Heterocyclic inhibitors of tyrosine kinases

Abstract

The present disclosure relates to heterocyclic compounds and methods that may be useful as inhibitors of HER2 or EGFR for the treatment or prevention of diseases, including cancer.

Description

[Technical field]

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 838,696, filed April 25, 2019, the disclosure of which is incorporated by reference herein as if set forth in its entirety.

[0002] Disclosed herein are novel heterocyclic compounds and compositions and their application as pharmaceutical agents for the treatment of diseases. Methods for the inhibition of tyrosine kinase activity in a human or animal subject for the treatment of diseases such as cancer are also provided. [Background technology]

[0003] Tyrosine kinases promote the phosphorylation of the phenolic hydroxyl of tyrosine, and this activity is commonly used to modulate protein functionality. Mutations in tyrosine kinases are suspected to cause unregulated cell proliferation and contribute to cancer. For this reason, tyrosine kinase inhibitors (TKIs) have been developed for their anticancer activity.

[0004] The ErbB protein family (named after the homologous erythroblastic leukemia viral oncogene) contains four tyrosine kinases structurally related to the human epidermal growth factor receptor (EGFR, also called Her1 or ErbB1) and was discovered by Stanley Cohen. Abnormalities in EGFR have been shown to be a cause of cancer. The ErbB family also includes HER2 (Neu or ErbB2), HER3 (ErbB3) and HER4 (ErbB4).

[0005] ErbB receptors are overexpressed or mutated in many cancers, including gastric cancer, colon cancer, rectal cancer, head and neck cancer, breast cancer, ovarian cancer, pancreatic cancer, lung cancer (NSCLC) and brain cancer (glioblastoma). Overexpression and overactivation of ErbB receptors are correlated with poor prognosis, drug resistance, cancer metastasis and poor survival rate. For this reason, ErbB receptors, especially EGFR and HER2, have been targeted in cancer chemotherapy.

[0006] The presence of ErbB protein mutations can affect the likelihood of successful treatment of certain cancers. Afatinib (GILOTRIF®), a TKI indicated for the treatment of certain NSCLC patients, inhibits WT EGFR and HER2, but does not substantially inhibit exon 20 mutant EGFR or HER2. Similarly, trastuzumab (HERCEPTIN®) alone has no effect on HER2 exon 20 insertions.

[0007] Besides NSCLC, EGFR and HER2 exon 20 insertions are also found in gastric cancer, breast cancer, glioblastoma, adenoid cystic carcinoma, and many gastrointestinal diseases. In fact, the number of non-lung cancer exon 20 mutations is greater than the number of lung cancer exon 20 mutations. Summary of the Invention [Problem to be solved by the invention]

[0008] NSCLC patients harboring in-frame mutations (usually insertions) with exon 20 are resistant to FDA-approved EGFR TKIs, with retrospective studies showing objective response rates of approximately 4-8% and median progression-free survival (PFS) of <2 months. Studies have demonstrated that exon 20 insertions have a stabilized active conformation of EGFR that lacks affinity for currently available EGFR TKIs. Other studies have reported that HER2 exon 20 mutations have heterogeneous responses to TKIs, but effective inhibitors of HER2 mutations have not been established. Furthermore, many patients experience dose-limiting toxicity with currently available EGFR and HER2 targeted agents, such as afatinib, dacomitinib, and neratinib, due to off-target inhibition of wild-type (WT) EGFR. To reduce toxicity of targeted agents and improve clinical outcomes, alternative agents with selective activity against exon 20 mutant EGFR and HER2, but not WT EGFR, are needed. Thus, there is an unmet need to develop and identify inhibitors that target both EGFR and HER2 exon 20 mutations, as well as other EGFR and HER2 activating mutations. [Means for solving the problem]

[0009] Novel compounds and pharmaceutical compositions, certain of which have been found to inhibit mutant HER2 and EGFR, have been found, along with methods of using the compounds, including methods of synthesizing the compounds and treating HER2- or EGFR-mediated diseases in patients by administering the compounds. Certain compounds have been found to be effective against exon 20 insertion mutations of both HER2 and EGFR. In addition, certain compounds have been found to be effective against other mutations of HER2 and EGFR. [Brief description of the drawings]

[0010] [Figure 1]Figure 2 shows, for example compounds 1 and 2, the IC50 values ​​(nM) against (a) WT EGFR (+10 ng / mL EGF), and (b) HER2 mutants, and (c) the selectivity index for HER2 mutants over WT EGFR. [Diagram 2] 4 shows the IC50 values ​​(nM) for (a) WT EGFR (+10 ng / mL EGF), and (b) EGFR exon 20 mutants, and (c) the selectivity index for EGFR exon 20 mutants over WT EGFR for example compounds 3 and 4. [Diagram 3] For example compound 5, IC50 values ​​(nM) against (a) WT EGFR (+10 ng / mL EGF), and (b) (i) EGFR exon 20, and (ii) HER2 mutants, and (c) selectivity indices against (i) EGFR exon 20, and (ii) HER2 mutants are shown. [Figure 4] For example compound 6, IC50 values ​​(nM) against (a) WT EGFR (+10 ng / mL EGF), and (b) (i) EGFR exon 20, and (ii) HER2 mutants, and (c) selectivity indices against (i) EGFR exon 20, and (ii) HER2 mutants are shown. [Diagram 5] Figure 2 shows the effect of daily treatment of mice with (a) EGFR H773insNPH PDX and (b) Y772dupYVMA PDX on tumor volume (mm3) with example compound 6: (i) and (iv) vehicle, (ii) 6 (2.5 mg / kg), (iii) 6 (5 mg / kg), (v) 6 (7.5 mg / kg), (vi) 6 (5 mg / kg). [Figure 6] Figure 1 shows the change (%) in (a) tumor volume and (b) mouse body weight upon treatment of EGFR H773insNPH PDX-implanted mice with example compound 6. (i) Vehicle, (ii) 6 (2.5 mg / kg), (iii) 6 (5 mg / kg). [Figure 7]Figure 1 shows the change (%) in tumor volume at (a) day 3 and (b) day 10 upon treatment of EGFR S768dupSVD (solid bars) and HER2 Y772dupYVMA (hashed bars) PDX-implanted mice with Example Compound 4 at doses of (i) 10mpk, (ii) 20mpk, (iii) 40mpk, and (iv) 60mpk. [Figure 8] Figure 1 shows the change (%) in mouse body weight on (a) day 3 and (b) day 10 upon treatment of EGFR S768dupSVD and HER2 Y772dupYVMA PDX engrafted mice with Example Compound 4 at doses of (i) 10mpk, (ii) 20mpk, (iii) 40mpk, and (iv) 60mpk. [Figure 9] Figure 2 shows the daily effect on PDX tumor volume (mm3) upon treatment of (a) EGFR H773insNPH and (b) EGFR S768dupSVD PDX-implanted mice with Example Compound 1: (i) Vehicle, (ii) Poziotinib 1 mpk, (iii) Poziotinib 2.5 mpk, (iv) 1 30 mpk, (v) 1 40 mpk. [Figure 10] Figure 1 shows the change (%) in PDX tumor volume upon treatment of (a) EGFR H773insNPH (day 28) and (b) EGFR S768dupSVD (day 17) PDX-implanted mice with Example Compound 1. (i) Vehicle, (ii) Poziotinib 1 mpk, (iii) Poziotinib 2.5 mpk, (iv) 1 30 mpk, (v) 1 40 mpk. [Figure 11] Figure 1 shows the change in mouse body weight (%) upon treatment of (a) EGFR H773insNPH (day 28) and (b) EGFR S768dupSVD (day 17) PDX-engrafted mice with Example Compound 1. (i) Vehicle, (ii) Poziotinib 1 mpk, (iii) Poziotinib 2.5 mpk, (iv) 1 30 mpk, (v) 1 40 mpk. Dotted line = euthanasia. [Figure 12]Figure 1 shows the daily effect on PDX tumor volume (mm3) upon treatment of HER2 Y772dupYVMA PDX-implanted mice with example compound 1 with and without co-administration of T-DM1. (a) (i) Vehicle, (ii) Poziotinib 2.5mpk, (iii) 1 30mpk, (iv) 1 50mpk, (v) 1 75mpk, (b) (i) Vehicle, (ii) Poziotinib 2.5mpk, (iii) T-DM1 10mpk, (iv) 1 30mpk, (v) 1 + T-DM1. [Figure 13] Figure 2 shows the change (%) in (a) PDX tumor volume and (b) mouse body weight at day 21 upon treatment of HER2 Y772dupYVMA PDX-implanted mice with example compound 1. (i) Poziotinib 2.5mpk, (ii) 1 30mpk, (iii) 1 50mpk, (iv) 1 75mpk; dotted line = euthanasia. [Figure 14] Figure 1 shows the change (%) in (a) and (b) PDX tumor volume and (c) mouse body weight upon treatment of HER2 Y772dupYVMA PDX-implanted mice with example compound 1 with and without co-administration of T-DM1. (a) Day 23, p=0.02, (i) T-DM1 10mpk, CR=3 / 8, (ii) 1+T-DM1, CR=6 / 6; (b) Day 39, p=0.0031, (i) T-DM1 10mpk, (ii) 1+T-DM1; (c) Day 39; (i) T-DM1 10mpk, (ii) 1+T-DM1, dotted line=euthanasia. [Figure 15] Figure 2 shows the change in PDX tumor volume (mm3) upon treatment of (a) EGFR H773insNPH and (b) EGFR S768dupSVD PDX-implanted mice with Example Compound 4. (i) Vehicle, (ii) Poziotinib 1 mpk, (iii) Poziotinib 2.5 mpk, (iv) 4 80 mpk, (v) 4 120 mpk. [Figure 16]Figure 1 shows the change (%) in PDX tumor volume upon treatment of (a) EGFR H773insNPH (day 28) and (b) EGFR S768dupSVD (day 15) PDX-implanted mice with example compound 4. (i) Vehicle, (ii) Poziotinib 1 mpk, (iii) Poziotinib 2.5 mpk, (iv) 4 80 mpk, (v) 4 120 mpk. [Figure 17] Figure 1 shows the change in mouse body weight (%) upon treatment of (a) EGFR H773insNPH (day 28) and (b) EGFR S768dupSVD (day 15) PDX-engrafted mice with Example Compound 4. (i) Vehicle, (ii) Poziotinib 1 mpk, (iii) Poziotinib 2.5 mpk, (iv) 4 80 mpk, (v) 4 120 mpk. Dotted line = euthanasia. [Figure 18] Figure 1 shows the daily change (%) in PDX tumor volume (mm3) upon treatment of (a) EGFR H773insNPH and (b) EGFR S768dupSVD PDX-implanted mice with example compound 13. (i) Vehicle, (ii) Poziotinib 1 mpk, (iii) Poziotinib 2.5 mpk, (iv) 13 75 mpk, (v) 13 150 mpk. [Figure 19] Shows the change (%) in PDX tumor volume on day 15 upon treatment of (a) EGFR H773insNPH and (b) EGFR S768dupSVD PDX-implanted mice with example compound 13. (i) Vehicle, (ii) Poziotinib 1 mpk, (iii) Poziotinib 2.5 mpk, (iv) 13 75 mpk, (v) 13 150 mpk. [Figure 20] Figure 1 shows the change (%) in mouse body weight on day 15 upon treatment of (a) EGFR H773insNPH and (b) EGFR S768dupSVD PDX-implanted mice with example compound 13. (i) Vehicle, (ii) Poziotinib 1 mpk, (iii) Poziotinib 2.5 mpk, (iv) 13 75 mpk, (v) 13 150 mpk. Dotted line = euthanasia. [Figure 21]Figure 1 shows the daily change (a) in PDX tumor volume (mm3), (b) the change (%) in PDX tumor volume (day 15), and (c) the change (%) in mouse body weight (day 15) upon treatment of HER2 Y772dupYVMA PDX-implanted mice with example compounds 4 and 13. (i) Vehicle, (ii) Poziotinib 2.5mpk, (iii) 4 80mpk, (iv) 13 150mpk. [Figure 22] Figure 1 shows the daily change in PDX tumor volume (mm3) upon treatment of EGFR S768dupSVD PDX-implanted mice with example compounds 100 and 101. (i) Vehicle, (ii) Poziotinib 2.5mpk, (iii) Osimertinib 5mpk, (iv) Osimertinib 25mpk, (v) 100 100mpk, (vi) 101 100mpk. [Figure 23] Figure 1 shows the (a) % change in PDX tumor volume (day 21) and (b) % change in mouse body weight (day 21) upon treatment of EGFR S768dupSVD PDX-implanted mice with example compounds 100 and 101. (i) Vehicle, (ii) Poziotinib 2.5mpk, (iii) Osimertinib 5mpk, (iv) Osimertinib 25mpk, (v) 100 100mpk, (vi) 101 100mpk; (b)(ii) lowest two symbols = euthanasia. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The present specification provides, in embodiment 1, a compound of structural formula (I): [ka] (In the formula, A 1 is C(R 1 ) and N; A 2 is C(R 2 ) and N; A 3 is C(R 3 ) and N; Ar 1is aryl and heteroaryl, either of which may be one or two R 4 groups, any of which may be substituted with one, two or three R 5 aryl and heteroaryl, optionally substituted with a substituted or unsubstituted aryl group; R A and R B is independently selected from H and alkyl; R C H, CH 3 and C.H. 2 NR 15 R 16 Selected from; R 1 , halo, -CN, -OR 6 , -NR 7a R 7b , -COOR 8 and -CONR 9a R 9b Selected from; R 2 and R 3 is independently selected from H, alkyl, and alkoxy; Each R 4 is alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any of which may be selected from one or two R 10 independently selected from alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, optionally substituted with alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups; Each R 5 , halo, -CN, -OR 11 , -NR 12a R 12b , -COOR 13 and -CONR 14a R 14b are independently selected from; Each R 6 , R 7a and R 7b is independently selected from H, alkyl, haloalkyl, and C(=O)alkyl; Each R 8 , R 9a and R 9bis independently selected from H and alkyl; Each R 10 is independently selected from halo, hydroxy, and alkoxy; Each R 11 , R 12a and R 12b , H, C 1~6 Alkyl, C 1~6 Haloalkyl and C(=O)C 1~6 independently selected from alkyl; Each R 13 , R 14a and R 14b H and C 1~6 independently selected from alkyl; R 15 and R 16 H and C 1~6 independently selected from alkyl, R 15 and R 16 together with the nitrogen to which they are both attached, combine to form a 5- to 7-membered heterocycloalkyl; m and n are independently selected from 1, 2, and 3; and Y 1 is selected from -NH- and -O- or a salt thereof.

[0012] Certain compounds disclosed herein may have useful HER2 inhibitory activity and can be used to treat or prevent diseases or conditions in which HER2 plays an active role. Thus, in a broad aspect, certain embodiments also provide pharmaceutical compositions comprising one or more compounds disclosed herein together with a pharma- ceutically acceptable carrier, as well as methods of making and using these compounds and compositions. Certain embodiments provide methods of inhibiting HER2. Certain embodiments provide selectivity for the inhibition of certain mutant forms of HER2 over wild-type (WT) EGFR. Other embodiments provide methods of treating HER2-mediated disorders in patients in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound or composition of the present disclosure. Also provided is the use of certain compounds disclosed herein for use in the manufacture of a medicament for treating a disease or condition ameliorated by the inhibition of HER2.

[0013] Certain compounds disclosed herein may have useful EGFR inhibitory activity and can be used to treat or prevent diseases or conditions in which EGFR plays an active role. Thus, in a broad aspect, certain embodiments also provide pharmaceutical compositions comprising one or more compounds disclosed herein together with a pharma- ceutically acceptable carrier, as well as methods of making and using these compounds and compositions. Certain embodiments provide methods of inhibiting EGFR. Certain embodiments provide selectivity for the inhibition of certain mutant forms of EGFR over wild-type (WT) EGFR. Other embodiments provide methods of treating EGFR-mediated disorders in patients in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound or composition of the present disclosure. Also provided is the use of certain compounds disclosed herein for use in the manufacture of a medicament for treating a disease or condition ameliorated by the inhibition of EGFR.

[0014] The following embodiments are also provided:

[0015] Embodiment 2: m is 2 and n is 2, and A 1 C(R1 ) and A 2 C(R 2 ) and A 3 C(R 3 ), and R 1 is CN and R 2 C 1 ~C 2 Alkoxy and R 3 is H, Ar 1 teeth, [ka] The compound of embodiment 1, which is not

[0016] Embodiment 3: A 1 When is C(CN), m is 2, and n is 2, Ar 1 teeth, [ka] The compound of embodiment 1, which is not

[0017] Embodiment 4: A 1 is C(R 1 4. The compound of any one of embodiments 1-3, wherein

[0018] Embodiment 5: R 1 The compound of embodiment 4, wherein is -CN.

[0019] Embodiment 6: R 1 -OR 6 and -NR 7a R 7b The compound of embodiment 4, selected from:

[0020] Embodiment 7: Each R 6 , R 7a and R 7b The compound of embodiment 6, wherein

[0021] Embodiment 8: Each R 6 , R 7a and R 7bThe compound of embodiment 6, wherein is alkyl.

[0022] Embodiment 9: Each R 6 , R 7a and R 7b The compound of embodiment 6, wherein is C(=O)alkyl.

[0023] Embodiment 10: R 1 -OR 6 The compound of any one of embodiments 6-9, wherein

[0024] Embodiment 11: R 1 -NR 7a R 7b The compound of any one of embodiments 6-9, wherein

[0025] Embodiment 12: R 1 -COOR 8 and -CONR 9a R 9b The compound of embodiment 4, selected from:

[0026] Embodiment 13: Each R 8 , R 9a and R 9b is H.

[0027] Embodiment 14: Each R 8 , R 9a and R 9b The compound of embodiment 12, wherein is alkyl.

[0028] Embodiment 15: R 1 -COOR 8 The compound of any one of embodiments 12-14, wherein

[0029] Embodiment 16: R 1 -CONR 9a R 9b The compound of any one of embodiments 12-14, wherein

[0030] Embodiment 17:A 1The compound of any one of embodiments 1 and 2, wherein

[0031] Embodiment 18:A 2 is C(R 2 18. The compound of any one of embodiments 1-17, wherein

[0032] Embodiment 19: R 2 The compound of embodiment 18, wherein is alkyl.

[0033] Embodiment 20: R 2 is C 1~6 The compound of embodiment 19, wherein the is alkyl.

[0034] Embodiment 21: R 2 The compound of embodiment 20, wherein is methyl.

[0035] Embodiment 22:R 2 The compound of embodiment 18, wherein is alkoxy.

[0036] Embodiment 23: R 2 is C 1~6 23. The compound of embodiment 22, which is alkoxy.

[0037] Embodiment 24: R 2 The compound of embodiment 23, wherein is methoxy.

[0038] Embodiment 25:R 2 is H.

[0039] Embodiment 26:A 2 The compound of any one of embodiments 1-17, wherein is N.

[0040] Embodiment 27:A 3 is C(R 3 27. The compound of any one of embodiments 1-26, wherein

[0041] Embodiment 28: R 3 The compound of embodiment 27, wherein is alkyl.

[0042] Embodiment 29:R 3 is C 1~6 The compound of embodiment 28, wherein the is alkyl.

[0043] Embodiment 30: R 3 is methyl.

[0044] Embodiment 31: R 3 28. The compound of embodiment 27, wherein is alkoxy.

[0045] Embodiment 32: R 3 is C 1~6 The compound of embodiment 31, wherein the aryl group is alkoxy.

[0046] Embodiment 33: R 3 The compound of embodiment 32, wherein is methoxy.

[0047] Embodiment 34: R 3 The compound of embodiment 27, wherein

[0048] Embodiment 35:A 3 The compound of any one of embodiments 1-26, wherein is N.

[0049] Embodiment 36: Structural Formula (II): [ka] (In the formula, Ar 1 is aryl and heteroaryl, either of which may be one or two R 4 groups, any of which may be substituted with one, two or three R 5 aryl and heteroaryl, optionally substituted with a substituted or unsubstituted aryl group; R A and R B is independently selected from H and alkyl; R C H, CH 3 and C.H.2 NR 15 R 16 Selected from; R 2 is selected from H, alkyl and alkoxy; Each R 4 is alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any of which may be selected from one or two R 10 independently selected from alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, optionally substituted with alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups; Each R 5 , halo, -CN, -OR 11 , -NR 12a R 12b , -COOR 13 and -CONR 14a R 14b are independently selected from; Each R 10 is independently selected from halo, hydroxy, and alkoxy; Each R 11 , R 12a and R 12b , H, C 1~6 Alkyl, C 1~6 Haloalkyl and C(=O)C 1~6 independently selected from alkyl; Each R 13 , R 14a and R 14b H and C 1~6 independently selected from alkyl; R 15 and R 16 H and C 1~6 independently selected from alkyl, R 15 and R 16 together with the nitrogen to which they are both attached, combine to form a 5- to 7-membered heterocycloalkyl; m and n are independently selected from 1, 2, and 3; and Y 1 is selected from -NH- and -O- Also provided is a compound having the formula:

[0050] Embodiment 37: R 2 The compound of embodiment 36, wherein is alkyl.

[0051] Embodiment 38: R 2 is C 1~6 The compound of embodiment 37, wherein the is alkyl.

[0052] Embodiment 39: R 2 is methyl.

[0053] Embodiment 40:R 2 The compound of embodiment 36, wherein is alkoxy.

[0054] Embodiment 41: R 2 is C 1~6 The compound of embodiment 40, wherein the aryl group is alkoxy.

[0055] Embodiment 42: R 2 The compound of embodiment 41, wherein is methoxy.

[0056] Embodiment 43: R 2 is H.

