BR112017017418B1 - BICYCLIC HETEROCYCLES AS FGFR INHIBITORS, THEIR USE AND THE PHARMACEUTICAL COMPOSITION INCLUDING THEM - Google Patents

Abstract

"BICYCLIC HETEROCYCLES AS FGFR INHIBITORS. The present description relates to bicyclic heterocycles and pharmaceutical compositions thereof, which are inhibitors of the enzyme FGFR3 and/or FGFR4 and which are useful in the treatment of diseases associated with FGFR.

Description

FIELD OF THE INVENTION

[001] The present invention relates to bicyclic heterocycles and pharmaceutical compositions thereof, which are inhibitors of the FGFR enzyme and which are useful in the treatment of diseases associated with FGFR, such as cancer.

BACKGROUND OF THE INVENTION

[002] Fibroblast growth factor receptors (FGFR) are receptor tyrosine kinases that bind to fibroblast growth factor (FGF) ligands. There are four FGFR proteins (FGFR1-4) that are capable of binding ligands and are involved in the regulation of many physiological processes, including tissue development, angiogenesis, wound healing and metabolic regulation. Upon ligand binding, receptors undergo dimerization and phosphorylation leading to stimulation of protein kinase activity and recruitment of intracellular anchoring proteins. These interactions facilitate the activation of a set of intracellular signaling pathways, including Ras-MAPK, AKT-PI3K, and phospholipase C, that are important for cell growth, proliferation, and survival (reviewed in Eswarakumar et al. Cytokine & Growth Factor Reviews, 2005).

[003] Aberrant activation of this pathway through overexpression of FGF or FGFR ligands or activation of mutations in the FGFRs can lead to tumor development, progression, and resistance to conventional cancer therapies. In human cancer, genetic alterations including gene amplification, chromosomal translocations and somatic mutations that lead to ligand-independent receptor activation have been described. Large-scale DNA sequencing of thousands of tumor samples has revealed that components of the FGFR pathway are among the most frequently mutated in human cancer. Many of these activating mutations are identical to the germline mutations that lead to skeletal dysplasia syndromes. Mechanisms that lead to aberrant ligand-dependent signaling in human disease include overexpression of FGFs and alterations in FGFR splicing that lead to receptors with more promiscuous ligand-binding abilities (reviewed in Knights and Cook Pharmacology & Therapeutics, 2010; Turner and Grose, Nature Reviews Cancer, 2010). Therefore, the development of targeted FGFR inhibitors may be useful in the clinical treatment of diseases that have elevated FGFR or FGF activity.

[004] Types of cancer in which FGF/FGFRs are implicated include, but are not limited to: carcinomas (e.g., bladder, breast, cervical, colorectal, endometrial, gastric, head and neck, kidney, liver, lung, ovary, prostate); hematopoietic malignancies (eg, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, acute myeloid leukemia, Hodgkin's lymphoma, myeloproliferative neoplasms, and Waldenstrom's macroglobulinemia); and other neoplasms (eg, glioblastoma, melanoma, and rhabdosarcoma). In addition to a role in oncogenic neoplasms, FGFR activation has also been implicated in skeletal and chondrocyte disorders including, but not limited to, acrondroplasia and craniosynostosis syndromes.

[005] The FGFR4 - FGF19 signaling axis, specifically, has been implicated in the pathogenesis of several cancers, including hepatocellular carcinoma (Heinzle et al., Cur. Pharm. Des. 2014, 20:2881). Ectopic expression of FGF19 in transgenic mice has been shown to lead to the formation of tumors in the liver and a neutralizing antibody against FGF19 has been shown to inhibit tumor growth in mice. Furthermore, overexpression of FGFR4 has been observed in several tumor types, including hepatocellular, colorectal, breast, pancreatic, prostate, lung, and thyroid cancers. Additionally, activating mutations in FGFR4 have been reported in rhabdomyosarcoma (Taylor et al. JCI 2009,119:3395). Targeting FGFR with selective small molecule inhibitors may therefore be beneficial in the treatment of cancers and other diseases.

SUMMARY OF THE INVENTION

[006] In one aspect, the present invention relates to compounds of Formula (I'):

[007] or a pharmaceutically acceptable salt thereof, wherein the constituent variables are defined herein.

[008] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of Formula (I'), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

[009] In another aspect, the present invention provides methods for inhibiting a FGFR3 and/or FGFR4 enzyme. The method includes bringing the enzyme into contact with a compound of formula (I'), or a pharmaceutically acceptable salt thereof, or a composition comprising compounds of formula (I').

[0010] In another aspect, the present invention provides a method for treating a disease associated with abnormal activity or expression of an FGFR enzyme, such as FGFR3 and/or FGFR4. The method includes administering an effective amount of a compound of Formula (I'), or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Formula (I') to a patient in need of the same.

