl" group means alkyl, preferably lower alkyl, that is substituted with a heteroaryl group; e.g., —CH2 pyridinyl, —(CH2)2pyrimidinyl, —(CH2)3imidazolyl, and the like, and derivatives thereof.

A pharmaceutically acceptable aryl is one that is sufficiently stable to be attached to a compound of the invention, formulated into a ceutical composition and subsequently administered to a patient in need thereof Examples of monocyclic heteroaryl groups include, but are not limited to: pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1,2,3— lyl, 1,3,4-triazolyl, l-oxa-2,3-diazolyl, l-oxa-2,4-diazolyl, l-oxa-2,5-diazolyl, l-oxa-3,4- diazolyl, l-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, l-thia-3,4-diazolyl tetrazolyl, nyl, pyridazinyl, pyrimidinyl, pyrazinyl.

Examples of fused ring aryl groups include, but are not limited to: benzoduranyl, benzothiophenyl, indolyl, idazolyl, indazolyl, benzotriazolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[4,5- b]pyridinyl, imidazo[4,5-c]pyridinyl, lo[4,3-d]pyridinyl, pyrazolo[4,3—c]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, isoindolyl, indazolyl, purinyl, indolinyl, imidazo[l,2-a]pyridinyl, imidazo[l,5—a]pyridinyl, pyrazolo[l ,5-a]pyridinyl, pyrrolo[l ,2- dazinyl, imidazo[l,2-c]pyrimidinyl, quinolinyl, isoquinolinyl, cinnolinyl, azaquinazoline, alinyl, phthalazinyl, 1,6—naphthyridinyl, phthyridinyl, phthyridinyl, 1,5- naphthyridinyl, 2,6-naphthyridinyl, 2,7-naphthyridinyl, pyrido[3,2-d]pyrimidinyl, [4,3- d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[2,3—d]pyrimidinyl, pyrido[2,3—b]pyrazinyl, pyrido[3,4-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl, pyrimido[2,3-b]pyrazinyl, do[4,5- d]pyrirnidinyl.

"Arylthio" means an —S-ary1 or an —S-heteroaryl group, as defined herein. entative examples include, but are not limited to, phenylthio, pyridinylthio, furanylthio, thienylthio, pyrimidinylthio, and the like and derivatives thereof.

The term "9-10 membered heterocyclic" means a fused 5,6 or 6,6 bicyclic heterocyclic ring moiety, which can be saturadated, unsaturated or aromatic. The term "9—10 membered fused bicyclic heterocyclic" also means a phenyl fused to one 5 or 6 membered cyclic group.

Examples include uranyl, benzothiophenyl, indolyl, benzoxazolyl, 3H—imidazo[4,5- c]pyridin-yl, dihydrophthazinyl, 1H-imidazo[4,5-c]pyridinyl, imidazo[4,5-b]pyridyl, 1,3 1,3]dioxolyl, 2H-chromanyl, isochromanyl, 2,3 dihydro-SH—[l,3]thiazolo[3,2- a]pyrimidyl, 1,3-benzothiazolyl, 1,4,5,6 tetrahydropyridazyl, 1,2,3,4,7,8hexahydropteridinyl, 2- thioxo-2,3,6,9-tetrahydro-1H—purinyl, 3,7-dihydro-1H—purinyl, 3,4-dihydropyrimidin-l-yl, 2,3-dihydro-1,4-benzodioxinyl, benzo[1,3]dioxolyl, 2H-chromenyl, chromanyl, 3,4— dihydrophthalazinyl, 2,3-ihydro-1H—indolyl, 1,3-dihydro-2H-isoindolyl, 2,4,7-trioxo- 1 ,2,3 ,4,7,8-hexahydropteridin—yl, thieno[3 ,2-d]pyrimidinyl, 4—oxo-4,7-dihydro-3H-pyrrolo[2,3- d]pyrimidin-yl, 1,3-dimethyloxothioxo-2,3,6,9-tetrahydro-1H-purinyl, 1,2- dihydroisoquinolinyl, 2—oxo- 1 ,3-benzoxazolyl, 2,3-dihydro-5H-1,3-thiazolo—[3,2-a]pyrimidinyl, ,6,7,8-tetrahydro-quinazolinyl, 4-oxochromanyl, 1,3-benzothiazolyl, benzimidazolyl, benzotriazolyl, purinyl, fiarylpyridyl, thiophenylpyrimidyl, thiophenylpyridyl, pyrrolylpiridyl, oxazolylpyridyl, thiazolylpiridyl, 3,4—dihydropyrimidinyl imidazolylpyridyl, quinoliyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pyrazolyl[3,4]pyridine, 1,2- dihydroisoquinolinyl, cinnolinyl, 2,3—dihydro-benzo[1,4]dioxin4-yl, 4,5,6,7—tetrahydro-benzo[b]— thiophenyl-Z-yl, 1,8-naphthyridinyl, 1,5-napthyridinyl, 1,6-naphthyridinyl, pthyridinyl, 3 ,4-dihydro-2H- 1 ,4-benzothiazine, 4,8-dihydroxy-quinolinyl, 1-oxo— 1 ydro-isoquinolinyl, 4-phenyl-[1,2,3]thiadiazolyl, and the like.

