FGFR inhibitors for cancer treatment

Abstract

The present disclosure provides novel pyridinylpyrimidine-based FGFR inhibitors. The present disclosure includes inhibitors with broad inhibitory activity against all FGFR isoforms and inhibitors with selective inhibition against FGFR4. These novel pyridinylpyrimidine-based FGFR inhibitors or their derivatives have great potential for use in cancer treatment.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Patent Application No. 62 / 805,854, filed February 14, 2019, the entire contents of which are incorporated herein by reference.

[0002] Incorporating sequence tables The contents of the attached sequence listing are incorporated by reference into this application. The attached sequence listing text file is named BRIDGE1100_1WO_Sequence_Listing.txt, was created on February 13, 2020, and is 1084kb. The file can be accessed using Microsoft Word on a computer using the Windows OS.

[0003] Field The present disclosure relates generally to novel fibroblast growth factor receptor (FGFR) inhibitors, and more specifically to the use of pyridinylpyrimidine-based FGFR4-specific inhibitors for the treatment of cancer. [Background technology]

[0004] background The human fibroblast growth factor receptor (FGFR) family is composed of four receptor tyrosine kinases that bind to 18 ligands called fibroblast growth factors (FGFs). The four members (FGFR1, FGFR2, FGFR3, and FGFR4) are highly conserved with each other and consist of an extracellular ligand-binding domain, a transmembrane segment, and a cytoplasmic tyrosine kinase domain. Upon ligand binding to the extracellular domain of FGFR, the kinase domain is activated by autophosphorylation, which then phosphorylates the cytoplasmic substrate, triggering downstream signaling cascades that control cell proliferation and differentiation.

[0005] The FGFR signaling pathway is an important and plausible target for cancer therapeutics because it plays a key role in tumor proliferation, angiogenesis, migration, and survival. Mutations and overexpression of FGFRs and their ligands have been reported in several cancers, including breast, lung, bladder, prostate, and gastric cancers. For example, FGFR1 amplifications have been found in approximately 10% of breast cancers (mainly estrogen receptor-positive disease), 10–20% of squamous non-small cell lung cancers (NSCLC), ovarian cancers (approximately 5%), and bladder cancers (3%). FGFR2 amplifications have been detected in gastric cancers (5–10%) and breast cancers (4% of triple-negative cases), and FGFR2 mutations occur in 12% of endometrial cancers. FGFR3 mutations have been identified in approximately 70% of non-muscle invasive bladder cancers and 10–20% of invasive high-grade bladder cancers. Amplification and activating mutations of FGFR4 have been described in 8% of rhabdomyosarcoma patients. Furthermore, numerous preclinical studies have reported overexpression of FGFR4 in prostate, colon, and liver cancers.

[0006] Many FGFR small molecule inhibitors have been developed and evaluated in clinical trials for cancer treatment, most of which are pan-FGFR inhibitors with promiscuous kinome activity, such as BGJ398 and LY-2874455. Sequence analysis has found that FGFR4 contains a cysteine ​​(Cys552) located near the ATP-binding site in the hinge region of the receptor, which is unique within the FGFR family and rare among other kinases. Indeed, BLU9931, a first-line FGFR4 inhibitor, was recently discovered to target this unique cysteine ​​and showed very good specificity and significant antitumor activity against hepatocellular carcinoma in vivo. However, the potency and bioavailability of BLU9931 are not optimal for clinical use. Summary of the Invention

[0007] overview Embodiments of the present disclosure include novel pyridinylpyrimidine-based compounds that are potent FGFR4-specific inhibitors, which can be used as targeted therapeutic agents for treating cancer.

[0008] In some embodiments, the present disclosure provides a compound of formula (I) TIFF0007658908000001.tif47128, or an optically pure stereoisomer, solvate, or pharma- ceutically acceptable salt thereof.

[0009] In some embodiments, each R, R, R, R, and R is independently H, F, Cl, Br, C 1-4 Alkyl, cyclopropyl, N3, NH2, NO2, CF3, OCF3, OCHF2, or OC 1-4 In some embodiments, R6 is (CH2) 0-5 CH=CH2, (CH2) 0-5 C≡CH, NHCO(CH2) 0-5 CH=CH2, NH(CH2) 0-5 CH=CH2, OCO(CH2) 0-5 CH=CH2, O(CH2) 0-5 CH=CH2, NHCO(CH2) 0-5 C≡CH, or OCO(CH2) 0-5 C≡CH can be.

[0010] In some embodiments, the linker is F, Cl, Br, C 1-4 Alkyl, CF3, CHF2, NO2, -NR7-(CH2) n -R8, -CONR7-(CH2) n -R8, -CO-(CH2) n -R8, -OCO-(CH2) n -R8, and -O-(CH2) n -R8, optionally substituted with one or more substituents selected from the group consisting of 1-20 Alkyl, COC 1-20 Alkyl, CO2C 1-20 Alkyl, TIFF0007658908000002.tif71162 Phenyl, naphthyl, anthracene, TIFF0007658908000003.tif137162.

[0011] In some embodiments, n can be an integer selected from 0 to 5. In some embodiments, R7 can be H, C 1-4 Alkyl, and COC 1-4 It may be selected from the group consisting of alkyl.

[0012] In some embodiments, R8 is F, Cl, Br, C 1-4 C, optionally substituted with one or more substituents selected from the group consisting of alkyl, CF3, CHF2, and NO2; 1-20 Alkyl, COC 1-20 Alkyl, CO2C 1-20 Alkyl, TIFF0007658908000004.tif39160.

[0013] The present disclosure also relates to a compound of formula (II) TIFF0007658908000005.tif47128, or an optically pure stereoisomer, solvate, or pharma- ceutically acceptable salt thereof.

[0014] In some embodiments, R is (CH) 0-5 CH=CH2, (CH2) 0-5 C≡CH, NHCO(CH2) 0-5 CH=CH2, NH(CH2) 0-5 CH=CH2, OCO(CH2) 0-5 CH=CH2, O(CH2) 0-5 CH=CH2, NHCO(CH2) 0-5 C≡CH, or OCO(CH2) 0-5 C≡CH can be.

[0015] The linker is F, Cl, Br, C 1-4Alkyl, CF3, CHF2, NO2, -NR2-(CH2) n -R3, -CONR2-(CH2) n -R3, -CO-(CH2) n -R3, -OCO-(CH2) n -R3, and -O-(CH2) n -R3, optionally substituted with one or more substituents selected from the group consisting of 1-20 Alkyl, COC 1-20 Alkyl, CO2C 1-20 Alkyl, TIFF0007658908000006.tif69162 Phenyl, naphthyl, anthracene, TIFF0007658908000007.tif60162.

[0016] In some embodiments, R2 is H, C 1-4 Alkyl, and COC 1-4 alkyl, and n is an integer selected from 0 to 5.

[0017] In some embodiments, R3 is F, Cl, Br, C 1-4 C, optionally substituted with one or more substituents selected from the group consisting of alkyl, CF3, CHF2, and NO2; 1-20 Alkyl, COC 1-20 Alkyl, CO2C 1-20 Alkyl, TIFF0007658908000008.tif39160.

[0018] The present disclosure also relates to a compound of formula (III) TIFF0007658908000009.tif57128, or an optically pure stereoisomer, solvate, or pharma- ceutically acceptable salt thereof.

[0019] In some embodiments, each R, R, R, R, and R is independently H, F, Cl, Br, C 1-4Alkyl, cyclopropyl, N3, NH2, NO2, CF3, OCF3, OCHF2, and OC 1-4 alkyl. n can be an integer selected from 0 to 5.

[0020] In some embodiments, R6 is F, Cl, Br, C 1-4 C, optionally substituted with one or more substituents selected from the group consisting of alkyl, CF3, CHF2, and NO2; 1-20 Alkyl, COC 1-20 Alkyl, CO2C 1-20 Alkyl, R7 can be selected from the group consisting of H, C 1-4 Alkyl, and COC 1-4 It may be selected from the group consisting of alkyl.

[0021] In some embodiments, the compound is TIFF0007658908000011.tif150153.

[0022] In some embodiments, the compound is TIFF0007658908000012.tif156139TIFF0007658908000013.tif103145.

[0023] The present disclosure also provides pharmaceutical formulations comprising a compound according to formula (I), formula (II), formula (III) or an optically pure stereoisomer or pharma- ceutically acceptable salt thereof. The present disclosure further provides a method for treating cancer in a subject, comprising administering to the subject a compound having the structure of formula (I), formula (II), formula (III) or an optically pure stereoisomer or pharma- ceutically acceptable salt thereof. In some embodiments, the compound targets amino acid residue 484 of SEQ ID NO:52, amino acid residue 512 of SEQ ID NO:56, or amino acid residue 552 of SEQ ID NO:50 or 54. The present disclosure also provides a method for inhibiting kinase activity, comprising contacting a cell with a compound having the structure of formula (I), formula (II), formula (III) or an optically pure stereoisomer or pharma- ceutically acceptable salt thereof. In some embodiments, the kinase can be anaplastic lymphoma kinase (ALK), epidermal growth factor receptor (EGFR), ephrin type 3 receptor 3 (EPH-B3), focal adhesion kinase (FAK), fibroblast growth factor receptor 1 (FGFR1), fibroblast growth factor receptor 2 (FGFR2), fibroblast growth factor receptor 3 (FGFR3), fibroblast growth factor receptor 4 (FGFR4), mast cell / stem cell growth factor receptor (SCFR or KIT), mitogen-activated protein kinase kinase 1 (MAP2K1 or MEK1), hepatocyte growth factor receptor (HGFR or MET), platelet-derived growth factor receptor alpha (PDGFRA), platelet-derived growth factor receptor beta (PDGFRB), proto-oncogene tyrosine kinase receptor (RET), proto-oncogene tyrosine protein kinase (ROS), or tyrosine protein kinase receptor (TYRO3). The cell can be a cancer cell. The cancer cells can be breast cancer, lung cancer, bladder cancer, prostate cancer, ovarian cancer, endometrial cancer, rhabdomyosarcoma, liver cancer, or gastric cancer cells.

[0024] [The present invention 1001] A compound according to formula (I) or an optically pure stereoisomer, solvate or pharma- ceutically acceptable salt thereof: TIFF0007658908000014.tif45128 During the ceremony, Each R 1 、R 2、R 3 、R 4 , and R 5 are independently H, F, Cl, Br, C 1-4 Alkyl, cyclopropyl, N 3 , N.H. 2 , NO 2 , C.F. 3 , OCF 3 , O.C.H.F. 2 , and O.C. 1-4 is selected from the group consisting of alkyl, R 6 is (CH 2 ) 0-5 CH=CH 2 , (CH 2 ) 0-5 C≡CH, NHCO(CH 2 ) 0-5 CH=CH 2 , NH(CH 2 ) 0-5 CH=CH 2 , OCO(CH 2 ) 0-5 CH=CH 2 , O(CH 2 ) 0-5 CH=CH 2 , NHCO(CH 2 ) 0-5 C≡CH, and OCO(CH 2 ) 0-5 C≡CH; The linker is F, Cl, Br, C 1-4 Alkyl, CF 3 , CHF 2 , NO 2 , -NR 7 -(CH 2 ) n -R 8 , -CONR 7 -(CH 2 ) n -R 8 , -CO-(CH 2 ) n -R 8 , -OCO-(CH 2 ) n -R 8 , and -O-(CH 2 ) n -R 8 C may be substituted with one or more substituents selected from the group consisting of 1-20 Alkyl, COC 1-20 Alkyl, CO 2 C 1-20 Alkyl, TIFF0007658908000015.tif69162 Phenyl, naphthyl, anthracene, TIFF0007658908000016.tif123162 is selected from the group consisting of n is an integer selected from 0 to 5; R 7 , H, C 1-4 Alkyl, and COC 1-4 is selected from the group consisting of alkyl, R 8 are F, Cl, Br, and C 1-4 Alkyl, CF 3 , CHF 2 , and NO 2 C may be substituted with one or more substituents selected from the group consisting of 1-20 Alkyl, COC 1-20 Alkyl, CO 2 C 1-20 Alkyl, TIFF0007658908000017.tif39145 is selected from the group consisting of: [The present invention 1002] R 1 and R 5 is Cl, and R 2 and R 4 is OMe, and R 3 The compound of the present invention 1001, wherein is H. [The present invention 1003] The compound of the present invention has the structure of formula (II) or an optically pure stereoisomer, solvate or pharma- ceutically acceptable salt thereof: TIFF0007658908000018.tif47128 During the ceremony, R 1 But (CH 2 ) 0-5 CH=CH 2 , (CH 2 ) 0-5 C≡CH, NHCO(CH 2 ) 0-5 CH=CH 2 , NH(CH 2 ) 0-5 CH=CH 2 , OCO(CH 2 ) 0-5 CH=CH 2 , O(CH 2 ) 0-5 CH=CH 2 , NHCO(CH 2 ) 0-5 C≡CH, and OCO(CH 2 ) 0-5 C≡CH; The linker is F, Cl, Br, C 1-4 Alkyl, CF 3 , CHF 2 , NO 2 , N.R. 2 -(CH 2 ) n -R 3 , -CONR 2 -(CH 2 ) n -R 3 , -CO-(CH 2 ) n -R 3 , -OCO-(CH 2 ) n -R 3 , and -O-(CH 2 ) n -R 3 C may be substituted with one or more substituents selected from the group consisting of 1-20 Alkyl, COC 1-20 Alkyl, CO 2 C 1-20 Alkyl, TIFF0007658908000019.tif69162 Phenyl, naphthyl, anthracene, TIFF0007658908000020.tif57162 is selected from the group consisting of R 2 But, H, C 1-4 Alkyl, and COC 1-4 is selected from the group consisting of alkyl, n is an integer selected from 0 to 5; R 3 But F, Cl, Br, C 1-4 Alkyl, CF 3 , CHF 2 , and NO 2 C may be substituted with one or more substituents selected from the group consisting of 1-20 Alkyl, COC 1-20 Alkyl, CO 2 C 1-20 Alkyl, TIFF0007658908000021.tif39137 is selected from the group consisting of: [The present invention 1004] The compound of the present invention has the structure of formula (III) or an optically pure stereoisomer, solvate or pharma- ceutically acceptable salt thereof: TIFF0007658908000022.tif57128 During the ceremony, Each R 1 、R 2 、R 3 、R 4 , and R 5 are independently H, F, Cl, Br, C 1-4 Alkyl, cyclopropyl, N 3 , N.H. 2 , NO 2 , C.F. 3 , OCF 3 , O.C.H.F. 2 , and O.C. 1-4 is selected from the group consisting of alkyl, n is an integer selected from 0 to 5; R 6 But F, Cl, Br, C 1-4 Alkyl, CF 3 , CHF 2 , and NO 2 C may be substituted with one or more substituents selected from the group consisting of 1-20 Alkyl, COC 1-20 Alkyl, CO 2 C 1-20 Alkyl, TIFF0007658908000023.tif39137 is selected from the group consisting of R 7 But, H, C 1-4 Alkyl, and COC 1-4 alkyl. [The present invention 1005] R 1 and R 5 is Cl, and R 2 and R 4 is OMe, and R 3 The compound of the present invention 1004, wherein is H. [The present invention 1006] The compound is TIFF0007658908000024.tif151147 1001 A compound of the present invention selected from the group consisting of: [The present invention 1007] The compound is TIFF0007658908000025.tif156139TIFF0007658908000026.tif103145 1001 A compound of the present invention selected from the group consisting of: [The present invention 1008] The linker is TIFF0007658908000027.tif12128 The compound of the present invention 1001, [The present invention 1009] The compound of the present invention, wherein said compound inhibits fibroblast growth factor receptor (FGFR). [The present invention 1010] The compound of the present invention, wherein said compound inhibits FGFR4. [The present invention 1011] A pharmaceutical formulation comprising a compound of the present invention. [The present invention 1012] A pharmaceutical formulation comprising a compound of the invention 1001, 1003, or 1004. [The present invention 1013] 1. A method for treating cancer in a subject, comprising administering to the subject a compound of formula (I), or an optically pure stereoisomer, solvate or pharma- ceutically acceptable salt thereof: TIFF0007658908000028.tif45128 During the ceremony, Each R 1 、R 2 、R 3 、R 4 , and R 5 are independently H, F, Cl, Br, C 1-4 Alkyl, cyclopropyl, N 3 , N.H. 2 , NO 2 , C.F. 3 , OCF 3 , O.C.H.F. 2 , and O.C. 1-4 is selected from the group consisting of alkyl, R 6 is (CH 2 ) 0-5 CH=CH 2 , (CH 2 ) 0-5 C≡CH, NHCO(CH 2 ) 0-5 CH=CH 2 , NH(CH 2 ) 0-5 CH=CH 2 , OCO(CH 2 ) 0-5 CH=CH 2 , O(CH 2 ) 0-5 CH=CH 2 , NHCO(CH 2 ) 0-5 C≡CH, and OCO(CH 2 ) 0-5 C≡CH; The linker is F, Cl, Br, C 1-4 Alkyl, CF 3 , CHF 2 , NO 2、 -NR 7 -(CH 2 ) n -R 8 , -CONR 7 -(CH 2 ) n -R 8 , -CO-(CH 2 ) n -R 8 , -OCO-(CH 2 ) n -R 8 , and -O-(CH 2 ) n -R 8 C may be substituted with one or more substituents selected from the group consisting of 1-20 Alkyl, COC 1-20 Alkyl, CO 2 C 1-20 Alkyl, TIFF0007658908000029.tif48153 Phenyl, naphthyl, anthracene, TIFF0007658908000030.tif122156 is selected from the group consisting of n is an integer selected from 0 to 5; R 7 , H, C 1-4 Alkyl, and COC 1-4 is selected from the group consisting of alkyl, R 8 are F, Cl, Br, and C 1-4 Alkyl, CF 3 , CHF 2 , and NO 2 C may be substituted with one or more substituents selected from the group consisting of 1-20 Alkyl, COC 1-20 Alkyl, CO 2 C 1-20 Alkyl, TIFF0007658908000031.tif39137 is selected from the group consisting of: [The present invention 1014] The compound is TIFF0007658908000032.tif47128 The method of the present invention 1013. [The present invention 1015] The method of claim 1013, wherein said cancer is selected from the group consisting of breast cancer, lung cancer, bladder cancer, prostate cancer, ovarian cancer, endometrial cancer, rhabdomyosarcoma, liver cancer, and gastric cancer. [The present invention 1016] The method of claim 10, wherein said compound inhibits FGFR. [The present invention 1017] The method of claim 1016, wherein said compound inhibits FGFR4. [The present invention 1018] The method of claim 1013, further comprising the step of administering a chemotherapeutic agent. [The present invention 1019] The method of claim 1018, wherein said compound is administered prior to, simultaneously with, or following administration of said chemotherapeutic agent. [The present invention 1020] A method of inhibiting kinase activity comprising contacting a cell with a compound of formula (I), or an optically pure stereoisomer, solvate, or pharma- ceutically acceptable salt thereof: TIFF0007658908000033.tif45128 During the ceremony, Each R 1 、R 2 、R 3 、R 4 , and R 5 are independently H, F, Cl, Br, C 1-4 Alkyl, cyclopropyl, N 3 , N.H. 2 , NO 2 , C.F. 3 , OCF 3 , O.C.H.F. 2 , O.C. 1-4 is selected from the group consisting of alkyl, R 6 is (CH 2 ) 0-5 CH=CH 2 , (CH 2 ) 0-5 C≡CH, NHCO(CH 2 ) 0-5 CH=CH 2 , NH(CH 2 ) 0-5 CH=CH 2 , OCO(CH 2 ) 0-5 CH=CH 2 , O(CH 2 ) 0-5 CH=CH 2 , NHCO(CH 2 ) 0-5 C≡CH, and OCO(CH 2 ) 0-5 C≡CH; The linker is F, Cl, Br, C 1-4 Alkyl, CF 3 , CHF 2 , NO 2、 -NR 7 -(CH 2 ) n -R 8 , -CONR 7 -(CH 2 ) n -R 8 , -CO-(CH 2 ) n -R 8 , -OCO-(CH 2 ) n -R 8 , and -O-(CH 2 ) n -R 8 C may be substituted with one or more substituents selected from the group consisting of 1-20 Alkyl, COC 1-20 Alkyl, CO 2 C1-20 Alkyl, TIFF0007658908000034.tif69162 Phenyl, naphthyl, anthracene, TIFF0007658908000035.tif124162 is selected from the group consisting of n is an integer selected from 0 to 5; R 7 , H, C 1-4 Alkyl, and COC 1-4 is selected from the group consisting of alkyl, R 8 are F, Cl, Br, and C 1-4 Alkyl, CF 3 , CHF 2 , and NO 2 C may be substituted with one or more substituents selected from the group consisting of 1-20 Alkyl, COC 1-20 Alkyl, CO 2 C 1-20 Alkyl, TIFF0007658908000036.tif39137 is selected from the group consisting of: [The present invention 1021] The compound is TIFF0007658908000037.tif47128 The method of the present invention 1020. [The present invention 1022] 1020. The method of claim 1020, wherein said kinase is selected from the group consisting of anaplastic lymphoma kinase (ALK), epidermal growth factor receptor (EGFR), ephrin type 3 receptor 3 (EPH-B3), focal adhesion kinase (FAK), fibroblast growth factor receptor 1 (FGFR1), fibroblast growth factor receptor 2 (FGFR2), fibroblast growth factor receptor 3 (FGFR3), fibroblast growth factor receptor 4 (FGFR4), mast cell / stem cell growth factor receptor (SCFR or KIT), mitogen-activated protein kinase kinase 1 (MAP2K1 or MEK1), hepatocyte growth factor receptor (HGFR or MET), platelet-derived growth factor receptor alpha (PDGFRA), platelet-derived growth factor receptor beta (PDGFRB), proto-oncogene tyrosine kinase receptor (RET), proto-oncogene tyrosine protein kinase (ROS), and tyrosine protein kinase receptor (TYRO3). [The present invention 1023] The method of claim 1022, wherein said kinase is FGFR1, FGFR2, FGFR3 and / or FGFR4. [The present invention 1024] The method of claim 1020, wherein the cell is a cancer cell. [The present invention 1025] The method of claim 1024, wherein said cancer cells are breast cancer, lung cancer, bladder cancer, prostate cancer, ovarian cancer, endometrial cancer, rhabdomyosarcoma, liver cancer, or gastric cancer cells. Other features and advantages may become apparent from the following detailed drawings and description. [Brief description of the drawings]