[0011] In yet another aspect, the present invention provides compounds of formula (I') for use in the treatment of a disease associated with abnormal activity or expression of an enzyme FGFR3 and/or FGFR4.

[0012] In another aspect, the present invention features a method of treating a disorder mediated by an enzyme FGFR3 and/or FGFR4, or a mutant thereof, in a patient in need of such treatment. The method includes administering to the patient a compound as described herein, or pharmaceutically acceptable salts thereof, or a composition comprising a compound as described in the present invention.

[0013] In another aspect, the present invention features the use of compounds of formula (I') in the preparation of a medicament for use in therapy.

DETAILED DESCRIPTION

[0014] Compounds

[0015] In one aspect, the present invention provides a compound having formula (I'):

[0016] or a pharmaceutically acceptable salt thereof, wherein:

[0017] Ring A is C6-10 aryl or a 5- to 10-membered heteroaryl having carbon and 1 to 4 heteroatoms as ring members selected from O, N, and S, where N and S are each , optionally oxidized;

[0018] each R12 is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4 to 10 membered, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5 to 10 membered heteroaryl)-C1-4 alkyl-, (4 to 10 membered heterocycloalkyl) -C1-4-alkyl, CN, NO2, ORa, SRa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NRaRa, NRaORa, NRaC (O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(=NRa)Ra, C(=NRa)NRaRa, NRaC(=NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra and S(O)2NRaRa , where a is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-4-alkyl, C3-10-cycloalkyl-C1-4-alkyl, (5-membered heteroaryl) to 10-membered)-C 1-4 alkyl- and (4 to 10-membered heterocycloalkyl)-C 1-4 alkyl- are each optionally substituted with 1, 2, 3 or 4 independently selected Rb substituents;

[0019] or two adjacent R12 substituents on ring A, together with the atoms to which they are attached, form a 5- or 6-membered cycloalkyl ring, 5- or 6-membered heterocycloalkyl ring, phenyl or 5- to 6-membered heteroaryl ring, in that the heterocycloalkyl or heteroaryl has 1 to 2 heteroatoms as ring members selected from O, N and S;

[0020] each Ra is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6- aryl 10-C1-4-alkyl, C3-10-cycloalkyl-C1-4-alkyl, (5- to 10-membered heteroaryl)-C1-4-alkyl- and (4- to 10-membered heterocycloalkyl)-C1-4- alkyl-, in than C1-6 alkyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-4-alkyl, C3-10 cycloalkyl -C1-4alkyl-, (5- to 10-membered heteroaryl)-C1-4-alkyl- and (4- to 10-membered heterocycloalkyl)-C1-4-alkyl- of Ra are each optionally substituted by 1, 2, 3, 4 or 5 independently selected Rd substituents;

[0021] or any two Ra substituents attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, or 3 Rh substituents independently selected;

[0022] each Rb is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-aryl 10-C1-4-alkyl, C3-10-cycloalkyl-C1-4-alkyl, (5- to 10-membered heteroaryl)-C1-4- alkyl- and (4- to 10-membered heterocycloalkyl)-C1-4- alkyl, CN , NO2, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, C(=NRc)NRcRc, NRcC(=NRc)NRcRc , NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S(O)Rc, S(O)NRcRc , S(O)2Rc and S(O)2NRcRc; wherein is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-alkyl 4-, C3-10 cycloalkyl-C1-4 alkyl-, (5- to 10-membered heteroaryl)-C1-4 alkyl- and (4- to 10-membered heterocycloalkyl)-C1-4 alkyl Rb are each optionally substituted by 1, 2, 3, 4 or 5 independently selected Rf substituents;

[0023] each Rc is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5- to 10-membered heteroaryl)-C1-4 alkyl- and (4- to 10-membered heterocycloalkyl) to 10-membered)-C1-4-alkyl, wherein said C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C6-10-aryl, C3-10-cycloalkyl, 5- to 10-membered heteroaryl , 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5- to 10-membered heteroaryl)-C1-4 alkyl- and (C1-4-membered heterocycloalkyl) 4 to 10 membered)-C 1-4 alkyl of Rc are each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rf substituents;

[0024] or any two Rc substituents attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, or 3 Rh substituents independently selected;

[0025] each Rd is independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, CN, ORe, SRe, C(O)Re, C(O)NReRe, C(O)ORe, OC(O)Re , OC(O)NReRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, C(=NRe)NReRe, NReC(=NRe)NReRe, S(O)Re, S(O) )NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe and S(O)2NReRe;