[0057] Embodiment 44: Structural Formula (III): [ka] (In the formula, Ar 1 is aryl and heteroaryl, either of which may be one or two R 4 groups, any of which may be substituted with one, two or three R 5 aryl and heteroaryl, optionally substituted with a substituted or unsubstituted aryl group; R A and R B is independently selected from H and alkyl; R C H, CH 3 and C.H.2 NR 15 R 16 Selected from; R 1 , halo, -CN, -OR 6 , -NR 7a R 7b , -COOR 8 and -CONR 9a R 9b Selected from; R 2 is selected from H, alkyl and alkoxy; Each R 4 is alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any of which may be selected from one or two R 10 independently selected from alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, optionally substituted with alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups; Each R 5 , halo, -CN, -OR 11 , -NR 12a R 12b , -COOR 13 and -CONR 14a R 14b are independently selected from; Each R 6 , R 7a and R 7b is independently selected from H, alkyl, haloalkyl, and C(=O)alkyl; Each R 8 , R 9a and R 9b is independently selected from H and alkyl; Each R 10 is independently selected from halo, hydroxy, and alkoxy; Each R 11 , R 12a and R 12b , H, C 1~6 Alkyl, C 1~6 Haloalkyl and C(=O)C 1~6 independently selected from alkyl; Each R 13 , R 14a and R 14b H and C1~6 independently selected from alkyl; R 15 and R 16 H and C 1~6 independently selected from alkyl, R 15 and R 16 together with the nitrogen to which they are both attached, combine to form a 5- to 7-membered heterocycloalkyl; m and n are independently selected from 1, 2, and 3; and Y 1 is selected from -NH- and -O- Also provided is a compound having the formula:

[0058] Embodiment 45: m is 2 and n is 2, and A 1 C(R 1 ) and A 2 C(R 2 ) and A 3 C(R 3 ), and R 1 is CN and R 2 C 1 ~C 2 Alkoxy and R 3 is H, Ar 1 teeth, [ka] The compound of embodiment 44, which is not

[0059] Embodiment 46:R 1 The compound of any one of embodiments 44 and 45, wherein is -CN.

[0060] Embodiment 47:R 1 -OR 6 and -NR 7a R 7b 46. ​​The compound of any one of embodiments 44 and 45, selected from:

[0061] Embodiment 48: Each R6 , R 7a and R 7b is H.

[0062] Embodiment 49: Each R 6 , R 7a and R 7b The compound of embodiment 47, wherein is alkyl.

[0063] Embodiment 50: Each R 6 , R 7a and R 7b The compound of embodiment 47, wherein is C(=O)alkyl.

[0064] Embodiment 51: R 1 -OR 6 The compound of any one of embodiments 47-50, wherein

[0065] Embodiment 52: R 1 -NR 7a R 7b The compound of any one of embodiments 47-50, wherein

[0066] Embodiment 53: R 1 -COOR 8 and -CONR 9a R 9b 46. ​​The compound of any one of embodiments 44 and 45, selected from:

[0067] Embodiment 54: Each R 8 , R 9a and R 9b is H.

[0068] Embodiment 55: Each R 8 , R 9a and R 9b The compound of embodiment 53, wherein is alkyl.

[0069] Embodiment 56: R 1 -COOR 8 The compound of any one of embodiments 53-55, wherein

[0070] Embodiment 57: R 1 -CONR 9a R 9b The compound of any one of embodiments 53-55, wherein

[0071] Embodiment 58: R 2 The compound of any one of embodiments 44-57, wherein is alkyl.

[0072] Embodiment 59: R 2 is C 1~6 The compound of embodiment 58, wherein the is alkyl.

[0073] Embodiment 60: R 2 is methyl.

[0074] Embodiment 61: R 2 The compound of any one of embodiments 44-57, wherein is alkoxy.

[0075] Embodiment 62: R 2 is C 1~6 The compound of embodiment 61, wherein the aryl group is alkoxy.

[0076] Embodiment 63: R 2 The compound of embodiment 62, wherein is methoxy.

[0077] Embodiment 64: R 2 The compound of any one of embodiments 44-57, wherein

[0078] Embodiment 65: Structural formula (IV): [ka] (In the formula, Ar 1 is aryl and heteroaryl, either of which may be one or two R 4 groups, any of which may be substituted with one, two or three R 5aryl and heteroaryl, optionally substituted with a substituted or unsubstituted aryl group; R A and R B is independently selected from H and alkyl; R C H, CH 3 and C.H. 2 NR 15 R 16 Selected from; Each R 4 is alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any of which may be selected from one or two R 10 independently selected from alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, optionally substituted with alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups; Each R 5 , halo, -CN, -OR 11 , -NR 12a R 12b , -COOR 13 and -CONR 14a R 14b are independently selected from; Each R 10 is independently selected from halo, hydroxy, and alkoxy; Each R 11 , R 12a and R 12b , H, C 1~6 Alkyl, C 1~6 Haloalkyl and C(=O)C 1~6 independently selected from alkyl; Each R 13 , R 14a and R 14b H and C 1~6 independently selected from alkyl; R 15 and R 16 H and C 1~6 independently selected from alkyl, R 15 and R 16 together with the nitrogen to which they are both attached, combine to form a 5- to 7-membered heterocycloalkyl; m and n are independently selected from 1, 2, and 3; and Y 1 is selected from -NH- and -O- Also provided is a compound having the formula:

[0079] Embodiment 66: Structural formula (V): [ka] (In the formula, Ar 1 is aryl and heteroaryl, either of which may be one or two R 4 groups, any of which may be substituted with one, two or three R 5 aryl and heteroaryl, optionally substituted with a substituted or unsubstituted aryl group; R A and R B is independently selected from H and alkyl; R C H, CH 3 and C.H. 2 NR 15 R 16 Selected from; R 1 , halo, -CN, -OR 6 , -NR 7a R 7b , -COOR 8 and -CONR 9a R 9b Selected from; R 2 is selected from H, alkyl and alkoxy; Each R 4 is alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any of which may be selected from one or two R 10 independently selected from alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, optionally substituted with a group; Each R 5 , halo, -CN, -OR 11 , -NR 12a R12b , -COOR 13 and -CONR 14a R 14b are independently selected from; Each R 6 , R 7a and R 7b is independently selected from H, alkyl, haloalkyl, and C(=O)alkyl; Each R 8 , R 9a and R 9b is independently selected from H and alkyl; Each R 10 is independently selected from halo, hydroxy, and alkoxy; Each R 11 , R 12a and R 12b , H, C 1~6 Alkyl, C 1~6 Haloalkyl and C(=O)C 1~6 independently selected from alkyl; Each R 13 , R 14a and R 14b H and C 1~6 independently selected from alkyl; R 15 and R 16 H and C 1~6 independently selected from alkyl, R 15 and R 16 together with the nitrogen to which they are both attached, combine to form a 5- to 7-membered heterocycloalkyl; m and n are independently selected from 1, 2, and 3; and Y 1 is selected from -NH- and -O- Also provided is a compound having the formula:

[0080] Embodiment 67: R 1 The compound of embodiment 66, wherein is -CN.

[0081] Embodiment 68: R 1 -OR 6 and -NR 7a R7b 67. The compound of embodiment 66, selected from:

[0082] Embodiment 69: Each R 6 , R 7a and R 7b is H.

[0083] Embodiment 70: Each R 6 , R 7a and R 7b The compound of embodiment 68, wherein is alkyl.

[0084] Embodiment 71: Each R 6 , R 7a and R 7b The compound of embodiment 68, wherein is C(=O)alkyl.

[0085] Embodiment 72:R 1 -OR 6 The compound of any one of embodiments 68-71, wherein

[0086] Embodiment 73:R 1 -NR 7a R 7b The compound of any one of embodiments 68-71, wherein

[0087] Embodiment 74: R 1 -COOR 8 and -CONR 9a R 9b 67. The compound of embodiment 66, selected from:

[0088] Embodiment 75: Each R 8 , R 9a and R 9b is H.

[0089] Embodiment 76: Each R 8 , R 9a and R 9b The compound of embodiment 74, wherein is alkyl.

[0090] Embodiment 77: R1 -COOR 8 The compound of any one of embodiments 74 to 76, wherein

[0091] Embodiment 78: R 1 -CONR 9a R 9b The compound of any one of embodiments 74-76, wherein

[0092] The following embodiments are also provided:

[0093] Embodiment 79: Ar 1 is phenyl and monocyclic heteroaryl, either of which may be selected from one or two R 4 groups, any of which may be substituted with one, two or three R 5 The compound of any one of embodiments 1-78, wherein the aryl is selected from phenyl and monocyclic heteroaryl, optionally substituted with a group.

[0094] Embodiment 80: Ar 1 is phenyl and monocyclic 6-membered heteroaryl, either of which may be selected from one or two R 4 groups, any of which may be substituted with one, two or three R 5 80. A compound of embodiment 79, wherein the aryl group is selected from phenyl and monocyclic 6-membered heteroaryl, optionally substituted with a group.

[0095] Embodiment 81: Ar 1 is phenyl, pyridyl, pyrimidyl, pyridazyl, and pyrazyl, any of which may be selected from one or two R 4 groups, any of which may be substituted with one, two or three R 5 81. A compound of embodiment 80, wherein the aryl group is selected from phenyl, pyridyl, pyrimidyl, pyridazyl, and pyrazyl, optionally substituted with a group.

[0096] Embodiment 82: Ar 1 is phenyl and one or two R 4group and one, two or three R 5 The compound of embodiment 81, optionally substituted with a group.

[0097] Embodiment 83: Ar 1 is pyridyl, pyrimidyl, pyridazyl, and pyrazyl, any of which may contain one or two R 4 groups, any of which may be substituted with one, two or three R 5 82. A compound of embodiment 81, wherein the R is selected from pyridyl, pyrimidyl, pyridazyl, and pyrazyl, optionally substituted with a group.

[0098] Embodiment 84: Ar 1 is pyridyl and one or two R 4 group and one, two or three R 5 The compound of embodiment 83, optionally substituted with a group.

[0099] Embodiment 85: Ar 1 pyrimidyl, pyridazyl and pyrazyl, any of which may contain one or two R 4 groups, any of which may be substituted with one, two or three R 5 84. A compound of embodiment 83, wherein the R is selected from pyrimidyl, pyridazyl, and pyrazyl, optionally substituted with a group.

[0100] Embodiment 86: Ar 1 naphthyl and bicyclic heteroaryl, either of which may be selected from one or two R 4 groups, any of which may be substituted with one, two or three R 5 The compound of any one of embodiments 1-78, wherein the compound is selected from naphthyl and bicyclic heteroaryl, optionally substituted with a group.

[0101] Embodiment 87: Ar 1 is a bicyclic heteroaryl and one or two R 4group and one, two or three R 5 The compound of embodiment 86, optionally substituted with a group.

[0102] Embodiment 88: Ar 1 is a bicyclic 10-membered heteroaryl and one or two R 4 group and one, two or three R 5 The compound of embodiment 87, optionally substituted with a group.

[0103] Embodiment 89: Ar 1 is quinolinyl and isoquinolinyl, either of which may be one or two R 4 groups, any of which may be substituted with one, two or three R 5 The compound of embodiment 88, wherein the quinolinyl is selected from quinolinyl and isoquinolinyl, optionally substituted with a group.

[0104] Embodiment 90: Ar 1 is a bicyclic 9-membered heteroaryl and one or two R 4 group and one, two or three R 5 The compound of embodiment 87, optionally substituted with a group.

[0105] Embodiment 91: Ar 1 is indolyl, benzimidazolyl, benzopyrrolyl, benzoxazolyl, and benzoisoxazolyl, any of which may be selected from one or two R 4 groups, any of which may be substituted with one, two or three R 5 91. A compound of embodiment 90, wherein the R is selected from indolyl, benzimidazolyl, benzopyrrolyl, benzoxazolyl, and benzoisoxazolyl, optionally substituted with a group.

[0106] Embodiment 92: Ar 1 is indolyl, benzimidazolyl, and benzopyrrolyl, any of which may have one or two R 4groups, any of which may be substituted with one, two or three R 5 92. A compound of embodiment 91, wherein the R is selected from indolyl, benzimidazolyl, and benzopyrrolyl, optionally substituted with a group.

[0107] Embodiment 93: Ar 1 is one R 4 The compound of any one of embodiments 1-92, optionally substituted with a group.

[0108] Embodiment 94: Ar 1 is one or two R 4 The compound of any one of embodiments 1-92, optionally substituted with a group.

[0109] Embodiment 95: Ar 1 is one R 4 95. The compound of embodiment 94, wherein the compound is substituted with a group.

[0110] Embodiment 96: Ar 1 There are two R 4 95. The compound of embodiment 94, wherein the compound is substituted with a group.

[0111] Embodiment 97: Each R 4 is C 1~6 Alkyl, C 3~7 Cycloalkyl, 4-7 membered heterocycloalkyl, C 6~10 aryl and 6- to 10-membered heteroaryl, any of which may be one or two R 10 optionally substituted with a C group; 1~6 Alkyl, C 3~7 Cycloalkyl, 4-7 membered heterocycloalkyl, C 6~10 The compound of any one of embodiments 1-96, wherein the compound is independently selected from aryl and 6-10 membered heteroaryl.

[0112] Embodiment 98: Each R 4 is C 3~7 Cycloalkyl and one or two R 10 98. The compound of embodiment 97, optionally substituted with a group.

[0113] Embodiment 99: Each R 4 is C 1~6 alkyl and one or two R 10 98. The compound of embodiment 97, optionally substituted with a group.

[0114] Embodiment 100: Each R 4 is C 1~6 alkyl and one or two R 10 98. The compound of embodiment 97, optionally substituted with a group.

[0115] Embodiment 101: Each R 4 is C 3~7 Cycloalkyl and 4- to 7-membered heterocycloalkyl, either of which may have one or two R 10 optionally substituted with a C group; 3~7 98. The compound of embodiment 97, wherein the is independently selected from cycloalkyl and 4- to 7-membered heterocycloalkyl.

[0116] Embodiment 102: Each R 4 is C 6~10 aryl and 6- to 10-membered heteroaryl, any of which may be one or two R 10 optionally substituted with a C group; 6~10 98. The compound of embodiment 97, wherein the is independently selected from aryl and 6-10 membered heteroaryl.

[0117] Embodiment 103: Each R 4 is a 6- to 10-membered heteroaryl, and one or two R 10 The compound of embodiment 102, optionally substituted with a group.

[0118] Embodiment 104: Each R 4 is a monocyclic 5- to 7-membered heteroaryl, and one or two R 10 The compound of embodiment 103, optionally substituted with a group.

[0119] Embodiment 105: Each R 4is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl and isoxazolyl, and one or two R 10 The compound of embodiment 104, optionally substituted with a group.

[0120] Embodiment 106: Each R 4 is oxazolyl and one or two R 10 The compound of embodiment 105, optionally substituted with a group.

[0121] Embodiment 107: Each R 4 is one R 10 The compound of any one of embodiments 1-106, optionally substituted with a group.

[0122] Embodiment 108: Each R 4 is one or two R 10 The compound of any one of embodiments 1-106, optionally substituted with a group.

[0123] Embodiment 109: Each R 4 is one R 10 The compound of embodiment 108, optionally substituted with a group.

[0124] Embodiment 110:R 10 The compound of any one of embodiments 1-109, wherein is halo.

[0125] Embodiment 111:R 10 The compound of any one of embodiments 1-109, wherein is hydroxy.

[0126] Embodiment 112:R 10 The compound of any one of embodiments 1-109, wherein is alkoxy.

[0127] Embodiment 113:R 10 is C 1~6 The compound of embodiment 112, wherein the aryl group is alkoxy.

[0128] Embodiment 114: Each R 4 is R10 The compound of embodiment 107, which is not substituted with a group.

[0129] Embodiment 115: Each R 4 is cyclopropyl.

[0130] Embodiment 116: Each R 4 is cyclobutyl.

[0131] Embodiment 117: Each R 4 is C 1~6 100. The compound of embodiment 99, wherein the is alkyl.

[0132] Embodiment 118: Each R 4 The compound of embodiment 117, wherein is methyl.

[0133] Embodiment 119: Each R 4 is hydroxyalkyl.

[0134] Embodiment 120: Each R 4 is hydroxymethyl.

[0135] Embodiment 121: Ar 1 is R 4 The compound of embodiment 93, which is not substituted with a group.

[0136] Embodiment 122: Ar 1 is one or two R 5 The compound of any one of embodiments 1 to 121, optionally substituted with a group.

[0137] Embodiment 123: Ar 1 is one R 5 The compound of embodiment 122, optionally substituted with a group.

[0138] Embodiment 124: Ar 1 1, 2 or 3 R 5The compound of any one of embodiments 1 to 121, optionally substituted with a group.

[0139] Embodiment 125: Ar 1 is one or two R 5 The compound of embodiment 124, wherein the compound is substituted with a group.

[0140] Embodiment 126: Ar 1 is one R 5 The compound of embodiment 125, wherein the compound is substituted with a group.

[0141] Embodiment 127: Each R 5 The compound of any one of embodiments 1-126, wherein is independently selected from halo and cyano.

[0142] Embodiment 128: Each R 5 The compound of embodiment 127, wherein is halo.

[0143] Embodiment 129: Each R 5 The compound of embodiment 128, wherein is independently selected from fluoro and chloro.

[0144] Embodiment 130:R 5 The compound of embodiment 129, wherein is chloro.

[0145] Embodiment 131: Each R 5 -OR 11 and -NR 12a R 12b The compound of any one of embodiments 1-126, independently selected from:

[0146] Embodiment 132: Each R 11 , R 12a and R 12b The compound of embodiment 131, wherein

[0147] Embodiment 133: Each R 5 -OR 11 The compound of embodiment 131, wherein

[0148] Embodiment 134: Each R 11 The compound of embodiment 133, wherein is alkyl.

[0149] Embodiment 135: Each R 11 is C 1~6 The compound of embodiment 131, wherein the is alkyl.

[0150] Embodiment 136: Each R 11 is C 1~6 The compound of embodiment 131, which is haloalkyl.

[0151] Embodiment 137: Each R 11 The compound of embodiment 136, wherein is halomethyl.

[0152] Embodiment 138: Each R 11 The compound of embodiment 137, wherein is difluoromethyl.

[0153] Embodiment 139: Each R 11 The compound of embodiment 137, wherein is trifluoromethyl.

[0154] Embodiment 140: Each R 11 , R 12a and R 12b The compound of embodiment 131, wherein is C(=O)alkyl.

[0155] Embodiment 141: Each R 11 , R 12a and R 12b is C(=O)C 1~6 The compound of embodiment 140, wherein the is alkyl.

[0156] Embodiment 142: Each R 5 -COOR 13 and -CONR 14a R 14b The compound of any one of embodiments 1-126, independently selected from:

[0157] Embodiment 143: Each R 13 , R 14a and R 14bThe compound of embodiment 142, wherein

[0158] Embodiment 144: Each R 13 , R 14a and R 14b The compound of embodiment 142, wherein is alkyl.

[0159] Embodiment 145: Each R 13 , R 14a and R 14b is C 1~6 The compound of embodiment 144, wherein the is alkyl.

[0160] Embodiment 146: Each R 5 -COOR 13 The compound of any one of embodiments 142-145, wherein

[0161] Embodiment 147: Each R 5 -CONR 14a R 14b The compound of any one of embodiments 142-145, wherein

[0162] Embodiment 148: Ar 1 is R 5 The compound of embodiment 123, which is not substituted with a group.

[0163] Embodiment 149: Ar 1 teeth, [ka] The compound of any one of embodiments 1-148, which is not:

[0164] Embodiment 150: Ar 1 teeth, [ka] 83. The compound of embodiment 82, selected from:

[0165] Embodiment 151: Ar 1 teeth, [ka] The compound of embodiment 150, selected from:

[0166] Embodiment 152: Ar 1 teeth, [ka] The compound of embodiment 150, selected from:

[0167] Embodiment 153: Ar 1 teeth, [ka] The compound of embodiment 152, selected from:

[0168] Embodiment 154: Ar 1 teeth, [ka] The compound of embodiment 90, wherein

[0169] Embodiment 155: m is 1 and n is 1 or m is 2 and n is 2, or The compound of any one of embodiments 1-154, wherein m is 1 and n is 3.

[0170] Embodiment 156: m is 1 and n is 1, or The compound of any one of embodiments 1-154, wherein m is 1 and n is 3.

[0171] Embodiment 157: m is 1 and n is 1, or The compound of embodiment 155, wherein m is 2 and n is 2.

[0172] Embodiment 158: A compound of embodiment 157, wherein m is 1 and n is 1.

[0173] Embodiment 159: The compound of any one of embodiments 1 to 154, wherein m is 1.

[0174] Embodiment 160: The compound of any one of embodiments 1 to 154, wherein m is 2.

[0175] Embodiment 161: The compound of any one of embodiments 1 to 154, wherein m is 3.

[0176] Embodiment 162: The compound of any one of embodiments 1 to 161, wherein n is 1.

[0177] Embodiment 163: The compound of any one of embodiments 1 to 160, wherein n is 2.

[0178] Embodiment 164: The compound of any one of embodiments 1 to 160, wherein n is 3.

[0179] Embodiment 165:Y 1 The compound of any one of embodiments 1-164, wherein is -NH-.

[0180] Embodiment 166:Y 1 The compound of any one of embodiments 1-164, wherein is -O-.

[0181] Embodiment 167:R A and R B H and C 1~6 The compound of any one of embodiments 1-166, wherein is independently selected from alkyl.

[0182] Embodiment 168:R A The compound of any one of embodiments 1-167, wherein

[0183] Embodiment 169:R A is C 1~6 The compound of any one of embodiments 1-167, wherein is alkyl.

[0184] Embodiment 170:R Ais methyl.

[0185] Embodiment 171:R B The compound of any one of embodiments 1-170, wherein

[0186] Embodiment 172:R B is C 1~6 The compound of any one of embodiments 1-170, wherein is alkyl.

[0187] Embodiment 173:R B The compound of embodiment 172, wherein is methyl.

[0188] Embodiment 174:R C The compound of any one of embodiments 1-173, wherein

[0189] Embodiment 175:R C is CH 3 The compound of any one of embodiments 1-173, wherein

[0190] Embodiment 176:R C is CH 2 NR 15 R 16 The compound of any one of embodiments 1-173, wherein

[0191] Embodiment 177:R 15 and R 16 H and C 1~6 The compound of embodiment 176, wherein each is independently selected from alkyl.

[0192] Embodiment 178:R 15 and R 16 is independently selected from H and methyl.

[0193] Embodiment 179:R 15 and R 16 is C 1~6 The compound of embodiment 176, wherein the is alkyl.

[0194] Embodiment 180:R 15 and R 16 The compound of embodiment 178, wherein is methyl.

[0195] Embodiment 181:R 15 and R 16 The compound of any one of embodiments 176-178, wherein at least one of is H.

[0196] Embodiment 182:R 15 and R 16 is H.

[0197] Embodiment 183:R 15 and R 16 The compound of embodiment 176, wherein, together with the nitrogen to which they are both attached, combine to form a 5- to 7-membered heterocycloalkyl.