[0025] To facilitate a thorough understanding of the present disclosure, reference is made to the accompanying drawings, in which like elements are referenced with like numerals. These drawings should not be construed as limiting the present disclosure, but are intended to be illustrative only. The drawings do not necessarily scale or include all elements of the system, but instead generally focus on illustrating the concepts, structures, and techniques sought to be protected herein.

[0026] [Figure 1] Schematic of FGFR kinases: A. Schematic of selective inhibition of FGFRs with electrophilic inhibitors by covalently targeting thiol groups (SH) in cysteine ​​residues: B. Partial sequence alignment of FGFR kinases within subdomain V highlighting the unique cysteine ​​residues that FGFR4 contains near the ATP binding site. [Diagram 2] Figure 2A shows pharmacokinetic data of Compound 1 administered to mice by intraperitoneal injection (IP) at 10 mg / kg according to some embodiments of the present disclosure. Figure 2B shows pharmacokinetic data of Compound 1 administered to mice by intravenous injection (IV) at 1 mg / kg and orally (PO) at 5 mg / kg according to some embodiments of the present disclosure. [Diagram 3] Figure 3A is a mean plasma concentration time profile of Compound 5 in female CD-1 mice following IP administration at 10 mg / kg, according to some embodiments of the present disclosure. Figure 3B is pharmacokinetic data of Compound 5 following IV administration at 5 mg / kg and PO administration at 100 mg / kg, according to some embodiments of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] explanation Disclosed herein is a class of compounds that are selective inhibitors of FGFR4. These small molecule inhibitors can be used as targeted therapeutics to treat cancer.

[0028] Fibroblast growth factor receptors (FGFRs) are highly conserved receptors consisting of an extracellular ligand-binding domain, a transmembrane segment, and a cytoplasmic tyrosine kinase domain. The human FRFR family includes four members, FGFR1, FGFR2, FGFR3, and FGFR4, which can be bound by 18 different ligands called fibroblast growth factors (FGFs). Each receptor is composed of an extracellular domain consisting of three immunoglobulin-like domains (IgI, IgII, and IgIII) and an acid box, an IgII and IgIII domain that constitute the FGF ligand-binding site, a transmembrane domain, and a tyrosine kinase cytoplasmic domain. FGFRs also contain a hinge region (subdomain V) located near the ATP-binding site (SEQ ID NO:57-60). The FGFR encoding mRNA is subject to alternative splicing resulting in several protein-coding splice variants or isoforms (SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, and 55). As shown in Table 3, the human FGFR1 gene encodes nine protein-coding splice variants (SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, and 18), the human FGFR2 gene encodes eleven protein-coding splice variants (SEQ ID NOs: 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, and 40), the human FGFR3 gene encodes four protein-coding splice variants (SEQ ID NOs: 42, 44, 46, and 48), and the human FGFR4 gene encodes four protein-coding splice variants (SEQ ID NOs: 50, 52, 54, and 56).

[0029] The FGF family of ligands has 18 members (FGF1-FGF10 and FGF16-FGF23). Ligand binding to the extracellular domain of FGFR leads to receptor dimerization, which results in activation of the tyrosine kinase domain by autophosphorylation. Activated FGFR subsequently phosphorylates cytoplasmic substrates, such as FGFR substrate 2 (FRS2) and phospholipase Cγ (PLCγ), which triggers downstream signaling cascades. Activated FRS2 promotes the RAS-mitogen-activated protein kinase (MAPK) or phosphoinositide 3-kinase (PI3K)-AKT pathways that regulate cell proliferation, differentiation, and survival. Meanwhile, activation of PLCγ leads to calcium release, regulating events that mediate cell motility.

[0030] Deregulation of FGFR signaling has been linked to carcinogenesis through several mechanisms, including activating mutations, gene amplification or altered post-transcriptional processing, and translocations, resulting in constitutive activation of the receptor.

[0031] Specifically, amplification and activating mutations of FGFR4 have been described in patients with rhabdomyosarcoma, and FGFR4 overexpression has been associated with prostate, colon, breast, and liver cancer. FGFR4 differs from other FGFRs by the presence of a cysteine ​​in the hinge region, which is unique within the FGFR family and rare among other kinases. Depending on the isoform, the cysteine ​​is located at different positions: Cys484 of SEQ ID NO:52, Cys512 of SEQ ID NO:56, or Cys552 of SEQ ID NO:50 or 54. This unique cysteine ​​can be targeted to design FGFR4-specific inhibitors that show very good specificity.

[0032] As used herein, the term "FGFR inhibitor" or "FGFRi" refers to any compound capable of inhibiting the enzymatic activity of FGFR, including the autophosphorylation and kinase activity of FGFR itself. Such inhibitors are said to effectively inhibit FGFR and "inhibit," "reduce," or "diminish" the biological activity of FGFR. The FGFR inhibitors of the present disclosure may be "pan-inhibitors" and may exhibit broad efficacy in inhibiting one or more of GFR1-FGFR4, or may exhibit specific efficacy in inhibiting only one FGFR, e.g., FGFR4.

[0033] The efficiency of a compound can be referred to by its IC50 value. "IC50" is the half-maximal inhibitory concentration (IC50) of a compound. As used herein, the IC50 of an FGFRi refers to the concentration of an inhibitor sufficient to induce inhibition of the enzyme activity of FGFR halfway between baseline and maximum after a specified exposure time. The IC50 value of the present disclosure specifically refers to the concentration of an FGFR inhibitor sufficient to induce inhibition of one or more FGFRs, namely FGFR1, FGFR2, FGFR3 and / or FGFR4.

[0034] In some embodiments, the present disclosure provides a compound of formula (I) TIFF0007658908000038.tif47128, or an optically pure stereoisomer, solvate, or pharma- ceutically acceptable salt thereof.

[0035] In some embodiments, each R, R, R, R, and R is independently H, F, Cl, Br, C 1-4 Alkyl, cyclopropyl, N3, NH2, NO2, CF3, OCF3, OCHF2, or OC 1-4 In some embodiments, R6 is (CH2) 0-5 CH=CH2, (CH2) 0-5 C≡CH, NHCO(CH2) 0-5 CH=CH2, NH(CH2) 0-5 CH=CH2, OCO(CH2)0-5 CH=CH2, O(CH2) 0-5 CH=CH2, NHCO(CH2) 0-5 C≡CH, or OCO(CH2) 0-5 C≡CH can be.

[0036] In some embodiments, the linker is F, Cl, Br, C 1-4 Alkyl, CF3, CHF2, NO2, -NR7-(CH2) n -R8, -CONR7-(CH2) n -R8, -CO-(CH2) n -R8, -OCO-(CH2) n -R8, and -O-(CH2) n -R8, optionally substituted with one or more substituents selected from the group consisting of 1-20 Alkyl, COC 1-20 Alkyl, CO2C 1-20 Alkyl, TIFF0007658908000039.tif74162 Phenyl, naphthyl, anthracene, TIFF0007658908000040.tif137162. The number of optional substituents may be an integer selected from 0 to 4.

[0037] In some embodiments, n can be an integer selected from 0 to 5. In some embodiments, R7 can be H, C 1-4 Alkyl, and COC 1-4 It may be selected from the group consisting of alkyl.

[0038] In some embodiments, R8 is F, Cl, Br, C 1-4 Alkyl, CF3, CHF2, and NO 2. C may be substituted with one or more substituents selected from the group consisting of 1-20 Alkyl, COC 1-20 Alkyl, CO2C 1-20 Alkyl, TIFF0007658908000041.tif41159.

[0039] In some embodiments, R1 and R5 are Cl, R2 and R4 are OMe, and R3 is H.

[0040] The present disclosure also relates to a compound of formula (II) TIFF0007658908000042.tif46128, or an optically pure stereoisomer, solvate, or pharma- ceutically acceptable salt thereof.

[0041] In some embodiments, R is (CH) 0-5 CH=CH2, (CH2) 0-5 C≡CH, NHCO(CH2) 0-5 CH=CH2, NH(CH2) 0-5 CH=CH2, OCO(CH2) 0-5 CH=CH2, O(CH2) 0-5 CH=CH2, NHCO(CH2) 0-5 C≡CH, or OCO(CH2) 0-5 C≡CH can be.

[0042] The linker is F, Cl, Br, C 1-4 Alkyl, CF3, CHF2, NO2, -NR2-(CH2) n -R3, -CONR2-(CH2) n -R3, -CO-(CH2) n -R3, -OCO-(CH2) n -R3, and -O-(CH2) n -R3, optionally substituted with one or more substituents selected from the group consisting of 1-20 Alkyl, COC 1-20 Alkyl, CO2C 1-20 Alkyl, TIFF0007658908000043.tif69162 Phenyl, naphthyl, anthracene, TIFF0007658908000044.tif57162. The number of optional substituents may be an integer selected from 0 to 4.

[0043] In some embodiments, R2 is H, C 1-4 Alkyl, and COC 1-4 alkyl, and n is an integer selected from 0 to 5.

[0044] In some embodiments, R3 is F, Cl, Br, C 1-4 C, optionally substituted with one or more substituents selected from the group consisting of alkyl, CF3, CHF2, and NO2; 1-20 Alkyl, COC 1-20 Alkyl, CO2C 1-20 Alkyl, TIFF0007658908000045.tif39160.

[0045] The present disclosure also relates to a compound of formula (III) TIFF0007658908000046.tif57128, or an optically pure stereoisomer, solvate, or pharma- ceutically acceptable salt thereof.

[0046] In some embodiments, each R, R, R, R, and R is independently H, F, Cl, Br, C 1-4 Alkyl, cyclopropyl, N3, NH2, NO2, CF3, OCF3, OCHF2, and OC 1-4 alkyl. n can be an integer selected from 0 to 5.

[0047] In some embodiments, R6 is F, Cl, Br, C 1-4 C, optionally substituted with one or more substituents selected from the group consisting of alkyl, CF3, CHF2, and NO2; 1-20 Alkyl, COC 1-20 Alkyl, CO2C 1-20 Alkyl, R7 can be selected from the group consisting of H, C 1-4 Alkyl, and COC 1-4The number of optional substituents may be an integer selected from 0 to 4.

[0048] In some embodiments, R1 and R5 are Cl, R2 and R4 are OMe, and R3 is H.

[0049] In some embodiments, the present disclosure provides a compound of formula (IV) TIFF0007658908000048.tif34153, or an optically pure stereoisomer, solvate, or pharma- ceutically acceptable salt thereof is provided.

[0050] In some embodiments, each R, R, R, R, and R is independently H, F, Cl, Br, C 1-4 Alkyl, cyclopropyl, N3, NH2, NO2, CF3, OCF3, OCHF2, or OC 1-4 In some embodiments, R6 is (CH2) 0-5 CH=CH2, (CH2) 0-5 C≡CH, NHCO(CH2) 0-5 CH=CH2, NH(CH2) 0-5 CH=CH2, OCO(CH2) 0-5 CH=CH2, O(CH2) 0-5 CH=CH2, NHCO(CH2) 0-5 C≡CH, or OCO(CH2) 0-5 C≡CH can be.