[0026] each Rf is independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, CN, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg , OC(O)NRgRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg, C(=NRg)NRgRg, NRgC(=NRg)NRgRg, S(O)Rg, S(O) )NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg and S(O)2NRgRg;

[0027] each Rh is independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-10 aryl, 5- to 6-membered heteroaryl, C1-6 haloalkyl, halo, CN, ORi, SRi , C(O)Ri, C(O)NRiRi, C(O)ORi, OC(O)Ri, OC(O)NRiRi, NRiRi, NRiC(O)Ri, NRiC(O)NRiRi, NRiC(O)ORi , C(=NRi)NRiRi, NRiC(=NRi)NRiRi, S(O)Ri, S(O)NRiRi, S(O)2Ri, NRiS(O)2Ri, NRiS(O)2NRiRi and S(O)2NRiRi , wherein said C1-6 alkyl, C3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-10 aryl and 5- to 6-membered heteroaryl of Rh are optionally substituted by 1, 2, or 3 substituents Rj independently selected;

[0028] each Rj is independently selected from halo, C1-4 alkyl, haloC1-4 alkyl, CN, ORk, SRk, C(O)Rk, C(O)NRkRk, C(O)ORk, OC(O)Rk , OC(O)NRkRk, NRkRk, NRkC(O)Rk, NRkC(O)NRkRk, NRkC(O)ORi, C(=NRk)NRkRk, NRkC(=NRk)NRkRk, S(O)Rk, S(O) )NRkRk, S(O)2Rk, NRkS(O)2Rk, NRkS(O)2NRkRk and S(O)2NRkRk;

[0029] each Re, Rg, Ri or Rk is independently selected from H, C1-4 alkyl, C6-10 aryl, C1-4 haloalkyl, C2-4 alkenyl and C2-4 alkyl, wherein the C1- 4, C6-10 aryl, C2-4 alkenyl, or C2-4 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-4 alkyl, C1-alkoxy 4, C1-4 alkylthio, C1-4 alkylamino, di(C1-4 alkyl)amino, C1-4 haloalkyl and C1-4 haloalkoxy;

[0030] or any two Re substituents attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, or 3 Rh substituents independently selected;

[0031] or any two Rg substituents attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, or 3 Rh substituents independently selected;

[0032] or any two Ri substituents attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 independently selected Rh substituents;

[0033] X1 is -CR10R11- or -NR7-

[0034] X2 is N or CR6;

[0035] R13 is H, CN, NRc4Rd4, OR1 or -C(O)NHRe, wherein R1 is C1-3 alkyl or C1-3 haloalkyl;

[0036] R2 is H, halo, C1-3 alkyl, C1-3 haloalkyl, CN or C1-3 alkoxy;

[0037] R3 is H, halo, C1-3 alkyl, C1-3 haloalkyl, CN or C1-3 alkoxy;

[0038] R14 is H, CN, NRc4Rd4, OR4 or -C(O)NHRg, wherein R4 is C1-3 alkyl or C1-3 haloalkyl;

[0039] R5 is H, halo, C1-3 alkyl, C1-3 haloalkyl, CN or C1-3 alkoxy;

[0040] R6 is selected from H, halo, CN, ORa4, SRa4, C(O)NRc4Rd4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4 , NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, S(O)2NRc4Rd4, C1-6 alkyl, C2 alkenyl -6, C2-6 alkynyl, C1-6 haloalkyl, phenyl, C3-6 cycloalkyl, a 5- to 6-membered heteroaryl having carbon and 1, 2, or 3 heteroatoms independently selected from N, O, and S, and a 4- to 7-membered heterocycloalkyl having carbon and 1, 2, or 3 heteroatoms selected from N, O, and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-6 cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups of R6 are each optionally substituted by 1, 2, or 3 substituents independently selected from R10A;

[0041] R7 is selected from H, C(O)NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, S(O)2NRc4Rd4, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 haloalkyl, phenyl, C3-6 cycloalkyl, 5- to 10-membered heteroaryl having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, 4-membered heterocycloalkyl to 10-membered having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (heteroaryl 5- to 10-membered)-C1-4-alkyl- and (4- to 10-membered heterocycloalkyl)-C1-4-alkyl-; wherein said groups are C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-6 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl -, C3-10 cycloalkyl-C1-4 alkyl-, (5- to 10-membered heteroaryl)-C1-4 alkyl-, and (4- to 10-membered heterocycloalkyl)-C1-4 alkyl- of R7 are each optionally substituted by 1, 2 or 3 substituents independently selected from R10A; or two R10A substituents attached to adjacent ring atoms of the aryl or heteroaryl ring of R7, together with the atoms to which they are attached, form a fused C5-6 cycloalkyl ring or a 5- to 6-membered heterocycloalkyl ring having 1 to 2 heteroatoms as ring members independently selected from O, N and S, wherein the nitrogen and sulfur atoms are each optionally oxidized and the fused C5-6 cycloalkyl or fused 5-6 membered heterocycloalkyl ring is optionally replaced by 1 or 2 independently selected R19 groups;