[0198] Embodiment 184:R 15 and R 16 The compound of embodiment 183, wherein, together with the nitrogen to which they are both attached, combine to form a 5-7 membered heterocycloalkyl selected from pyrrolidine, piperidine, piperazine, and morpholine.

[0199] Embodiment 185: Structural formula (VI): [ka] (In the formula, Ar 1 is aryl and heteroaryl, any of which may contain one, two or three R 5 aryl and heteroaryl, optionally substituted with a substituted or unsubstituted aryl group; Each R 5 , halo, -CN, -OR 11 , -NR 12a R 12b , -COOR 13 and -CONR 14a R 14b are independently selected from; Each R 11, R 12a and R 12b , H, C 1~6 Alkyl, C 1~6 Haloalkyl and C(=O)C 1~6 alkyl; and Each R 13 , R 14a and R 14b H and C 1~6 alkyl) Also provided is a compound having the formula:

[0200] Embodiment 186: Ar 1 is phenyl and one, two or three R 5 The compound of embodiment 185, optionally substituted with a group.

[0201] Embodiment 187:R 5 The compound of embodiment 186, wherein is halo.

[0202] Embodiment 188: Ar 1 teeth, [ka] The compound of embodiment 185, selected from:

[0203] Embodiment 189: Structural formula (VII): [ka] (In the formula, Ar 1 is aryl and heteroaryl, any of which may contain one, two or three R 5 aryl and heteroaryl, optionally substituted with a substituted or unsubstituted aryl group; Each R 5 , halo, -CN, -OR 11 , -NR 12a R 12b , -COOR 13 and -CONR 14a R 14b are independently selected from; Each R11 , R 12a and R 12b , H, C 1~6 Alkyl, C 1~6 Haloalkyl and C(=O)C 1~6 alkyl; and Each R 13 , R 14a and R 14b H and C 1~6 alkyl) Also provided is a compound having the formula:

[0204] Embodiment 190: Ar 1 is phenyl and one, two or three R 5 189. The compound of embodiment 189, wherein the compound is substituted with a group.

[0205] Embodiment 191:R 5 The compound of embodiment 190, wherein is halo.

[0206] Embodiment 192: Ar 1 teeth, [ka] 190. The compound of embodiment 189, selected from:

[0207] Embodiment 193: Structural formula (VIII): [ka] (In the formula, Ar 1 is aryl and heteroaryl, any of which may contain one, two or three R 5 aryl and heteroaryl, optionally substituted with a substituted or unsubstituted aryl group; Each R 5 , halo, -CN, -OR 11 , -NR 12a R 12b , -COOR 13 and -CONR 14a R 14b are independently selected from; Each R 11 , R 12a and R 12b , H, C 1~6 Alkyl, C 1~6 Haloalkyl and C(=O)C 1~6 alkyl; and Each R 13 , R 14a and R 14b H and C 1~6 alkyl) Also provided is a compound having the formula:

[0208] Embodiment 194: m is 2 and n is 2, and A 1 C(R 1 ) and A 2 C(R 2 ) and A 3 C(R 3 ), and R 1 is CN and R 2 C 1 ~C 2 Alkoxy and R 3 is H, Ar 1 teeth, [ka] The compound of embodiment 193, which is not

[0209] Embodiment 195: Ar 1 is phenyl and one, two or three R 5 The compound of any one of embodiments 193 and 194, optionally substituted with a group.

[0210] Embodiment 196:R 5 The compound of embodiment 195, wherein is halo.

[0211] Embodiment 197: Ar 1 teeth, [ka] The compound of embodiment 193, wherein

[0212] The following embodiments are also provided:

[0213] Embodiment 198: Each R 5 -Halo, -CN and -OR 11 The compound of any one of embodiments 185, 189, and 193, independently selected from:

[0214] Embodiment 199: Each R 5 The compound of embodiment 198, wherein is independently selected from halo and -CN.

[0215] Embodiment 200: Each R 5 The compound of embodiment 199, wherein is halo.

[0216] Embodiment 201: Each R 5 The compound of embodiment 200, wherein is selected from fluoro and chloro.

[0217] Embodiment 202: Each R 5 The compound of embodiment 201, wherein is chloro.

[0218] Embodiment 203: Ar 1 is phenyl and monocyclic heteroaryl, any of which may contain one, two or three R 5 The compound of any one of embodiments 185, 189, 193, and 198-202, wherein the compound is selected from phenyl and monocyclic heteroaryl, optionally substituted with a group.

[0219] Embodiment 204: Ar 1 is phenyl, pyridyl, pyrimidyl, pyridazyl, and pyrazyl, any of which may contain one, two, or three R 5 The compound of embodiment 203, wherein the aryl group is selected from phenyl, pyridyl, pyrimidyl, pyridazyl, and pyrazyl, optionally substituted with a group.

[0220] Embodiment 205: Ar1 is phenyl and one, two or three R 5 The compound of embodiment 203, wherein the compound is substituted with a group.

[0221] Embodiment 206: Ar 1 teeth, [ka] The compound of embodiment 205, which is not

[0222] Embodiment 207: Ar 1 is one or two R 5 The compound of any one of embodiments 204 and 205, wherein the compound is substituted with a group.

[0223] Embodiment 208: Ar 1 is one R 5 The compound of embodiment 207, wherein the compound is substituted with a group.

[0224] Embodiment 209: Ar 1 teeth, [ka] The compound of embodiment 205, selected from:

[0225] Embodiments are further provided herein, any one or more of which may be combined with any of the embodiments described above, provided that such combinations are not mutually exclusive.

[0226] As used herein, two embodiments are "mutually exclusive" when one is defined as being different from the other. For example, an embodiment in which two groups are linked to form a cycloalkyl is mutually exclusive from an embodiment in which one group is ethyl and the other group is hydrogen. Similarly, an embodiment in which one group is -CH 2 The embodiment where - is mutually exclusive with the embodiment where the same group is -NH-.

[0227] EMBODIMENT 210: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] Also provided is a compound selected from:

[0228] EMBODIMENT 211: [ka] Also provided is a compound selected from:

[0229] EMBODIMENT 212: [ka] Also provided is a compound selected from:

[0230] EMBODIMENT 213: [ka] Also provided is a compound selected from:

[0231] The following embodiments are also provided:

[0232] Embodiment 214: A method for inhibiting HER2, comprising contacting HER2 with a compound according to any one of embodiments 1 to 213 or a salt thereof.

[0233] Embodiment 215: A method for inhibiting EGFR, comprising contacting EGFR with a compound according to any one of embodiments 1 to 213 or a salt thereof.

[0234] Embodiment 216: A method for the treatment of a HER2-mediated disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1 to 213 or a salt thereof.

[0235] Embodiment 217: A method for the treatment of an EGFR-mediated disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1 to 213 or a salt thereof.

[0236] Embodiment 218: The method of any one of embodiments 216 and 217, wherein the disease is cancer.

[0237] Embodiment 219: The method of embodiment 218, wherein the cancer is selected from small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, gastric cancer and uterine cancer.

[0238] Embodiment 220: The method of embodiment 218, wherein the cancer is non-small cell lung cancer.

[0239] Embodiment 221: A method of treatment of a HER2 mediated disease, comprising: a. a therapeutically effective amount of a compound according to any one of embodiments 1-213 or a salt thereof; and b. Another medication Administering

[0240] Embodiment 222: A method for treating an EGFR mediated disease, comprising: a. a therapeutically effective amount of a compound according to any one of embodiments 1-213 or a salt thereof; and b. Another medication Administering

[0241] Embodiment 223: A method for treating a HER2-mediated disease in a population of subjects, the population of subjects being characterized as comprising a HER2 mutation, comprising administering a compound or salt thereof according to any one of embodiments 1 to 213.

[0242] Embodiment 224: The method of embodiment 223, wherein the HER2-mediated disease is cancer.

[0243] Embodiment 225: The method of any one of embodiments 223 and 224, wherein the HER2 mutation is an exon 20 insertion mutation excluding C805S.

[0244] Embodiment 226: The method of any one of embodiments 223 and 224, wherein the HER2 mutation is an activating mutation.

[0245] Embodiment 227: The method of embodiment 226, wherein the activating mutation is selected from an extracellular mutation, an exon 19 point mutation, and an exon 21 point mutation.

[0246] Embodiment 228: The method of embodiment 226, wherein the activating mutation is selected from L755 and D769.

[0247] Embodiment 229: The method of embodiment 226, wherein the activating mutation is selected from V842I and L869R.

[0248] Embodiment 230: The method according to any one of embodiments 223 and 224, wherein the HER2 mutation is selected from YVMA, GSP, VC, V754M, L755S, L755P, D769H, D769N, Y772dupYVMA, V773M, G776del insVC, G776delinsVV, G776delinsLC, G778insLPS, G778dupGSP, V777L, G778insLPS, G778dupGSP, L786V, V842I and L869R.

[0249] Embodiment 231: The method according to any one of embodiments 223 to 230, wherein the selectivity of the compound or its salt for HER2 mutations over WT EGFR is less than or equal to 0.5.

[0250] Embodiment 232: The method of embodiment 231, wherein the selectivity of the compound or its salt for HER2 mutations over WT EGFR is 0.1 or less.

[0251] Embodiment 233: A method for treating an EGFR-mediated disease in a population of subjects, the population of subjects being characterized in that they contain an EGFR mutation, comprising administering a compound or salt thereof according to any one of embodiments 1 to 213.

[0252] Embodiment 234: The method of embodiment 233, wherein the EGFR-mediated disease is cancer.

[0253] Embodiment 235: The method of any one of embodiments 233 and 234, wherein the EGFR mutation is an exon 20 insertion mutation excluding C797S.

[0254] Embodiment 236: The method of any one of embodiments 233 and 234, wherein the HER2 mutation is an atypical mutation.

[0255] Embodiment 237: The method of embodiment 236, wherein the atypical mutation is selected from L719, G724 and L792.

[0256] Embodiment 238: The EGFR mutation is A763insFQEA, A767insASV, A767insTLA, S768dupSVD, S768dupSVD / C797S, S768dupSVD / T790M, S768I, S768I T790M, V769insASV, V769insGSV, V769insGVV, V769insMASVD, V769L, D770del insGY, D770insG, D770insNPG, D770insNPG / C797S, D770insNPG / T790M, D770insSVD, D770insY The method of any one of embodiments 233 and 234, wherein said indium is selected from H773Y, N771insHH, N771insSVDNR, P772insDNP, H773insAH, H773insH, H773insNPH, H773L / V774M, H773L V774M and V774insHV.

[0257] Embodiment 239: The method according to any one of embodiments 233 to 238, wherein the selectivity of the compound or its salt for EGFR mutations over WT EGFR is less than or equal to 0.5.

[0258] Embodiment 240: The method of embodiment 239, wherein the selectivity of the compound or salt thereof for EGFR mutations over WT EGFR is 0.1 or less.

[0259] Embodiment 241: A method of treating a cancer or tumor in a subject in need thereof, comprising: (a) determining the HER2 genotype of a subject; (b) identifying the presence of a HER2 mutation in the subject's genotype; and (c) administering a compound of any one of embodiments 1 to 213 or a salt thereof. wherein the compound or salt thereof is selective for HER2 mutations over WT EGFR.

[0260] Embodiment 242: The method of embodiment 241, wherein the selectivity of the compound or its salt for HER2 mutations over WT EGFR is equal to or less than 0.5.

[0261] Embodiment 243: The method of embodiment 242, wherein the selectivity of the compound or its salt for HER2 mutations over WT EGFR is 0.1 or less.

[0262] Embodiment 244: The method according to any one of embodiments 241 to 243, wherein the HER2 mutation is selected from YVMA, GSP, VC, V754M, L755S, L755P, D769H, D769N, Y772dupYVMA, V773M, G776del insVC, G776delinsVV, G776delinsLC, G778insLPS, G778dupGSP, V777L, G778insLPS, G778dupGSP, L786V, V842I and L869R.

[0263] Embodiment 245: A method of treating a cancer or tumor in a subject in need thereof, comprising: (a) determining the EGFR genotype of a subject; (b) identifying the presence of an EGFR mutation in the subject's genotype; and (c) administering a compound according to claim 1 or a salt thereof. wherein the compound or salt thereof is selective for EGFR mutations over WT EGFR.

[0264] Embodiment 246: The method of embodiment 245, wherein the selectivity of the compound or salt thereof for EGFR mutations over WT EGFR is 0.5 or less.

[0265] Embodiment 247: The method of embodiment 246, wherein the selectivity of the compound or salt thereof for EGFR mutations over WT EGFR is 0.1 or less.

[0266] Embodiment 248: The EGFR mutation is A763insFQEA, A767insASV, A767insTLA, S768dupSVD, S768dupSVD / C797S, S768dupSVD / T790M, S768I, S768I T790M, V769insASV, V769insGSV, V769insGVV, V769insMASVD, V769L, D770del insGY, D770insG, D770insNPG, D770insNPG / C797S, D770insNPG / T790M, D770insSVD, D770insY The method of any one of embodiments 245 to 247, wherein the isoform is selected from H773Y, N771insHH, N771insSVDNR, P772insDNP, H773insAH, H773insH, H773insNPH, H773L / V774M, H773L V774M and V774insHV.

[0267] In one aspect, the present disclosure provides a method of inhibiting at least one HER2 function, which comprises contacting HER2 with a compound described herein. The cell phenotype, cell proliferation, activity of HER2, changes in biochemical outcomes caused by active HER2, expression of HER2, or binding of HER2 to a natural binding partner can be monitored. Such a method can be a method of treating a disease, a biological assay, a cellular assay, a biochemical assay, etc.

[0268] Also provided herein is a method of treating a HER2-mediated disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a salt thereof.

[0269] In certain embodiments, the HER2-mediated disease is cancer.

[0270] Also provided herein are the compounds disclosed herein for use as pharmaceutical agents.

[0271] Also provided herein are the compounds disclosed herein for use as pharmaceutical agents for the treatment of a HER2-mediated disease.

[0272] Also provided herein is the use of the compounds disclosed herein as pharmaceutical agents.

[0273] Also provided herein is the use of the compounds disclosed herein as pharmaceutical agents for the treatment of HER2-mediated diseases.

[0274] Also provided is a compound disclosed herein for use in the manufacture of a medicament for the treatment of a HER2-mediated disease.

[0275] Also provided is the use of the compounds disclosed herein for the treatment of a HER2-mediated disease.

[0276] Also provided herein is a method of inhibiting HER2, comprising contacting HER2 with a compound disclosed herein, or a salt thereof.

[0277] The compounds of the present disclosure may be selective for mutant forms of HER2 over WT EGFR in a variety of ways. In one aspect, the compounds described herein may be selective for mutant forms of HER2 over WT EGFR, where HER2 contains an exon 20 insertion mutation (defined as an insertion of 1-18 amino acids from amino acids E770 to R786 in HER2). In another aspect, the compounds described herein may be selective for mutant forms of HER2 over WT EGFR, where HER2 contains an exon 20 point mutation, excluding C805S in HER2. In yet another aspect, the compounds described herein may be selective for mutant forms of HER2 over WT EGFR, where HER2 contains an activating mutation, including but not limited to, extracellular mutations, exon 19 point mutations such as mutations at L755 or D769, and exon 21 point mutations such as mutations at V842I or L869R. In yet another aspect, the compounds described herein may be selective for HER2 mutants over WT EGFR, wherein the HER2 mutants are selected from YVMA, GSP, VC, V754M, L755S, L755P, D769H, D769N, Y772dupYVMA, V773M, G776del insVC, G776delinsVV, G776delinsLC, G778insLPS, G778dupGSP, V777L, G778insLPS, G778dupGSP, L786V, V842I, and L869R.

[0278] Certain compounds may exhibit selectivity for mutant HER2, determined as a ratio IC50(mutant HER2) / IC50(wtEGFR) of 0.5 or less. Certain compounds may exhibit selectivity for mutant HER2 of 0.2 or less. Certain compounds may exhibit selectivity for mutant HER2 of 0.05 or less. Certain compounds may exhibit selectivity for mutant HER2 of 0.02 or less.

[0279] Also provided is a method of modulating a HER2-mediated function in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein.

[0280] Also provided is a method of treating a subject having a HER2-mediated disease or disorder, such as cancer or a tumor, comprising determining that the subject's genotype comprises a mutated form of HER2 and administering to the subject a compound disclosed herein, or a salt thereof.

[0281] Also provided is a method of treating a HER2-mediated disease or disorder, such as cancer or tumor, in a subpopulation of subjects, the subpopulation being characterized by the presence of a mutant form of HER2 in the genotype of the subjects of the subpopulation, the method comprising administering to the subpopulation of subjects a compound disclosed herein, or a salt thereof.

[0282] Also provided is a method of stratifying a subject for response to a therapy comprising administration of a compound disclosed herein or a salt thereof, the method comprising determining the presence of a HER2 mutation in the subject's genotype and administering a compound disclosed herein or a salt thereof to the subject.

[0283] In one aspect, the present disclosure provides a method of inhibiting at least one EGFR function, comprising contacting EGFR with a compound described herein. Cell phenotype, cell proliferation, activity of EGFR, changes in biochemical outcomes caused by active EGFR, expression of EGFR, or binding of EGFR to natural binding partners can be monitored. Such methods can be methods of treating disease, biological assays, cellular assays, biochemical assays, etc.

[0284] Also provided herein is a method of treating an EGFR-mediated disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a salt thereof.

[0285] In certain embodiments, the EGFR-mediated disease is cancer.

[0286] Also provided herein are the compounds disclosed herein for use as pharmaceutical agents.

[0287] Also provided herein are the compounds disclosed herein for use as pharmaceutical agents for the treatment of an EGFR-mediated disease.

[0288] There is also provided the use of the compounds disclosed herein as pharmaceutical agents.

[0289] Also provided is the use of the compounds disclosed herein as pharmaceutical agents for the treatment of EGFR-mediated diseases.

[0290] Also provided is a compound disclosed herein for use in the manufacture of a medicament for the treatment of an EGFR-mediated disease.

[0291] Also provided is the use of the compounds disclosed herein for the treatment of a HER2-mediated disease.

[0292] Also provided herein is a method of inhibiting EGFR, comprising contacting EGFR with a compound disclosed herein, or a salt thereof.

[0293] The compounds of the present disclosure may be selective for mutant forms of EGFR over WT EGFR in a variety of ways. In one aspect, the compounds described herein may be selective for mutant forms of EGFR over WT EGFR, where EGFR includes an exon 20 insertion mutation (defined as an insertion of 1-18 amino acids from amino acids A763 to R776 in EGFR). In another aspect, the compounds described herein may be selective for mutant forms of EGFR over WT EGFR, where EGFR includes an exon 20 point mutation, excluding C797S in EGFR. In yet another aspect, the compounds described herein may be selective for mutant forms of EGFR over WT EGFR, where EGFR includes atypical mutations, including but not limited to L719, G724, and L792. In yet another aspect, the compounds described herein may be selective for mutant forms of EGFR over WT EGFR, the mutant forms of EGFR being A763insFQEA, A767insASV, A767insTLA, S768dupSVD, S768dupSVD / C797S, S768dupSVD / T790M, S768I, S768I T790M, V769insASV, V769insGSV, V769insGVV, V769insMASVD, V769L, D770del insGY, D770insG, D770insNPG, D770insNPG / C797S, D770insNPG / T790M, D770insSVD, D770insY H773Y, N771insHH, N771insSVDNR, P772insDNP, H773insAH, H773insH, H773insNPH, H773L / V774M, H773L V774M and V774insHV.

[0294] Certain compounds may exhibit selectivity for mutant EGFR, determined as a ratio IC50(mutant EGFR) / IC50(wtEGFR) of 0.5 or less. Certain compounds may exhibit selectivity for mutant EGFR of 0.2 or less. Certain compounds may exhibit selectivity for mutant EGFR of 0.05 or less. Certain compounds may exhibit selectivity for mutant EGFR of 0.02 or less.

[0295] Also provided is a method of modulating EGFR-mediated function in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein.

[0296] Also provided is a method of treating a subject having an EGFR-mediated disease or disorder, such as cancer or a tumor, comprising determining that the subject's genotype comprises a mutant form of EGFR and administering to the subject a compound disclosed herein, or a salt thereof.

[0297] Also provided is a method of treating an EGFR-mediated disease or disorder, such as cancer or tumor, in a subpopulation of subjects, the subpopulation being characterized by the presence of a mutation in EGFR in the genotype of the subjects of the subpopulation, the method comprising administering to the subpopulation of subjects a compound disclosed herein or a salt thereof.

[0298] Also provided is a method of stratifying a subject for response to a therapy comprising administration of a compound disclosed herein or a salt thereof, the method comprising determining the presence of an EGFR mutation in the subject's genotype and administering a compound disclosed herein or a salt thereof.

[0299] Accordingly, in another aspect, certain embodiments provide a method of treating a disorder mediated by HER2 or EGFR in a human or animal subject in need of such treatment, comprising administering to the subject a compound disclosed herein in an amount effective to alleviate or prevent said disorder in the subject.