The term "aryloxy" means an —O-aryl or an —O-heteroaryl group, as defined herein.

Representative examples include, but are not limited to, phenoxy, pyridinyloxy, furanyloxy, loxy, pyrimidinyloxy, pyrazinyloxy, and the like, and derivatives thereof.

The term "oxo" means a compound containing a carbonyl group. One in the art understands that an "oxo" requires a second bond from the atom to which the oxo is attached.

The term "halo" or "halogen" means fluoro, chloro, bromo, or iodo.

"Acyl" means a —C(O)R group, where R can be selected from the nonlimiting group of en or optionally substituted lower alkyl, trihalomethyl, unsubstituted cycloalkyl, aryl, or other suitable substituent.

"Thioacyl" or "thiocarbonyl" means R" group, with R as defined above.

The term "protecting group" means a suitable chemical group that can be attached to a functional group and removed at a later stage to reveal the intact functional group. Examples of suitable protecting groups for various onal groups are described in T. W. Greene and P. G.

M. Wuts, Protective Groups in Organic Synthesis, 2d Ed, John Wiley and Sons (1991 and later editions); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed. Encyclopedia of Reagents for c Synthesis, John Wiley and Sons . The term "hydroxy ting , as used herein, unless otherwise indicated, includes Ac, CBZ, and various hydroxy protecting groups familiar to those skilled in the art including the groups referred to in Greene.

The term "linear structure" means a moiety having substituents that do not cyclize to form a ring system. A representative example es, but is not limited to, a compound including —NRXRY where any atoms of " X" and any atoms of "RY" do not connect to form a ring.

As used herein, the term "pharmaceutically acceptable salt" means those salts which retain the biological effectiveness and properties of the parent compound and do not t safety or toxicity issues. The term "pharmaceutically acceptable )" is known in the art and includes salts of acidic or basic groups which can be present in the compounds and prepared or resulting from pharmaceutically acceptable bases or acids.

The term "pharmaceutical composition" means an active compound in any form suitable for effective administration to a subject, e.g., a mixture of the compound and at least one pharmaceutically acceptable carrier.

As used herein, a "physiologically/pharmaceutically acceptable carrier" means a carrier or diluent that does not cause cant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

A "pharmaceutically acceptable excipient" means an inert substance added to a pharmaceutical ition to further facilitate administration of a compound. Examples, t limitation, of excipients include calcium carbonate, calcium phosphate, s sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

The terms "treat,3, CEtreatment," and "treating" means reversing, alleviating, inhibiting the progress of, or lly or completely preventing the disorder or condition to which such term applies, or one or more symptoms of such er or condition. "Preventing" means treating before an infection occurs.

"Therapeutically effective amount" means that amount of the compound being stered which will relieve to some extent one or more of the symptoms of the disorder being treated, or result in inhibition of the progress or at least partial reversal of the condition.