[0042] R10 and R11 are each independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5 to 10 heteroaryl moiety members having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4- to 10-membered heterocycloalkyl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl groups of R10 and R11 are each one, optionally substituted with 1, 2 or 3 R10A;

[0043] Alternatively, R10 and R11, together with the carbon to which they are attached, form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group or a 4-, 5-, 6-, 7-, 8-, 9-membered heterocycloalkyl group or 10 members; wherein said 3, 4, 5, 6 or 7 membered cycloalkyl group and said 4, 5, 6, 7, 8, 9 or 10 membered heterocycloalkyl group are each optionally substituted by 1, 2, 3 or 4 R10A;

[0044] each R10A is independently selected from halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C (=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4 , S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, S(O)2NRc4Rd4, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, phenyl, C3-cycloalkyl 6, a 5- to 6-membered heteroaryl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4- to 7-membered heterocycloalkyl moiety having carbon and 1, 2 or 3 heteroatoms independently selected among N, O and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-6 cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups of R10A are each optionally substituted with 1, 2, or 3 substituents independently selected from R19;

[0045] each Ra4, Rb4, Rc4 and Rd4 is independently selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkyl, C1-4 haloalkyl, phenyl, C3-6 cycloalkyl, a heteroaryl moiety of 5 to 6 membered having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4 to 7 membered heterocycloalkyl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S ; wherein said C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, C3-6 cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups of Ra4, Rb4, Rc4 and Rd4 are each optionally substituted with 1, 2 or 3 substituents independently selected from R19;

[0046] Alternatively, Rc4 and Rd4, together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group which is optionally substituted by 1, 2, or 3 substituents independently selected from R19;

[0047] each Re4 is independently H or C1-4 alkyl;

[0048] each R19 is independently selected from halo, CN, NO2, ORa9, SRa9, C(O)Rb9, C(O)NRc9Rd9, C(O)ORa9, OC(O)Rb9, OC(O)NRc9Rd9, NRc9Rd9 , NRc9C(O)Rb9, NRc9C(O)ORa9, NRc9C(O)NRc9Rd9, NRc9S(O)Rb9, NRc9S(O)2Rb9, NRc9S(O)2NRc9Rd9, S(O)Rb9, S(O)NRc9Rd9, S (O)2Rb9, S(O)2NRc9Rd9, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, 3-6 cycloalkyl and C1-4 haloalkyl; wherein the C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl and C1-4 haloalkyl of R19 are each optionally substituted with 1 or 2 R20 substituents independently selected from H, halo , CN, NO2, ORq, SRq, C(O)Rq, C(O)NRqRq, C(O)ORq, OC(O)Rq, OC(O)NRqRq, NRqRq, NRqC(O)Rq, NRqC(O) )ORq, NRqC(O)NRqRq, NRqS(O)Rq, NRqS(O)2Rq, NRqS(O)2NRqRq, S(O)Rq, S(O)NRqRq, S(O)2Rq, S(O)2NRqRq , C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl- and C1-4 haloalkyl, wherein each Rq is independently H or C1-4 alkyl.

[0049] each Ra9, Rc9 and Rd9 is independently selected from H and C1-4 alkyl;

[0050] each Rb9 is independently C1-4 alkyl; It is

[0051] the n subscript is 0, 1, 2 or 3.

[0052] In some embodiments, the present invention provides a compound having formula (I):

[0053] or a pharmaceutically acceptable salt thereof, wherein:

[0054] Ring A is C6-10 aryl or a 5- to 6-membered heteroaryl having carbon and 1 to 4 heteroatoms as ring members selected from O, N and S;

[0055] each R12 is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4 to 10 membered, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5 to 10 membered heteroaryl)-C1-4 alkyl-, (4 to 10 membered heterocycloalkyl) -C1-4-alkyl, CN, NO2, ORa, SRa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NRaRa, NRaORa, NRaC (O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(=NRa)Ra, C(=NRa)NRaRa, NRaC(=NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra and S(O)2NRaRa, where a is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-4-alkyl, C3-10-cycloalkyl-C1-4-alkyl, (5-membered heteroaryl) to 10-membered)-C 1-4 alkyl- and (4 to 10-membered heterocycloalkyl)-C 1-4 alkyl- are each optionally substituted with 1, 2, 3 or 4 independently selected Rb substituents;