[0051] In some embodiments, each A and B can independently be NR7, CONR7, O, CO, or OCO.

[0052] In some embodiments, the core comprises: TIFF0007658908000049.tif31128. Each D can independently be N or CH.

[0053] In some embodiments, the linker is F, Cl, Br, C1-4 Alkyl, CF3, CHF2, NO2, -NR7-(CH2) n -R8, -CONR7-(CH2) n -R8, -CO-(CH2) n -R8, -OCO-(CH2) n -R8, and -O-(CH2) n -R8, optionally substituted with one or more substituents selected from the group consisting of 1-20 Alkyl, COC 1-20 Alkyl, CO2C 1-20 Alkyl, TIFF0007658908000050.tif70144 Phenyl, naphthyl, anthracene, TIFF0007658908000051.tif137151. The number of optional substituents may be an integer selected from 0 to 4.

[0054] In some embodiments, n can be an integer selected from 0 to 5. In some embodiments, R7 can be H, C 1-4 Alkyl, and COC 1-4 It may be selected from the group consisting of alkyl.

[0055] In some embodiments, R8 is F, Cl, Br, C 1-4 Alkyl, CF3, CHF2, and NO 2. C may be substituted with one or more substituents selected from the group consisting of 1-20 Alkyl, COC 1-20 Alkyl, CO2C 1-20 Alkyl, TIFF0007658908000052.tif40147.

[0056] In some embodiments, the compound of the present disclosure is selected from the group consisting of compounds 1-4 and 6-16 shown in Table 1.

[0057] Table 1. FGFR inhibitor compounds of the present disclosure TIFF0007658908000053.tif143128TIFF0007658908000054.tif221128TIFF0007658908 000055.tif220128TIFF0007658908000056.tif220128TIFF0007658908000057.tif60128

[0058] The present disclosure also provides a pharmaceutical formulation comprising a compound according to formula (I), formula (II), formula (III) or an optically pure stereoisomer or a pharma- ceutically acceptable salt thereof. The present disclosure further provides a method for treating cancer in a subject, comprising administering to the subject a compound having the structure of formula (I), formula (II), formula (III) or an optically pure stereoisomer or a pharma- ceutically acceptable salt thereof. The present disclosure also provides a method for inhibiting kinase activity, comprising contacting a cell with a compound having the structure of formula (I), formula (II), formula (III) or an optically pure stereoisomer or a pharma- ceutically acceptable salt thereof. In some embodiments, the kinase can be anaplastic lymphoma kinase (ALK), epidermal growth factor receptor (EGFR), ephrin type 3 receptor 3 (EPH-B3), focal adhesion kinase (FAK), fibroblast growth factor receptor 1 (FGFR1), fibroblast growth factor receptor 2 (FGFR2), fibroblast growth factor receptor 3 (FGFR3), fibroblast growth factor receptor 4 (FGFR4), mast cell / stem cell growth factor receptor (SCFR or KIT), mitogen-activated protein kinase kinase 1 (MAP2K1 or MEK1), hepatocyte growth factor receptor (HGFR or MET), platelet-derived growth factor receptor alpha (PDGFRA), platelet-derived growth factor receptor beta (PDGFRB), proto-oncogene tyrosine kinase receptor (RET), proto-oncogene tyrosine protein kinase (ROS), or tyrosine protein kinase receptor (TYRO3). The cell can be a cancer cell. The cancer cells can be breast cancer, lung cancer, bladder cancer, prostate cancer, ovarian cancer, endometrial cancer, rhabdomyosarcoma, liver cancer, or gastric cancer cells.

[0059] The present disclosure relates to compound 5 having the following structure: Specifically provided is a compound having unobvious property improvements compared to control structures such as TIFF0007658908000058.tif49128. The IUPAC name of the compound is N-(2-((6-(2-((2,6-dichloro-3,5-dimethoxyphenyl)amino)pyridin-3-yl)pyrimidin-4-yl)amino)-3-methylphenyl)acrylamide.

[0060] The term "about" will be understood by those of ordinary skill in the art. Whether or not the term "about" is explicitly used, all amounts given herein refer to the actual given value, which is also meant to refer to an approximation to such a given value that would be reasonably estimated based on one of ordinary skill in the art.

[0061] Alkyl groups refer to monovalent groups derived from an alkane by removing a hydrogen atom from any carbon atom, including straight and branched chains having 1 to 12 carbon atoms, typically 1 to about 10 carbons, or in some embodiments 1 to about 6 carbon atoms, or in other embodiments 1, 2, 3, or 4 carbon atoms. Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl groups. Examples of branched chain alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, and tert-butyl groups. Alkyl groups may be substituted or unsubstituted. Representative substituted alkyl groups may be mono- or di- or more substituted, such as, but not limited to, mono-, di-, or tri-substituted. As used herein, the term alkyl refers to both cyclic and acyclic groups, unless otherwise specified.

[0062] The term "cyclic alkyl" or "cycloalkyl" refers to a monovalent group derived from a cycloalkane by removing a hydrogen atom from a ring carbon atom. Cycloalkyl groups are saturated or partially saturated non-aromatic structures having single or multiple rings, including isolated, fused, bridged, and spiro ring systems, having 3 to 14 carbon atoms, or in some embodiments, 3 to 12, or 3 to 10, or 3 to 8, or 3, 4, 5, 6, or 7 carbon atoms. Cycloalkyl groups may be substituted or unsubstituted. Representative substituted cycloalkyl groups may be mono- or multiply substituted, such as, but not limited to, mono-, di-, or tri-substituted. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. Examples of polycyclic ring systems include, but are not limited to, bis[4.4.0]decane, bis[2.2.1]heptane, spiro[2.2]pentane, and the like.

[0063] Alkenyl groups refer to straight and branched chain and cycloalkyl groups as defined above having one or more double bonds between two carbon atoms. Alkenyl groups may have from 2 to about 12 carbon atoms, or in some embodiments, from 1 to about 10 carbons, or in other embodiments, from 1 to about 6 carbon atoms, or in other embodiments, from 1, 2, 3, or 4 carbon atoms. Alkenyl groups may be substituted or unsubstituted. Representative substituted alkenyl groups may be mono- or multiply substituted, such as, but not limited to, mono-, di-, or tri-substituted. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, cyclopentenyl, cyclohexenyl, butadienyl, pentadienyl, and hexadienyl, among others.

[0064] Alkynyl groups refer to straight and branched chain and cycloalkyl groups as defined above having one or more triple bonds between two carbon atoms. Alkynyl groups may have from 2 to about 12 carbon atoms, or in some embodiments, from 1 to about 10 carbons, or in other embodiments, from 1 to about 6 carbon atoms, or in other embodiments, from 1, 2, 3, or 4 carbon atoms. Alkynyl groups may be substituted or unsubstituted. Representative substituted alkynyl groups may be mono- or multiply substituted, such as, but not limited to, mono-, di-, or tri-substituted. Exemplary alkynyl groups include, but are not limited to, ethynyl, propargyl, and -C≡C(CH3), among others.

[0065] Aryl groups are cyclic aromatic hydrocarbons, including single and multiple ring compounds, including multiple ring compounds containing another aryl group and / or fused aryl groups. Aryl groups may have 6 to about 18 ring carbons, or in some embodiments, 6 to 14 ring carbons, or even 6 to 10 ring carbons in other embodiments. Aryl groups also include heteroaryl groups, which are aromatic ring compounds containing 5 or more ring members, in which one or more ring carbon atoms are substituted with heteroatoms, such as, but not limited to, N, O, and S. Aryl groups may be substituted or unsubstituted. Representative substituted aryl groups may be mono- or multiply substituted, such as, but not limited to, mono-, di-, or tri-substituted. Aryl groups include, but are not limited to, phenyl, biphenylenyl, triphenylenyl, naphthyl, anthryl, and pyrenyl groups.

[0066] Suitable heterocyclyl groups include cyclic groups having atoms of at least two different elements as ring members, one or more of which are heteroatoms, such as, but not limited to, N, O, or S. Heterocyclyl groups may contain from 3 to about 20 ring members, or in some embodiments, from 3 to 18 ring members, or from about 3 to 15, 3 to 12, 3 to 10, or 3 to 6 ring members. The ring system in a heterocyclyl group may be unsaturated, partially saturated, and / or saturated. Heterocyclyl groups may be substituted or unsubstituted. Representative substituted heterocyclyl groups may be mono- or multiply substituted, such as, but not limited to, mono-, di-, or tri-substituted. Exemplary heterocyclyl groups include pyrrolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothienyl, tetrahydrothiopyranyl, piperidyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, azetidinyl, aziridinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazolinyl, triazolyl, and the like. Examples of aryl groups include, but are not limited to, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, oxetanyl, thietanyl, homopiperidyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxolanyl, dioxanyl, purinyl, quinolizinyl, cinnolinyl, phthalazinyl, pteridinyl, and benzothiazolyl groups.

[0067] A polycyclic or polycyclyl group refers to two or more rings in which two or more carbons are common to two adjacent rings and the rings are "fused rings"; if the rings are linked by one common carbon atom, they are "spiro" ring systems. Rings that are linked through non-adjacent atoms are "bridged" rings. Polycyclic groups may be substituted or unsubstituted. Representative polycyclic groups may be substituted one or more times.

[0068] Halogen groups include F, Cl, Br, and I, nitro groups refer to -NO2, cyano groups refer to -CN, isocyano groups refer to -N≡C, and epoxy groups encompass what are essentially cyclic ether structures, in which an oxygen atom is directly bonded to two adjacent or non-adjacent carbon atoms of a carbon chain or ring system. Epoxides are cyclic ethers with a ring of three atoms.

[0069] An alkoxy group is a substituted or unsubstituted alkyl group as defined above, which is single-bonded to oxygen. An alkoxy group may be substituted or unsubstituted. Representative substituted alkoxy groups may be substituted by one or more. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, isopropoxy, sec-butoxy, tert-butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.

[0070] The terms "amine" and "amino" refer to derivatives of ammonia in which one or more hydrogen atoms have been replaced by substituents including, but not limited to, alkyl, alkenyl, aryl, and heterocyclyl groups. A carbamate group refers to -O(C=O)NR1R2, where R1 and R2 are independently hydrogen, an aliphatic group, an aryl group, or a heterocyclyl group.

[0071] The term "optionally substituted" means that the above described group may be substituted or unsubstituted. When substituted, the substituents of an "optionally substituted" group may, alone or in combination, include one or more substituents independently selected from the following groups or the set of specific specified groups: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester, lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhalo ... perhaloalkylthio), arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N3, SH, SCH3, C(O)CH3, CO2CH3, CO2H, pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Two substituents may be joined together to form a fused 5-, 6-, or 7-membered carbocyclic or heterocyclic ring of 0-3 heteroatoms, forming, for example, methylenedioxy or ethylenedioxy. Optionally substituted groups may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between fully and monosubstituted (e.g., -CH2CF3). When a substituent is described unqualified as to substitution, both substituted and unsubstituted forms are encompassed. When a substituent is qualified as "substituted," the substituted form is specifically intended. Additionally, a different set of optional substituents for a particular moiety may be defined as needed. In these cases, the optional substitutions are often defined immediately following the phrase "optionally substituted."

[0072] The pharma- ceutically acceptable salts of the compounds described herein include conventional non-toxic salts or quaternary ammonium salts of the compounds, for example, from non-toxic organic or inorganic acids.For example, such conventional non-toxic salts include salts from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isothioic acid, and the like.In other cases, the compounds described may contain one or more acidic functional groups, and thus can form pharma- ceutically acceptable salts with pharma- ceutical acceptable bases. These salts can also be prepared in situ during the administration vehicle or dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a pharma-ceutically acceptable metal cation, ammonia, or a pharma-ceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.

[0073] The term "treatment" is used interchangeably herein with the term "therapeutic method" and refers to both 1) curing, slowing, alleviating symptoms, and / or halting the progression of a diagnosed pathological condition, disease, or disorder, and 2) prevention / prophylactic measures. Those in need of treatment may include individuals already with a particular medical disease or disorder, as well as individuals who may eventually acquire the disorder (i.e., individuals in need of preventative measures).

[0074] The term "subject," as used herein, refers to any individual or patient on whom a subject method is performed. Generally, a subject is a human, although as will be understood by those of skill in the art, a subject may also be an animal.

[0075] The terms "therapeutically effective amount", "effective dose", "therapeutically effective dose", "effective amount" and the like refer to the amount of the subject compound that induces a biological or medical response in a tissue, system, animal, or human, as desired by administering the subject compound. Generally, the response is either an alleviation of symptoms or a desired biological outcome in a patient. Such an amount should be sufficient to inhibit FGFR enzyme activity.

[0076] Also disclosed herein are pharmaceutical compositions comprising compounds having the structure of formula (I), formula (II), or formula (III). "Pharmaceutically acceptable carrier" refers to a non-toxic carrier that may be administered to a patient together with the compound of the present disclosure and does not destroy its pharmacological activity. Pharmaceutically acceptable carriers that may be used in these compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0077] Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions of the present disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, and self-emulsifying drug delivery systems (SEDDS), such as α-tocopherol, polyethylene glycol 1000 succinate, or other similar polymeric delivery polymatrices.

[0078] In pharmaceutical compositions that contain only the compounds described herein as active ingredients, the method of administering these compositions may further include administering additional drugs or therapies to the subject. Such therapies include, but are not limited to, anemia therapy, diabetes therapy, hypertension therapy, cholesterol therapy, neuropharmacological drugs, drugs that regulate cardiovascular function, drugs that regulate inflammation, immune function, blood cell production, hormones and antagonists, drugs that affect gastrointestinal function, chemotherapy for microbial diseases, and / or chemotherapy for neoplastic diseases. Other pharmacological therapies can include any other drug or biological agent found in any drug class. For example, other drug classes can include allergy / cold / ENT therapy, painkillers, anesthetics, anti-inflammatory agents, antibacterial agents, antiviral agents, asthma / pulmonary therapy, cardiovascular therapy, dermatology therapy, endocrine / metabolic therapy, gastrointestinal therapy, cancer therapy, immunotherapy, neurotherapy, ophthalmology therapy, psychiatric therapy, or rheumatology therapy. Other examples of drugs or therapies that can be administered with the compounds described herein include matrix metalloprotease inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressants, cytokines, growth factors, immunomodulators, prostaglandins, or anti-vascular hyperproliferative compounds.

[0079] As used herein, the term "therapeutically effective amount" refers to an amount of an active compound or agent that elicits a biological or medical response in a tissue, system, animal, individual, or human that is desired by a researcher, veterinarian, physician, or other clinician, the response including one or more of the following: (1) preventing a disease, e.g., preventing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder but has not yet experienced or exhibited the pathology or symptoms of the disease; (2) inhibiting a disease, e.g., inhibiting a disease, condition, or disorder in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder (i.e., arresting further development of the pathology and / or symptoms); and (3) ameliorating a disease, e.g., ameliorating a disease, condition, or disorder in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder (i.e., reversing the pathology and / or symptoms).

[0080] The compounds of the present disclosure may be used in conventional methods for controlling diseases described herein, including but not limited to cancer.Such treatment methods, their dosage levels and requirements may be selected by those skilled in the art from available methods and techniques.For example, the compounds of the present disclosure may be combined with pharmaceutically acceptable adjuvants for administration to patients suffering from cancer in a pharmaceutically acceptable manner and in an amount effective for treating cancer.

[0081] Alternatively, the compounds of the present disclosure may be used in compositions and methods for treating or protecting individuals against diseases described herein, including but not limited to cancer, over a long period of time.The compounds may be used in such compositions alone or together with other compounds of the present disclosure in a manner consistent with the conventional use of such compounds in pharmaceutical compositions.For example, the compounds of the present disclosure may be combined with pharma- ceutically acceptable adjuvants that are conventionally used in vaccines and are administered in prophylactically effective amounts to protect individuals against diseases described herein, including but not limited to cancer, over a long period of time.

[0082] As used herein, "combination," "combined," and related terms refer to simultaneous or sequential administration of therapeutic agents according to the present disclosure. For example, the described compound may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form. Thus, the present disclosure provides a single unit dosage form that includes the described compound, an additional therapeutic agent, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle. Two or more agents are typically considered to be administered "in combination" when a patient or individual is exposed to both agents simultaneously. In many embodiments, two or more agents are considered to be administered "in combination" when a patient or individual simultaneously exhibits therapeutically relevant drug levels in a particular target tissue or sample (e.g., in the brain, in serum, etc.).