NMR Nuclear magnetic resonance MDP(S) Mass-directed HPLC purification (system) LC/MS Liquid chromatography mass spectrometry LDA Lithium diisopropylamide tert-BuOH tert-Butanol AcOH Acetic acid CDI 1,1 onyldiimidazole DCE 1,1-Dichloroethane DCM Dichloromethane DMF Dimethylformamide THF Tetrahydrofuran MeOH Methanol EtOH Ethanol EtOAc Ethyl e MeCN Acetonitrile DMSO Dimethylsulfoxide Boc tert-Butyloxycarbonyl DME 1,2-Dimethoxyethane DMF N,N—Dimethylformamide DIEA Diisopropylethylamine PS—DIEA Polymer—supported diisopropylethylamine PS—PPhg-Pd Polymer-supported Pd(PPh3)4 LAH Lithium aluminum hydride EDC 1-(3-Dimethylaminopropyl)ethylcarbodiimide HATU: l- [bis(dimethylamino)methylene] - l H— l ,2,3—triazolo[4,5 -b]pyridinium—3 -oxide hexafluorophosphate HOBt l-Hydroxybenzotnazole DMAP 4-Dimethylaminopyridine SEM-Cl 2-(Trimethylsilyl)ethoxymethyl chloride TBTU O-(Benzotriazolyl)-N,N,N',N’-tetramethyluronium tetrafluoroborate TEMPO 2,2,6,6-Tetramethylpiperidine- l -oxyl TFA (A) Trifluoroacetic acid (anhydride) TLC Thin layer chromatography TMSCN Trimethylsilyl cyanide Min Minute(s) NMO N—Methylmorpholine N—oxide d Day(s) RT, R.T., r.t., r.t or rt Room temperature tR ion time Conc. Concentrated

Claims (10)