[0056] or two adjacent R12 substituents on ring A, together with the atoms to which they are attached, form a 5- or 6-membered cycloalkyl ring, 5- or 6-membered heterocycloalkyl ring, phenyl or 5- to 6-membered heteroaryl ring, in that the heterocycloalkyl or heteroaryl has 1 to 2 heteroatoms as ring members selected from O, N and S;

[0057] each Ra is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6- aryl 10-C1-4-alkyl, C3-10-cycloalkyl-C1-4-alkyl, (5- to 10-membered heteroaryl)-C1-4-alkyl- and (4- to 10-membered heterocycloalkyl)-C1-4-alkyl-, in which is C1-6 alkyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-4-alkyl, C3-10 cycloalkyl-C1 alkyl -4-, (5- to 10-membered heteroaryl)-C 1-4 alkyl- and (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl such as Ra are each optionally substituted by 1, 2, 3, 4 or 5 substituents Rd independently selected;

[0058] or any two Ra substituents attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, or 3 Rh substituents independently selected;

[0059] each Rb is independently selected from halo, C1-4 alkyl, haloC1-4 alkyl, CN, NO2, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC (O)Rc, OC(O)NRcRc, C(=NRc)NRcRc, NRcC(=NRc)NRcRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc , NRcS(O)2Rc, NRcS(O)2NRcRc, S(O)Rc, S(O)NRcRc, S(O)2Rc and S(O)2NRcRc;

[0060] each Rc is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5- to 10-membered heteroaryl)-C1-4 alkyl- and (4- to 10-membered heterocycloalkyl) to 10-membered)-C1-4-alkyl, wherein said C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C6-10-aryl, C3-10-cycloalkyl, 5- to 10-membered heteroaryl , 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5- to 10-membered heteroaryl)-C1-4 alkyl- and (C1-4-membered heterocycloalkyl) 4- to 10-membered)-C1-4 alkyl- are each optionally substituted by 1, 2, 3, 4 or 5 independently selected Rf substituents;

[0061] or any two Rc substituents attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, or 3 Rh substituents independently selected, wherein the C1-6 alkyl, C3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-10 aryl aryl, or 5- to 6-membered heteroaryl as Rh is optionally substituted with 1, 2, or 3 substituents Rj independently selected;

[0062] each Rd is independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, CN, ORe, SRe, C(O)Re, C(O)NReRe, C(O)ORe, OC(O)Re , OC(O)NReRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, C(=NRe)NReRe, NReC(=NRe)NReRe, S(O)Re, S(O) )NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe and S(O)2NReRe;

[0063] each Rf is independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, CN, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg , OC(O)NRgRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg, C(=NRg)NRgRg, NRgC(=NRg)NRgRg, S(O)Rg, S(O) )NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg and S(O)2NRgRg;

[0064] each Rh is independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-10 aryl, 5- to 6-membered heteroaryl, C1-6 haloalkyl, halo, CN, ORi, SRi , C(O)Ri, C(O)NRiRi, C(O)ORi, OC(O)Ri, OC(O)NRiRi, NRiRi, NRiC(O)Ri, NRiC(O)NRiRi, NRiC(O)ORi , C(=NRi)NRiRi, NRiC(=NRi)NRiRi, S(O)Ri, S(O)NRiRi, S(O)2Ri, NRiS(O)2Ri, NRiS(O)2NRiRi, and S(O) 2NRiRi, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-10 aryl and 5- to 6-membered heteroaryl are optionally substituted by 1, 2 or 3 independently selected substituents Rj births;

[0065] each Rj is independently selected from halo, C1-4 alkyl, haloC1-4 alkyl, CN, ORk, SRk, C(O)Rk, C(O)NRkRk, C(O)ORk, OC(O)Rk , OC(O)NRkRk, NRkRk, NRkC(O)Rk, NRkC(O)NRkRk, NRkC(O)ORi, C(=NRk)NRkRk, NRkC(=NRk)NRkRk, S(O)Rk, S(O) )NRkRk, S(O)2Rk, NRkS(O)2Rk, NRkS(O)2NRkRk and S(O)2NRkRk;

[0066] each Re, Rg, Ri or Rk is independently selected from H, C1-4 alkyl, C6-10 aryl, C1-4 haloalkyl, C2-4 alkenyl and C2-4 alkyl, wherein the C1- 4, C6-10 aryl, C2-4 alkenyl, or C2-4 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-4 alkyl, C1-alkoxy 4, C1-4 alkylthio, C1-4 alkylamino, di(C1-4 alkyl)amino, C1-4 haloalkyl and C1-4 haloalkoxy;

[0067] or any two Re substituents attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, or 3 Rh substituents independently selected;