[0083] When the compounds of the present disclosure are administered in combination therapy with other agents, they may be administered sequentially or simultaneously to a patient. Alternatively, a pharmaceutical or prophylactic composition according to the present disclosure includes a combination of ivermectin or any other compound described herein with another therapeutic or prophylactic agent. Additional therapeutic agents that are normally administered to treat a particular disease or condition may be referred to as "agents appropriate for the disease or condition being treated."

[0084] The compounds utilized in the compositions and methods of the present disclosure may be modified by adding appropriate functional groups to enhance selective biological properties. Such modifications are known in the art and include modifications that increase biological penetration into a given biological system (e.g., blood, lymphatic system, or central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism, and / or alter excretion rate.

[0085] According to a preferred embodiment, the compositions of the present disclosure are formulated for pharmaceutical administration to a subject or patient, such as a mammal, preferably a human. Such pharmaceutical compositions are used to ameliorate, treat, or prevent any of the diseases described herein, including but not limited to cancer, in a subject.

[0086] The agents of the present disclosure are often administered as pharmaceutical compositions containing an active therapeutic agent, i.e., and various other pharma- ceutical acceptable components. See Remington's Pharmaceutical Science (15th ed., Mack Publishing Company, Easton, Pa., 1980). The preferred form depends on the intended mode of administration and therapeutic application. The composition may also contain a pharma- ceutical acceptable non-toxic carrier or diluent, defined as a vehicle commonly used to formulate pharmaceutical compositions for animal or human administration, depending on the desired formulation. The diluent is selected so as not to affect the biological activity of the combination. Examples of such diluents are distilled water, phosphate-buffered saline, Ringer's solution, dextrose solution, and Hank's solution. In addition, the pharmaceutical composition or formulation may also contain other carriers, adjuvants, or non-toxic, non-therapeutic, non-immunogenic stabilizers, and the like.

[0087] In some embodiments, the present disclosure provides pharma- ceutically acceptable compositions comprising a therapeutically effective amount of one or more of the described compounds, formulated with one or more pharma- ceutically acceptable carriers (additives) and / or diluents, for use in the treatment of diseases described herein, including but not limited to cancer. Although it is possible to administer the described compounds alone, it is preferred to administer the described compounds as pharmaceutical formulations (compositions) as described herein. The described compounds, like other pharmaceuticals, may be formulated for administration in any convenient manner for use in human or veterinary medicine.

[0088] As described in detail, the pharmaceutical compositions of the present disclosure may be specifically formulated for administration in solid or liquid form, including, for example, those adapted for oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., buccal, sublingual, and tablets targeted for systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, e.g., subcutaneous, intramuscular, intravenous, or epidural injection, e.g., sterile solutions or suspensions, or sustained release formulations; topical application, e.g., as creams, ointments, or controlled release patches applied to the skin, lungs, or buccal cavity, or as sprays; vaginal, rectal, e.g., as pessaries, creams, or foams; sublingual; ocular; transdermal; or nasal, pulmonary, and other mucosal surfaces.

[0089] Wetting agents, emulsifying agents, and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants can also be present in the composition.

[0090] Examples of pharma- ceutically acceptable antioxidants include water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, and the like; and metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0091] Formulations for use according to the present disclosure include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and / or parenteral administration. The formulations may be conveniently presented in unit dosage form and may be prepared by any method well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, this amount will range from about 1% to about 99% of the active ingredient. In some embodiments, this amount will range from about 5% to about 70%, about 10% to about 50%, or about 20% to about 40%.

[0092] In certain embodiments, the formulations described herein comprise an excipient selected from the group consisting of cyclodextrins, liposomes, micelle forming agents, such as bile acids, and polymeric carriers, such as polyesters and polyanhydrides, and a compound of the present disclosure. In certain embodiments, the formulations described herein render the compounds of the present disclosure orally bioavailable.

[0093] The method for preparing the formulation or composition containing the described compound comprises combining the compound of the present disclosure with carrier and optionally one or more accessory ingredients.Generally, the formulation can be prepared by uniformly and intimately combining the compound of the present disclosure with liquid carrier or finely divided solid carrier or both, and then shaping the product as necessary.

[0094] The pharmaceutical composition may be in the form of a sterile injectable preparation, for example, a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any bland fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharma- ceutical acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as those described in the Pharmacopeia Helvetica, or similar alcohols. Other commonly used surfactants, such as Tweens, Spans, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharma- ceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0095] In some cases, it may be desirable to delay the absorption of drugs from subcutaneous or intramuscular injection in order to prolong the effect of drugs.This can be achieved by using liquid suspensions of crystalline or amorphous materials with poor water solubility.The absorption rate of the drug then depends on its dissolution rate, which in turn depends on the crystal size and crystalline form.Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oil vehicle.

[0096] Injectable depot forms are prepared by forming microencapsule matrices of the described compounds in biodegradable polymers such as polylactide-polyglycolide.Depending on the ratio of drug to polymer and the nature of the particular polymer used, the drug release rate can be controlled.Other examples of biodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by encapsulating the drug in liposomes or microemulsions that are compatible with body tissues.

[0097] The pharmaceutical composition of the present disclosure may be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, and aqueous suspensions and solutions.For oral tablets, commonly used carriers include lactose and corn starch.Lubricants such as magnesium stearate are also typically added.For oral administration in capsule form, useful diluents include lactose and dried corn starch.For oral administration of aqueous suspensions, solutions, and propylene glycol, the active ingredient is combined with emulsifying and suspending agents.If desired, certain sweeteners and / or flavors and / or colorants may be added.

[0098] Formulations described herein suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia), and / or as mouthwash, each containing a predetermined amount of a compound of the present disclosure as an active ingredient. Compounds described herein may also be administered as a bolus, electuary, or paste.

[0099] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredient is mixed with one or more pharma- ceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; wetting agents, such as glycerol; Disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarders such as paraffin; absorption accelerators such as quaternary ammonium compounds; wetting agents such as cetyl alcohol, glycerol monostearate, and nonionic surfactants; absorbents such as kaolin and bentonite clay; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof, and coloring agents. In the case of capsules, tablets, and pills, the pharmaceutical composition may also contain buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard shell gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols.

[0100] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents, or dispersants. Molded tablets may be made in a suitable machine in which a mixture of powdered compounds is moistened with an inert liquid diluent. When a solid carrier is used, the preparation may be in tablet form, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. The amount of solid carrier varies, for example, from about 25 to 800 mg, preferably from about 25 mg to 400 mg. When a liquid carrier is used, the preparation may be in the form of a sterile injectable liquid, such as, for example, a syrup, emulsion, soft gelatin capsule, ampoule, or non-aqueous liquid suspension. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the above carriers in a hard gelatin capsule shell.

[0101] Tablets and other solid dosage forms, such as dragees, capsules, pills, and granules, may be obtained or prepared with optional coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. Alternatively or additionally, they may be formulated to provide delayed or controlled release of the active ingredient therein, for example, using various proportions of hydroxypropylmethylcellulose, other polymer matrices, liposomes, and / or microspheres to provide the desired release profile. They may be formulated for rapid release, such as lyophilization. They may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents, and may be compositions that release the active ingredient only, or preferentially, in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, where appropriate, with one or more of the above-mentioned excipients.

[0102] The liquid dosage form for oral administration of the compound of the present disclosure includes pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.In addition to active ingredient, liquid dosage form may contain inert diluent commonly used in the art, such as water or other solvent, solubilizer and emulsifier, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid ester of sorbitan, and mixtures thereof.

[0103] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.

[0104] Suspensions may contain, in addition to the active compound, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0105] The pharmaceutical composition of the present disclosure may also be administered in the form of suppositories for rectal administration.These compositions can be prepared by mixing the compound of the present disclosure with suitable non-irritating excipients, which are solid at room temperature but liquid at rectal temperature, and therefore melt in rectum to release active ingredient.Such materials include but are not limited to cocoa butter, beeswax, and polyethylene glycol.

[0106] Topical administration of the pharmaceutical composition of the present disclosure is particularly useful when the desired treatment involves areas or organs easily accessible by topical application. For topical application to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active ingredient suspended or dissolved in a carrier. Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petroleum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical composition of the present disclosure may also be applied topically to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically administered transdermal patches are also included in the present disclosure.

[0107] The pharmaceutical compositions of the present disclosure may be administered by nasal aerosol or inhalation. Such compositions may be prepared according to techniques known in the art of pharmaceutical formulations and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0108] For ophthalmic use, the pharmaceutical composition may be formulated as a micronized suspension in isotonic pH-adjusted sterile saline or, preferably, as a solution in isotonic pH-adjusted sterile saline with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated in an ointment such as petrolatum.

[0109] Transdermal patch has the additional advantage of providing controlled delivery of the compound of the present disclosure to the body.The compound can be dissolved or dispersed in suitable medium to produce such dosage form.Absorption enhancers can also be used to increase the flux of the compound through the skin.The rate of such flux can be controlled by either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0110] Examples of suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0111] Such compositions may also contain auxiliary agents such as preservatives, wetting agents, emulsifiers, and dispersing agents. In certain embodiments, it may be desirable to include one or more antibacterial and / or antifungal agents, such as parabens, chlorobutanol, phenol sorbic acid, etc. Alternatively or additionally, it may be desirable to include isotonic agents, such as sugars, sodium chloride, etc., in the composition. In addition, prolonged absorption of injectable pharmaceutical forms may be brought about by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0112] In certain embodiments, the compounds or pharmaceutical preparations described are administered orally. In other embodiments, the compounds or pharmaceutical preparations described are administered intravenously. Alternative routes of administration include sublingual, intramuscular, and transdermal administration.

[0113] When the compounds described herein are administered to humans and animals as pharmaceuticals, the compounds can be administered by themselves or in combination with a pharma- ceutically acceptable carrier, for example, as a pharmaceutical composition containing 0.1% to 99.5% (more preferably, 0.5% to 90%) of the active ingredient.

[0114] The preparations described herein may be given orally, parenterally, topically, or rectally. They are, of course, given in a form suitable for the relevant administration route. For example, they are given in tablets or capsules by injection, infusion, eye lotion, ointment, suppository, etc. by injection, infusion, or inhalation, topically by lotion or ointment, and rectally by suppository. Oral administration is preferred.

[0115] Such compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, e.g., by sprays, rectally, vaginally, parenterally, intracisternally, and topically, e.g., by powders, ointments, drops, and the like, including buccal and sublingual.

[0116] Regardless of the route of administration selected, the compounds described herein, which may be used in a suitable hydrated form, and / or pharmaceutical compositions of the disclosure, are formulated into pharma- ceutical acceptable dosage forms by conventional methods known to those of skill in the art.

[0117] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied to obtain an amount of the active ingredient effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without toxicity to the patient.

[0118] The terms "administration" and / or "administering" should be understood to mean providing a therapeutically effective amount of a pharmaceutical composition to a subject in need of treatment. The route of administration can be enteral, topical, or parenteral. Thus, the routes of administration include, but are not limited to, intracutaneous, subcutaneous, intravenous, intraperitoneal, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, transdermal, transtracheal, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal, oral, sublingual, buccal, rectal, intravaginal, nasal, ocular administration, as well as injection, inhalation, and spray.

[0119] The term "cancer" refers to a group of diseases characterized by abnormal and uncontrolled cell proliferation beginning at one site (primary site) with the potential to invade and spread to other sites (secondary sites, metastases) differentiating cancer (malignant tumors) from benign tumors. Almost every organ can be affected, giving rise to over 100 types of cancer that can affect humans. Cancer can result from many causes, including genetic predisposition, viral infection, exposure to ionizing radiation, exposure to environmental pollutants, tobacco and / or alcohol use, obesity, poor diet, lack of physical activity, or any combination thereof.

[0120] Exemplary cancers described by the National Cancer Institute include acute lymphoblastic leukemia, adult;acute lymphoblastic leukemia, pediatric;acute myeloid leukemia, adult;adrenal cortical carcinoma;adrenal cortical carcinoma, pediatric;AIDS-related lymphoma;AIDS-related malignancies;anal cancer;astrocytoma, pediatric cerebellum;astrocytoma, pediatric brain;cholangiocarcinoma, extrahepatic;bladder cancer;bladder cancer, pediatric;bone cancer, osteosarcoma / malignant fibrous histiocytoma;brain stem glioma, pediatric;brain tumor, adult;brain tumor, brain stem glioma, pediatric;brain tumor, cerebellar astrocytoma, pediatric;brain tumor, brain astrocytoma / malignant glioma, pediatric;brain tumor, ependymoma, pediatric;brain tumor, medulloblastoma, pediatric;brain tumor, supratentorial primitive neuroectodermal tumor , Children;Brain Tumors, Visual Pathway and Hypothalamic Glioma, Children;Brain Tumors, Children (Other);Breast Cancer;Breast Cancer and Pregnancy;Breast Cancer, Children;Breast Cancer, Male;Bronchial Adenoma / Carcinoid, Children:Carcinoid Tumors, Children;Carcinoid Tumors, Gastrointestinal Tract;Carcinoma, Adrenal Cortex;Carcinoma, Islet Cell;Carcinoma of Unknown Primary;Central Nervous System Lymphoma, Primary;Cerebellar Astrocytoma, Children;Brain Astrocytoma / Malignant Glioma, Children;Cervical Cancer;Childhood Cancer;Chronic Lymphocytic Leukemia;Chronic Myeloid Leukemia;Chronic Myeloproliferative Disorders;Clear Cell Sarcoma of Tendon Sheath;Colon Cancer;Colorectal Cancer, Children;Cutaneous T-Cell Lymphoma;Endometrial Cancer;Ependymoma, Children;Epithelial Cancer, Ovarian;Esophageal Cancer;Esophageal Cancer Cancer), pediatric;Ewing family tumors;Extracranial germ cell tumors, pediatric;Extragonadal germ cell tumors;Extrahepatic bile duct cancer;Eye cancer, intraocular melanoma;Eye cancer, retinoblastoma;Gallbladder cancer;Gastric (Stomach) cancer;Gastric (Stomach) cancer, pediatric;Gastrointestinal carcinoid tumors;Germ cell tumors, extracranial, pediatric;Germ cell tumors, extragonadal;Germ cell tumors, ovarian;Gestational trophoblastic tumors;Glioma, pediatric brain stem;Glioma, Pediatric visual pathway and hypothalamus;Hairy cell leukemia;Head and neck cancer;Hepatocellular (liver) cancer, adult (primary);Hepatocellular (liver) cancer, childhood (primary);Hodgkin lymphoma, adult;Hodgkin lymphoma, childhood;Hodgkin lymphoma in pregnancy;Hypopharyngeal cancer;Hypothalamus and visual pathway glioma, childhood;Intraocular melanoma;Islet cell carcinoma (endocrine pancreas);Kaposi's sarcoma;Kidney cancer;Laryngeal cancer;Laryngeal cancer, childhood;Leukemia, acute lymphoblastic, adult;Leukemia, acute lymphoblastic, childhood;Leukemia, acute myeloid, adult;Leukemia, acute myeloid, childhood;Leukemia, chronic lymphocytic;Leukemia, chronic myeloid;Leukemia, hairy cell;Lip and oral cancer;Liver cancer, adult (primary);Liver cancer, childhood (primary);Lung cancer, non-small cell;Lung cancer, small cell;Lymphoblastic leukemia, adult acute;Lymphoblastic leukemia, childhood acute;Lymphocytic leukemia, chronic;Lymphoma, AIDS-related;Lymphoma, central nervous system (primary);Lymphoma, cutaneous T-cell;Lymphoma, Hodgkin's lymphoma, adult;Lymphoma, Hodgkin's lymphoma, childhood;Lymphoma, Hodgkin's during pregnancy;Lymphoma, non-Hodgkin's Lymphoma, adult;Lymphoma, non-Hodgkin's lymphoma, childhood;Lymphoma, non-Hodgkin's during pregnancy;Lymphoma, primary central nervous system;Macroglobulinemia, Waldenstrom type;Male breast cancer;Malignant mesothelioma, adult;Malignant mesothelioma, childhood;Malignant thymoma;Medulloblastoma, childhood;Melanoma;Melanoma, intraocular;Merkel cell carcinoma;Mesothelioma, malignant;Metastatic squamous cervical carcinoma of unknown primary;Multiple endocrine neoplasia syndrome, childhood;Multiple myeloma / plasma cell neoplasm;Mycosis fungoides;Myelodysplastic syndrome;Myeloid leukemia, chronic;Myeloid leukemia, childhood acute;Myeloma, multiple;Myeloproliferative disorders, chronic;Nasal and paranasal Nasal cavity cancer;Nasopharyngeal cancer;Nasopharyngeal cancer, children;Neuroblastoma;Non-Hodgkin's lymphoma, adults;Non-Hodgkin's lymphoma, children;Non-Hodgkin's lymphoma during pregnancy;Non-small cell lung cancer;Oral cavity cancer, children;Oral cavity and lip cancer;Oropharyngeal cancer;Osteosarcoma / malignant fibrous histiocytoma of bone;Ovarian cancer, children;Ovarian epithelial cancer;Ovarian germ cell tumors;Ovarian low malignant potential tumors;Pancreatic cancer;Pancreatic cancer, children,Pancreatic islet cell cancer;Sino-nasal and nasal cancer;Parathyroid cancer;Penile cancer;Pheochromocytoma;Pineal and supratentorial primitive neuroectodermal tumors, children;Pituitary tumors;Plasma cell neoplasms / multiple myeloma;Breast Membrane pulmonary blastoma;Pregnancy and breast cancer;Pregnancy and Hodgkin's lymphoma;Pregnancy and non-Hodgkin's lymphoma;Primary central nervous system lymphoma;Primary liver cancer, adult;Primary liver cancer, pediatric;Prostate cancer;Rectal cancer;Renal cell (kidney) cancer;Renal cell carcinoma, pediatric;Renal pelvis and ureter, transitional cell carcinoma;Retinoblastoma;Rhabdomyosarcoma, pediatric;Salivary gland cancer;Salivary gland cancer, pediatric;Sarcoma, Ewing family tumor;Sarcoma, Kaposi's sarcoma;Sarcoma (osteosarcoma V malignant fibrous histiocytoma of bone;Sarcoma, rhabdomyosarcoma, pediatric;Sarcoma, soft tissue, adult;Sarcoma, soft tissue, pediatric;Sezary syndrome;Skin cancer;Skin cancer, pediatric;Skin cancer (melanoma);Skin cancer, Merkel cell;Small cell lung cancer;Small intestine cancer;Soft tissue sarcoma, adult;Soft tissue sarcoma, childhood;Cervical squamous cell carcinoma of unknown primary, metastatic;Stomach (gastric) cancer;Stomach (Gastric) cancer, childhood;Supratentorial primary neuroectodermal tumor, childhood;T-cell lymphoma, skin;Testicular cancer;Thymoma, childhood;Thymoma, malignant;Thyroid cancer;Thyroid cancer, childhood;Transitional cell carcinoma of the renal pelvis and ureter;Chloroblastic tumor, pregnancy;Carcinoma of unknown primary site, childhood;Unusual cancer of childhood;Ureter and renal pelvis, transitional cell carcinoma;Urethral cancer;Uterine sarcoma;Vaginal cancer;Optical pathway and hypothalamic glioma, childhood;Vulvar cancer;Waldenstrom macroglobulinemia;and Wilms' tumor.