[0300] In certain embodiments, the disorder is cancer. The cancer can be any currently known cancer or a cancer that will be discovered later, including, but not limited to, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, AIDS-related cancer (Kaposi's sarcoma and lymphoma), anal cancer, appendix cancer, atypical teratoid / rhabdoid tumor, basal cell carcinoma, cholangiocarcinoma (including extrahepatic bile duct), bladder cancer, bone cancer (including osteosarcoma and malignant fibrous histiocytoma), brain tumors (astrocytoma, brain and spinal cord tumors, brain stem glioma, central nervous system atypical teratoid / rhabdoid tumor, central nervous system embryonal tumors, cranial Pharyngoma, ependymoblastoma, ependymoma, medulloblastoma, medulloepithelioma, intermediate pineal parenchymal tumor, supratentorial primitive neuroectodermal tumor, and pineoblastoma), breast cancer, bronchial tumor, Burkitt's lymphoma, basal cell carcinoma, cholangiocarcinoma (including extrahepatic bile duct), bladder cancer, bone cancer (including osteosarcoma and malignant fibrous histiocytoma), carcinoid tumor, cancer of unknown primary site, central nervous system (atypical teratoid / rhabdoid tumor, embryonal tumor, and lymphoma, etc.), cervical cancer, childhood cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell Lymphoma (mycosis fungoides and Sézary syndrome), ductal bile (extrahepatic), ductal carcinoma in situ (DCIS), embryonal tumors (central nervous system), endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma family tumors, extracranial germ cell tumors, extragonadal germ cell tumors, extrahepatic bile duct carcinoma, eye cancer (intraocular melanoma, retinoblastoma, etc.), fibrous histiocytoma of bone (including malignant and osteosarcoma), bladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumors (extracranial, extragonadal, ovarian), gestational trophoblastic tumor, neuroblastoma, hairy cell leukemia, Head and neck cancer, heart cancer, hepatocellular (liver) carcinoma, histiocytosis, Langerhans cell, Hodgkin's lymphoma, hypopharyngeal carcinoma, intraocular melanoma, islet cell tumors (endocrine, pancreatic), Kaposi's sarcoma, kidney (including renal cell), Langerhans cell histiocytosis, laryngeal cancer, leukemia (including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), hairy leukemia), lip and oral cavity cancer, liver cancer (primary), lobular carcinoma in situ (LCIS), lung cancer (non-small cell and small cell), lymphoma (AIDS-related, Burkitt's,Cutaneous T-cell (Mycosis Fungoides and Sézary Syndrome), Hodgkin, Non-Hodgkin, Primary Central Nervous System (CNS), Macroglobulinemia, Waldenstrom, Male Breast Cancer, Malignant Fibrous Histiocytoma and Osteosarcoma of Bone, Medulloblastoma, Medullary Ependymoma, Melanoma (Including Intraocular (Ocular)), Merkel Cell Carcinoma, Mesothelioma (Malignant), Metastatic Neck Squamous Cell Carcinoma of Unknown Primary, Midline Carcinoma Involving NUT Gene, Mouth Cancer, Multiple Endocrine Neoplasia Syndromes, Multiple Myeloma / Plasma Cell Neoplasms, Mycosis Fungoides, Myelodysplastic Syndromes, Myelodysplastic / Myeloproliferative Neoplasms, Myeloid Leukemia, Chronic (CML), Myeloid Leukemia, Acute (AML), Myeloma and Multiple Myeloma, Myeloproliferative Disorders (Chronic), Nasal and Paranasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer Cancer), Oral Cavity Cancer, Lip and Oropharyngeal Cancer, Osteosarcoma and Malignant Fibrous Histiocytoma of Bone, Ovarian Cancer (epithelial, germ cell, low-grade and high-grade ovarian cancer, etc.), Pancreatic Cancer (including Islet Cell Tumors), Papillomatosis, Paraganglioma, Paranasal Sinus and Nasal Cancer, Parathyroid Cancer, Penile Cancer, Pheochromocytoma, Intermediate Pineal Parenchymal Tumor, Pineoblastoma and Supratentorial Primitive Neuroectodermal Tumor, Pituitary Tumor, Plasma Cell Neoplasms / Multiple Myeloma, Pleuropulmonary Blastoma, Pregnancy and Breast Cancer, Primary Central Nervous System (CNS) Lymphoma, Prostate Cancer, Rectal Cancer, Renal Cell (Kidney) Cancer, Renal Pelvis and Ureter, Transitional Cell Carcinoma, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer, Sarcoma (Ewing's Sarcoma) family tumors, Kaposi, soft tissue, uterine), Sezary syndrome, skin cancer (melanoma, Merkel cell carcinoma, non-melanoma), small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, cervical squamous cell carcinoma of unknown primary, metastatic, gastric (stomach) cancer, supratentorial primitive neuroectodermal tumor, T-cell lymphoma (skin, mycosis fungoides and Sezary syndrome), testicular cancer, pharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor (gestational), unknown primary, rare childhood cancer, ureter and renal pelvis, transitional cell carcinoma, urethral cancer, uterine cancer, endometrium, uterine sarcoma, Waldenstrom's hypergammaglobulinemia and Wilms' tumor or variants thereof.

[0301] In certain embodiments, the cancer is selected from small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, gastric cancer, and uterine cancer.

[0302] Additionally, there is provided a pharmaceutical composition comprising a compound disclosed herein together with a pharma- ceutically acceptable carrier.

[0303] In certain embodiments, the pharmaceutical composition is formulated for oral administration. In certain embodiments, the pharmaceutical composition is formulated for parenteral administration. In certain embodiments, the pharmaceutical composition is formulated for intravenous administration. In certain embodiments, the pharmaceutical composition is formulated for intramuscular administration. In certain embodiments, the pharmaceutical composition is formulated for subcutaneous administration.

[0304] In certain embodiments, the oral pharmaceutical composition is selected from a tablet and a capsule.

[0305] definition As used herein, the following terms have the meanings indicated.

[0306] The range of values ​​is disclosed and "n 1 ...~n 2 " or "n 1 ... and n 2 Between (where n 1 and n 2 When the notation "a" is used, "a" is a number, and "b" is a number, the notation is intended to include the numbers themselves and the ranges between these numbers, unless otherwise specified. The ranges may be integers or continuous between the endpoints, and are inclusive. As an example, the range "2 to 6 carbons" is intended to include 2, 3, 4, 5, and 6 carbons, since carbon is an integer unit. Compare, as an example, the range "1 to 3 μM (micromolar)", which is intended to include 1 μM, 3 μM, and all significant digits of any number therebetween (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[0307] The term "about" as used herein is intended to indicate that the numerical value it modifies represents such value as a variable within a margin of error. In the absence of a specific margin of error, such as a standard deviation for an average value given in a chart or table of data, the term "about" should be understood to mean a range that may encompass the stated value, and also a range that may be encompassed by rounding up or down to that number, taking into account significant digits.

[0308] The term "acyl," as used herein, alone or in combination, refers to a carbonyl bonded to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety, where the atom bonded to the carbonyl is carbon. An "acetyl" group is -C(O)CH 3 An "alkylcarbonyl" or "alkanoyl" group refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl, and aroyl.

[0309] The term "alkenyl", as used herein, alone or in combination, refers to a straight or branched chain hydrocarbon group having one or more double bonds and containing 2 to 20 carbon atoms. In certain embodiments, said alkenyl may contain 2 to 6 carbon atoms. The term "alkenylene" refers to a carbon-carbon double bond system bonded at two or more positions, such as ethenylene [(-CH=CH-), (-C::C-)]. Examples of suitable alkenyl groups include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl, and the like. Unless otherwise specified, the term "alkenyl" may include an "alkenylene" group.

[0310] The term "alkoxy," as used herein, alone or in combination, refers to an alkyl ether group, where the term alkyl is as defined below. Examples of suitable alkyl ether groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.

[0311] The term "alkyl," as used herein, alone or in combination, refers to a straight or branched chain alkyl group containing 1 to 20 carbon atoms. In certain embodiments, the alkyl may contain 1 to 10 carbon atoms. In further embodiments, the alkyl may contain 1 to 8 carbon atoms. An alkyl group may be optionally substituted as defined below. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, nonyl, and the like. The term "alkylene," as used herein, alone or in combination, refers to methylene (-CH 2 "alkyl" refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon bonded at two or more positions, such as -. Unless otherwise specified, the term "alkyl" can include "alkylene" groups.

[0312] The term "alkylamino," as used herein, alone or in combination, refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups can be mono- or dialkylated forming groups, such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-ethylmethylamino, and the like.

[0313] The term "alkylidene," as used herein, alone or in combination, refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached.

[0314] The term "alkylthio" as used herein, alone or in combination, refers to an alkylthioether (RS-) group, where the term alkyl is as defined above and the sulfur may be singly or doubly oxidized. Examples of suitable alkylthioether groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

[0315] The term "alkynyl" as used herein, alone or in combination, refers to a straight or branched chain hydrocarbon group having one or more triple bonds and containing 2 to 20 carbon atoms. In certain embodiments, said alkynyl contains 2 to 6 carbon atoms. In further embodiments, said alkynyl contains 2 to 4 carbon atoms. The term "alkynylene" refers to a carbon-carbon triple bond attached at two positions, such as ethynylene (-C:::C-, -C≡C-). Examples of alkynyl groups include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, and the like. Unless otherwise specified, the term "alkynyl" can include "alkynylene" groups.

[0316] The terms "amido" and "carbamoyl", as used herein, alone or in combination, refer to an amino group, as described below, attached to the parent molecular moiety through a carbonyl group (or vice versa). The term "C-amido", as used herein, alone or in combination, refers to the -C(O)N(RR') group, where R and R' are as defined herein or as defined by a specifically enumerated designated "R" group. The term "N-amido", as used herein, alone or in combination, refers to the RC(O)N(R')- group, where R and R' are as defined herein or as defined by a specifically enumerated designated "R" group. The term "acylamino", as used herein, alone or in combination, encompasses an acyl group attached to the parent moiety through an amino group. One example of an "acylamino" group is acetylamino (CH 3 C(O)NH-).

[0317] The term "amino" as used herein, alone or in combination, refers to -NRR', where R and R' are independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted. Additionally, R and R' may join to form a heterocycloalkyl, any of which may be optionally substituted.

[0318] The term "aryl" as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings, where such polycyclic ring systems are fused. The term "aryl" embraces aromatic groups such as phenyl, naphthyl, anthracenyl and phenanthryl.

[0319] The terms "arylalkenyl" or "aralkenyl," as used herein, alone or in combination, refer to an aryl group attached to the parent molecular moiety through an alkenyl group.

[0320] The term "arylalkoxy" or "aralkoxy," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkoxy group.

[0321] The terms "arylalkyl" or "aralkyl," as used herein, alone or in combination, refer to an aryl group attached to the parent molecular moiety through an alkyl group.

[0322] The term "arylalkynyl" or "aralkynyl," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkynyl group.

[0323] The terms "arylalkanoyl" or "aralkanoyl" or "aroyl", as used herein, alone or in combination, refer to acyl groups derived from aryl-substituted alkanecarboxylic acids, such as benzoyl, naphthoyl, phenylacetyl, 3-phenylpropionyl(hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.

[0324] The term aryloxy, as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an oxy.

[0325] The terms “benzo” and “benz” as used herein, alone or in combination, refer to the divalent radical C derived from benzene. 6 H 4 = Examples include benzothiophene and benzimidazole.

[0326] The term "carbamate," as used herein, alone or in combination, refers to an ester of carbamic acid (-NHCOO-), which may be attached to the parent molecular moiety through either the nitrogen or the acid terminus, and may be optionally substituted as defined herein.

[0327] The term "O-carbamyl" as used herein, alone or in combination, refers to a -OC(O)NRR' group, with R and R' as defined herein.

[0328] The term "N-carbamyl," as used herein, alone or in combination, refers to a ROC(O)NR'- group, with R and R' as defined herein.

[0329] The term "carbonyl" as used herein includes formyl [-C(O)H] when alone and in combination is a -C(O)- group.

[0330] The term "carboxyl" or "carboxy" as used herein refers to -C(O)OH or the corresponding "carboxylate" anion (such as in carboxylate salts). An "O-carboxy" group refers to a RC(O)O- group, where R is as defined herein. A "C-carboxy" group refers to a -C(O)OR group, where R is as defined herein.

[0331] The term "cyano," as used herein, alone or in combination, refers to --CN.

[0332] The term "cycloalkyl" or alternatively "carbocycle", as used herein, alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl group, where each cyclic moiety contains 3 to 12 carbon atom ring members, and may be an optionally substituted benzo-fused ring system as defined herein. In certain embodiments, said cycloalkyl may contain 5 to 7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl, and the like. As used herein, "bicyclic ring system" and "tricyclic ring system" are intended to include both fused ring systems, such as decahydronaphthalene, octahydronaphthalene, and the like, as well as polycyclic (multi-center) saturated or partially saturated types. Examples of the latter type of isomers include, in general, bicyclo-[1,1,1]pentane, camphor, adamantane, and bicyclo[3,2,1]octane.

[0333] The term "ester," as used herein, alone or in combination, refers to a carboxy group bridging two moieties which are joined at a carbon atom.

[0334] The term "ether," as used herein, alone or in combination, refers to an oxy group bridging two moieties which are joined at a carbon atom.

[0335] The terms "halo" or "halogen," as used herein, alone or in combination, refer to fluorine, chlorine, bromine, or iodine.

[0336] The term "haloalkoxy," as used herein, alone or in combination, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

[0337] The term "haloalkyl", as used herein, alone or in combination, refers to an alkyl group having the meaning as defined above in which one or more hydrogens have been replaced by halogen. In particular, monohaloalkyl, dihaloalkyl and polyhaloalkyl groups are included. As an example, monohaloalkyl groups can have iodo, bromo, chloro or fluoro atoms within the group. Dihalo and polyhaloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. "Haloalkylene" refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF 2 -), chloromethylene (-CHCl-), etc.

[0338] The term "heteroalkyl," as used herein, alone or in combination, refers to a stable linear, branched, or combination thereof, which is fully saturated or contains one to three degrees of unsaturation and consists of the specified number of carbon atoms and one to three heteroatoms selected from N, O, and S, where the N and S atoms can be optionally oxidized or the N heteroatom can be optionally quaternized. The heteroatoms can be located at any interior position of the heteroalkyl group. For example, -CH 2 -NH-OCH 3 and so forth, up to two heteroatoms may be consecutive.

[0339] The term "heteroaryl" as used herein, alone or in combination, refers to a 3-15 membered unsaturated heteromonocyclic ring or fused monocyclic, bicyclic, or tricyclic ring system, where at least one of the fused rings is aromatic containing at least one atom selected from N, O, and S. In certain embodiments, the heteroaryl can contain 1-4 heteroatoms as ring members. In further embodiments, the heteroaryl can contain 1-2 heteroatoms as ring members. In certain embodiments, the heteroaryl can contain 5-7 atoms. The term also encompasses fused polycyclic groups in which a heterocyclic ring is fused to an aryl ring, a heteroaryl ring is fused to another heteroaryl ring, a heteroaryl ring is fused to a heterocycloalkyl ring, or a heteroaryl ring is fused to a cycloalkyl ring. Examples of heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

[0340] The terms "heterocycloalkyl" and, interchangeably, "heterocycle", as used herein, alone or in combination, refer to a saturated, partially unsaturated or fully unsaturated (but non-aromatic), monocyclic, bicyclic or tricyclic heterocyclic group each containing at least one heteroatom as a ring member, where each of said heteroatoms may be independently selected from nitrogen, oxygen and sulfur. In certain embodiments, said heterocycloalkyl may contain 1 to 4 heteroatoms as ring members. In other embodiments, said heterocycloalkyl may contain 1 to 2 heteroatoms as ring members. In certain embodiments, said heterocycloalkyl may contain 3 to 8 ring members in each ring. In further embodiments, said heterocycloalkyl may contain 3 to 7 ring members in each ring. In yet other embodiments, said heterocycloalkyl may contain 5 to 6 ring members in each ring. "Heterocycloalkyl" and "heterocycle" are intended to include sulfone, sulfoxide, N-oxide of a tertiary nitrogen ring member, and carbocyclic fused and benzofused ring systems; in addition, both terms also include systems in which a heterocycle is fused to an aryl group or an additional heterocyclic group as defined herein. Examples of heterocyclic groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. Unless specifically prohibited, a heterocycle group may be optionally substituted.

[0341] The term "hydrazinyl," as used herein, alone or in combination, refers to two amino groups joined by a single bond, i.e., --NN--.

[0342] The term "hydroxy," as used herein, alone or in combination, refers to --OH.

[0343] The term "hydroxyalkyl," as used herein, alone or in combination, refers to a hydroxy group attached to the parent molecular moiety through an alkyl group.

[0344] The term "imino," as used herein, alone or in combination, refers to =N-.

[0345] The term "iminohydroxy," as used herein, alone or in combination, refers to =N(OH) and =NO-.

[0346] The phrase "in the backbone" refers to the longest contiguous or adjacent chain of carbon atoms beginning from the point of attachment of a group to a compound of any one of the formulas disclosed herein.

[0347] The term "isocyanato" refers to a -NCO group.

[0348] The term "isothiocyanato" refers to the group -NCS.

[0349] The phrase "linear chain of atoms" refers to the longest linear chain of atoms independently selected from carbon, nitrogen, oxygen, and sulfur.

[0350] The term “lower” as used herein, alone or in combination, unless otherwise specifically defined, refers to an alkyl group having 1 to 6 carbon atoms (i.e., C 1 ~C 6 It means that it contains (alkyl).

[0351] The term "lower aryl," as used herein, alone or in combination, means phenyl or naphthyl, either of which may be optionally substituted as specified.

[0352] The term "lower heteroaryl," as used herein, alone or in combination, means either 1) a monocyclic heteroaryl containing 5 or 6 ring members, of which 1 to 4 ring members can be heteroatoms selected from N, O, and S, or 2) a bicyclic heteroaryl in which any of the fused rings contains 5 or 6 ring members and between them contains 1 to 4 heteroatoms selected from N, O, and S.

[0353] The term “lower cycloalkyl,” as used herein, alone or in combination, refers to a monocyclic cycloalkyl having 3 to 6 ring members (i.e., C 3 ~C 6 Lower cycloalkyl may be unsaturated. Examples of lower cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0354] The term “lower heterocycloalkyl,” as used herein, alone or in combination, refers to a monocyclic heterocycloalkyl (i.e., C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 3 ~C 6 Examples of lower heterocycloalkyl include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl. Lower heterocycloalkyl can be unsaturated.

[0355] The term "lower amino," as used herein, alone or in combination, refers to --NRR', where R and R' are independently selected from hydrogen and lower alkyl, either of which may be optionally substituted.

[0356] The term "mercaptyl" as used herein, alone or in combination, refers to an RS-group, where R is as defined herein.

[0357] The term "nitro" as used herein, alone or in combination, means -NO 2 Refers to...

[0358] The terms "oxy" or "oxa," as used herein, alone or in combination, refer to --O--.

[0359] The term "oxo" as used herein, alone or in combination, refers to =O.

[0360] The term "perhaloalkoxy" refers to an alkoxy group in which all of the hydrogen atoms have been replaced by halogen atoms.

[0361] The term "perhaloalkyl," as used herein, alone or in combination, refers to an alkyl group having all of the hydrogen atoms replaced by halogen atoms.

[0362] The terms "sulfonate", "sulfonic acid" and "sulfonic" as used herein, alone or in combination, refer to -SO 3 H group and its anion (when the sulfonic acid is used in the form of a salt).

[0363] The term "sulfanyl" as used herein, alone or in combination, refers to --S--.

[0364] The term "sulfinyl" as used herein, alone or in combination, refers to -S(O)-.

[0365] The term "sulfonyl," as used herein, alone or in combination, refers to -S(O) 2 - refers to.

[0366] The term "N-sulfonamide" refers to RS(=O) 2 It refers to the group NR'--, where R and R' are as defined herein.

[0367] The term "S-sulfonamide" refers to -S(=O)2 It refers to the group NRR', where R and R' are as defined herein.

[0368] The terms "thia" and "thio," as used herein, alone or in combination, refer to an -S- group or an ether where the oxygen is replaced with a sulfur. The oxidized derivatives of the thio group, namely, sulfinyl and sulfonyl, are included in the definition of thia and thio.

[0369] The term "thiol", as used herein, alone or in combination, refers to a -SH group.

[0370] The term "thiocarbonyl" as used herein includes thioformyl-C(S)H when alone and in combination is a -C(S)- group.

[0371] The term "N-thiocarbamyl" refers to a ROC(S)NR'- group, with R and R' as defined herein.

[0372] The term "O-thiocarbamyl" refers to a -OC(S)NRR' group, with R and R' as defined herein.

[0373] The term "thiocyanato" refers to the group -CNS.

[0374] The term "trihalomethanesulfonamide" means X 3 CS(O) 2 It refers to the group NR--, where X is a halogen and R is as defined herein.

[0375] The term "trihalomethanesulfonyl" means X 3 CS(O) 2 - group where X is a halogen.

[0376] The term "trihalomethoxy" means X 3 It refers to a CO-group where X is a halogen.

[0377] The term "trisubstituted silyl," as used herein, alone or in combination, refers to a silicone group in which the three free valences in the definition of substituted amino are replaced with groups listed herein. Examples include trimethylsilyl, tert-butyldimethylsilyl, triphenylsilyl, and the like.

[0378] Any definition herein can be used in combination with any other definition to describe a composite structural group.By convention, the latter element of any such definition is the element that is attached to the parent moiety.For example, the composite group alkylamide can represent an alkyl group that is attached to the parent molecule via an amide group, and the term alkoxyalkyl can represent an alkoxy group that is attached to the parent molecule via an alkyl group.

[0379] When a group is defined as "null", what is meant is that said group is not present.

[0380] The term "optionally substituted" means that the preceding group can be substituted or unsubstituted. When substituted, the substituents of an "optionally substituted" group may include, alone or in combination, 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 perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N 3 , S.H., S.C.H. 3 , C(O)CH 3, CO 2 CH 3 , CO 2 H, pyridinyl, thiophene, furanyl, lower carbamates, and lower ureas. If structurally feasible, two substituents may be joined together to form a fused 5-, 6-, or 7-membered carbocyclic or heterocyclic ring consisting of 0-3 heteroatoms, for example, methylenedioxy or ethylenedioxy. Optionally substituted groups may be unsubstituted (e.g., -CH 2 CH 3 ), or completely substituted (e.g., -CF 2 CF 3 ), monosubstituted (e.g., -CH 2 CH 2 F) or can be substituted at any level between fully substituted and monosubstituted (e.g., -CH 2 CF 3 ). When a substituent is described without qualification as to substitution, both substituted and unsubstituted forms are encompassed. When a substituent is qualified as "substituted," the substituted form is specifically intended. Additionally, where appropriate, different optional sets of substituents may be defined for a particular moiety, and in these cases the optional substitutions will often be as defined immediately following the phrase "optionally substituted with."

[0381] The term R or R', appearing alone and without a number designation, unless otherwise defined, refers to a moiety selected from hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, and heterocycloalkyl, any of which may be optionally substituted. Such R and R' groups should be understood to be optionally substituted as defined herein. Regardless of whether an R group has a number designation, R, R', and R nAll R groups, including (where n=(1, 2, 3, ... n)), all substituents, as well as all terms, should be understood to be independent of all others with respect to selection from a group. If any variable, substituent, or term (e.g., aryl, heterocycle, R, etc.) occurs more than one time in a formula or generic structure, its definition at each occurrence is independent of its definition at every other occurrence. One of skill in the art will further recognize that certain groups may be attached to a parent molecule or may occupy a position in the chain of elements from either end as depicted. For example, an unsymmetrical group such as -C(O)N(R)- may be attached to the parent moiety at either the carbon or the nitrogen.