[0068] or any two Rg substituents attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, or 3 Rh substituents independently selected;

[0069] or any two Ri substituents attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 independently selected Rh substituents;

[0070] X1 is -CR10R11- or -NR7-

[0071] X2 is N or CR6;

[0072] R1 is C1-3 alkyl or C1-3 haloalkyl;

[0073] R2 is H, halo, C1-3 alkyl, C1-3 haloalkyl, CN or C1-3 alkoxy;

[0074] R3 is H, halo, C1-3 alkyl, C1-3 haloalkyl, CN or C1-3 alkoxy;

[0075] R4 is C1-3 alkyl or C1-3 haloalkyl;

[0076] R5 is H, halo, C1-3 alkyl, C1-3 haloalkyl, CN or C1-3 alkoxy;

[0077] R6 and R7 are each independently selected from H, halo, CN, ORa4, SRa4, C(O)NRc4Rd4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O) ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, S(O)2NRc4Rd4, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, phenyl, C3-6 cycloalkyl, a 5- to 6-membered heteroaryl having carbon and 1, 2 or 3 independently selected heteroatoms from N, O and S, and a 4- to 7-membered heterocycloalkyl having carbon and 1, 2 or 3 heteroatoms selected from N, O and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-6 cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups of R6 and R7 are each optionally substituted with 1, 2, or 3 substituents independently selected from R10A;

[0078] R10 and R11 are each independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5 to 10 heteroaryl moiety members having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4- to 10-membered heterocycloalkyl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl groups of R10 and R11 are each one, optionally substituted with 1, 2 or 3 R10A;

[0079] Alternatively, R10 and R11, together with the carbon to which they are attached, form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group or a 4-, 5-, 6-, 7-, 8-, 9-membered heterocycloalkyl group or 10 members; wherein said 3, 4, 5, 6 or 7 membered cycloalkyl group and said 4, 5, 6, 7, 8, 9 or 10 membered heterocycloalkyl group are each optionally substituted by 1, 2, 3 or 4 R10A;

[0080] each R10A is independently selected from halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C (=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4 , S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, S(O)2NRc4Rd4, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, phenyl, C3-cycloalkyl 6, a 5- to 6-membered heteroaryl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4- to 7-membered heterocycloalkyl moiety having carbon and 1, 2 or 3 heteroatoms independently selected among N, O and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-6 cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups of R10A are each optionally substituted with 1, 2, or 3 substituents independently selected from R19;

[0081] each Ra4, Rb4, Rc4 and Rd4 is independently selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkyl, C1-4 haloalkyl, phenyl, C3-6 cycloalkyl, a heteroaryl moiety of 5- to 6-membered moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4- to 7-membered heterocycloalkyl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N , O and S; wherein said C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, C3-6 cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups of Ra4, Rb4, Rc4 and Rd4 are each optionally substituted with 1, 2 or 3 substituents independently selected from R19;

[0082] Alternatively, Rc4 and Rd4, together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group which is optionally substituted by 1, 2, or 3 substituents independently selected from R19;

[0083] each Re4 is independently H or C1-4 alkyl;

[0084] each R19 is independently selected from halo, CN, NO2, ORa9, SRa9, C(O)Rb9, C(O)NRc9Rd9, C(O)ORa9, OC(O)Rb9, OC(O)NRc9Rd9, NRc9Rd9 , NRc9C(O)Rb9, NRc9C(O)ORa9, NRc9C(O)NRc9Rd9, NRc9S(O)Rb9, NRc9S(O)2Rb9, NRc9S(O)2NRc9Rd9, S(O)Rb9, S(O)NRc9Rd9, S (O)2Rb9, S(O)2NRc9Rd9, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, 3-6 cycloalkyl and C1-4 haloalkyl; wherein the C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl and C1-4 haloalkyl are each optionally substituted with 1 or 2 R20 substituents independently selected from H, halo, CN, NO2 , ORq, SRq, C(O)Rq, C(O)NRqRq, C(O)ORq, OC(O)Rq, OC(O)NRqRq, NRqRq, NRqC(O)Rq, NRqC(O)ORq, NRqC (O)NRqRq, NRqS(O)Rq, NRqS(O)2Rq, NRqS(O)2NRqRq, S(O)Rq, S(O)NRqRq, S(O)2Rq, S(O)2NRqRq, C1-alkyl 4, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, and C1-4 haloalkyl, wherein each Rq is independently H or C1-4 alkyl.

[0085] each Ra9, Rc9 and Rd9 is independently selected from H and C1-4 alkyl;

[0086] each Rb9 is independently C1-4 alkyl; It is

[0087] the n subscript is 0, 1, 2 or 3.