[0121] In certain aspects, the cancer includes lung cancer, breast cancer, colorectal cancer, prostate cancer, gastric cancer, liver cancer, cervical cancer, esophageal cancer, bladder cancer, non-Hodgkin's lymphoma, leukemia, pancreatic cancer, kidney cancer, endometrial cancer, head and neck cancer, lip cancer, oral cavity cancer, thyroid cancer, brain cancer, ovarian cancer, melanoma, gallbladder cancer, laryngeal cancer, multiple myeloma, nasopharyngeal cancer, Hodgkin's lymphoma, testicular cancer, and Kaposi's sarcoma.

[0122] In certain embodiments, the method further comprises administering a chemotherapeutic agent. The compound of the present disclosure can be administered in combination with one or more additional therapeutic agents. The phrases "combination therapy," "combined with," and the like refer to the simultaneous use of two or more drugs or treatments to increase response. The FGFR inhibitor of the present disclosure can be combined with other drugs or treatments, for example, used to treat cancer. In various embodiments, the compound is administered before, simultaneously, or after the administration of the chemotherapeutic agent.

[0123] The term "anti-cancer therapy" refers to any therapy or treatment that can be used to treat cancer. Anti-cancer therapies include, but are not limited to, surgery, radiation therapy, chemotherapy, immunotherapy, and targeted therapy.

[0124] Examples of chemotherapeutic or anticancer drugs include actinomycin, azacitidine, azathioprine, bleomycin, bortezomib, carboplatin, capecitabine, cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, etoposide, fluorouracil, gemcitabine, hydroxyurea, Idarubicin, imatinib, irinotecan, mechlorethamine, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, teniposide, thioguanine, topotecan, barbicine, vinblastine, vincristine, vindesine, vinorelbine, panitumamab, erbitux (cetuximab), matuzumab, IMC-IIF8, TheraCIMhR3, denosumab, Avastin (bevacizumab), Humira (adalimumab), Herceptin (trastuzumab), Remicade (infiliximab), rituximab, Synagis (palivizumab), Milotarg (gemtuzumab ozogamicin), Raptiva (efalizumab), Tysabri (natalizumab), Zenapax (dacliximab), NeutroSpec (Technetium (99mTc)-fanolesomab), tocilizumab, ProstaScint (Indium-Ill-labeled capromab pentaerythrocyte serine monophosphate) Detide), Bexar (tositumomab), Zevalin bound to yttrium-90 (ibritumomab tiuxetan (IDEC-Y2B8), Xolair (omalizumab), MabThera (rituximab), ReoPro (abciximab), MabCampath (basiliximab), LeukoScan (sulesomab), CEA-scan (arcitumomab), Veluma (nofetumomab), Panorex (edrecolomab), alemtuzumab, CDP870, natalizumab gilotrif (afatinib) ), Lynparza (olaparib), Perjeta (pertuzumab), Optivo (nivolumab), Bosulif (bosutinib), Cabometyx (cabozantinib), Ogibli (trastuzumab-dkst), Sutent (sunitinib malate), Adcetris (brentuximab vedotin), Alecensa (alectinib), Calquence (acalabrutinib), Yescarta (ciloleucel), Verzenio (abemaciclib), Keytruda (pembrolizumab), Alicopa (copanlisib), Nerlink Examples of immunotherapeutic agents include, but are not limited to, sirolimus (neratinib), Imfinzi (durvalumab), Darazalex (daratumumab), Tecentriq (atezolizumab), and Tarceva (erlotinib). Examples of immunotherapeutic agents include, but are not limited to, interleukins (Il-2, Il-7, Il-12), cytokines (interferon, G-CSF, imiquimod), chemokines (CCL3, CCl26, CXCL7), immunomodulatory imids (thalidomide and its analogs).

[0125] In further embodiments, the disclosure provides a method of inhibiting kinase activity comprising contacting a cell with a compound of formula (I), formula (II), or formula (III). In one aspect, the kinase is selected from the group consisting of ALK, EGFR, EPH-B3, FAK, FGFR1, FGFR2, FGFR3, FGFR4, KIT, MEK1, MET, PDGFR-ALPHA, PDGFR-BETA, RET, ROS, and TYRO3. In a particular aspect, the kinase is FGFR1, FGFR2, FGFR3, and / or FGFR4. In another aspect, the kinase is FGFR4. In various aspects, the cell is a cancer cell. In many aspects, the cancer cell is a breast cancer, lung cancer, bladder cancer, prostate cancer, ovarian cancer, endometrial cancer, rhabdomyosarcoma, liver cancer, or gastric cancer cell.

[0126] Referring to Figure 1, FGFR4 kinase contains a cysteine ​​(Cys552) located near the ATP binding site in the hinge region of the receptor, which is unique within the FGFR family and rare among other kinases. Covalent inhibitors of FGFR4 kinase provide potent and selective inhibition of FGFR by covalently targeting the thiol group (SH) in the cysteine ​​residue.

[0127] The screening method used in the present disclosure according to some embodiments is described as follows: Screening probes for live cells or living animals can include the steps of (1) treating live cells with electrophilic probes to generate covalent bonds between target proteins and probes, (2) lysing cells, (3) adding biotin-azide to conjugate biotin to probe-modified proteins by copper-catalyzed azide-alkyne cycloaddition (CuAAC) click reaction, (4) using streptavidin resin to pull down and enrich biotin-bound proteins, (5) digesting resin-bound proteins with trypsin, (6) analyzing the resulting tryptic peptides by liquid chromatography-mass spectrometry (LC-MS) or MS, and (7) obtaining information on the identity of the target protein and the strength of the probe-target interaction in cells. Target validation and selection can include (1) using orthogonal methods, such as Western blot, to confirm that the identified proteins actually bind to the probes, and (2) selecting the most disease-relevant target-lead pairs for further preclinical and clinical studies.

[0128] Below, examples are presented that discuss the design and efficacy evaluation of novel pyridinyl pyrimidine-based FGFR inhibitors that are intended for the discussed applications.The following examples are provided to further illustrate the embodiments of the present disclosure, but are not intended to limit the scope of the present disclosure.They are representative of those that can be used, but other procedures, methods, or techniques known to those skilled in the art may be used instead. EXAMPLES

[0129] Example 1: Synthesis and characterization of pyridinylpyrimidine FGFR inhibitors (compounds 1-4) TIFF0007658908000059.tif119165 Scheme 1. Synthesis of compound 1

[0130] Compound 1 was synthesized according to Synthesis Scheme 1.

[0131] TIFF0007658908000060.tif110164 Scheme 2. Synthesis of compound 2

[0132] Compound 2 was synthesized according to Synthesis Scheme 2.

[0133] TIFF0007658908000061.tif114164 Scheme 3. Synthesis of compound 3

[0134] Compound 3 was synthesized according to Synthesis Scheme 3.

[0135] TIFF0007658908000062.tif118164 Scheme 4. Synthesis of compound 4

[0136] Compound 4 was synthesized according to Synthesis Scheme 4.

[0137] Example 2: Synthesis of Compound 6 (N-[2-[[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]amino]-5-(1-methylazetidin-3-yl)oxy-phenyl]prop-2-enamide) TIFF0007658908000063.tif162160 Scheme 5. Synthesis of compound 6

[0138] Compound 6 was synthesized according to Synthesis Scheme 5. The synthetic process of each step is described below.

[0139] TIFF0007658908000064.tif26128

[0140] Step 1 for the synthesis of compound 6: A solution of 4-amino-3-nitro-phenol (3 g, 19.46 mmol), tert-butyl 3-iodoazetidine-1-carboxylate (6.06 g, 21.41 mmol), Cs2CO3 (9.51 g, 29.20 mmol) in DMF (60 mL) was stirred at 90 °C for 16 h under N2 atmosphere. The mixture was diluted with water (5 mL) and extracted with EtOAc (10 mL x 3), then the combined organic layers were washed with saturated aqueous NaCl (5 mL x 7), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 3 / 1) to give tert-butyl 3-(4-amino-3-nitro-phenoxy)azetidine-1-carboxylate (5.4 g, 17.46 mmol, 90% yield) as a red solid. TIFF0007658908000065.tif12152

[0141] TIFF0007658908000066.tif41167

[0142] Step 2 for the synthesis of compound 6: To a solution of N-(2,6-dichloro-3,5-dimethoxy-phenyl)-3-(6-methylsulfonylpyrimidin-4-yl)pyridin-2-amine (800 mg, 1.76 mmol), tert-butyl 3-(4-amino-3-nitro-phenoxy)azetidine-1-carboxylate (652 mg, 2.11 mmol) in DMAc (15 mL), t-BuOK (595 mg, 5.31 mmol) was added. The mixture was stirred at 45° C. for 2 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL×3), then the combined organic layers were washed with saturated aqueous NaCl (20 mL×7), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (PE / EtOAc=1 / 0 to 3 / 1) to give tert-butyl 3-[4-[[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]amino]-3-nitro-phenoxy]azetidine-1-carboxylate (648 mg, 0.947 mmol, 54% yield) as a yellow solid.

[0143] TIFF0007658908000067.tif34162

[0144] Step 3 for the synthesis of compound 6: To a solution of tert-butyl 3-[4-[[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]amino]-3-nitro-phenoxy]azetidine-1-carboxylate (648 mg, 0.947 mmol) in dioxane (10 mL) was added HCl / dioxane (4 M, 2.37 mL). The mixture was stirred at 25° C. for 2 h. The mixture was concentrated to give N-[4-(azetidin-3-yloxy)-2-nitro-phenyl]-6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-amine (550 mg, 0.886 mmol, 93% yield, HCl salt) as a yellow solid.

[0145] TIFF0007658908000068.tif33164

[0146] Step 4 for the synthesis of compound 6: To a solution of N-[4-(azetidin-3-yloxy)-2-nitro-phenyl]-6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-amine (550 mg, 0.886 mmol, HCl salt) in MeOH (15 mL) was added aqueous HCHO (2.88 g, 35.43 mmol, 2.64 mL, 37% purity), NaBH(OAc)3 (376 mg, 1.77 mmol), CH3COOH (213 mg, 3.54 mmol). The mixture was stirred at 25° C. for 4 h. The mixture was concentrated, and the residue was purified by silica gel chromatography (DCM / MeOH=1 / 0-10 / 1) to give 6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]-N-[4-(1-methylazetidin-3-yl)oxy-2-nitro-phenyl]pyrimidin-4-amine (450 mg, 0.752 mmol, 85% yield) as a red solid.

[0147] TIFF0007658908000069.tif35167

[0148] Step 5 for the synthesis of compound 6: To a solution of 6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]-N-[4-(1-methylazetidin-3-yl)oxy-2-nitro-phenyl]pyrimidin-4-amine (450 mg, 0.752 mmol) in THF (15 mL) and HO (15 mL) was added NH4Cl (201 mg, 3.76 mmol), Fe (210 mg, 3.76 mmol). The mixture was stirred at 65° C. for 4 h. The mixture was filtered and the filtrate was concentrated to give N1-[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]-4-(1-methylazetidin-3-yl)oxy-benzene-1,2-diamine (400 mg, 0.704 mmol, 93% yield) as a yellow solid.

[0149] TIFF0007658908000070.tif43170

[0150] Step 6 for the synthesis of compound 6: To a solution of N1-[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]-4-(1-methylazetidin-3-yl)oxy-benzene-1,2-diamine (200 mg, 0.352 mmol) in DCM (10 mL) was added Et3N (36 mg, 0.352 mmol) and prop-2-enoyl chloride (32 mg, 0.352 mmol). The mixture was stirred at 25° C. for 0.5 h. The mixture was diluted with water (10 mL) and extracted with DCM (10 mL×3), then the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (water (0.225% FA)-ACN) to give N-[2-[[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]amino]-5-(1-methylazetidin-3-yl)oxy-phenyl]prop-2-enamide (8.5 mg, 4% yield, 96% purity) as a white solid. LCMS:t R=2.928min in 0-60CD_4min_Pos_220&254_Shimadzu.lcm, TIFF0007658908000071.tif34162

[0151] Example 3: Synthesis of Compound 7 N-[2-[[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]amino]-5-[(1-methylazetidin-3-yl)methoxy]phenyl]prop-2-enamide TIFF0007658908000072.tif191168 Scheme 6. Synthesis of compound 7

[0152] Compound 7 was synthesized according to Synthesis Scheme 6. The synthesis process of each step is described below.

[0153] TIFF0007658908000073.tif21128

[0154] Step 1 for the synthesis of compound 7: To a solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (2 g, 10.68 mmol) in DCM (5 mL) was added DABCO (2.40 g, 21.36 mmol) and TsCl (2.44 g, 12.82 mmol). The mixture was stirred at 0 °C for 0.5 h. The mixture was filtered, and the filtrate was diluted with H2O (50 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl 3-(p-tolylsulfonyloxymethyl)azetidine-1-carboxylate (3 g, 8.79 mmol, 82% yield) as a colorless oil, which was used directly in the next step.

[0155] TIFF0007658908000074.tif29128

[0156] Step 2 for the synthesis of compound 7: To a solution of tert-butyl 3-(p-tolylsulfonyloxymethyl)azetidine-1-carboxylate (2 g, 5.86 mmol) in DMF (20 mL) was added Cs2CO3 (3.82 g, 11.72 mmol) and 4-amino-3-nitro-phenol (1.35 g, 8.79 mmol). The mixture was stirred at 80 °C for 12 h. The mixture was quenched by adding H2O (50 mL) at 25 °C, then diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was then purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent of 0-50% ethyl acetate / petroleum ether gradient (40 mL / min)) to give tert-butyl 3-[(4-amino-3-nitro-phenoxy)methyl]azetidine-1-carboxylate (1.4 g, 4.33 mmol, 74% yield) as a brown solid.