[0382] Asymmetric centers exist in the compounds disclosed herein. These centers are represented by the symbols "R" or "S" depending on the configuration of the substituents around the chiral carbon atom. It should be understood that the present disclosure encompasses all stereochemical isomers, including diastereomeric, enantiomeric and epimeric forms as well as d- and l-isomers and mixtures thereof. Individual stereoisomers of the compounds can be prepared synthetically from commercially available starting materials containing chiral centers, or by preparation of a mixture of enantiomeric products followed by separation, such as conversion to a diastereomeric mixture, followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on a chiral chromatographic column, or any other suitable method known in the art. Starting compounds of a particular stereochemistry are commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds disclosed herein can exist as geometric isomers. The present disclosure includes all cis, trans, syn, anti, entgegen (E) and zusammen (Z) isomers and the appropriate mixtures thereof. Furthermore, the compounds may exist as tautomers; all tautomers are provided by the present disclosure. In addition, the compounds disclosed herein may exist in unsolvated forms as well as solvated forms with pharma- ceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.

[0383] The term "bond" refers to a covalent bond between two atoms or between two moieties when the atoms joined by the bond are considered to be part of a larger substructure. The bond may be a single, double or triple bond unless otherwise specified. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond may or may not be present at that position.

[0384] The term "disease" as used herein is generally intended to be synonymous with, and is used interchangeably with, the terms "disorder," "syndrome," and "condition" (as in medical condition), all of which refer to an abnormal condition of the human or animal body or one of its organs that impairs the normal functioning, is usually manifested by prominent signs and symptoms, and causes a decrease in the life span or quality of life of the human or animal.

[0385] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in this disclosure. Such administration includes the co-administration of these therapeutic agents substantially simultaneously (e.g., in a single capsule having a fixed ratio of active ingredients or in multiple separate capsules for each active ingredient). Moreover, such administration also includes the sequential use of each type of therapeutic agent. In either case, the treatment regimen will provide the beneficial effects of the drug combination in treating the condition or disorder described herein.

[0386] "HER2 inhibitor" refers herein to a compound that exhibits an IC50 for HER2 activity of about 100 μM or less, more typically about 50 μM or less, as measured by the HER2 assay generally described herein. "IC50" is the concentration of an inhibitor that reduces the activity of an enzyme (e.g., HER2) to half-maximum. Certain compounds disclosed herein have been found to exhibit inhibition against HER2. In certain embodiments, the compound exhibits an IC50 for HER2 of about 10 μM or less, as measured by the HER2 assay described herein; in other embodiments, the compound exhibits an IC50 for HER2 of about 1 μM or less; in yet other embodiments, the compound exhibits an IC50 for HER2 of about 200 nM or less; and in yet other embodiments, the compound may exhibit an IC50 for HER2 of about 50 nM or less.

[0387] Certain compounds show selectivity for certain mutant forms of HER2 over WT EGFR. For certain compounds and certain mutants, the IC 50 (HER2 mutant) / IC 50 The mutant HER2 selectivity, determined as a ratio of (WT EGFR), is less than or equal to 0.5. For certain compounds and certain mutants, the mutant HER2 selectivity is less than or equal to 0.2. For certain compounds and certain mutants, the mutant HER2 selectivity is less than or equal to 0.1.

[0388] An "EGFR inhibitor" is an inhibitor that has an IC50 of about 100 μM or less, more typically about 50 μM or less, for EGFR activity as measured in the EGFR assay outlined herein. 50 "IC" is used to refer to compounds that exhibit 50 " is the concentration of an inhibitor that reduces the activity of an enzyme (e.g., EGFR) to half of its maximal level. Certain compounds disclosed herein have been found to exhibit inhibition against EGFR. In certain embodiments, a compound has an IC of about 10 μM or less for EGFR as measured in the EGFR assay described herein. 50 in another embodiment, the compound exhibits an IC50 in another embodiment, the compound exhibits an IC for EGFR of about 200 nM or less. 50 in another embodiment, the compound exhibits an IC of about 50 nM or less for EGFR. 50 is presented.

[0389] Certain compounds show selectivity for certain mutant forms of EGFR over WT EGFR. For certain compounds and certain mutants, the IC 50 (EGFR mutant) / IC 50 The mutant EGFR selectivity, determined as a ratio of (WT EGFR), is less than or equal to 0.5. For certain compounds and certain mutants, the mutant EGFR selectivity is less than or equal to 0.2. For certain compounds and certain mutants, the mutant EGFR selectivity is less than or equal to 0.1.

[0390] The phrase "therapeutically effective" is intended to qualify the amount of active ingredient used in the treatment of a disease or disorder or in the achievement of a clinical endpoint.

[0391] The term "therapeutically acceptable" refers to a compound (or a salt, prodrug, tautomer, zwitterionic form, etc.) that is suitable for use in contact with the tissues of a patient without undue toxicity, irritation, or allergic response, commensurate with a reasonable benefit / risk ratio, and is effective for its intended use.

[0392] As used herein, reference to "treatment" of a patient is intended to include prevention. Treatment may be proactive in nature, i.e., include prevention of disease. Prevention of disease may include complete protection from disease, such as, for example, in the case of prevention of infection by a pathogen, or may include prevention of disease progression. For example, prevention of disease does not mean complete elimination of all effects associated with the disease at any level, but may instead mean preventing symptoms of the disease to a clinically significant or detectable level. Prevention of disease may also mean preventing a disease from progressing to a late stage of the disease.

[0393] The term "patient" is generally synonymous with the term "subject" and includes all mammals, including humans. Examples of patients include humans, farm animals such as cows, goats, sheep, pigs and rabbits, and companion animals such as dogs, cats, rabbits and horses. Preferably, the patient is a human.

[0394] The term "prodrug" refers to a compound that is more active in vivo. Certain compounds disclosed herein can also exist as prodrugs, as described in "Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology" (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described herein are structurally modified forms of the compounds that readily undergo chemical changes under physiological conditions to provide the compounds. Additionally, prodrugs can be converted to the compounds by chemical or biochemical methods in an ex vivo environment. For example, a prodrug can be slowly converted to a compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because in some situations they may be easier to administer than the compound or parent drug. Prodrugs may be bioavailable by oral administration, for example, whereas the parent drug is not. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug. Various types of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. One non-limiting example of a prodrug may be a compound that is administered as an ester (the "prodrug"), but is subsequently metabolically hydrolyzed to the carboxylic acid, which is the active entity. Additional examples include peptidyl derivatives of the compound.

[0395] The compounds disclosed herein can exist as therapeutically acceptable salts. The present disclosure includes the above compounds in the form of salts, including acid addition salts. Suitable salts include salts formed with both organic and inorganic acids. Such acid addition salts will usually be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be useful in the preparation and purification of the compound in question. Base addition salts may also be formed and may be pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, see Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

[0396] The term "therapeutically acceptable salt" as used herein refers to a water- or oil-soluble or dispersible salt or zwitterionic form of a compound disclosed herein that is therapeutically acceptable as defined herein. The salt may be prepared by reacting the appropriate compound in the form of a free base with an appropriate acid during the final isolation and purification of the compound or separately. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, malon ... The salts of the basic salts include, for example, methyl, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate (p-tosylate) and undecanoate. The basic groups in the compounds disclosed herein can also be quaternized with methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dimethyl, diethyl, dibutyl and diamyl sulfate; decyl chlorides, bromides and iodides, lauryl, myristyl and steryl; and benzyl and phenethyl bromides. Examples of acids that can be used to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. Salts can also be formed by coordination of the compound with an alkali metal or alkaline earth metal ion. Thus, the present disclosure contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.

[0397] Base addition salts can be prepared during the final isolation and purification of the compounds by reacting the carboxyl group with a suitable base, such as the hydroxide, carbonate or bicarbonate of a metal cation, or ammonia or an organic primary, secondary or tertiary amine. Therapeutically acceptable salt cations include lithium, sodium, potassium, calcium, magnesium and aluminum, as well as non-toxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine and N,N'-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine and piperazine.

[0398] Pharmaceutical Compositions Although it may be possible for the compounds of the present disclosure to be administered as raw chemicals, they may also be provided as pharmaceutical formulations. Thus, pharmaceutical formulations are provided herein that include one or more of the specific compounds disclosed herein or one or more pharma-ceutically acceptable salts, esters, prodrugs, amides or solvates thereof, together with one or more pharma-ceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof. Appropriate formulations depend on the route of administration selected. Any well-known techniques, carriers and excipients as appropriate and understood in the art may be used. The pharmaceutical compositions disclosed herein may be manufactured by any method known in the art, for example, by conventional mixing, dissolving, granulating, dragee-making, gelling, emulsifying, encapsulating, entrapping or compressing processes.

[0399] The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual and intraocular) administration, although the most suitable route may depend, for example, on the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art. In general, these methods include the step of bringing into association a compound of the present disclosure or a pharma-ceutically acceptable salt, ester, amide, prodrug or solvate thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation.

[0400] Oral route Compounds of the disclosure can be administered orally, including by swallowing, so that the compound enters the gastrointestinal tract or is absorbed into the blood stream directly from the mouth, including by sublingual or buccal administration.

[0401] Compositions suitable for oral administration include solid preparations such as tablets, pills, cachets, lozenges and hard or soft capsules, which may contain liquids, gels, powders or granules, solutions or suspensions in aqueous or non-aqueous liquids or oil-in-water or water-in-oil liquid emulsions. The active ingredient may also be presented as a bolus, electuary or paste.

[0402] In tablet or capsule form, the amount of drug present may range from about 0.05% to about 95% by weight, more typically from about 2% to about 50% by weight of the dosage form.

[0403] In addition, the tablet or capsule may contain a disintegrant, which comprises from about 0.5% to about 35% by weight of the dosage form, more typically from about 2% to about 25% by weight. Examples of disintegrants include methylcellulose, sodium or calcium carboxymethylcellulose, croscarmellose sodium, polyvinylpyrrolidone, hydroxypropylcellulose, starch, and the like.

[0404] Suitable binders for use in tablets include gelatin, polyethylene glycol, sugars, gums, starch, hydroxypropylcellulose, etc. Suitable diluents for use in tablets include mannitol, xylitol, lactose, dextrose, sucrose, sorbitol and starch.

[0405] Suitable surfactants and lubricants for use in the tablet or capsule may be present in amounts of about 0.1% to about 3% by weight and include polysorbate 80, sodium dodecyl sulfate, talc, and silicon dioxide.

[0406] Suitable lubricants for use in tablets or capsules may be present in amounts from about 0.1% to about 5% by weight and include calcium, zinc or magnesium stearate, sodium stearyl fumarate, and the like.

[0407] Tablets can be produced by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as powder or granules, optionally mixed with a binder, an inert diluent, or a lubricant, surfactant, or dispersant, in a suitable machine. Molded tablets can be produced by molding a mixture of the powdered compound moistened with a liquid diluent in a suitable machine. Dyes or pigments can be added to the tablets for identification or to characterize different combinations of active compound doses.

[0408] Liquid formulations can include emulsions, solutions, syrups, elixirs and suspensions, which can be used in soft or hard capsules. Such formulations can include pharma- ceutically acceptable carriers, such as water, ethanol, polyethylene glycol, cellulose or oil. Formulations can include one or more emulsifying agents and / or suspending agents.

[0409] Compositions for oral administration may be formulated as immediate release or modified release, such as delayed or sustained release, optionally with an enteric coating.

[0410] In another embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0411] Pharmaceutical preparations that can be used orally include tablets, push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as powder or granules, optionally mixed with a binder, inert diluent or lubricant, surfactant or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Tablets can optionally be coated or scored, and can also be formulated to provide sustained or controlled release of the active ingredient therein. All preparations for oral administration should be in dosages suitable for such administration. Push-fit capsules can contain the active ingredient mixed with a filler, such as lactose, a binder, such as starch, and / or a lubricant, such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, active compounds can be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin or liquid polyethylene glycol. In addition, stabilizers can be added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0412] Parenteral Administration The compounds of the present disclosure can be administered directly into the bloodstream, muscle or internal organs by injection, for example, bolus injection or continuous infusion. Suitable means for parenteral administration include intravenous, intramuscular, subcutaneous intra-arterial, intraperitoneal, intrathecal, intracranial, etc. Suitable devices for parenteral administration include syringes (including needle and needle-free syringes) and infusion methods. Preparations can be provided in unit dose or multi-dose containers, for example sealed ampoules and vials.

[0413] Most parenteral formulations are aqueous solutions that contain excipients such as salts, buffers, suspending agents, stabilizers and / or dispersing agents, antioxidants, bacteriostats, preservatives and solutes that render the formulation isotonic with the blood of the intended recipient, and carbohydrates.

[0414] Parenteral preparations may be prepared in dehydrated form (e.g., by lyophilization) or as sterile non-aqueous solutions. These preparations may be used with a suitable vehicle, such as sterile water. Dissolution enhancers may also be used in the preparation of parenteral solutions. Compositions for parenteral administration may be formulated as immediate release or modified release, such as delayed or sustained release. Furthermore, the compounds may be formulated as depot preparations. Such long-acting preparations may be administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as sparingly soluble salts.

[0415] The compounds can be formulated for parenteral administration by injection, for example, bolus injection or continuous infusion. Injectable preparations can be provided in unit dosage form, for example, in ampoules or in multi-dose containers, with added preservatives. The compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous media, and can contain formulatory agents, such as suspending, stabilizing and / or dispersing agents. The preparations can be provided in single-dose or multi-dose containers, for example, sealed ampoules and vials, and can be stored in powder form or freeze-dried (lyophilized) condition, requiring only the addition of a sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the kind described above.

[0416] Preparations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound, which may contain antioxidants, buffers, bacteriostats, and solutes that render the preparation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds, allowing for the preparation of highly concentrated solutions.

[0417] In addition to the above-mentioned preparations, the compound can be formulated as a depot preparation.Such long-acting preparations can be administered by implantation (for example, subcutaneously or intramuscularly) or intramuscular injection.Thus, for example, the compound can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as sparingly soluble salts.

[0418] Topical administration The compounds of the present disclosure can be administered topically (e.g., to the skin, mucous membranes, ears, nose, or eyes) or transdermally. Formulations for topical administration can include, but are not limited to, lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches, and the like. Pharmaceutically acceptable carriers for topical formulations can include water, alcohol, mineral oil, glycerin, polyethylene glycol, and the like. Topical administration can also be achieved, for example, by electroporation, iontophoresis, photophoresis, and the like.

[0419] Typically, the active ingredient for topical administration may comprise from about 0.001% to about 10% w / w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10% w / w of the formulation; less than 5% w / w; 2% w / w to 5% w / w; or 0.1% to 1% w / w.

[0420] Compositions for topical administration may be formulated as immediate or modified release, such as delayed or sustained release.

[0421] Certain compounds disclosed herein can be administered locally, i.e., by non-systemic administration. This includes external application of the compounds disclosed herein to epithelium or buccal cavity, as well as instillation of such compounds into the ear, eye and nose, so that the compounds do not enter the bloodstream as much. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

[0422] Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation, such as gels, liniments, lotions, creams, ointments or pastes, as well as drops suitable for administration to the eye, ear or nose. The active ingredient for topical administration may, for example, comprise 0.001% to 10% w / w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10% w / w. In other embodiments, it may comprise less than 5% w / w. In certain embodiments, the active ingredient may comprise 2% w / w to 5% w / w. In other embodiments, it may comprise 0.1% to 1% w / w of the formulation.

[0423] Rectal, buccal and sublingual administration Suppositories for rectal administration of the compounds of the present disclosure can be prepared by mixing the active agent with a suitable non-irritating excipient such as cocoa butter, synthetic mono-, di-, or triglycerides, fatty acids, or polyethylene glycols, which are solid at ordinary temperatures but liquid at rectal temperature and therefore will melt in the rectum and release the drug.

[0424] For buccal or sublingual administration, the compositions can take the form of tablets, lozenges, pastilles, or gels formulated in a conventional manner. Such compositions may contain the active ingredient in a flavored base, such as sucrose and acacia or tragacanth.

[0425] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter, polyethylene glycol or other glycerides.

[0426] Inhalation administration For administration by inhalation, the compound can be conveniently delivered from an insufflator, a nebulizer pressurized pack or other means convenient for delivering an aerosol spray. The pressurized pack can contain a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. For pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compound according to the present disclosure can be in the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base, such as lactose or starch. The powder composition can be provided in unit dosage form, for example in capsules, cartridges, gelatin or blister packs, from which the powder can be administered using an inhaler or insufflator.

[0427] Other carrier materials and administration methods known in the art of formulation may also be used. The pharmaceutical compositions of the present disclosure may be prepared by any of the known techniques of pharmacy, including effective formulation and administration procedures. Preferred unit dosage formulations are those that contain an effective dose or an appropriate fraction thereof of active ingredient, as described herein below.

[0428] It should be understood that in addition to the ingredients specifically listed above, the formulations described above may include other agents conventional in the art having regard to the type of formulation; for example, those suitable for oral administration may include flavoring agents.

[0429] The compounds may be administered orally or by injection at a dose of 0.1 to 500 mg / kg per day. The adult dose range is generally 5 mg to 2 g / day. Tablets or other presentation forms provided in discrete units may conveniently contain one or more compounds in such a dosage amount or multiples thereof that are effective, for example, a unit containing 5 mg to 500 mg, usually about 10 mg to 200 mg.

[0430] The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

[0431] The compound may be administered in various modes, for example orally, topically or by injection. The exact amount of compound administered to a patient may be the responsibility of the attending physician. The specific dose level for any particular patient may depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, route of administration, excretion rate, drug combination, the exact disorder being treated and the severity of the symptom or condition being treated. Furthermore, the route of administration may vary depending on the condition and its severity. The above considerations regarding effective formulations and administration procedures are well known in the art and are described in standard textbooks.

[0432] Preferred unit dosage forms are those containing an effective dose, as hereinbelow recited, or an appropriate fraction thereof, of an active ingredient.

[0433] It should be understood that in addition to the ingredients particularly listed above, the above formulations may include other agents conventional in the art having regard to the type of formulation; for example, those suitable for oral administration may include flavoring agents.

[0434] The compounds may be administered orally or by injection at a dose of 0.1 to 500 mg / kg per day. The dose range for adults is generally 5 mg to 2 g / day. Tablets or other presentation forms provided in discrete units may conveniently contain one or more compounds in such a dosage amount or multiples thereof that are effective, for example, a unit containing 5 mg to 500 mg, usually about 10 mg to 200 mg.

[0435] The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

[0436] The compound may be administered in various modes, for example, orally, topically or by injection. The exact amount of compound administered to a patient may be the responsibility of the attending physician. The specific dose level for any particular patient may depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, route of administration, excretion rate, drug combination, the exact disorder being treated and the severity of the symptom or condition being treated. The route of administration may also vary depending on the condition and its severity.

[0437] Combination and Combined Therapies In certain instances, it may be appropriate to administer at least one of the compounds described herein (or a pharma- ceutically acceptable salt, ester, or prodrug thereof) in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient when receiving one of the compounds described herein is hypertension, it may be appropriate to administer an antihypertensive drug in combination with the first therapeutic agent. Alternatively, by way of example only, the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjunct (i.e., the adjunct may have only minimal therapeutic benefit by itself, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Alternatively, by way of example only, the benefit experienced by the patient may be increased by administering one of the compounds described herein with another therapeutic agent (including a treatment regimen) that also has a therapeutic benefit. By way of example only, in the treatment of diabetes that includes administering one of the compounds described herein, an increased therapeutic benefit may occur by also providing the patient with another therapeutic agent for diabetes. In any case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient may simply be the additive benefit of the two therapeutic agents, or the patient may experience a synergistic benefit.

[0438] In another aspect, as disclosed herein, compounds with EGFR or HER2 inhibitory properties are optionally used in combination with treatments that provide another benefit to the patient. The inhibitor and any other therapy are optionally administered before, during or after the onset of a disease or condition, and the timing of administering the composition containing the inhibitor varies in some embodiments. Thus, for example, the inhibitor can be used as a prophylactic agent and is administered continuously to a subject prone to developing a condition or disease to prevent the onset of the disease or condition. The inhibitor or composition is optionally administered to the subject during or as early as possible after the onset of symptoms.

[0439] As disclosed herein, compounds with EGFR or HER2 inhibitory properties may be used in combination with anti-cancer drugs, including, but not limited to, the following classes: alkylating agents, antimetabolites, plant alkaloids and terpenoids, topoisomerase inhibitors, cytotoxic antibiotics, angiogenesis inhibitors, and tyrosine kinase inhibitors.