1. A compound ed from the group consisting of: 6-(3-acrylamidophenyl)(4-phenoxyphenyl)nicotinamide; 6-(1-acryloylpiperidinyl)(4-phenoxyphenyl)nicotinamide; 6-(4-acryloylpiperazinyl)(4-phenoxyphenyl)nicotinamide; N N 6-(1-acryloylpyrrolidinyl)(4-phenoxyphenyl)nicotinamide; N N 6-(4-acrylamidophenyl)(4-phenoxyphenyl)nicotinamide; O N N O 6-(1-acryloylpiperidinyl)(4-phenoxyphenyl)nicotinamide; O NH2 N N 6-(4-acrylamidopiperidinyl)(4-phenoxyphenyl)nicotinamide; O N N N O crylamidopyrrolidinyl)(4-phenoxyphenyl)nicotinamide; HN N N 1-(1-acryloylpyrrolidinyl)(4-phenoxyphenyl)-1H-pyrazolecarboxamide; O N N O 1-(1-acryloylazetidinyl)(4-phenoxyphenyl)-1H-pyrazolecarboxamide; N O 1-(4-acrylamidophenyl)(4-phenoxyphenyl)-1H-pyrazolecarboxamide; N O 1-(3-acrylamidophenyl)(4-phenoxyphenyl)-1H-pyrazolecarboxamide; N N N O (S)(1-acryloylpyrrolidinyl)(4-phenoxyphenyl)-1H-pyrazolecarboxamide; O N N N O (1-acryloylpyrrolidinyl)(4-phenoxyphenyl)-1H-pyrazolecarboxamide; O N O N N 2-(1-acryloylpyrrolidinyl)(4-phenoxyphenyl)pyrimidinecarboxamide; N NH2 N N (E)(4-(4-(dimethylamino)butenoyl)piperazinyl)(4- phenoxyphenyl)nicotinamide; N N N O cryloylpiperazinyl)(4-(cyclohexyloxy)phenyl)nicotinamide; N N 6-(4-acryloylpiperazinyl)(3-methoxymethylphenyl)nicotinamide; N N 6-(4-acryloylpiperazinyl)-6'-phenoxy-2,3'-bipyridinecarboxamide; N N N O 6-(4-acryloylpiperazinyl)(4-(pyridinyloxy)phenyl)nicotinamide; N N O N 1-(1-(4-(dimethylamino)butenoyl)pyrrolidinyl)(4-phenoxyphenyl)-1H-pyrazole- 4-carboxamide; O N N O 6-(4-acryloylpiperazinyl)(4-(3-fluorophenoxy)phenyl)nicotinamide; N N O F cryloylpiperazinyl)(3-fluorophenoxyphenyl)nicotinamide; N N 6-(4-acryloylpiperazinyl)(4-(4-fluorophenoxy)phenyl)nicotinamide; N N 6-(4-acryloylpiperazinyl)(4-(2-fluorophenoxy)phenyl)nicotinamide; N N 6-(4-acryloylpiperazinyl)(2-fluorophenoxyphenyl)nicotinamide; N N F O 2-(1-acryloylpiperidinyl)(4-phenoxyphenyl)thiazolecarboxamide; O S N N cryloylpyrrolidinyl)(4-phenoxyphenyl)thiazolecarboxamide; N N 2-(1-acryloylpiperidinyl)(4-phenoxyphenyl)oxazolecarboxamide; O O N N O 2-(1-acryloylpyrrolidinyl)(4-phenoxyphenyl)oxazolecarboxamide; N N 2-(1-acryloylpyrrolidinyl)(4-phenoxyphenyl)thiazolecarboxamide; S O 2-(1-acryloylpiperidinyl)(4-phenoxyphenyl)thiazolecarboxamide; O N N S O cryloylpiperidinyl)(4-phenoxyphenyl)oxazolecarboxamide; N O 2-(1-acryloylpyrrolidinyl)(4-phenoxyphenyl)oxazolecarboxamide; N O O cryloylpiperidinyl)(4-phenoxyphenyl)thiazolecarboxamide; S O 2-(1-acryloylpiperidinyl)(4-phenoxyphenyl)thiazolecarboxamide; N O 2-(1-acryloylpiperidinyl)(4-phenoxyphenyl)oxazolecarboxamide; O N N O 5-(1-acryloylpiperidinyl)-4'-phenoxybiphenylcarboxamide; 5-(4-acryloylpiperazinyl)-4'-phenoxybiphenylcarboxamide; 6-(1-acryloylpiperidinyl)(4-(hydroxy(phenyl)methyl)phenyl)nicotinamide; O OH (E)(1-(2-cyanobutenoyl)azetidinyl)(4-phenoxyphenyl)-1H-pyrazole carboxamide; N O cryloylpiperazinyl)(4-((4,4-difluorocyclohexyl)oxy)phenyl)nicotinamide; N N F 6-(1-acryloylpiperidinyl)(4-(phenylcarbamoyl)phenyl)nicotinamide; N N O O henoxyphenyl)(4-(vinylsulfonyl)piperazinyl)nicotinamide; N N S O 2-(4-phenoxyphenyl)(1-(vinylsulfonyl)piperidinyl)nicotinamide; S O or a pharmaceutically acceptable salt thereof.