[0157] TIFF0007658908000075.tif40164

[0158] Step 3 for the synthesis of compound 7: To a solution of tert-butyl 3-[(4-amino-3-nitro-phenoxy)methyl]azetidine-1-carboxylate (1.4 g, 4.33 mmol) in DMF (5 mL) was added t-BuOK (583 mg, 5.20 mmol) and N-(2,6-dichloro-3,5-dimethoxy-phenyl)-3-(6-methylsulfonylpyrimidin-4-yl)pyridin-2-amine (1.97 g, 4.33 mmol). The mixture was stirred at 40° C. for 2 h. The mixture was quenched by adding H2O (50 mL) at 25° C., then diluted with H2O (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was then purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent with 0-70% ethyl acetate / petroleum ether gradient (40 mL / min)) to give tert-butyl 3-[[[4-[[6-[2-(2,6-dichloro-3,5-dimethoxyanilino)-3-pyridyl]pyrimidin-4-yl]amino]-3-nitro-phenoxy]methyl]azetidine-1-carboxylate (1 g, 1.29 mmol, 30% yield, 90% purity) as a yellow solid.

[0159] TIFF0007658908000076.tif33170

[0160] Step 4 for the synthesis of compound 7: A solution of tert-butyl 3-[[4-[[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]amino]-3-nitro-phenoxy]methyl]azetidine-1-carboxylate (0.95 g, 1.36 mmol) in HCl / dioxane (4 M, 10 mL) was stirred for 0.5 h at 25° C. The mixture was concentrated under reduced pressure to give N-[4-(azetidin-3-ylmethoxy)-2-nitro-phenyl]-6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-amine (1.17 g, 1.35 mmol, 99% yield, 69% purity) as a yellow solid, which was used directly in the next step.

[0161] TIFF0007658908000077.tif33170

[0162] Step 5 for the synthesis of compound 7: To a solution of N-[4-(azetidin-3-ylmethoxy)-2-nitro-phenyl]-6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-amine (1 g, 1.22 mmol) in MeOH (10 mL) was added aqueous HCHO (3.96 g, 48.79 mmol, 3.63 mL, 37% purity), CH3COOH (293 mg, 4.88 mmol), and NaBH(OAc)3 (517 mg, 2.44 mmol). The mixture was stirred at 25° C. for 4 h. The mixture was concentrated under reduced pressure to give a residue. The residue was then purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent of 0-80% ethyl acetate / petroleum ether gradient (60 mL / min)) to give 6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]-N-[4-[(1-methylazetidin-3-yl)methoxy]-2-nitro-phenyl]pyrimidin-4-amine (0.5 g, 0.735 mmol, 60% yield, 90% purity) as a yellow solid.

[0163] TIFF0007658908000078.tif33167

[0164] Step 6 for the synthesis of compound 7: To a solution of 6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]-N-[4-[(1-methylazetidin-3-yl)methoxy]-2-nitro-phenyl]pyrimidin-4-amine (0.5 g, 0.816 mmol) in THF (1 mL) and HO (1 mL) was added Fe (228 mg, 4.08 mmol) and NH4Cl (218 mg, 4.08 mmol). The mixture was stirred at 60 °C for 5 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The mixture was then quenched by adding HO (50 mL) at 25 °C, then diluted with HO (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give N1-[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]-4-[(1-methylazetidin-3-yl)methoxy]benzene-1,2-diamine (350 mg, 0.60 mmol, 74% yield) as a brown solid.

[0165] TIFF0007658908000079.tif39163

[0166] Step 7 for the synthesis of compound 7: To a solution of N1-[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]-4-[(1-methylazetidin-3-yl)methoxy]benzene-1,2-diamine (0.2 g, 0.343 mmol) in DCM (5 mL) was added DIEA (133 mg, 1.03 mmol) and prop-2-enoyl chloride (34 mg, 0.378 mmol). The mixture was stirred at 0° C. for 0.5 h. The mixture was quenched by adding H2O (50 mL) at 25° C., then diluted with H2O (50 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was then purified by preparative HPLC (water (0.225% FA)-ACN) to give N-[2-[[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]amino]-5-[(1-methylazetidin-3-yl)methoxy]phenyl]prop-2-enamide (4.8 mg, 2% yield, 92.8% purity) as a white solid. LCMS:t R =1.425 min in 10-80AB_4min_220&254_Shimadzu.lcm, TIFF0007658908000080.tif27162

[0167] Example 4: Synthesis of Compound 8 N-[2-[[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]amino]-5-[(1-methyl-4-piperidyl)oxy]phenyl]prop-2-enamide TIFF0007658908000081.tif122168 Scheme 7. Synthesis of compound 8

[0168] Compound 8 was synthesized according to Synthesis Scheme 7. The synthetic process of each step is described below.

[0169] TIFF0007658908000082.tif22128

[0170] Step 1 for the synthesis of compound 8: To a solution of 1-methylpiperidin-4-ol (1.3 g, 11.29 mmol) in THF (10 mL), KOH (2.53 g, 45.15 mmol) and TsCl (3.23 g, 16.93 mmol) were added at 0° C. The mixture was stirred at 25° C. for 16 h. The mixture was poured into water (30 mL) and filtered. The filter cake was collected and dried to give (1-methyl-4-piperidyl) 4-methylbenzenesulfonate (1.8 g, 6.68 mmol, 59% yield) as a yellow oil.

[0171] TIFF0007658908000083.tif33128

[0172] Step 2 for the synthesis of compound 8: To a solution of 4-amino-3-nitro-phenol (400 mg, 2.60 mmol) and (1-methyl-4-piperidyl) 4-methylbenzenesulfonate (1.05 g, 3.89 mmol) in DMF (20 mL) was added Cs2CO3 (1.69 g, 5.19 mmol). The mixture was stirred at 80 °C for 8 h. The residue was diluted with EtOAc (20 mL) and extracted with H2O (60 mL). The combined organic layers were washed with H2O (30 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent of 0-10% methanol / dichloromethane (40 mL / min)) to give 5-[(1-methyl-4-piperidyl)oxy]-2-nitro-aniline (230 mg, 0.915 mmol, 35% yield) as a brown solid.

[0173] TIFF0007658908000084.tif43165

[0174] Step 3 for the synthesis of compound 8: To a solution of 4-[(1-methyl-4-piperidyl)oxy]-2-nitro-aniline (138 mg, 0.549 mmol) and N-(2,6-dichloro-3,5-dimethoxy-phenyl)-3-(6-methylsulfonylpyrimidin-4-yl)pyridin-2-amine (300 mg, 0.659 mmol) in DMAc (10 mL), tBuOK (123 mg, 1.10 mmol) was added. The mixture was stirred at 50° C. for 2 h. The residue was diluted with H2O (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with H2O (30 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent of 0–10% methanol / dichloromethane (40 mL / min)) to give 6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]-N-[4-[(1-methyl-4-piperidyl)oxy]-2-nitro-phenyl]pyrimidin-4-amine (200 mg, 0.16 mmol, 29% yield) as a brown solid.

[0175] TIFF0007658908000085.tif33165

[0176] Step 4 for the synthesis of compound 8: To a solution of 6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]-N-[4-[(1-methyl-4-piperidyl)oxy]-2-nitro-phenyl]pyrimidin-4-amine (200 mg, 0.16 mmol) in THF (10 mL) was added NH4Cl (43 mg, 0.8 mmol) and Fe (45 mg, 0.8 mmol). The mixture was stirred at 65° C. for 3 h. The mixture was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent of 0–10% methanol / dichloromethane (40 mL / min)) to give N-[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]-4-[(1-methyl-4-piperidyl)oxy]benzene-1,2-diamine (38 mg, 0.064 mmol, 40% yield) as a yellow solid.

[0177] TIFF0007658908000086.tif39163

[0178] Step 5 for the synthesis of compound 8: To a solution of N1-[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]-4-[(1-methyl-4-piperidyl)oxy]benzene-1,2-diamine (38 mg, 0.064 mmol) in DCM (10 mL) and DIEA (16 mg, 0.127 mmol), prop-2-enoyl chloride (7 mg, 0.076 mmol) was added. The mixture was stirred at 0° C. for 0.5 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (water (0.225% FA)-ACN) to give N-[2-[[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]amino]-5-[(1-methyl-4-piperidyl)oxy]phenyl]prop-2-enamide (11.1 mg, 0.017 mmol, 27% yield, 99.30% purity) as a yellow solid.

[0179] Example 5: Synthesis of Compound 9 N-[2-[[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]amino]-5-(1-methylpyrrolidin-3-yl)oxy-phenyl]prop-2-enamide TIFF0007658908000087.tif136162 Scheme 8. Synthesis of compound 9

[0180] Compound 9 was synthesized according to Synthesis Scheme 8. The synthetic process of each step is described below.

[0181] TIFF0007658908000088.tif23128

[0182] Step 1 for the synthesis of compound 9: To a solution of 1-methylpyrrolidin-3-ol (1.0 g, 9.89 mmol) and KOH (2.22 g, 39.55 mmol) in THF (30 mL), TsCl (2.83 g, 14.83 mmol) was added at 0° C. The mixture was stirred at 25° C. for 16 h. The mixture was filtered and the filtrate was concentrated to give (1-methylpyrrolidin-3-yl) 4-methylbenzenesulfonate (1.1 g, 4.31 mmol, 44% yield) as a yellow oil.

[0183] TIFF0007658908000089.tif37128

[0184] Step 2 for the synthesis of compound 9: To a solution of 4-amino-3-nitro-phenol (600 mg, 3.89 mmol) in DMF (20 mL) was added Cs2CO3 (2.54 g, 7.79 mmol). The mixture was stirred at 25° C. for 0.5 h, then (1-methylpyrrolidin-3-yl) 4-methylbenzenesulfonate (1.09 g, 4.28 mmol) was added. The mixture was stirred at 80° C. for 6 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (50 mL×3), then the combined organic layers were washed with saturated aqueous NaCl (20 mL×7), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (DCM / MeOH=1 / 0-10 / 1) to give 4-(1-methylpyrrolidin-3-yl)oxy-2-nitro-aniline (600 mg, 2.53 mmol, 65% yield) as a red solid.

[0185] TIFF0007658908000090.tif42158

[0186] Step 3 for the synthesis of compound 9: To a solution of 4-(1-methylpyrrolidin-3-yl)oxy-2-nitro-aniline (200 mg, 0.843 mmol), N-(2,6-dichloro-3,5-dimethoxy-phenyl)-3-(6-methylsulfonylpyrimidin-4-yl)pyridin-2-amine (422 mg, 0.927 mmol) in DMAC (10 mL), t-BuOK (286 mg, 2.55 mmol) was added. The mixture was stirred at 40° C. for 2 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (50 mL×3), then the combined organic layers were dried over Na2SO4, filtered and concentrated to give 6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]-N-[4-(1-methylpyrrolidin-3-yl)oxy-2-nitro-phenyl]pyrimidin-4-amine (500 mg, crude) as a yellow solid.

[0187] TIFF0007658908000091.tif35161

[0188] Step 4 for the synthesis of compound 9: To a solution of 6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]-N-[4-(1-methylpyrrolidin-3-yl)oxy-2-nitro-phenyl]pyrimidin-4-amine (300 mg, 0.49 mmol) in THF (10 mL) and HO (10 mL) was added Fe (137 mg, 2.45 mmol) and NHCl (131 mg, 2.45 mmol). The mixture was stirred at 65° C. for 4 h. The mixture was filtered and the filtrate was extracted with EtOAc (30 mL×3), then the combined organic layers were dried over Na2SO4, filtered and concentrated to give N1-[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]-4-(1-methylpyrrolidin-3-yl)oxy-benzene-1,2-diamine (150 mg, 0.258 mmol, 52% yield) as a yellow solid.

[0189] TIFF0007658908000092.tif43165

[0190] Step 5 for the synthesis of compound 9: To a solution of N1-[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]-4-(1-methylpyrrolidin-3-yl)oxy-benzene-1,2-diamine (120 mg, 0.206 mmol) in DCM (10 mL) was added prop-2-enoyl chloride (19 mg, 0.206 mmol) and DIEA (27 mg, 0.206 mmol). The mixture was stirred at 25° C. for 1 h. The mixture was diluted with water (5 mL) and extracted with DCM (10 mL×3), then the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (water (0.225% FA)-ACN) to give N-[2-[[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]amino]-5-(1-methylpyrrolidin-3-yl)oxy-phenyl]prop-2-enamide (50 mg, 0.0778 mmol, 38% yield, 99% purity) as a yellow solid. LCMS:t R=1.129min in10-80AB_4 min_220&254_Shimadzu.lcm, TIFF0007658908000093.tif41162

[0191] Example 6: Synthesis of Compound 10 N-[2-[[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]amino]-5-tetrahydrofuran-3-yloxy-phenyl]prop-2-enamide TIFF0007658908000094.tif128166 Scheme 9. Synthesis of compound 10

[0192] Compound 10 was synthesized according to Synthesis Scheme 9. The synthetic process of each step is described below.

[0193] TIFF0007658908000095.tif31128

[0194] Step 1 for the synthesis of compound 10: To a solution of 4-amino-3-nitro-phenol (4 g, 25.95 mmol), tetrahydrofuran-3-ol (2.29 g, 25.95 mmol), and PPh3 (8.17 g, 31.14 mmol) in THF (25 mL) was added dropwise at 0 °C under N2 a solution of DTBAD (8.96 g, 38.93 mmol) in THF (25 mL). The mixture was stirred at 0 °C for 0.5 h and then warmed to 25 °C for 15.5 h. The mixture was concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 3 / 1) and the residue was recrystallized from CH3CN to give 2-nitro-4-tetrahydrofuran-3-yloxy-aniline (1.1 g, 4.78 mmol, 18% yield, 97.5% purity) as a red solid. LCMS:t R =0.824 min in0-30AB_4 min_220&254_Shimadzu.lcm, TIFF0007658908000096.tif20162

[0195] TIFF0007658908000097.tif39165

[0196] Step 2 for the synthesis of compound 10: To a solution of N-(2,6-dichloro-3,5-dimethoxy-phenyl)-3-(6-methylsulfonylpyrimidin-4-yl)pyridin-2-amine (300 mg, 0.66 mmol) and 2-nitro-4-tetrahydrofuran-3-yloxy-aniline (296 mg, 1.32 mmol) in DMAc (30 mL), tBuOK (148 mg, 1.32 mmol) was added. The mixture was stirred at 40° C. for 2 h. The mixture was poured into water (60 mL), filtered, and the filter cake was collected in vacuo to give 6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]-N-(2-nitro-4-tetrahydrofuran-3-yloxy-phenyl)pyrimidin-4-amine (240 mg, 0.40 mmol, 61% yield) as a yellow solid.

[0197] TIFF0007658908000098.tif35167

[0198] Step 3 for the synthesis of compound 10: To a solution of 6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]-N-(2-nitro-4-tetrahydrofuran-3-yloxy-phenyl)pyrimidin-4-amine (240 mg, 0.40 mmol) in THF (10 mL) and HO (10 mL) was added Fe (112 mg, 2.00 mmol) and NHCl (107 mg, 2.00 mmol). The mixture was stirred at 65° C. for 3 h. The mixture was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure to give N1-[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]-4-tetrahydrofuran-3-yloxy-benzene-1,2-diamine (300 mg, 0.368 mmol, 92% yield, 90% purity) as a red solid. LCMS:t R =0.922min in0-60AB_2min_220&254_Shimadzu.lcm,MS(ESI)m / z=569.1 [M+H] + .

[0199] TIFF0007658908000099.tif42161

[0200] Step 4 for the synthesis of compound 10: A solution of N1-[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]-4-tetrahydrofuran-3-yloxy-benzene-1,2-diamine (220 mg, 0.386 mmol) in DCM (10 mL) with DIEA (100 mg, 0.772 mmol) and prop-2-enoyl chloride (31 mg, 0.348 mmol) at 0° C. The mixture was stirred at 0° C. for 0.5 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (water (0.225% FA)-ACN) to give N-[2-[[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]amino]-5-tetrahydrofuran-3-yloxy-phenyl]prop-2-enamide (100 mg, 0.159 mmol, 41% yield, 99.2% purity) as a yellow solid. LCMS:t R =2.148min in 0-60AB_4min_220&254_Shimadzu.lcm, TIFF0007658908000100.tif27162

[0201] Example 7: Synthesis of Compound 11 N-[2-[[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]amino]-5-(oxetan-3-yloxy)phenyl]prop-2-enamide TIFF0007658908000101.tif125158 Scheme 10. Synthesis of compound 11

[0202] Compound 11 was synthesized according to Synthesis Scheme 10. The synthesis process of each step is described below.