[0088] In some embodiments of the compounds of formula (I') or (I):

[0089] ring A is C6-10 aryl or a 5- to 6-membered heteroaryl having carbon and 1 to 4 heteroatoms as ring members selected from O, N and S;

[0090] each R12 is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4 to 10 membered, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5 to 10 membered heteroaryl)-C1-4 alkyl-, (4 to 10 membered heterocycloalkyl) -C1-4-alkyl, CN, NO2, ORa, SRa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NRaRa, NRaORa, NRaC (O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(=NRa)Ra, C(=NRa)NRaRa, NRaC(=NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra and S(O)2NRaRa, where a is C1-6 alkyl, C2-6 alkylkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-4-alkyl, C3-10-cycloalkyl-C1-4-alkyl, (5-membered heteroaryl) to 10-membered)-C 1-4 alkyl- and (4 to 10-membered heterocycloalkyl)-C 1-4 alkyl- are each optionally substituted with 1, 2, 3 or 4 independently selected Rb substituents;

[0091] or two adjacent R12 substituents on ring A, together with the atoms to which they are attached, form a 5- or 6-membered cycloalkyl ring, 5- or 6-membered heterocycloalkyl ring, phenyl or 5- to 6-membered heteroaryl ring, in that the heterocycloalkyl or heteroaryl has 1 to 2 heteroatoms as ring members selected from O, N and S;

[0092] each Ra is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-aryl 10-C1-4-alkyl, C3-10-cycloalkyl-C1-4-alkyl, (5- to 10-membered heteroaryl)-C1-4-alkyl- and (4- to 10-membered heterocycloalkyl)-C1-4- alkyl-, in which is C1-6 alkyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-4-alkyl, C3-10 cycloalkyl-C1-alkyl -4-, (5- to 10-membered heteroaryl)-C 1-4 alkyl- and (4- to 10-membered heterocycloalkyl)- C 1-4 alkyl such as Ra are each optionally substituted by 1, 2, 3, 4 or 5 substituents Rd independently selected;

[0093] or any two Ra substituents attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, or 3 Rh substituents independently selected;

[0094] each Rb is independently selected from halo, C1-4 alkyl, C1-4 alkyl, C1-4 haloalkyl, CN, NO2, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O )ORc, OC(O)Rc, OC(O)NRcRc, C(=NRc)NRcRc, NRcC(=NRc)NRcRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS (O)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S(O)Rc, S(O)NRcRc, S(O)2Rc and S(O)2NRcRc;

[0095] each Rc is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5- to 10-membered heteroaryl)-C1-4 alkyl- and (4- to 10-membered heterocycloalkyl) to 10-membered)-C1-4-alkyl, wherein said C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C6-10-aryl, C3-10-cycloalkyl, 5- to 10-membered heteroaryl , 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5- to 10-membered heteroaryl)-C1-4 alkyl- and (C1-4-membered heterocycloalkyl) 4 to 10 membered)-C 1-4 alkyl- are each optionally substituted by 1, 2, 3, 4 or 5 independently selected Rf substituents;

[0096] Any two Rc substituents attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, or 3 Rh substituents independently selected;

[0097] each Rd is independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, CN, ORe, SRe, C(O)Re, C(O)NReRe, C(O)ORe, OC(O)Re , OC(O)NReRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, C(=NRe)NReRe, NReC(=NRe)NReRe, S(O)Re, S(O) )NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe and S(O)2NReRe;

[0098] each Rf is independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, CN, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg , OC(O)NRgRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg, C(=NRg)NRgRg, NRgC(=NRg)NRgRg, S(O)Rg, S(O) )NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg and S(O)2NRgRg;

[0099] each Rh is independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-10 aryl, 5- to 6-membered heteroaryl, C1-6 haloalkyl, halo, CN, ORi, SRi , C(O)Ri, C(O)NRiRi, C(O)ORi, OC(O)Ri, OC(O)NRiRi, NRiRi, NRiC(O)Ri, NRiC(O)NRiRi, NRiC(O)ORi , C(=NRi)NRiRi, NRiC(=NRi)NRiRi, S(O)Ri, S(O)NRiRi, S(O)2Ri, NRiS(O)2Ri, NRiS(O)2NRiRi, and S(O) 2NRiRi, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-10 aryl and 5- to 6-membered heteroaryl are optionally substituted by 1, 2 or 3 independently selected substituents Rj births;

[00100] each Rj is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, ORk, SRk, C(O)Rk, C(O)NRkRk, C(O)ORk, OC(O)Rk , OC(O)NRkRk, NRkRk, NRkC(O)Rk, NRkC(O)NRkRk, NRkC(O)ORi, C(=NRk)NRkRk, NRkC(=NRk)NRkRk, S(O)Rk, S(O) )NRkRk, S(O)2Rk, NRkS(O)2Rk, NRkS(O)2NRkRk and S(O)2NRkRk;