[0440] For use in the treatment or amelioration of cancer and neoplastic diseases, compounds with EGFR or HER2 inhibitory properties, as disclosed herein, may be optimally used in conjunction with one or more of the following non-limiting examples of anti-cancer drugs: 1) Inhibitors or modulators of proteins involved in one or more DNA damage repair (DDR) pathways, such as a.PARP1 / 2, including but not limited to olaparib, niraparib, and rucaparib; b. Checkpoint kinase 1 (CHK1), including but not limited to UCN-01, AZD7762, PF477736, SCH900776, MK-8776, LY2603618, V158411, and EXEL-9844; c. Checkpoint kinase 2 (CHK2), including but not limited to PV1019, NSC109555, and VRX0466617; d. Dual CHK1 / CHK2, including but not limited to XL-844, AZD7762, and PF-473336; e. WEE1, including but not limited to MK-1775 and PD0166285; f. ATMs, including but not limited to KU-55933; g. DNA-dependent protein kinases, including but not limited to, NU7441 and M3814; and h.Another protein involved in DDR; 2) One or more immune checkpoint inhibitors or modulators, including but not limited to: PD-1 inhibitors such as nivolumab (OPDIVO), pembrolizumab (KEYTRUDA), pidilizumab (CT-011), and AMP-224 (AMPLIMMUNE); b. PD-L1 inhibitors such as atezolizumab (TECENTRIQ), avelumab (BAVENCIO), durvalumab (IMFINZI), MPDL3280A (TECENTRIQ), BMS-936559 and MEDI4736; c. Anti-CTLA-4 antibodies such as ipilimumab (YERVOY) and CP-675,205 (TREMELIMUMAB); dT-cell immunoglobulin and mucin domain 3 (Tim-3) inhibitor; e Inhibitor of V-domain Ig suppressor of T cell activation (Vista); fB and T lymphocyte attenuator (BTLA) inhibitors; g. Lymphocyte activation gene 3 (LAG3) inhibitors; and hInhibitor of T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT); 3) telomerase inhibitors or telomeric DNA binding compounds; 4) Alkylating agents, including but not limited to chlorambucil (LEUKERAN), oxaliplatin (ELOXATIN), streptozocin (ZANOSAR), dacarbazine, ifosfamide, lomustine (CCNU), procarbazine (MATULAN), temozolomide (TEMODAR) and thiotepa; 5) DNA cross-linking agents, including but not limited to carmustine, chlorambucil (LEUKERAN), carboplatin (PARAPLATIN), cisplatin (PLATIN), busulfan (MYLERAN), melphalan (ALKERAN), mitomycin (MITOSOL), and cyclophosphamide (ENDOXAN); 6) Antimetabolites, including but not limited to, cladribine (LEUSTATIN), cytabine, (ARA-C), mercaptopurine (PURINETHOL), thioguanine, pentostatin (NIPENT), cytosine arabinoside (cytarabine, ARA-C), gemcitabine (GEMZAR), fluorouracil (5-FU, CARAC), capecitabine (XELODA), leucovorin (FUSILEV), methotrexate (RHEUMATREX), and raltitrexed; 7) Antimitotics (which are often plant alkaloids and terpenoids) or derivatives thereof, including but not limited to taxanes such as docetaxel (TAXITERE), paclitaxel (ABRAXANE, TAXOL), vinca alkaloids such as vincristine (ONCOVIN), vinblastine, vindesine, and vinorelbine (NAVELBINE); 8) Topoisomerase inhibitors, including but not limited to amsacrine, camptothecin (CTP), genistein, irinotecan (CAMPTOSAR), topotecan (HYCAMTIN), doxorubicin (ADRIAMYCIN), daunorubicin (CERUBIDINE), epirubicin (ELLENCE), ICRF-193, teniposide (VUMON), mitoxantrone (NOVANTRONE) and etoposide (EPOSIN); 9) DNA replication inhibitors, including but not limited to fludarabine (FLUDARA), aphidicolin, ganciclovir and cidofovir; 10) Ribonucleoside diphosphate reductase inhibitors, including but not limited to hydroxyurea; 11) Transcription inhibitors, including but not limited to actinomycin D (dactinomycin, COSMEGEN) and plicamycin (mithramycin); 12) DNA cleaving agents, including but not limited to, bleomycin (BLENOXANE), idarubicin; 13) Cytotoxic antibiotics, including but not limited to actinomycin D (dactinomycin, COSMEGEN); 14) Aromatase inhibitors, including but not limited to aminoglutethimide, anastrozole (ARIMIDEX), letrozole (FEMARA), vorozole (RIVIZOR), and exemestane (AROMASIN); 15) Angiogenesis inhibitors, including but not limited to, genistein, sunitinib (SUTENT), ramucirumab (CYRAMZA), and bevacizumab (AVASTIN); 16) Antisteroids and antiandrogens, including but not limited to aminoglutethimide (CYTADREN), bicalutamide (CASODEX), cyproterone, flutamide (EULEXIN), nilutamide (NILANDRON); 17) Tyrosine kinase inhibitors, including but not limited to imatinib (GLEEVEC), erlotinib (TARCEVA), lapatinib (TYKERB), sorafenib (NEXAVAR) and axitinib (INLYTA); 18) mTOR inhibitors, including but not limited to everolimus, temisirolimus (TORISEL), and sirolimus; 19) Monoclonal antibodies, including but not limited to trastuzumab (HERCEPTIN) and rituximab (RITUXAN); 20) Drug-antibody conjugates including, but not limited to, transtuzumab emtansine (T-DM1 or KADCYLA™), lorvotuzumab mertansine, cantuzumab mertansine, bivatuzumab mertansine, cantuzumab mertansine, lorvotuzumab mertansine, gemtuzumab ozogamicin, brentuximab vedotin, trastuzumab deruxtecan, enfortumab vedotin, polatuzumab vedotin-piiq, and inotuzumab ozogamicin; 21) Apoptosis derivatives such as cordycepin; 22) Protein synthesis inhibitors, including but not limited to clindamycin, chloramphenicol, streptomycin, anisomycin and cycloheximide; 23) Antidiabetic drugs, including but not limited to metformin and phenformin; 24) but is not limited to: a. Tetracyclines, such as but not limited to doxycycline; b. Erythromycin, such as but not limited to azithromycin; c. Glycylglycines, such as, but not limited to, tigecycline; d. Antiparasitic drugs, such as, but not limited to, pyrvinium pamoate; e. β-lactams, such as, but not limited to, penicillins and cephalosporins; f. Anthracycline antibiotics, such as, but not limited to, daunorubicin and doxorubicin; g. Other antibiotics, such as, but not limited to, chloramphenicol, mitomycin C, and actinomycin. Antibiotics, including; 25) Antibody therapeutics, including, but not limited to, muromonab-CD3, infliximab (REMICADE), adalimumab (HUMIRA), omalizumab (XOLAIR), daclizumab (ZENAPAX), rituximab (RITUXAN), ibritumomab (ZEVALIN), tositumomab (BEXXAR), cetuximab (ERBITUX), trastuzumab (HERCEPTIN), ADCETRIS, alemtumab (CAMPATH-1H), Lym-1 (ONCOLYM), ipilimumab (YERVOY), vitaxin, bevacizumab (AVASTIN) and abciximab (REOPRO); and 26) Bacillus Calmette-Guerin (BCG) vaccine; Buserelin (ETILAMIDE); Chloroquine (ARALEN); Clodronate, pamidronate and other bisphosphonates; Colchicine; Demethoxyviridine; Dichloroacetate; Estramustine; Filgrastim (NEUPOGEN); Fludrocortisone (FLORINEF); Goserelin (ZOLADEX); Interferon; Leucovorin; Leuprolide (LUPRON); Levamisole; Lonidamine; Mesna; Metformin; Mitotane (o,p'-DDD, LY SODREN); nocodazole; octreotide (SANDOSTATIN); perifosine; porfimer (especially in combination with photo- and radiotherapy); suramin; tamoxifen; titanocene dichloride; tretinoin; anabolic steroids such as fluoxymesterone (HALOTESTIN); estrogens such as estradiol, diethylstilbestrol (DES) and dienestrol; progestins such as medroxyprogesterone acetate (MPA) and megestrol; and other agents such as testosterone.

[0441] If the subject is suffering from or at risk of suffering from an inflammatory disease, the compounds with EGFR or HER2 inhibitory properties disclosed herein are optionally used together with any combination of one or more agents or methods for treating the inflammatory disease. Therapeutic agents / therapies for treating autoimmune and / or inflammatory diseases include, but are not limited to, any of the examples listed below: 1) Corticosteroids, including but not limited to cortisone, dexamethasone, and methylprednisolone; 2) Nonsteroidal anti-inflammatory drugs (NSAIDs), including but not limited to ibuprofen, naproxen, acetaminophen, aspirin, fenoprofen (NALFON), flurbiprofen (ANSAID), ketoprofen, oxaprozin (DAYPRO), diclofenac sodium (VOLTAREN), diclofenac potassium (CATAFLAM), etodolac (LODINE), indomethacin (INDOCIN), ketorolac (TORADOL), sulindac (CLINORIL), tolmetin (TOLECTIN), meclofenamate (MECLOMEN), mefenamic acid (PONSTEL), nabumetone (RELAFEN), and piroxicam (FELDENE); 3) Immunosuppressants, including but not limited to methotrexate (RHEUMATREX), leflunomide (ARAVA), azathioprine (IMURAN), cyclosporine (NEORAL, SANDIMMUNE), tacrolimus, and cyclophosphamide (CYTOXAN); 4) CD20 blocking agents, including but not limited to rituximab (RITUXAN); 5) Tumor necrosis factor (TNF) blockers, including but not limited to etanercept (ENBREL), infliximab (REMICADE), and adalimumab (HUMIRA); 6) Interleukin-1 receptor antagonists, including but not limited to anakinra (KINERET); 7) Interleukin-6 inhibitors, including but not limited to tocilizumab (ACTEMRA); 8) Interleukin-17 inhibitors, including but not limited to AIN457; 9) Janus kinase inhibitors, including but not limited to tasocitinib; and 10) syk inhibitors, including but not limited to fostamatinib.

[0442] In either case, the multiple therapeutic agents (at least one of which is a compound disclosed herein) may be administered in any order or simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, combined form or in multiple forms (by way of example only, as a single pill or two separate pills). One of the therapeutic agents may be administered in multiple doses, or both may be administered in multiple doses. If not simultaneously, the timing between the multiple doses may be any period ranging from a few minutes to four weeks.

[0443] In addition to being useful for human treatment, certain compounds and formulations disclosed herein may also be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, etc. More preferred animals include horses, dogs and cats.

[0444] compound synthesis The compounds of the present disclosure can be prepared using the methods shown in the general synthetic schemes and experimental procedures detailed below. The general synthetic schemes and experimental procedures are provided for illustrative purposes and are not intended to be limiting. The starting materials used to prepare the compounds of the present disclosure are commercially available or can be prepared using routine methods known in the art.

[0445] Abbreviation Ac 2 O = acetic anhydride; AcCl = acetyl chloride; AcOH = acetic acid; AIBN = azobisisobutyronitrile; aq. = aqueous; Bu 3 SnH = tributyltin hydride; CD 3 OD = deuterated methanol; CDCl 3= deuterated chloroform; CDI = 1,1'-carbonyldiimidazole; CR = complete response (no palpable tumor); DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM = dichloromethane; DEAD = diethyl azodicarboxylate; DIBAL-H = di-iso-butylaluminum hydride; DIEA = DIPEA = N,N-diisopropylethylamine; DMAP = 4-dimethylaminopyridine; DMF = N,N-dimethylformamide; DMSO-d 6 = deuterated dimethyl sulfoxide; DMSO = dimethyl sulfoxide; DPPA = diphenylphosphoryl azide; EDC.HCl = EDCI.HCl = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; EGFR = HER1 = ErbB1 = human epidermal growth factor receptor); Et 2 O = diethyl ether; EtOAc = ethyl acetate; EtOH = ethanol; h = time; FACS = fluorescence activated cell sorting; FBS = fetal bovine serum; FITC = fluorescein isothiocyanate; HATU = 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methaneaminium; HER2 = Neu = ErbB2 = human epidermal growth factor receptor 2; HMDS = hexamethyldisilazane; HOBT = 1-hydroxybenzotriazole; i-PrOH = isopropanol; IL-3 = interleukin-3; LAH = LiAlH 4 = lithium aluminum hydride; LiHMDS = lithium bis(trimethylsilyl)amide; MeCN = acetonitrile; MeOH = methanol; MP-carbonate resin = macroporous triethylammonium methyl polystyrene carbonate resin; MsCl = mesyl chloride; MTBE = methyl tertiary butyl ether; MW = microwave irradiation; n-BuLi = n-butyl lithium; NaHMDS = sodium bis(trimethylsilyl)amide; NaOMe = sodium methoxide; NaOtBu = sodium t-butoxide; NBS = N-bromosuccinimide; NCS = N-chlorosuccinimide; NMP = N-methyl-2-pyrrolidone; PDF = patient-derived xenograft; Pd(Ph 3 ) 4= Tetrakis(triphenylphosphine)palladium(0); Pd 2 (dba) 3 = Tris(dibenzylideneacetone)-dipalladium(0); PdCl 2 (PPh 3 ) 2 = Bis(triphenylphosphine)palladium(II) dichloride;PE = phycoerythrin;PG = protecting group;prep-HPLC = preparative high performance liquid chromatography;PyBop = (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate;Pyr = pyridine;RT = room temperature;RuPhos = 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl;sat. = saturated;ss = saturated solution;t-BuOH = tert-butanol;T3P = propylphosphinic anhydride;TBS = TBDMS = tert-butyldimethylsilyl;TBSCl = TBDMSCl = tert-butyldimethylchlorosilane;TEA = Et 3 N=triethylamine; TFA=trifluoroacetic acid; TFAA=trifluoroacetic anhydride; THF=tetrahydrofuran; Tol=toluene; TsCl=p-toluenesulfonyl chloride; XPhos=2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[0446] General synthetic methods for preparing compounds The following schemes can be used to practice the present disclosure. Scheme I [ka]

[0447] The following general synthetic procedure, shown in Scheme I, can be used to synthesize the specific examples disclosed herein. The functional groups of starting material 101 are manipulated by a series of Fisher ester synthesis, Williamson ether synthesis, and nitro group reduction to give functionalized benzene 102. Condensation with DMF dimethyl acetal gives amidine 103, which is converted to chloroquinoline 104 by ring formation with acetonitrile anion, followed by chlorination of the intermediate quinoline (not shown). Mitsunobu-style coupling reaction of secondary alcohol 105 with phenol 104 gives ether 106. S-coupling with arylamine 107 gives ether 108. N Ar reaction gives the displacement product 108. After removal of the Boc protecting group, the secondary amine 109 is reacted with acryloyl chloride to give the amide 110. Scheme II [ka]

[0448] The following general synthetic procedure, shown in Scheme II, can be used to synthesize specific examples disclosed herein. The synthesis is carried out similarly to Scheme I, except in this case the choice of quinoline starting material 201 differs. Scheme III [ka]

[0449] The following general synthetic procedure, shown in Scheme III, can be used to synthesize specific examples disclosed herein. Heterocyclic tosylates 301 are prepared in three steps from Boc-protected hydroxycycloamines 105 (Scheme I). Anthranilic acid analogs 302 are converted to bicyclic arenes with formamidine, followed by displacement of the chloride to form phenolic ethers 303. The amide functionality is converted to the chloro compound 304 by reaction with phosphorus oxychloride. R 301 NH 2Reaction of the tosylate 301 with phenol under Williamson ether synthesis conditions affords 307. Scheme IV [ka]

[0450] The following general synthetic procedure, shown in Scheme IV, can be used to synthesize specific examples disclosed herein. Pyrido[3,4-d]pyrimidine derivative 401 is selectively reacted at the 4-position to give aniline compound 402. Reaction with hydroxycycloamine 105 (Scheme 1) gives ether 403. Removal of the Boc protecting group under acidic conditions gives secondary amine 404, which is then reacted with acryloyl chloride to give amide 405. EXAMPLES

[0451] The present disclosure will now be described in further detail with reference to the following examples. Intermediate A [ka] 4-Chloro-6-hydroxy-7-methoxyquinoline-3-carbonitrile Step 1 [ka]

[0452] Methyl 5-hydroxy-4-methoxy-2-nitrobenzoate 5-Hydroxy-4-methoxy-2-nitrobenzoic acid (5.3 g, 24.9 mmol) and SOCl in MeOH (50 mL) 2 A solution of (2 ml, 28 mmol) was stirred at 80° C. for 16 h. The solvent was removed to give the title compound (5.3 g, 94%) as a white solid. MS(ES+)C 9 H 9 NO6 Theoretical value: 227, Measured value: 228 [M+H] + . Step 2 [ka]

[0453] Methyl 5-(benzyloxy)-4-methoxy-2-nitrobenzoate The product from the previous step (5.3 g, 23 mmol), (bromomethyl)benzene (6.0 g, 35 mmol) and K in MeCN (100 mL) 2 CO 3 A solution of (6.3 g, 46 mmol) was stirred at 80 °C for 4 h. The solvent was removed, the residue was dissolved in water, and the product was extracted with EtOAc. The combined organics were washed with brine and added Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give the title compound (7 g, 97%) as a yellow solid. MS(ES+)C 16 H 15 NO 6 Theoretical value: 317, Measured value: 318 [M+H] + . Step 3 [ka]

[0454] Methyl 2-amino-5-(benzyloxy)-4-methoxybenzoate A solution of the product from the previous step (3.17 g, 10 mmol) in EtOH (100 mL) was added with SnCl 2 .H 2 O (11.3 g, 55 mmol) was added and the mixture was stirred at 80 °C overnight. The mixture was diluted with sat.NaHCO 3 The mixture was quenched with a solution of 100 ml of ethyl acetate. The insoluble material was removed by filtration and the filtrate was extracted with EtOAc. The organic layer was washed with brine and MgSO. 4 The mixture was dried at 40° C., filtered and concentrated to give the title compound (4.2 g, 70% crude) as a white solid. MS(ES+)C 11 H 10BrN Theoretical value: 287, Measured value: 288 [M+H] + . Step 4 [ka]

[0455] (E)-Methyl 5-(benzyloxy)-2-((dimethylamino)methyleneamino)-4-methoxybenzoate A solution of the product from the previous step (4.1 g, 14.3 mmol) and DMF dimethyl acetal (10 mL) in DMF (20 mL) was heated at 110° C. for 3 h, diluted with water, and then extracted with EtOAc. The combined organic layers were washed with brine and concentrated to 100 mL with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give the title compound (4.5 g, 87.%) as a yellow solid. MS(ES+)C 19 H 22 N 2 O 4 Theoretical value: 342, Measured value: 343 [M+H] + . Step 5 [ka]

[0456] 6-(Benzyloxy)-7-methoxy-4-oxo-3,4-dihydroquinoline-3-carbonitrile To a solution of MeCN (180 mg, 4.38 mmol) in THF (6 mL) at -78 °C was slowly added n-BuLi (2.2 ml, 4.38 mmol). The solution was stirred at -78 °C for 30 min, after which a solution of the product from the previous step (600 mg, 1.75 mmol) in THF (4 mL) was slowly added. The mixture was stirred at -78 °C for 1 h. AcOH (0.2 ml) was added and the mixture was diluted with water and CHCl 3 The mixture was diluted with ethyl acetate, filtered and dried under vacuum to give the title compound (260 mg, 48%) as a yellow solid. MS(ES+)C 18 H 14 N 2 O 3Theoretical value: 306, Measured value: 307 [M+H] + . Step 6 [ka]

[0457] 6-(Benzyloxy)-4-chloro-7-methoxyquinoline-3-carbonitrile POCl 3 A mixture of the product from the previous step in (5 ml) was stirred at 115 °C for 2 h. After evaporation of the solvent, the residue was dissolved in aqueous NaHCO 3 The combined organic layers were washed with brine and then with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give the title compound (300 mg, 92%) as a yellow solid. MS(ES+)C 18 H 13 ClN 2 O 2 Theoretical value: 324, Measured value: 325 [M+H] + . Step 7 [ka]

[0458] 4-Chloro-6-hydroxy-7-methoxyquinoline-3-carbonitrile (Intermediate A) A mixture of the product from the previous step (300 mg, 0.93 mmol) and PhSMe (2 ml, 17.0 mmol) in TFA (15 ml) was stirred at 80° C. for 2 h. After removal of the solvent, the residue was stirred with ice water and NH 4 OH was added slowly. The reaction mixture was filtered and the solid was washed with EtOAc to give the title compound (180 mg, 83%) as a yellow solid. MS(ES+)C 11 H 7 ClN 2 O 2 Theoretical value: 234, Measured value: 235 [M+H] + .

[0459] Intermediate B tert-Butyl 4-((4-chloro-3-cyano-7-methoxyquinolin-6-yl)oxy)piperidine-1-carboxylate [ka]

[0460] Intermediate A (235 mg, 1 mmol), PPh in THF (8 ml) at 0° C. 3 To a mixture of DIAD (393 mg, 1.5 mmol) and tert-butyl 4-hydroxypiperidine-1-carboxylate (201 mg, 1 mmol) in THF (2 ml) was slowly added DIAD (303 mg, 1.5 mmol). The mixture was stirred at RT for 16 h and then purified by silica gel column (0-30% EtOAc in PE) to give a white solid (300 mg, 72%). MS (ES+) C 21 H 24 ClN 3 O 4 Theoretical value: 417, Measured value: 418 [M+H] + .

[0461] Intermediate C tert-Butyl 3-((4-chloro-7-methoxyquinolin-6-yl)oxy)azetidine-1-carboxylate [ka]

[0462] PPh in dioxane (60 ml) 3To a suspension of (4.23 mg, 16.14 mmol) was added diisopropyl(E)-diazene-1,2-dicarboxylate (2.88 g, 14.24 mmol) and the resulting mixture was stirred at room temperature for 20 min. tert-Butyl 3-hydroxyazetidine-1-carboxylate (1.809 g, 10.45 mmol) was added and the reaction was stirred at room temperature for an additional 20 min. 4-Chloro-7-methoxyquinolin-6-ol (2.00 g, 9.50 mmol) was then added and the reaction was heated at 70 °C overnight. The volatiles were removed under reduced pressure. The residue was purified by silica gel chromatography (20-100% EtOAc in hexanes) to give the title compound (3.00 g, 8.20 mmol, 86%) as a white solid. The product was a mixture of the desired product and tert-butyl 3-hydroxyazetidine-1-carboxylate, which was carried on as is to the next reaction. MS (ES+)C 17 H 20 ClN 3 O 4 Theoretical value: 365, Measured value: 366 [M+H] + .

[0463] Intermediate D tert-Butyl 3-((4-chloro-3-cyano-7-methoxyquinolin-6-yl)oxy)azetidine-1-carboxylate [ka]

[0464] Intermediate A (235 mg, 1 mmol) in THF (8 ml), PPh 3 To a mixture of DIAD (393 mg, 1.5 mmol) and tert-butyl 3-hydroxyazetidine-1-carboxylate (173 mg, 1 mmol) in THF (2 ml) was slowly added DIAD (303 mg, 1.5 mmol). The mixture was stirred at RT for 16 h and then purified by silica gel column (0-30% EtOAc in PE) to give a white solid (260 mg, 67%). MS(ES+)C 19 H 20 ClN 3 O 4Theoretical value: 389, Measured value: 390 [M+H] + .