[0203] TIFF0007658908000102.tif36128

[0204] Step 1 for the synthesis of compound 11: To a solution of 4-amino-3-nitro-phenol (200 mg, 1.30 mmol) in DMF (5 mL) was added Cs2CO3 (846 mg, 2.60 mmol). The mixture was stirred at 25 °C for 0.5 h, then oxetan-3-yl 4-methylbenzenesulfonate (444 mg, 1.95 mmol) was added. The mixture was heated to 80 °C for 6 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL x 3), then the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 3 / 1) to give 2-nitro-4-(oxetan-3-yloxy)aniline (100 mg, 0.476 mmol, 37% yield) as a red solid. TIFF0007658908000103.tif12130

[0205] TIFF0007658908000104.tif42153

[0206] Step 2 for the synthesis of compound 11: To a solution of N-(2,6-dichloro-3,5-dimethoxy-phenyl)-3-(6-methylsulfonylpyrimidin-4-yl)pyridin-2-amine (300 mg, 0.659 mmol), 2-nitro-4-(oxetan-3-yloxy)aniline (138 mg, 0.659 mmol) in DMAc (10 mL) was added t-BuOK (223 mg, 1.99 mmol) at 0° C. The mixture was then heated to 40° C. for 2 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were then washed with saturated aqueous NaCl (10 mL×7), dried over Na2SO4, filtered and concentrated. The residue was triturated with CH3CN (5 mL) at 25° C. for 5 min. The precipitate was filtered and dried to give 6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]-N-[2-nitro-4-(oxetan-3-yloxy)phenyl]pyrimidin-4-amine (300 mg, 0.512 mmol, 78% yield) as a yellow solid.

[0207] TIFF0007658908000105.tif37164

[0208] Step 3 for the synthesis of compound 11: To a solution of 6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]-N-[2-nitro-4-(oxetan-3-yloxy)phenyl]pyrimidin-4-amine (200 mg, 0.34 mmol) in THF (10 mL) and HO (10 mL) was added Fe (95 mg, 1.71 mmol) and NH4Cl (91 mg, 1.71 mmol). The mixture was stirred at 65° C. for 4 h. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated to give N1-[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]-4-(oxetan-3-yloxy)benzene-1,2-diamine (180 mg, crude) as a yellow solid.

[0209] TIFF0007658908000106.tif41160

[0210] Step 4 for the synthesis of compound 11: To a solution of N1-[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]-4-(oxetan-3-yloxy)benzene-1,2-diamine (150 mg, 0.27 mmol) in DCM (15 mL) was added prop-2-enoyl chloride (19 mg, 0.216 mmol) at 0° C. The mixture was stirred at 25° C. for 0.5 h. The mixture was quenched with water (10 mL) and then extracted with DCM (50 mL×3), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (Column: Xtimate C18100*30mm*3um, water (0.04% NH3·H2O+10mM NH4HCO3)-ACN; 63-83% B; gradient time: 30min; flow rate: 25mL / min) and then by chiral SFC (Instrument: CAS-QD-ANA-SFC-SD (Agilent 1260 with DAD detector), Column: Chiralcel OJ-3 100×4.6mm i.d., 3um. Mobile phase: A:CO2 B:Ethanol (0.05% Further purification by DEA), gradient: 5% to 40% B for 4.5 min, 40% held for 2.5 min, then 5% B for 1 min, flow rate: 2.8 mL / min, column temperature: 40 °C) afforded N-[2-[[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]amino]-5-(oxetan-3-yloxy)phenyl]prop-2-enamide (30 mg, 0.049 mmol, 18% yield, 100% purity) as a yellow solid. LCMS: t R =2.023 min in:10-80CD_4min_Pos_220&254_Shimadzu.lcm, TIFF0007658908000107.tif34162

[0211] Example 8: Synthesis of Compound 12 N-[2-[[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]amino]-5-(2-pyrrolidin-1-ylethoxy)phenyl]prop-2-enamide TIFF0007658908000108.tif148166 Scheme 11. Synthesis of compound 12

[0212] Compound 12 was synthesized according to Synthesis Scheme 11. The synthesis process of each step is described below.

[0213] TIFF0007658908000109.tif27128

[0214] Step 1 for the synthesis of compound 12: 4-amino-3-nitro-phenol (1.5 g, 9.73 mmol), Boc2O (3.19 g, 14.60 mmol), and Et3NN (984 mg, 9.73 mmol) dissolved in DCM (10 mL). Then, a solution of DMAP (118 mg, 0.973 mmol) in DCM (10 mL) was slowly added dropwise to the above solution. The mixture was then stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure to remove DCM. The residue was purified by silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent of 0-30% ethyl acetate / petroleum ether gradient (40 mL / min)) to give tert-butyl N-(4-hydroxy-2-nitro-phenyl)carbamate (2.35 g, 95% yield) as a yellow solid. LCMS:t R =1.169min in 10-80AB_2min_220&254_Shimadzu.lcm,MS(ESI)m / z=255.1[M+H] + .

[0215] TIFF0007658908000110.tif30128

[0216] Step 2 for the synthesis of compound 12: A solution of 1-(2-chloroethyl)pyrrolidine (2.25 g, 13.22 mmol, HCl salt), tert-butyl N-(4-hydroxy-2-nitro-phenyl)carbamate (2.8 g, 11.01 mmol), Cs2CO3 (7.18 g, 22.03 mmol) in DMF (100 mL) was stirred at 50° C. for 8 h. The mixture was extracted with EtOAc (200 mL×5). The combined organic layers were washed with H2O (50 mL×6), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent of 0-35% ethyl acetate / petroleum ether gradient (40 mL / min)) to give tert-butyl N-[2-nitro-4-(2-pyrrolidin-1-ylethoxy)phenyl]carbamate (1.2 g, 31% yield) as a black solid. LCMS:t R =0.980min in 10-80 AB_2min_220&254_Shimadzu.lcm,MS(ESI)m / z=352.1[M+H] + .

[0217] TIFF0007658908000111.tif25135

[0218] Step 3 for the synthesis of compound 12: A mixture of tert-butyl N-[2-nitro-4-(2-pyrrolidin-1-ylethoxy)phenyl]carbamate (1.2 g, 3.41 mmol), HCl / dioxane (4 M, 0.85 mL) in MeOH (20 mL) was stirred at 25° C. for 1 h. The mixture was adjusted to pH=8 by adding saturated aqueous NaHCO3, and the resulting mixture was concentrated to give 2-nitro-4-(2-pyrrolidin-1-ylethoxy)aniline (1.0 g, crude) as a yellow solid. LCMS:t R =0.882 min in 0-60 AB_2min_220&254_Shimadzu.lcm,MS(ESI)m / z=252.1[M+H] + .

[0219] TIFF0007658908000112.tif72136

[0220] Step 4 for the synthesis of compound 12: To a solution of N-(2,6-dichloro-3,5-dimethoxy-phenyl)-3-(6-methylsulfonylpyrimidin-4-yl)pyridin-2-amine (352 mg, 0.659 mmol), 2-nitro-4-(2-pyrrolidin-1-ylethoxy)aniline (500 mg, 1.99 mmol) in DMF (30 mL) was added t-BuOK (223 mg, 1.99 mmol) at 0° C. Then the mixture was stirred under N2 atmosphere at 40° C. for 2 h. The mixture was extracted with EtOAc (150 mL×5). The combined organic layer was washed with H2O (30 mL×6), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, elution with 0-15% MeOH / DCM gradient (20 mL / min)) to give 6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]-N-[2-nitro-4-(2-pyrrolidin-1-ylethoxy)phenyl]pyrimidin-4-amine (539 mg, 69% yield, 53% purity) as a yellow solid. LCMS:t R =1.004 min in 10-80 AB_2min_220&254_Shimadzu.lcm,MS(ESI)m / z=626.1[M+H] + .

[0221] TIFF0007658908000113.tif74128

[0222] Step 5 for the synthesis of compound 12: A mixture of 6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]-N-[2-nitro-4-(2-pyrrolidin-1-ylethoxy)phenyl]pyrimidin-4-amine (400 mg, 0.638 mmol) and Pd / C (500 mg, 10% purity) in MeOH (30 mL) was stirred at 25° C. under H2 atmosphere for 2 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The mixture was concentrated to give N1-[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]-4-(2-pyrrolidin-1-ylethoxy)benzene-1,2-diamine (200 mg, crude) as a black solid. LCMS:t R =1.218min in 10-80 AB_4min_220&254_Shimadzu.lcm,MS(ESI)m / z=596.3[M+H] + .

[0223] TIFF0007658908000114.tif71132

[0224] Step 6 for the synthesis of compound 12: To a solution of N1-[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]-4-(2-pyrrolidin-1-ylethoxy)benzene-1,2-diamine (150 mg, 0.251 mmol) and Et3N (28 mg, 0.277 mmol) in DCM (4 mL) was added dropwise a solution of prop-2-enoyl chloride (25 mg, 0.277 mmol) in DCM (3 mL) at 0° C. The mixture was stirred at 25° C. for 0.5 h. The mixture was concentrated under reduced pressure to remove DCM. The residue was purified by preparative HPLC (column: Xtimate C18100*30mm*3um water (0.04% NH3.H2O+10mM NH4HCO3)-ACN; 63-83% B; gradient time: 30min; flow rate: 25mL / min) to give N-[2-[[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]amino]-5-(2-pyrrolidin-1-ylethoxy)phenyl]prop-2-enamide (9.1mg, 5% yield, 98% purity) as a white solid. LCMS:t R =1.550min in 10-80CD_4min_220&254_Shimadzu.lcm, TIFF0007658908000115.tif27162

[0225] Example 9: Synthesis of Compound 13 N-[5-[[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]amino]-1-methyl-imidazol-4-yl]prop-2-enamide TIFF0007658908000116.tif129151 Scheme 12. Synthesis of compound 13

[0226] Compound 13 was synthesized according to Synthesis Scheme 12. The synthetic process of each step is described below.

[0227] TIFF0007658908000117.tif24128

[0228] Step 1 for the synthesis of compound 13: A mixture of 5-chloro-1-methyl-4-nitroimidazole (2 g, 12.38 mmol) in NH3 / MeOH (10 mL, 7 M) was stirred in an autoclave at 100° C. for 16 h. The mixture was cooled to room temperature and the precipitate was filtered, washed with MeOH (10 mL×2) and dried to give 3-methyl-5-nitro-imidazol-4-amine (1.6 g, 11.26 mmol, 91% yield) as a yellow solid. TIFF0007658908000118.tif5132

[0229] TIFF0007658908000119.tif45136

[0230] Step 2 for the synthesis of compound 13: To a solution of N-(2,6-dichloro-3,5-dimethoxy-phenyl)-3-(6-methylsulfonylpyrimidin-4-yl)pyridin-2-amine (500 mg, 1.10 mmol) and 3-methyl-5-nitro-imidazol-4-amine (312 mg, 2.20 mmol) in DMF (20 mL) was added tBuOK (246 mg, 2.20 mmol). The mixture was stirred at 40° C. under N atmosphere for 12 h. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (10 mL×2). The combined organic layers were washed with H2O (10 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent of 0-10% ethyl acetate / petroleum ether gradient (50 mL / min)) to give 6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]-N-(3-methyl-5-nitro-imidazol-4-yl)pyrimidin-4-amine (320 mg, 0.619 mmol, 56% yield) as a yellow solid.

[0231] TIFF0007658908000120.tif45144

[0232] Step 3 for the synthesis of compound 13: To a solution of 6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]-N-(3-methyl-5-nitro-imidazol-4-yl)pyrimidin-4-amine (300 mg, 0.58 mmol) in MeOH (5 mL) was added Pd / C (5 mg, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 (15 psi) at 25°C for 2 h. The liquid was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure to give N5-[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]-1-methyl-imidazole-4,5-diamine (200 mg, 0.41 mmol, 71% yield) as a brown solid.

[0233] TIFF0007658908000121.tif50145

[0234] Step 4 for the synthesis of compound 13: To a solution of N5-[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]-1-methyl-imidazole-4,5-diamine (100 mg, 0.205 mmol) and DIEA (53 mg, 0.41 mmol) in DCM (10 mL) was added prop-2-enoyl chloride (15 mg, 0.164 mmol) at 0° C. The mixture was stirred at 0° C. for 0.5 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Phenomenex Luna C18 100*40mm*3um; water (0.225% FA)-ACN; 20-40% B; gradient time: 9 min; flow rate: 25mL / min) to give N-[5-[[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]amino]-1-methyl-imidazol-4-yl]prop-2-enamide (13.6mg, 0.024mmol, 12% yield, 95.34% purity) as a yellow solid. LCMS:t R =0.968min in10-80AB_4 min_220&254_Shimadzu.lcm, TIFF0007658908000122.tif19162

[0235] Example 10: Synthesis of Compound 14 TIFF0007658908000123.tif132164 Scheme 13. Synthesis of compound 14

[0236] Compound 14 was synthesized according to Synthesis Scheme 13. The synthetic process of each step is described below.

[0237] TIFF0007658908000124.tif21141

[0238] Step 1 for the synthesis of compound 14: To a mixture of compound 14-2 (30.0 g, 194.8 mmol, 1.0 equiv.) in ethyl acetate (600 mL), compound 14-1 (19 g, 214 mmol, 1.1 equiv.) and triphenylphosphine (56.0 g, 214.1 mmol, 1.1 equiv.) were added. Then, diethyl azodicarboxylate (33.5 mL, 214.1 mmol, 1.1 equiv.) was added dropwise. The mixture was stirred at room temperature overnight. The reaction was monitored by TLC. Then, the mixture was filtered through a pad of Celite and the funnel was sintered. The resulting mixture was extracted with ethyl acetate (3×600 mL), and 1N HCl and water were added. The aqueous phase was extracted with ethyl acetate and ammonium hydroxide. The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol, 100:1 to 50:1 to 30:1) to give compound 14-3 (4.6 g, 11%).

[0239] TIFF0007658908000125.tif38163

[0240] Step 2 for synthesizing compound 14: To a mixture of compound 14-3 (10.0 g, 44.4 mmol, 1.1 equiv.) and compound 14-4 (18.4 g, 40.4 mmol, 1.0 equiv.) in dimethylformamide (60 mL), potassium tert-butoxide (13.6 g, 121.2 mmol, 3.0 equiv.) was added under nitrogen atmosphere. The mixture was then stirred at 40 °C for 2 h. TLC analysis of the reaction mixture showed partial conversion to the desired product. The mixture was cooled to room temperature and extracted with ethyl acetate and water. The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol, 100:1 to 50:1) to give compound 14-5 (5 g, 21%).

[0241] TIFF0007658908000126.tif41146

[0242] Step 3 for synthesizing compound 14: To a mixture of compound 14-5 (5.0 g, 8.3 mmol, 1.0 equiv.) in ethanol / water (100 mL / 20 mL), Fe (2.33 g, 41.7 mmol, 5.0 equiv.) and ammonium chloride (4.46 g, 83.4 mmol, 10.0 equiv.) were added. The mixture was then stirred at 85° C. for 2 h. TLC analysis of the reaction mixture showed partial conversion to the desired product. The mixture was filtered and extracted with ethyl acetate (120 mL×3). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol, 10:1) to give compound 14-6 (4 g, 85%).

[0243] TIFF0007658908000127.tif48163

[0244] Step 4 for the synthesis of compound 14: To a mixture of compound 14-6 (4.0 g, 7.03 mmol, 1.0 equiv) in dichloromethane (40 mL) was added compound 14-7 (632.6 mg, 7.03 mmol, 1.0 equiv) at 0° C. The mixture was stirred at room temperature for 2 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The mixture was then quenched with water (200 mL) and extracted with dichloromethane (40 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol, 10:1) to give the crude product (purity: 90%). The crude product was dissolved in dichloromethane (50 mL). The mixture was then added to 20% sodium hydroxide solution (10 mL). The mixture was stirred at room temperature for 30 min. The mixture was then extracted with dichloromethane and washed with brine. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 14 (2.0 g, 46%) as a yellow solid. TIFF0007658908000128.tif27162

[0245] Example 11: Synthesis of Compound 15 TIFF0007658908000129.tif127159 Scheme 14. Synthesis of compound 15

[0246] Compound 15 was synthesized according to Synthesis Scheme 14. The synthetic process of each step is described below.

[0247] TIFF0007658908000130.tif21134

[0248] Step 1 for the synthesis of compound 15: To a mixture of compound 15-2 (30.0 g, 194.6 mmol, 1.0 equiv.) in ethyl acetate (600 mL), compound 15-1 (25.1 g, 214 mmol, 1.1 equiv.) and triphenylphosphine (56.0 g, 214.1 mmol, 1.1 equiv.) were added. Then, diethyl azodicarboxylate (33.5 mL, 214.1 mmol, 1.1 equiv.) was added dropwise. The mixture was stirred overnight at room temperature. The reaction was monitored by TLC. Then, the mixture was filtered through a pad of Celite and the funnel was sintered. The resulting mixture was extracted with ethyl acetate (3×600 mL), and 1N HCl and water were added. The aqueous phase was extracted with ethyl acetate and ammonium hydroxide. The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol, 100:1 to 50:1 to 30:1) to give compound 15-3 (17.5 g, 36%).