2. The compound according to Claim 1, wherein the compound is: 6-(3-acrylamidophenyl)(4-phenoxyphenyl)nicotinamide; 6-(1-acryloylpiperidinyl)(4-phenoxyphenyl)nicotinamide; 6-(4-acryloylpiperazinyl)(4-phenoxyphenyl)nicotinamide; N N 6-(1-acryloylpyrrolidinyl)(4-phenoxyphenyl)nicotinamide; N N crylamidophenyl)(4-phenoxyphenyl)nicotinamide; O N N O 6-(1-acryloylpiperidinyl)(4-phenoxyphenyl)nicotinamide; O NH2 N N 6-(4-acrylamidopiperidinyl)(4-phenoxyphenyl)nicotinamide; O N N N O 6-(3-acrylamidopyrrolidinyl)(4-phenoxyphenyl)nicotinamide; HN N N (4-(4-(dimethylamino)butenoyl)piperazinyl)(4- phenoxyphenyl)nicotinamide; N N N O 6-(4-acryloylpiperazinyl)(4-(cyclohexyloxy)phenyl)nicotinamide; N N 6-(4-acryloylpiperazinyl)(3-methoxymethylphenyl)nicotinamide; N N 6-(4-acryloylpiperazinyl)-6'-phenoxy-2,3'-bipyridinecarboxamide; N N N O 6-(4-acryloylpiperazinyl)(4-(pyridinyloxy)phenyl)nicotinamide; N N O N cryloylpiperazinyl)(4-(3-fluorophenoxy)phenyl)nicotinamide; N N O F 6-(4-acryloylpiperazinyl)(3-fluorophenoxyphenyl)nicotinamide; N N 6-(4-acryloylpiperazinyl)(4-(4-fluorophenoxy)phenyl)nicotinamide; N N 6-(4-acryloylpiperazinyl)(4-(2-fluorophenoxy)phenyl)nicotinamide; N N 6-(4-acryloylpiperazinyl)(2-fluorophenoxyphenyl)nicotinamide; N N F O cryloylpiperidinyl)-4'-phenoxybiphenylcarboxamide; 5-(4-acryloylpiperazinyl)-4'-phenoxybiphenylcarboxamide; 6-(1-acryloylpiperidinyl)(4-(hydroxy(phenyl)methyl)phenyl)nicotinamide; O OH 6-(4-acryloylpiperazinyl)(4-((4,4-difluorocyclohexyl)oxy)phenyl)nicotinamide; N N F 6-(1-acryloylpiperidinyl)(4-(phenylcarbamoyl)phenyl)nicotinamide; N N O O 2-(4-phenoxyphenyl)(4-(vinylsulfonyl)piperazinyl)nicotinamide; N N S O 2-(4-phenoxyphenyl)(1-(vinylsulfonyl)piperidinyl)nicotinamide; S O or a pharmaceutically acceptable salt thereof.

3. The compound ing to Claim 2, wherein the compound is N N O .

4. A compound selected from the group consisting of: 2-(4-phenoxyphenyl)(piperidinyl)nicotinamide; henoxyphenyl)(piperazinyl)nicotinamide; N N 1-(azetidinyl)(4-phenoxyphenyl)-1H-pyrazolecarboxamide; N O 1-(3-aminophenyl)(4-phenoxyphenyl)-1H-pyrazolecarboxamide; H2N N O 6-(1-acryloylpiperidinyl)(4-phenoxyphenyl)pyridinecarbonitrile; 6-(4-acryloylpiperazinyl)(4-phenoxyphenyl)pyridinecarboxylic acid; N N 2-(4-acryloylpiperazinyl)-N-methyl(4-phenoxyphenyl)thiazolecarboxamide; N N O .

5. A compound having a Formula IId, or a ceutically acceptable salt or solvate thereof: R3 X Z R2 O O Formula IId wherein X is N , N , N , or ; Z is C or N; G1, G2, and G3 are selected from the group consisting of one or more H, D (deuterium), C1-12 alkyl, halogen, and CF3; R2 and R3 are each independently selected from the group ting of H, D, C1-12 alkyl, halogen, CN, and CF3, wherein C1-12 alkyl is optionally substituted with NR11R12; R4 is selected from the group consisting of H, D, C1-12 alkyl, halogen, CN, and CF3; and R11 and R12 are independently H or C1-6 alkyl.

6. The compound according to Claim 5, n X is N or N .

7. The compound according to Claim 5, wherein G1, G2, and G3 are one or more H, or halogen.

8. The compound ing to Claim 5, wherein R2 and R3 are H or C1-12 alkyl, wherein C1- 11R12, and R11 and R12 are H or CH 12 alkyl is optionally tuted with NR 3.

9. A pharmaceutical composition for treating a disease mediated by Bruton’s tyrosine Kinase (BTK), comprising the compound of any one of Claims 1-3 and 5-8, and a pharmaceutically acceptable salt thereof.

10. Use of the compound or the pharmaceutically acceptable salt thereof of any one of Claims 1-3 and 5-8, in the manufacture of a medicament for ng of at least one of cancer, chronic inflammation, and autoimmune disease mediated at least in part by BTK. Guangzhou Innocare Pharma Tech Co., Ltd. By the Attorneys for the Applicant SPRUSON & FERGUSON