[0465] Example 1 1-(4-((4-((2,4-dichlorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-prop-2-en-1-one [ka] Step 1 [ka]

[0466] tert-Butyl 4-((4-chloro-7-methoxyquinazolin-6-yl)oxy)piperidine-1-carboxylate PPh in dioxane (3 ml) 3 To a suspension of (210 mg, 0.80 mmol) was added diisopropyl(E)-diazene-1,2-dicarboxylate (140 μL, 0.72 mmol) and the resulting mixture was stirred at room temperature for 20 min. tert-Butyl 4-hydroxypiperidine-1-carboxylate (143 mg, 0.72 mmol) was added and the reaction was stirred at room temperature for an additional 20 min. 4-Chloro-7-methoxyquinazolin-6-ol (100 mg, 0.48 mmol) was then added and the reaction was heated at 70 °C overnight. The volatiles were removed under reduced pressure. The residue was purified by silica gel chromatography (25-100% EtOAc in hexanes) to give the title compound (144 mg, 0.37 mmol, 77%) as a white solid. MS(ES+)C 19 H 24 ClN 3 O 4 Theoretical value: 393, Measured value: 394 [M+H] + . Step 2 [ka]

[0467] N-(2,4-dichlorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine trifluoroacetate To a solution of tert-butyl 4-((4-chloro-7-methoxyquinazolin-6-yl)oxy)piperidine-1-carboxylate (50 mg, 0.127 mmol) and 2,4-dichloroaniline (41 mg, 0.254 mmol) in 2-propanol (3 ml) was added toluenesulfonic acid (2.2 mg, 0.0127 mmol) and the resulting mixture was stirred at 80° C. for 16 h. Volatiles were removed under reduced pressure. The residue was purified by mass-triggered preparative HPLC (mobile phase: A=0.1% TFA / H 2 0, B=0.1% TFA / MeCN; gradient: B=10-60%; 12 min; column: C18) to give the title compound (impure) as a brown amorphous mass, which was carried on to the next step. MS (ES+) C 20 H 20 Cl 2 N 4 O 2 Theoretical value: 418, Measured value: 419 [M+H] + . Step 3 [ka]

[0468] 1-(4-((4-(2,4-dichlorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one trifluoroacetate CH 2 Cl 2 A solution of the product from the previous step in (3 ml) of iPr 2 NEt (67 μL, 0.382 mmol) and acryloyl chloride (10.2 μL, 0.129 mmol) were added. The resulting mixture was stirred at room temperature for 30 min and then concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / H 20, B=0.1% TFA / MeCN; gradient: B=30-70%; 12 min; column: C18) to give the title compound as a brown amorphous material. MS(ES+)C 23 H 22 Cl 2 N 4 O 3 Theoretical value: 472, Measured value: 473 [M+H] + .

[0469] Example 2 1-(3-((4-(2,4-dichlorophenyl)amino)pyrido[3,4-d]pyrimidin-yl)oxy)azetidin-1-yl)prop-2-en-1-one [ka] Step 1 [ka]

[0470] 6-Chloro-N-(2,4-dichlorophenyl)pyrido[3,4-d]pyrimidin-4-amine To a solution of 4,6-dichloropyrido[3,4-d]pyrimidine (3 g, 15.00 mmol, 1 eq), 2,4-dichloroaniline (2.43 g, 15.00 mmol, 1 eq) in t-BuOH (30 ml) was added HCl (0.1 M, 3.00 mL, 0.02 eq). The mixture was stirred at 25° C. for 2 h. The mixture was filtered and the cake was dried under vacuum to give the title compound (3.7 g, raw) as a yellow solid. Step 2 [ka]

[0471] 4-((2,4-dichlorophenyl)amino)pyrido[3,4-d]pyrimidin-6-ol A solution of the product from the previous step (3 g, 9.21 mmol, 1 eq), KOH (1.55 g, 27.64 mmol, 3 eq) in dioxane (30 ml) was treated with tBuXPhos Pd G3 (365.98 mg, 460.72 umol, 0.05 eq) was added. The mixture was then diluted with N 2 The mixture was stirred at 130° C. for 16 h under reduced pressure. The mixture was filtered and the cake was dried under vacuum to give the title compound (1.6 g, untreated) as a yellow solid. MS (ES + ) C 13 H 8 Cl 2 N 4 O Theoretical value: 306, Measured value: 307 and 309 [M+H] + . Step 3 [ka]

[0472] tert-Butyl 3-((4-((2,4-dichlorophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)oxy)azetidine-1-carboxylate A mixture of the product from the previous step (0.5 g, 1.24 mmol, 1 eq) and tert-butyl 3-(tosyloxy)azetidine-1-carboxylate (810.13 mg, 2.47 mmol, 2 eq) in DMA (10 mL) was treated with Cs 2 CO 3 (1.21 g, 3.71 mmol, 3 eq) was added. The mixture was stirred at 50° C. for 5 h. The mixture was diluted with H 2 The mixture was diluted with 2×O (50 mL) and then extracted with EtOAc (100 mL×3). The combined organic phase was washed with brine (100 mL×2) and diluted with Na 2 SO 4 The residue was purified by silica gel chromatography (SiO 2 , petroleum ether:ethyl acetate=10:1 to 3:1) to give the title compound (130 mg, 0.281 mmol, 22.7% yield) as a yellow solid. Step 4 [ka]

[0473] 6-(azetidin-3-yloxy)-N-(2,4-dichlorophenyl)pyrido[3,4-d]pyrimidin-4-amine trifluoroacetate To a mixture of the product from the previous step (160 mg, 0.346 mmol, 1 eq) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 25° C. for 2 h. The mixture was concentrated in vacuo to give the title compound (150 mg, untreated) as a yellow oil. MS (ES + ) C 16 H 13 Cl 2 N 5 O Theoretical values: 361 and 363, Measured values: 362 and 364 [M+H] + . Step 5 [ka]

[0474] 1-(3-((4-((2,4-dichlorophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)oxy)azetidin-1-yl)prop-2-en-1-one To a mixture of the product from the previous step (150 mg, 0.314 mmol, 1 eq) and DIEA (161 mg, 1.24 mmol, 216 uL, 3 eq) in DCM (3 mL) was added acryloyl chloride (45 mg, 0.497 mmol, 41 uL, 1.2 eq). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated under vacuum. The residue was purified by Prep-HPLC (Column: Shim-pack C18 150 x 25 x 10 um; Mobile phase: [water (0.225% FA)-ACN] B%: 36%-56%, 8 min) to give the title compound (25.8 mg, 0.062 mmol, 19.7% yield, 100% purity) as a yellow solid. MS(ES + ) C 19 H 15 Cl 2 N 5 O 2 Theoretical values: 415 and 417, Measured values: 416 and 418 [M+H] + . 1H NMR (400MHz, DMSO-d 6 )δ 10.37(bs,1H),8.86(bs,1H),8.34(bs,1H),7.73-7.83(m,2H),7.45-7.59 (m,2H),6.36(dd,J=16.9,10.3Hz,1H),6.13(dd,J=16.9,2.1Hz,1H),5.69( dd,J=10.3,2.0Hz,1H),5.42-5.53(m,1H),4.67-4.78(m,1H),4.42(dd,J=1 0.8,6.8Hz,1H),4.27(dd,J=9.6,3.1Hz,1H),3.97(dd,J=10.9,3.1Hz,1H).

[0475] Example 3 1-(3-((4-((3,4-dichlorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-1-yl)prop-2-en-1-one [ka] Step 1 [ka]

[0476] 6-(azetidin-3-yloxy)-N-(3,4-dichlorophenyl)-7-methoxyquinazolin-4-amine trifluoroacetate To a solution of intermediate C (50 mg, 0.137 mmol) and 3,4-dichloroaniline (44 mg, 0.274 mmol) in 2-propanol (3 mL) was added toluenesulfonic acid (2.4 mg, 0.0137 mmol) and the resulting mixture was stirred at 80° C. for 16 h. The volatiles were removed under reduced pressure. The residue was purified by mass-triggered preparative HPLC (mobile phase: A=0.1% TFA / H 2 0, B=0.1% TFA / MeCN; gradient: B=10-30%; 12 min; column: C18) to give the title compound (28.6 mg, 0.0566 mmol, 41.3%) as a brown amorphous material. MS(ES+)C 18 H 16 Cl 2 N4 O 2 Theoretical value: 390, Measured value: 391 [M+H] + . Step 2 [ka]

[0477] 1-(3-((4-((3,4-dichlorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-1-yl)prop-2-en-1-one trifluoroacetate CH 2 Cl 2 A solution of the product from the previous step (28.6 mg, 0.0566 mmol) in 10 mL of iPr 2 NEt (29.6 μL, 0.170 mmol) and acryloyl chloride (4.55 μL, 0.0566 mmol) were added. The resulting mixture was stirred at room temperature for 30 min and then concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / H 2 0, B=0.1% TFA / MeCN; gradient: B=20-50%; 12 min; column: C18) to give the title compound (18.8 mg, 0.034 mmol, 59%) as a brown amorphous solid. MS(ES+)C 21 H 18 Cl 2 N 4 O 3 Theoretical value: 444, Measured value: 445 [M+H] + .

[0478] Example 4 6-((1-Acryloylpiperidin-4-yl)oxy)-4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxy-quinoline-3-carbonitrile [ka] Step 1 [ka]

[0479] 4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxy-6-(piperidin-4-yloxy)-quinoline-3-carbonitrile To a solution of intermediate B (425 mg, 1.02 mmol) in 2-propanol (18 mL) was added 3,4-dichloro-2-fluoroaniline (366 mg, 2.03 mmol) and toluenesulfonic acid (19.34 mg, 0.102 mmol). The resulting mixture was stirred at 80° C. for 16 h. The volatiles were removed under reduced pressure. The residue was purified by mass-triggered preparative HPLC (mobile phase: A=0.1% TFA / H 2 0, B=0.1% TFA / MeCN; gradient: B=10-50%; 16 min; column: C18) to give the title compound (433 mg, 0.753 mmol, 74.0%) as a yellow amorphous material. MS(ES+)C 22 H 19 Cl 2 N 4 O 2 Theoretical value: 460, Measured value: 461 [M+H] + . Step 2 [ka]

[0480] 6-((1-acryloylpiperidin-4-yl)oxy)-4-((3,4-dichlorophenyl)amino)-7-methoxyquinoline-3-carbonitrile CH 2 Cl 2 A solution of the product from the previous step (433 mg, 0.753 mmol) in 10 mL of iPr 2 NEt (0.657 ml, 3.76 mmol) and acryloyl chloride (0.073 ml, 0.903 mmol) were added. The resulting mixture was stirred at room temperature for 30 min and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-7% MeOH in DCM) to give the title compound (145 mg, 0.281 mmol, 37.4% yield) as a yellow solid. MS(ES+)C 25 H 21 Cl2 FN 4 O 3 Theoretical value: 514, Measured value: 515 [M+H] + .

[0481] Example 5 1-(3-((4-((2,4-dichlorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-1-yl)-prop-2-en-l-one [ka] Step 1 [ka]

[0482] 6-(azetidin-3-yloxy)-N-(2,4-dichlorophenyl)-7-methoxyquinazolin-4-amine trifluoroacetate To a solution of intermediate C (50 mg, 0.137 mmol) and 2,4-dichloroaniline (44 mg, 0.274 mmol) in 2-propanol (3 mL) was added toluenesulfonic acid (2.4 mg, 0.0137 mmol) and the resulting mixture was stirred at 80° C. for 16 h. The volatiles were removed under reduced pressure. The residue was purified by mass-triggered preparative HPLC (mobile phase: A=0.1% TFA / H 2 The mixture was purified by HPLC using a 50 mL column (C18, B = 0.1% TFA / MeCN; gradient: B = 10-30%; 12 min; column: C18) to give the title compound (13.9 mg, 0.0275 mmol, 20.1%) as a brown amorphous material. 18 H 16 Cl 2 N 4 O 2 Theoretical value: 390, Measured value: 391 [M+H] + . Step 2 [ka]

[0483] 1-(3-((4-((2,4-dichlorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-1-yl)prop-2-en-1-one trifluoroacetate CH 2 Cl 2 A solution of the product from the previous step (13.9 mg, 0.0275 mmol) in 1 mL of iPr 2 NEt (13.9 μL, 0.0800 mmol) and acryloyl chloride (2.21 μL, 0.0275 mmol) were added. The resulting mixture was stirred at room temperature for 30 min and then concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (mobile phase: A = 0.1% TFA / H 2 0, B=0.1% TFA / MeCN; gradient: B=20-50%; 12 min; column: C18) to give the title compound (6.6 g, 0.012 mmol, 43%) as a brown amorphous solid. MS(ES+)C 21 H 18 Cl 2 N 4 O 3 Theoretical value: 444, Measured value: 445 [M+H] + .

[0484] Example 6 1-(3-((4-((3,4-dichlorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-1-yl)prop-2-en-1-one [ka] Step 1 [ka]

[0485] 6-(azetidin-3-yloxy)-N-(3,4-dichloro-2-fluorophenyl)-7-methoxyquinazolin-4-amine trifluoroacetate To a solution of intermediate C (3.00 g, 8.20 mmol) and 3,4-dichloro-2-fluoroaniline (1.919 g, 10.66 mmol) in 2-propanol (90 mL) was added p-toluenesulfonic acid (0.624 mg, 3.28 mmol) and the resulting mixture was stirred at 80° C. for 36 h. The volatiles were removed under reduced pressure. The residue was purified by mass-triggered preparative HPLC (mobile phase: A=0.1% TFA / H 2 0, B=0.1% TFA / MeCN; gradient: B=10-50%; 16 min; column: C18) to give the title compound (2.86 g, 5.47 mmol, 66.6%) as a white solid. 18 H 15 Cl 2 FN 4 O 2 Theoretical value: 408, Measured value: 409 [M+H] + . Step 2 [ka]

[0486] 1-(3-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-1-yl)prop-2-en-1-one CH 2 Cl 2 A solution of the product from the previous step (1000 mg, 1.911 mmol) in 10 mL of iPr 2 NEt (1.669 ml, 9.56 mmol) and acryloyl chloride (0.185 mL, 2.293 mmol) were added. The resulting mixture was stirred at room temperature for 30 min and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-7% MeOH in DCM) to give the title compound (307 mg, 0.663 mmol, 34.7% yield) as a yellow solid. MS(ES+)C 21 H 17 Cl 2 FN 4 O 3 Theoretical value: 462, Measured value: 463 [M+H] +. 1 H NMR(600MHz,d6-DMSO)δ 9.67(s,1H),8.42(s,1H),7.64-7.56(m,2H),7.50(s,1H),7.28(s,1H),6.37(dd,J=10.3,16.9Hz,1H),6.14(dd,J=1.7,16.9Hz,1H),5. 70(dd,J=1.7,10.3Hz,1H),5.24-5.16(m,1H),4.83-4.76(m,1H),4.60-4.52(m,1H),4.34-4.25(m,1H),4.01-3.92(m,1H),3.97(s,3H).

[0487] Example 7 6-((1-acryloylpiperidin-4-yl)oxy)-4-((3,4-dichlorophenyl)amino)-7-methoxyquinoline-3-carbonitrile [ka] Step 1 [ka]

[0488] tert-Butyl 4-(3-cyano-4-(3,4-dichlorophenylamino)-7-methoxyquinolin-6-yloxy)piperidine-1-carboxylate A mixture of intermediate B (100 mg, 0.24 mmol), 3,4-dichloroaniline (78 mg, 0.48 mmol) and TsOH (5 mg, 0.024 mmol) in i-PrOH (3 ml) was stirred at 150° C. for 4 h. The solvent was removed to give a white solid (182 mg, 100% crude). MS (ES+) C 27 H 28 Cl 2 N 4 O 4 Theoretical value: 542, Measured value: 543 [M+H] + . Step 2 [ka]

[0489] 4-(3,4-Dichlorophenylamino)-7-methoxy-6-(piperidin-4-yloxy)-quinoline-3-carbonitrile A mixture of the product from the previous step (182 mg, 0.24 mmol) and TFA (3 ml) in DCM (3 ml) was stirred at RT for 4 h. The solvent was removed to give a yellow oil (100 mg, 100%). MS (ES+) C 22 H 20 Cl 2 N 4 O 2 Theoretical value: 442, Measured value: 443 [M+H] + . Step 3 [ka]

[0490] 6-(1-Acryloylpiperidin-4-yloxy)-4-(3,4-dichlorophenylamino)-7-methoxy-quinoline-3-carbonitrile The product from the previous step (45 mg, 0.1 mmol) and iPr in DCM (3 ml) 2 To a mixture of NEt (39 mg, 0.3 mmol) was added acryloyl chloride (10 mg, 0.1 mmol). The mixture was stirred at 0° C. for 30 min. The solvent was removed and the residue was purified by Prep-HPLC to give a white solid (5 mg, 10%). MS(ES+)C 25 H 22 Cl 2 N 4 O 3 Theoretical value: 496, Measured value: 497 [M+H] + . 1 H NMR (500MHz, d 6-DMSO)δ 9.56(s,1H),8.59(s,1H),7.69(s,1H),7.61(d,J=8.7Hz,1H),7.43(d,J=23.1Hz,2H),7.19(d,J=11.1Hz,1H),6.82(dd,J=16.7,10.5 Hz,1H),6.10(dd,J=16.7,2.4Hz,1H),5.68(dd,J=10.4,2.4Hz,1H),4.73(m,1H),3.84(m,2H),3.45(m,2H),1.95(m,2H),1.63(m,2H). Example 8 [ka] 1-(4-((4-(3,4-dichloro-2-fluorophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one Step 1 [ka]

[0491] tert-Butyl 4-(tosyloxy)piperidine-1-carboxylate tert-Butyl 4-hydroxypiperidine-1-carboxylate (10 g, 49.7 mmol, 1 eq), p-toluenesulfonyl chloride (10.4 g, 54.6 mmol, 1.1 eq), DMAP (607 mg, 5.0 mmol, 0.1 eq) and Et 3 A mixture of N (12.6 g, 124.1 mmol, 17.3 mL, 2.5 eq) was stirred at 25 °C for 12 h. The reaction mixture was diluted with DCM (200 mL) and then washed with 0.5 M HCl (200 mL x 2), followed by brine (200 mL). The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo. The residue was triturated with (petroleum ether:ethyl acetate=5:1, 60 mL) and filtered, and the filter cake was collected to give two batches of the title compound (8.0 g, 22.5 mmol, 45.3% yield) as an off-white solid. Step 2 [ka]

[0492] Piperidin-4-yl 4-methylbenzenesulfonate trifluoroacetate To a solution of the product from the previous step (8 g, 22.5 mmol, 1 eq) in DCM (5 mL) was added TFA (16.00 mL) and the mixture was stirred for 2 h at 30° C. The mixture was concentrated under reduced pressure to give the title compound (5.9 g, 16.0 mmol, 71.0% yield) as a yellow oil, which was used in the next step without further purification. Step 3 [ka]

[0493] 1-Acryloylpiperidin-4-yl 4-methylbenzenesulfonate THF (20 mL) and H 2 A mixture of the product from the previous step (5.9 g, 16.0 mmol, 1 eq) in HO (25 mL) was added to NaHCO 3 (4.03 g, 47.9 mmol, 1.86 mL, 3 eq) was added and the mixture was cooled to 0° C. A solution of acryloyl chloride (1.45 g, 16.0 mmol, 1.30 mL, 1 eq) in THF (5 mL) was added to the reaction mixture over 5 min and the reaction was stirred at 0° C. for 1 h. The reaction mixture was cooled to H 2 The mixture was poured into 200 mL of ethyl acetate (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (200 mL) and 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=10 / 1 to 5 / 1) to give the title compound (3.3 g, 10.7 mmol, 66.8% yield) as a colorless oil. Step 4 [ka]

[0494] 6-Chloropyrido[3,4-d]pyrimidin-4(3H)-one A mixture of 5-amino-2-chloro-isonicotinic acid (30 g, 173.8 mmol, 1 eq) and acetic acid formimidamide (36.20 g, 347.7 mmol, 2 eq) in 1,2-dimethoxyethane (100 mL) was stirred at 125° C. for 16 h. The mixture was filtered and the filter cake was washed with ethyl acetate (60 mL×2) and then dried under vacuum to give the title compound (25 g, raw) as a white solid. MS (ES) + ) C 7 H 4 ClN 3 O Theoretical value: 181, Measured value: 182 [M+H] + . Step 5 [ka]

[0495] 6-Methoxypyrido[3,4-d]pyrimidin-4(3H)-one A solution of the product from the previous step (3 g, 16.5 mmol, 1 eq) in MeONa / MeOH (16.5 mmol, 60 mL, 30% purity, 1 eq) in a 100 mL sealed tube was stirred at 100 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with H 2 The filtrate was extracted with EtOAc (150 mL×3) and the combined organic layers were washed with NaCl, diluted with 2M HCl (pH=4-6), acidified with 4M HCl (pH=4-6), filtered, and the filter cake was dried under vacuum to give the title compound (1.36 g, 7.14 mmol, 43.21% yield, 93% purity) as a white solid. 2 SO 4 The mixture was dried at 40° C. for 1 hour, filtered, and concentrated under reduced pressure to give another batch of the title compound (1.72 g, 9.32 mmol, 56.4% yield, 96% purity) as a white solid. MS (ES + ) C 8 H 7 N 3 O 2 Theoretical value: 177, Measured value: 178 [M+H] + . Step 6 [ka]

[0496] 4-Chloro-6-methoxypyrido[3,4-d]pyrimidine POCl 3 A mixture of the product from the previous step (2.4 g, 13.5 mmol, 1 eq) in (49.5 g, 322.8 mmol, 30 mL, 23.8 eq) was stirred at 100 °C for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (80 mL) and then treated with NaHCO 3 (100 mL) was slowly added to a saturated solution of 100 mL of ethyl acetate at 0° C. Then the mixture was extracted with EtOAc (80 mL×2), and the combined organic layers were washed with brine (60 mL×2) and Na 2 SO 4 Drying at 40° C., filtering and concentrating under reduced pressure afforded the title compound (2.3 g, crude) as a yellow solid which was used in the next step without further purification. Step 7 [ka]

[0497] N-(3,4-dichloro-2-fluorophenyl)-6-methoxypyrido[3,4-d]pyrimidin-4-amine To a mixture of the product from the previous step (2.3 g, 11.76 mmol, 1 eq) and 3,4-dichloro-2-fluoroaniline (2.12 g, 11.76 mmol, 1 eq) in t-BuOH (23 mL) was added HCl (0.1 M, 5.88 mL, 0.05 eq) and the mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered and the filter cake was washed with methyl tert-butyl ether (40 mL) and then dried under vacuum to give the title compound (2.4 g, 6.9 mmol, 59.0% yield, 98% purity) as a yellow solid. MS (ES) + ) C 14 H 9 Cl 2 FN 4 O Theoretical value: 338, Measured value: 339 [M+H] + . Step 8 [ka]

[0498] 4-(3,4-dichloro-2-fluorophenyl)amino)pyrido[3,4-d]pyrimidin-6-ol To a mixture of the product from the previous step (600 mg, 1.77 mmol, 1 eq) in DMF (6 mL) was added pyridine hydrochloride (5.11 g, 44.23 mmol, 25 eq). The mixture of the four batches was stirred at 130° C. for 20 h. The reaction mixture of the four batches was heated to 100° C. for 20 h. 2 After pouring into 2H2O (100 mL), filtering, washing the filter cake with ethyl acetate (50 mL) and drying under vacuum, the crude product was purified by prep-HPLC (column: Xbridge BEH C18, 250 mm x 50 mm, 10 um; mobile phase [water (0.05% ammonia hydroxide v / v)-ACN]: B%: 5%~30%, 43 min) to give the title compound (760 mg, 2.06 mmol, 29.3% yield, 88% purity) as a yellow solid. MS (ES) + ) C 13 H 7 Cl 2 FN 4 O Theoretical value: 324, Measured value: 325 [M+H] + . Step 9 [ka]

[0499] 1-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one N 2 A mixture of the product from the previous step (100 mg, 307.6 umol, 1 eq) and 1-acryloylpiperidin-4-yl 4-methylbenzenesulfonate (114.2 mg, 369.1 umol, 1.2 eq) in DMF (4 mL) was added at 25 °C under 5 °C. 2 CO3 (300.64 mg, 922.7 umol, 3 eq) was added. The mixture was stirred at 70° C. for 16 h. The reaction mixture was diluted with H 2 The mixture was poured into 200 mL of EtOAc (20 mL×3) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (15 mL×2) and 2 SO 4 The residue was analyzed by Prep-TLC (SiO 2 , petroleum ether:ethyl acetate=1:1), followed by prep-HPLC (column: Phenomenex Synergi C18 150*30*4um; mobile phase: water (0.225% FA)-ACN]:B%:40%~70%, 10min) to give the title compound (9.1mg, 18.7umol, 3.0% yield, 95% purity) as a yellow solid. MS(ES + ) C 21 H 18 Cl 2 FN 5 O 2 Theoretical value: 461, Measured value: 462 [M+H] + . 1 H NMR(400MHz,MeOD)δ 8.92(s,1H),8.46(s,1H),7.71-7.58(m,2H),7.47(br d,J=7.6Hz,1H),6.82(dd,J=10.6,16.9Hz,1H),6.22(dd,J=2.0,16.8Hz,1H),5.76(dd,J=2.0,10.6Hz ,1H),5.48-5.37(m,1H),4.06-3.90(m,2H),3.71-3.59(m,2H),2.30-2.05(m,2H),1.95-1.75(m,2H).