[0249] TIFF0007658908000131.tif41162

[0250] Step 2 for synthesizing compound 15: To a mixture of compound 15-3 (2.2 g, 8.8 mmol, 2.0 equiv.) and compound 15-4 (2.0 g, 4.4 mmol, 1.0 equiv.) in dimethylformamide (30 mL), potassium tert-butoxide (1.48 g, 13.2 mmol, 3.0 equiv.) was added under nitrogen atmosphere. The mixture was then stirred at 40 °C for 2 h. TLC analysis of the reaction mixture showed partial conversion to the desired product. The mixture was cooled to room temperature and extracted with ethyl acetate and water. The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol, 100:1 to 50:1) to give compound 15-5 (550 mg, 20%).

[0251] TIFF0007658908000132.tif44155

[0252] Step 3 for synthesizing compound 15: To a mixture of compound 15-5 (1.0 g, 1.6 mmol, 1.0 equiv) in ethanol / water (20 mL / 4 mL), Fe (446 mg, 8.0 mmol, 5.0 equiv) and ammonium chloride (880 mg, 16 mmol, 10.0 equiv) were added. The mixture was then stirred at 80° C. for 2 h. TLC analysis of the reaction mixture showed partial conversion to the desired product. The mixture was filtered and extracted with ethyl acetate (20 mL×3). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol, 10:1) to give compound 15-6 (280 mg, 29%).

[0253] TIFF0007658908000133.tif48162

[0254] Step 4 for the synthesis of compound 15: To a mixture of compound 15-6 (280 mg, 0.47 mmol, 1.0 equiv) in dichloromethane (5 mL) was added compound 15-7 (42.5 mg, 0.47 mmol, 1.0 equiv) at 0° C. The mixture was stirred at room temperature for 2 h. TLC analysis of the reaction mixture showed complete conversion to the desired product. The mixture was then quenched with water (20 mL) and extracted with dichloromethane (5 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol, 10:1) to give compound 15 (81 mg, 29%) as a yellow solid. TIFF0007658908000134.tif27162

[0255] Example 12: Synthesis of Compound 16 TIFF0007658908000135.tif200141 Scheme 15. Synthesis of compound 16

[0256] Compound 16 was synthesized according to Synthesis Scheme 15. The synthetic process of each step is described below.

[0257] TIFF0007658908000136.tif26128

[0258] Step 1 for the synthesis of compound 16: To a solution of 6-oxabicyclo[3.1.0]hexane (7 g, 83.22 mmol) in I-PrOH (40 mL) was added NH3·H2O (35.00 g, 249.65 mmol, 25% purity). The mixture was stirred at 60 °C for 16 h in a sealed tube. The mixture was concentrated under reduced pressure to give trans-2-aminocyclopentanol (26 g, crude) as a brown oil. TIFF0007658908000137.tif20162

[0259] TIFF0007658908000138.tif26128

[0260] Step 2 for the synthesis of compound 16: To a solution of trans-2-aminocyclopentanol (22 g, 217.51 ​​mmol) in THF (220 mL) was added TEA (26.41 g, 261.01 mmol) and Boc2O (52.22 g, 239.26 mmol, 54.97 mL, 1.1 equiv). The mixture was stirred at 15° C. for 16 h. The mixture was concentrated under reduced pressure to remove THF. The residue was diluted with EtOAc (20 mL), extracted with H2O (20 mL×3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluent of 0-30% ethyl acetate / petroleum ether gradient (60 mL / min)) to give tert-butyl N-[trans-2-hydroxycyclopentyl]carbamate (14 g, 69.56 mmol, 32% yield) as a white solid. TIFF0007658908000139.tif19162

[0261] TIFF0007658908000140.tif27128

[0262] Step 3 for the synthesis of compound 16: A mixture of tert-butyl N-[trans-2-hydroxycyclopentyl]carbamate (14 g, 69.56 mmol), isoindoline-1,3-dione (11.26 g, 76.52 mmol), PPh3 (20.07 g, 76.52 mmol), and DIAD (16.18 g, 80.00 mmol) in THF (150 mL) was degassed and purged with N2 three times, then stirred at 0 °C for 1 h. The mixture was concentrated under reduced pressure to remove THF. The residue was diluted with H2O (150 mL), extracted with EtOAc (150 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, elution with 0-30% ethyl acetate / petroleum ether gradient (80 mL / min)). The crude product was further recrystallized from EtOH (100 mL) at 80° C., then the precipitate was filtered and dried to give tert-butyl N-[cis-2-(1,3-dioxoisoindolin-2-yl)cyclopentyl]carbamate (15 g, 45.40 mmol, 65% yield) as a white solid. TIFF0007658908000141.tif12151

[0263] TIFF0007658908000142.tif27128

[0264] Step 4 for the synthesis of compound 16: To a solution of tert-butyl N-[cis-2-(1,3-dioxoisoindolin-2-yl)cyclopentyl]carbamate (5 g, 15.13 mmol) in MeOH (50 mL) was added NH2NH2 (709 mg, 16.65 mmol, 80% purity). The mixture was stirred at 50 °C for 1.5 h. The mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O (50 mL) and then extracted with EtOAc (50 mL x 3), dried over Na2SO4, filtered and concentrated to give tert-butyl N-[cis-2-aminocyclopentyl]carbamate (1.1 g, 5.49 mmol, 36% yield) as a yellow oil.

[0265] TIFF0007658908000143.tif63128

[0266] Step 5 for the synthesis of compound 16: To a solution of N-(2,6-dichloro-3,5-dimethoxy-phenyl)-3-(6-methylsulfonylpyrimidin-4-yl)pyridin-2-amine (758 mg, 1.66 mmol) and tert-butyl N-[cis-2-aminocyclopentyl]carbamate (1 g, 4.99 mmol) in DMAc (10 mL) was added DIEA (430 mg, 3.33 mmol). The mixture was stirred at 130° C. for 12 h. The mixture was diluted with H2O (20 mL), extracted with EtOAc (20 mL×3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, elution with 0-30% ethyl acetate / petroleum ether gradient (40 mL / min)) to give tert-butyl N-[2-[[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]amino]cyclopentyl]carbamate (cis mixture, 500 mg, 0.869 mmol, 52% yield) as a yellow solid. LCMS:t R =1.412 min in 10-80AB_2min_220&254_Shimadzu.lcm,MS(ESI)m / z=575.2[M+H] + .

[0267] TIFF0007658908000144.tif61128

[0268] Step 6 for the synthesis of compound 16: A solution of tert-butyl N-[2-[[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]amino]cyclopentyl]carbamate (500 mg, 0.868 mmol, cis mixture) in HCl / dioxane (4 M, 10 mL) was stirred for 0.5 h at 25° C. The mixture was concentrated to give N1-[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]cyclopentane-1,2-diamine (800 mg, crude) as a white solid.

[0269] TIFF0007658908000145.tif123128

[0270] Step 7 for the synthesis of compound 16: To a solution of N1-[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]cyclopentane-1,2-diamine (700 mg, 1.47 mmol, cis mixture) in DCM (10 mL) was added DIEA (190 mg, 1.47 mmol) and prop-2-enoyl chloride (67 mg, 0.736 mmol). The mixture was stirred at 0° C. for 0.5 h. The residue was diluted with H2O (20 mL), extracted with EtOAc (20 mL×3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent of 0-10% dichloromethane / petroleum ether gradient (40 mL / min)) to give the desired product (170 mg, 94% purity) as a white solid, which was purified by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [0.1% NH3·H2O ETOH]; B%: 35% to 35%, 30 min) to give (+)N-[cis-2-[[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]amino]cyclopentyl]prop-2-enamide (43.7 mg, 0.081 mmol, 98.85% purity, single cis isomer) and (-)N-[cis-2-[[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]amino]cyclopentyl]prop-2-enamide (46.5 mg, 0.87 mmol, 99.10% purity, single cis isomer) as white solids.

[0271] (+) N-[cis-2-[[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]amino]cyclopentyl]prop-2-enamide (first peak in chiral SFC). LCMS:t R =1.476min in10-80AB_4 min_220&254_Shimadzu.lcm, TIFF0007658908000146.tif27162 Chiral SFC:t R = 5.118 min (instrument column: Chiralpak AD-3 100 x 4.6 mm i.d., 3 um, mobile phase: A:CO2 B:ethanol (0.05% DEA), gradient: 5% to 40% B for 4.5 min, hold 40% for 2.5 min, then 5% B for 1 min; flow rate: 2.8 mL / min column temperature: 40 °C, UV detection: 220 nm), ee% = 99%. [α] D 20 =+13(c=0.10, MeOH).

[0272] (-)N-[cis-2-[[6-[2-(2,6-dichloro-3,5-dimethoxy-anilino)-3-pyridyl]pyrimidin-4-yl]amino]cyclopentyl]prop-2-enamide (second peak in chiral SFC). LCMS:t R =1.481 min in10-80AB_4 min_220&254_Shimadzu.lcm, TIFF0007658908000147.tif27162 Chiral SFC:t R = 6.002 min (Instrument column: Chiralpak AD-3 100 x 4.6 mm i.d., 3 um, Mobile phase: A:CO2 B:Ethanol (0.05% DEA), Gradient: 5% to 40% B for 4.5 min, hold 40% for 2.5 min, then 5% B for 1 min; Flow rate: 2.8 mL / min Column temperature: 40°C, UV detection: 220 nm), ee% = 99.1%. [α] D 20 =-13 (c=0.10, MeOH).

[0273] Example 13: Evaluation of in vitro efficacy of FGFR inhibitors TIFF0007658908000148.tif60140

[0274] The following table 2 compares the properties of compound 1 of the present invention and control compound 5, which shows that compound 1 shows superior properties in solubility, permeability, mouse plasma stability, mouse liver microsome stability, in vivo exposure and bioavailability than control compound 5. Compound 1 of the present invention improves FGFR4 selective inhibition effect. More importantly, the plasma stability of compound of the present invention is significantly improved. Also, control compound 5 has poor solubility in the solution of 5% DMSO and 95% PBS (20% HPBC in PBS). On the other hand, compound 1 of the present invention shows significantly improved solubility, which facilitates administration.

[0275] Table 2: Comparison of properties between compound 1 of the present invention and control compound 5 TIFF0007658908000149.tif114137

[0276] 2 and 3, compound 5 of the present invention also shows unobvious improvement in pharmacokinetic data when administered to mice. Table 3 below summarizes the key pharmacokinetic data from these experiments.

[0277] Table 3: Pharmacokinetic data of compound 1 of the present invention and control compound 5 TIFF0007658908000150.tif107166

[0278] Table 4: FGFR Inhibition Data of Disclosed Compounds TIFF0007658908000151.tif103162TIFF0007658908000152.tif233162TIFF0007658908000153.tif195162IC for kinases in the table 50 The evaluation criteria for the values ​​are as follows: +++ 10nM or less ++ 10~100nM + 100~1000nM - 1000nM or more ND Not decided

[0279] FGFR inhibition data for the disclosed compounds is shown in Table 4. Compound 5 is used as a control.

[0280] Table 5. FGFR sequences TIFF0007658908000154.tif229168TIFF0007658908000155.tif241168TIFF0007658908000156.tif242165TIFF0007658908000157.tif242165TIFF0007658908000158.tif242166TIFF0007658908000159.tif242165TIFF0007658908000160.tif242166TIFF0007658908000161.tif242165TIFF0007658908000162.tif242165TIFF0007658908000163.tif242165TIFF0007658908000164.tif242165TIFF0007658908000165.tif242165TIFF0007658908000166.tif242165TIFF0007658908000167.tif242165TIFF0007658908000168.tif242165TIFF0007658908000169.tif242165TIFF0007658908000170.tif242165TIFF0007658908000171.tif242165TIFF0007658908000172.tif242165TIFF0007658908000173.tif242165TIFF0007658908000174.tif233168TIFF0007658908000175.tif242160TIFF0007658908000176.tif242165TIFF0007658908000177.tif242165TIFF0007658908000178.tif242165TIFF0007658908000179.tif242165TIFF0007658908000180.tif242165TIFF0007658908000181.tif242165TIFF0007658908000182.tif242165TIFF0007658908000183.tif242165TIFF0007658908000184.tif242165TIFF0007658908000185.tif242165TIFF0007658908000186.tif242165TIFF0007658908000187.tif242165TIFF0007658908000188.tif242165TIFF0007658908000189.tif242165TIFF0007658908000190.tif255158Bold: FGFR subdomain V. Underlined: cysteine ​​in FGFR4 subdomain V

[0281] Although the invention has been described with reference to the above examples, it will be understood that modifications and variations are encompassed within the spirit and scope of the invention. Accordingly, the invention is limited only by the appended claims.

Claims

1. A compound according to formula (I), or an optically pure stereoisomer, solvate, or pharma- ceutically acceptable salt thereof: During the ceremony, R １ and R ５ is Cl, R ２ and R ４ is OMe, R ３ is H, R ６ is NHCOCH=CH ２ and The linker is F, Cl, Br, C １－４ Alkyl, CF ３ , C.H.F. ２ , NO ２ , -NR ７ - (CH ２ ) ｎ -R ８ , -CONR ７ - (CH ２ ) ｎ -R ８ , -CO-(CH ２ ) ｎ -R ８ , -OCO-(CH ２ ) ｎ -R ８ and —O—(CH ２ ) ｎ -R ８ may be substituted with one or more substituents selected from the group consisting of Phenyl, and is selected from the group consisting of n is an integer selected from 0 to 5; R ７ is H, C １－４ Alkyl, and COC １－４ is selected from the group consisting of alkyl, R ８ is F, Cl, Br, C １－４ Alkyl, CF ３ , C.H.F. ２ , and NO ２ C may be substituted with one or more substituents selected from the group consisting of １－２０ Alkyl, COC １－２０ Alkyl, CO ２ C １－２０ Alkyl, is selected from the group consisting of:

2. The linker is C １－４ Alkyl and -O-(CH ２ ) ｎ -R ８ may be substituted with one or more substituents selected from the group consisting of and phenyl; n is an integer selected from 0 to 2; R ６ NHCOCH=CH ２ and R ８ but, is selected from the group consisting of R ７ H, and C １－４ selected from the group consisting of alkyl, The compound of claim 1.

3. The compound is 2. The compound of claim 1 selected from the group consisting of:

4. below: or an optically pure stereoisomer, solvate, or pharma- ceutically acceptable salt thereof.

5. The compound according to any one of claims 1 to 4, wherein the compound inhibits fibroblast growth factor receptor (FGFR).

6. The compound of claim 5 , wherein the compound inhibits FGFR4.

7. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 6.

8. 8. The pharmaceutical formulation of claim 7 for use in a method for treating cancer.

9. (a) the cancer is selected from the group consisting of breast cancer, lung cancer, bladder cancer, prostate cancer, ovarian cancer, endometrial cancer, rhabdomyosarcoma, liver cancer, and gastric cancer; or (b) the method comprises administering a chemotherapeutic agent, and optionally the compound is administered prior to, simultaneously with, or after administration of the chemotherapeutic agent; 9. The pharmaceutical formulation of claim 8.

10. 8. A pharmaceutical formulation as claimed in claim 7 for use in inhibiting kinase activity.

11. The kinase may be anaplastic lymphoma kinase (ALK), epidermal growth factor receptor (EGFR), ephrin type 3 receptor 3 (EPH-B3), focal adhesion kinase (FAK), fibroblast growth factor receptor 1 (FGFR1), fibroblast growth factor receptor 2 (FGFR2), fibroblast growth factor receptor 3 (FGFR3), fibroblast growth factor receptor 4 (FGFR4), mast cell / stem cell growth factor receptor (SCFR or KIT), mitogen-activated protein kinase kinase 1 (MAP2K1 or 11. The pharmaceutical formulation of claim 10, wherein the kinase is selected from the group consisting of FGFR1, FGFR2, FGFR3 and / or FGFR4, and optionally the kinase is selected from the group consisting of FGFR1, FGFR2, FGFR3 and / or FGFR4, FGFR2, FGFR3 and / or FGFR4, FGFR1 or MEK1, Hepatocyte Growth Factor Receptor (HGFR or MET), Platelet-Derived Growth Factor Receptor Alpha (PDGFRA), Platelet-Derived Growth Factor Receptor Beta (PDGFRB), Proto-Oncogene Tyrosine Kinase Receptor (RET), Proto-Oncogene Tyrosine Protein Kinase (ROS), and Tyrosine Protein Kinase Receptor (TYRO3), and optionally the kinase is FGFR1, FGFR2, FGFR3 and / or FGFR4.

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