[0500] Example 9 [ka] 1-(3-((4-((3,4-dichlorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)azetidin-1-yl)prop-2-en-1-one Step 1 [ka]

[0501] 4,6-Dichloropyrido[3,2-d]pyrimidine SOCl 2 To a mixture of 6-chloropyrido[3,2-d]pyrimidin-4(H)-one (4.5 g, 24.8 mmol, 1 eq) in (49.20 g, 413.35 mmol, 30 mL, 16.69 eq) was added DMF (90.57 mg, 1.24 mmol, 95.34 uL, 0.05 eq). The mixture was stirred at 80 °C for 2 h. The solvent was evaporated. The residue was dissolved in EtOAc (300 mL) and diluted with NaHCO 3 After washing with aqueous solution (100 mL), the organic layer was 2 SO 4 and concentrated to give the title compound (4.6 g, 23.00 mmol, 92.8% yield) as a yellow solid, which was used directly in the next step without further purification. Step 2 [ka]

[0502] 6-Chloro-N-(3,4-dichlorophenyl)pyrido[3,2-d]pyrimidin-4-amine To a mixture of the product from the previous step (0.5 g, 2.50 mmol, eq) and 3,4-dichloroaniline (405.04 mg, 2.50 mmol, 1 eq) in t-BuOH (5 mL) was added HCl (0.1 M, 2.50 mmol, 0.1 eq). The mixture was stirred at 25° C. for 3 h. The solvent was evaporated. After triturating the residue with EtOAc (10 mL) at 25° C. for 30 min, the mixture was filtered and the filter cake was collected to afford the title compound (0.75 g, 2.30 mmol, 92.1% yield) as a yellow solid, which was used in the next step without further purification. Step 3 [ka]

[0503] tert-Butyl 3-((4-((3,4-dichlorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)azetidine-1-carboxylate To a mixture of tert-butyl 3-hydroxyazetidine-1-carboxylate (425.60 mg, 2.46 mmol, 4 eq) and the product from the previous step (0.2 g, 614.3 umol, 1 eq) in NMP (3 ml) was added t-BuOK (275.72 mg, 2.46 mmol, 4 eq). The mixture was heated at 150° C. and stirred in a microwave reactor for 1 h. The mixture was poured into water (20 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., concentrated, and the residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=10:1 to 3:1) to give the title compound (262 mg, 512.29 umol, 83.4% yield, 90.4% purity) as a pale yellow solid. MS (ES) + ) C 21 H 21 Cl 2 N 5 O 3 Theoretical values: 461 and 463, Measured values: 462 and 464 [M+H] + . Step 4 [ka]

[0504] 6-(azetidin-3-yloxy)-N-(3,4-dichlorophenyl)pyrido[3,2-d]pyrimidin-4-amine trihydrochloride A mixture of the product from the previous step (262 mg, 512.3 umol, 1 eq) and HCl / dioxane (4M, 5 mL, 39.0 eq) was stirred at 25° C. for 1 h. The solvent was evaporated to give the title compound (241 mg, 511.0 umol, 99.8% yield) as a yellow solid, which was used in the next step without further purification. MS (ES) + ) C 16 H 13 Cl 2 N5 O Theoretical values: 361 and 363, Measured values: 362 and 364 [M+H] + . Step 5 [ka]

[0505] 1-(3-((4-((3,4-dichlorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)azetidin-1-yl)prop-2-en-1-one A mixture of the product from the previous step (241 mg, 511.0 umol, 1 eq) in DCM (2 ml) was diluted with iPr 2 Net (264.18 mg, 2.04 mmol, 356.0 uL, 4 eq) and acryloyl chloride (50.88 mg, 562.1 umol, 45.8 uL, 1.1 eq) were added. The mixture was stirred at 25 °C for 1 h. The solvent was evaporated. The residue was purified by prep-HPLC (column: Shim-pack C18 150 × 25, 10 um; mobile phase: [water (0.225% FA)-ACN] B%: 40% ~ 70%, 10 min) to give the title compound (67.6 mg, 157.36 mmol, 30.8% yield, 96.9% purity) as a white solid. MS(ES + ) C 19 H 15 Cl 2 N 5 O 2 Theoretical values: 415 and 417, Measured values: 416 and 418 [M+H] + . 1H NMR(400MHz,MeOD)δ 8.63(s,1H),8.35(d,J=2.7Hz,1H),8.13(d,J=9.0Hz,1H),7.86(dd,J=2.4,8.8Hz ,1H),7.51(d,J=8.8Hz,1H),7.45(d,J=9.0Hz,1H),6.48-6.38(m,1H),6.35-6.27( m,1H),5.88(s,1H),5.79(dd,J=2.0,10.3Hz,1H),4.93(ddd,J=1.3,6.7,10.0Hz,1 H),4.72-4.64(m,1H),4.42(dd,J=2.9,10.3Hz,1H),4.19(dd,J=3.2,11.7Hz,1H).

[0506] Example 10 6-((1-Acryloylazetidin-3-yl)oxy)-4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinoline-3-carbonitrile [ka] Step 1 [ka]

[0507] 6-(azetidin-3-yloxy)-4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinoline-3-carbonitrile To a solution of intermediate D (200 mg, 0.513 mmol) in 2-propanol (12 mL) was added 3,4-dichloro-2-fluoroaniline (185 mg, 1.03 mmol) and p-toluenesulfonic acid (9.76 mg, 0.051 mmol). The resulting mixture was stirred at 80° C. for 16 h. The volatiles were removed under reduced pressure. The residue was purified by mass-triggered preparative HPLC (mobile phase: A=0.1% TFA / H 2 0, B=0.1% TFA / MeCN; gradient: B=10-50%; 16 min; column: C18) to give the title compound (256 mg, 0.468 mmol, 91.0%) as a yellow amorphous material. MS(ES+)C 20 H15 Cl 2 FN 4 O 2 Theoretical value: 432, Measured value: 433 [M+H] + . Step 2 [ka]

[0508] 6-((1-Acryloylazetidin-3-yl)oxy)-4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinoline-3-carbonitrile CH 2 Cl 2 A solution of the product from the previous step (256 mg, 0.426 mmol) in 12 ml of iPr 2 NEt (0.223 ml, 1.28 mmol) and acryloyl chloride (0.034 ml, 0.426 mmol) were added. The resulting mixture was stirred at room temperature for 30 min and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-7% MeOH in DCM) to give the title compound (121 mg, 0.248 mmol, 58.3% yield) as a yellow solid. MS(ES+)C 23 H 17 Cl 2 FN 4 O 3 Theoretical value: 486, Measured value: 487 [M+H] + . 1 H NMR(600MHz,d6-DMSO)δ 9.57(s,1H),8.55(s,1H),7.64-7.52(m,1H),7.52-7.33(m,3H),6.35(dd,J=10.3,16.9Hz,1H),6.12(dd,J=1.7,16.9Hz,1H),5.69( dd,J=1.7,10.3Hz,1H),5.26-5.16(m,1H),4.78-4.66(m,1H),4.57-4.43(m,1H),4.31-4.21(m,1H),3.99(s,3H),3.98-3.91(m,1H).

[0509]

Table 1

[0510]

Table 2

[0511]

Table 3

[0512]

Table 4

[0513]

Table 5

[0514]

Table 6

[0515]

Table 7

[0516]

Table 8

[0517]

Table 9

[0518]

Table 10

[0519]

Table 11

[0520] [Table 12]

[0521] [Table 13]

[0522] [Table 14]

[0523] [Table 15]

[0524] [Table 16]

[0525] [Table 17]

[0526] [Table 18]

[0527] [Table 19]

[0528] The activity of the compounds of Examples 1-101 as HER2 and EGFR inhibitors is demonstrated in the following assays.

[0529] Bioactivity assays Ba / F3 cell line generation and IL-3 depletion Ba / F3 cell line was cultured under sterile conditions in incomplete RPMI-1640 medium (R8758; Sigma Life Science) supplemented with L-glutamine, 10% heat-inactivated FBS (Gibco), 1% penicillin-streptomycin (Sigma Life Science), and 10 ng / ml mouse IL-3 (R&D systems). Stable cell lines were generated by retroviral transduction of Ba / F3 cell line for 12 h. Retrovirus was generated by transfecting Phoenix 293 T Ampho packaging cell line (Orbigen) with pBABE-Puro-based vectors using Lipofectamine 2000 (Invitrogen). 72 h after transduction, 2 μg / ml puromycin (Invitrogen) was added to the medium. After 5 days of selection, cells were stained with FITC-conjugated HER2 (BioLegend) or phycoerythrin (PE)-conjugated EGFR (Biolegend) and then sorted by FACS. Cell lines were then grown in the absence of IL-3 for 15 days and cell viability was determined every 3 days using the Cell Titer Glo assay (Promega). The resulting stable cell lines were maintained in complete RPMI-1640 medium as described above without IL-3.

[0530] Cell viability assay and IC 50 Estimation Cell viability was determined using the Cell Titer Glo assay (Promega) as previously described. Briefly, 2000–3000 cells per well were plated in technical triplicates in 384-well plates (Greiner Bio-One). Cells were treated with seven different concentrations of tyrosine kinase inhibitors or vehicle alone in a final volume of 40 μL per well. After 3 days, 11 μL of Cell Titer Glo was added to each well. Plates were shaken for 15 min and bioluminescence was determined using a FLUOstar OPTIMA multimode microplate reader (BMG LABTECH). Bioluminescence values ​​were normalized to DMSO-treated cells and normalized values ​​were plotted in GraphPad Prism using a nonlinear regression fit to the normalized data with variable slope. IC values ​​at 50% inhibition were calculated by GraphPad Prism. 50 values ​​were calculated.

[0531] Inhibition of HER2 mutations For selected examples for three common HER2 mutations: A775_G776insYVMA (YVMA), P780_Y781insGSP (GSP) and G776delinsVC (VC), IC 50 The estimation was performed and the results are shown in Table 2.

[0532] [Table 20]

[0533] [Table 21]

[0534] Selectivity for mutant HER2 over WT EGFR A population of 16Ba / F3 cell lines expressing HER2 activating mutations, including mutations within the tyrosine kinase domain of HER2 (spanning exons 19-21), was generated. The mutations were then evaluated for their transforming potential as indicated by cell viability upon IL-3 deprivation. Next, for Examples 1, 2, 5 and 6, IC 50 The estimation was performed and the results are shown in Table 3.

[0535] [Table 22]

[0536] Ratio: (HER2 mutant IC 50 Value / WT EGFRIC 50 A selectivity index, defined as the selectivity ratio (p < 0.01) was calculated for each mutant-inhibitor combination. Thus, for a given mutant-inhibitor combination, a selectivity ratio of less than 1 represents inhibition of the mutant by the inhibitor at a lower concentration than inhibition of WT EGFR by the same inhibitor. Selectivity ratios for HER2 mutants are disclosed in Table 4.

[0537] [Table 23]

[0538] Inhibition of mutant EGFR over WT EGFR

[0539] [Table 24]

[0540] [Table 25]

[0541] [Table 26]

[0542] [Table 27]

[0543] [Table 28]

[0544] [Table 29]

[0545] Selectivity for mutant EGFR over WT EGFR A population of Ba / F3 cell lines expressing EGFR exon 20 mutations was generated. The mutations were then evaluated for their transforming potential as indicated by cell viability upon IL-3 deprivation. IC 50 The estimation was performed and the results are shown in Table 9.

[0546] [Table 30]

[0547] Ratio:(EGFR mutant IC 50 Value / WT EGFR IC 50 A selectivity index, defined as the selectivity ratio (p < 0.01) was calculated for each mutant-inhibitor combination. Thus, for a given mutant-inhibitor combination, a selectivity ratio of less than 1 represents inhibition of the mutant by the inhibitor at a lower concentration than inhibition of WT EGFR by the same inhibitor. Selectivity ratios for EGFR mutants are disclosed in Table 10.

[0548] [Table 31]

[0549] For example, the EGFR IC of compounds 10, 100 and 101 50 The values ​​are disclosed in FIG.

[0550] [Table 32]

[0551] [Table 33]

[0552] [Table 34]

[0553] In vivo activity assay In vivo patient-derived xenograft (PDX) studies HER2 Y772dupYVMA PDX mice were purchased from Jax Labs (Model # TM01446) and EGFR H773insNPH mice were generated as part of the MD Anderson Cancer Center Lung Cancer Moon shot. Fragments from tumors expressing HER2 Y772dupYVMA or EGFR H773insNPH were inoculated into 5-6 week old female NSG mice (Jax Labs #005557). Mice were measured 3 times weekly and tumors were measured at 275-325 mm 3 Once the volume reached 100 mg / kg, mice were transferred to treatment groups: vehicle control (dH 2Mice were randomized to receive either 0.5% methylcellulose, 0.05% Tween-80 in O or the indicated dose of a tyrosine kinase inhibitor compound. Tumor volumes and body weights were measured three times weekly. Mice were administered drugs orally Monday through Friday (5 days per week). Experiments were performed in accordance with Good Animal Practices and with approval from the MD Anderson Cancer Center Institutional Animal Care and Use Committee (Houston, TX). Mice with rapid weight loss of >15% or persistent weight loss of >25% were humanely euthanized in accordance with Good Animal Practices and excluded from tumor volume assessment.

[0554] Tumor inhibition of PDX by Example Compound 6 EGFR H773insNPH and HER2 Y772dupYVMA mice were treated with (a) vehicle, (b) 2.5 mg / kg, or (c) 5 mg / kg of example compound 6. EGFR and HER2 PDX mice are shown in Figure 5. The tumor volume change (%) of EGFR mice on day 17 is shown in Figure 6(a). The body weight change (%) of EGFR mice on day 17 is shown in Figure 6(b).

[0555] EGFR S768dupSVD and HER2 Y772dupYVMA mice were treated with (a) vehicle, (b) 2.5 mg / kg, or (c) 5 mg / kg of Example Compound 6. Tumor volumes in EGFR (solid bars) and HER2 (hashed bars) mice are shown in Figures 7(a) and (b) (days 3 and 10, respectively). Figures 8(a) and (b) show the changes in body weight of both EGFR and HER2 mice treated with the indicated doses of inhibitors on days 3 and 10, respectively.

[0556] All references, patents, or patent applications (U.S. or foreign) cited in this application are hereby incorporated by reference as if set forth in their entirety herein. In the event of any conflict, the material literally disclosed herein will control.

[0557] From the foregoing description, those skilled in the art can easily ascertain the essential features of the present disclosure, and can make various changes and modifications to the present disclosure to adapt it to various uses and conditions without departing from the spirit and scope thereof.

Claims

1. Structural formula I [Formula 1] (In the formula, A 1 is C(R 1 ), A 2 is C(R 2 ) and A 3 is C(R 3 ); or A 1 is N, A 2 is N and A 3 is C(R 3 ); or A 1 is N, A 2 is C(R 2 ) and A 3 is N; Ar １ is aryl and heteroaryl, any of which may be one or two R ４ groups, any of which may be substituted with one, two or three R ５ aryl and heteroaryl, optionally substituted with a radical; R Ａ and R Ｂ is independently selected from H and alkyl; R Ｃ is H, CH ３ and C.H. ２ N.R. １５ R １６ Selected from: R １ is halo, -CN, -OR ６ , -NR ７ａ R ７ｂ , -COOR ８ and -CONR ９ａ R ９ｂ Selected from: R ２ is selected from H, alkyl and alkoxy; R ３ is selected from H and alkyl; Each R ４ is alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any of which may be selected from one or two R １０ independently selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, optionally substituted with a group; Each R ５ is halo, -CN, -OR １１ , -NR １２ａ R １２ｂ , -COOR １３ and -CONR １４ａ R １４ｂ are independently selected from; Each R ６ , R ７ａ and R ７ｂ is independently selected from H, alkyl, and C(=O)alkyl; Each R ８ , R ９ａ and R ９ｂ is independently selected from H and alkyl; Each R １０ is independently selected from halo, hydroxy, and alkoxy; Each R １１ , R １２ａ and R １２ｂ is H, C １～６ Alkyl, C １～６ Haloalkyl and C(=O)C １～６ independently selected from alkyl; Each R １３ , R １４ａ and R １４ｂ is H and C １～６ independently selected from alkyl; R １５ and R １６ is H and C １～６ independently selected from alkyl, R １５ and R １６ together with the nitrogen to which they are both attached, join to form a 5- to 7-membered heterocycloalkyl; m is 1 and n is selected from 1, 2 and 3; or m is 2 and n is selected from 1 and 2; and Y １ is selected from -NH- and -O-; With the proviso that m is 2 and n is 2, and A １ C(R １ ) and A ２ C(R ２ ) and A ３ C(R ３ ) and R １ is CN, and R ２ C １ ~C ２ Alkoxy, and R ３ is H, Ar １ teeth, [chemical 2] isn't it, Alternatively, when m is 2 and n is 2, Ar １ teeth, [C3] isn't it) or a salt thereof.

2. Ar １ teeth, [C4] 2. The compound of claim 1 , selected from:

3. Ar １ teeth, [C5] 2. The compound of claim 1 ,

4. Y １ The compound according to any one of claims 1 to 3, wherein is -O- or -NH-.

5. m is 1 and n is 1; or m is 1 and n is 3; The compound according to any one of claims 1 to 4.

6. The compound according to any one of claims 1 to 4, wherein m is 2 and n is 2.

7. A １ The compound according to any one of claims 1 to 6, wherein is C(CN).

8. A ２is C(OCH ３ ) and A ３ is C(H).

9. A １ is N; A ２ is C(H); and A ３ The compound according to any one of claims 1 to 6, wherein is N.

10. Structural formula (VII): [C6] (In the formula, Ar １ is aryl and heteroaryl, any of which may be one, two or three R ５ aryl and heteroaryl, optionally substituted with a radical; Each R ５ is halo, -CN, -OR １１ , -NR １２ａ R １２ｂ , -COOR １３ and -CONR １４ａ R １４ｂ are independently selected from; Each R １１ , R １２ａ and R １２ｂ is H, C １～６ Alkyl, C １～６ Haloalkyl and C(=O)C １～６ alkyl; and Each R １３ , R １４ａ and R １４ｂ is H and C １～６ alkyl) having Or, Structural formula (VIII): [C7] (In the formula, Ar １ is aryl and heteroaryl, any of which may be one, two or three R ５aryl and heteroaryl, optionally substituted with a radical; Each R ５ is halo, -CN, -OR １１ , -NR １２ａ R １２ｂ , -COOR １３ and -CONR １４ａ R １４ｂ are independently selected from; Each R １１ , R １２ａ and R １２ｂ is H, C １～６ Alkyl, C １～６ Haloalkyl and C(=O)C １～６ alkyl; and Each R １３ , R １４ａ and R １４ｂ is H and C １～６ alkyl, m is 2 and n is 2; and A １ C(R １ ) and A ２ C(R ２ ) and A ３ C(R ３ ) and R １ is CN, and R ２ C １ ~C ２ Alkoxy, and R ３ is H, Ar １ teeth, [C8] isn't it) having The compound according to claim 1 or a salt thereof.

11. Ar １ is phenyl and one, two or three R are selected from halo and -CN; ５ is substituted with a group, Furthermore, Ar １ is two or three R selected from F and Cl; ５may be substituted with a group, Ar １ teeth, [C9] may be a group selected from The compound of claim 10.

12.

10. [C11] [C12] [C13] [C14] The compound or salt thereof according to claim 1, selected from:

13.

15. [C16] [C17] or a salt thereof.

14. A pharmaceutical composition comprising the compound or a salt thereof according to any one of claims 1 to 13.

15. A medicament comprising a compound or a salt thereof according to any one of claims 1 to 13 for use in the treatment of cancer.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, together with a pharma- ceutically acceptable carrier.

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