[00101] each Re, Rg, Ri or Rk is independently selected from H, C1-4 alkyl, C6-10 aryl, C1-4 haloalkyl, C2-4 alkenyl and C2-4 alkyl, wherein the C1- 4, C6-10 aryl, C2-4 alkenyl, or C2-4 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-4 alkyl, C1-alkoxy 4, C1-4 alkylthio, C1-4 alkylamino, di(C1-4 alkyl)amino, C1-4 haloalkyl and C1-4 haloalkoxy;

[00102] or any two Re substituents attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 independently selected Rh substituents;

[00103] or any two substituents Rg attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted by 1, 2 or 3 independently selected Rh substituents;

[00104] or any two Ri substituents attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 independently selected Rh substituents;

[00105] X1 is -CR10R11- or -NR7-

[00106] X2 is N or CR6;

[00107] R1 is C1-3 alkyl or C1-3 haloalkyl;

[00108] R2 is H, halo, C1-3 alkyl, C1-3 haloalkyl, CN or C1-3 alkoxy;

[00109] R3 is H, halo, C1-3 alkyl, C1-3 haloalkyl, CN or C1-3 alkoxy;

[00110] R4 is C1-3 alkyl or C1-3 haloalkyl;

[00111] R5 is H, halo, C1-3 alkyl, C1-3 haloalkyl, CN or C1-3 alkoxy;

[00112] R6 is selected from H, halo, CN, ORa4, SRa4, C(O)NRc4Rd4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4 , NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, S(O)2NRc4Rd4, C1-6 alkyl, C2 alkenyl -6, C2-6 alkynyl, C1-6 haloalkyl, phenyl, C3-6 cycloalkyl, a 5- to 6-membered heteroaryl having carbon and 1, 2, or 3 heteroatoms independently selected from N, O, and S, and a 4- to 7-membered heterocycloalkyl having carbon and 1, 2, or 3 heteroatoms selected from N, O, and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-6 cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups of R6 are each optionally substituted by 1, 2, or 3 substituents independently selected from R10A;

[00113] R7 is selected from H, C(O)NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, S(O)2NRc4Rd4, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 haloalkyl, phenyl, C3-6 cycloalkyl, 5- to 6-membered heteroaryl having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a moiety 4- to 7-membered heterocycloalkyl having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-6 cycloalkyl, 5- to 7-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups of R6 are each optionally substituted by 1, 2, or 3 substituents independently selected from R10A;

[00114] R10 and R11 are each independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkylkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5 to 10 heteroaryl moiety members having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4- to 10-membered heterocycloalkyl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl groups of R10 and R11 are each one, optionally substituted with 1, 2 or 3 R10A;

[00115] Alternatively, R10 and R11, together with the carbon to which they are attached, form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group or a 4-, 5-, 6-, 7-, 8-, 9-membered heterocycloalkyl group or 10 members; wherein said 3, 4, 5, 6 or 7 membered cycloalkyl group and said 4, 5, 6, 7, 8, 9 or 10 membered heterocycloalkyl group are each optionally substituted with 1, 2, 3 or 4 R10A;

[00116] each R10A is independently selected from halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C (=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4 , S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, S(O)2NRc4Rd4, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, phenyl, C3-cycloalkyl 6, a 5- to 6-membered heteroaryl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4- to 7-membered heterocycloalkyl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-6 cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups of R10A are each optionally substituted by 1, 2, or 3 independently selected substituents from R19;

[00117] each Ra4, Rb4, Rc4 and Rd4 is independently selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkyl, C1-4 haloalkyl, phenyl, C3-6 cycloalkyl, a heteroaryl moiety of 5 to 6 membered having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4 to 7 membered heterocycloalkyl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N , O and S; wherein said C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, C3-6 cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups of Ra4, Rb4, Rc4 and Rd4 are each optionally substituted with 1, 2 or 3 substituents independently selected from R19;

[00118] Alternatively, Rc4 and Rd4, together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group that is optionally substituted by 1, 2, or 3 substituents independently selected from R19;

[00119] each Re4 is independently H or C1-4 alkyl;

[00120] each R19 is independently selected from halo, CN, NO2, ORa9, SRa9, C(O)Rb9, C(O)NRc9Rd9, C(O)ORa9, OC(O)Rb9, OC(O)NRc9Rd9, NRc9Rd9 , NRc9C(O)Rb9, NRc9C(O)ORa9, NRc9C(O)NRc9Rd9, NRc9S(O)Rb9, NRc9S(O)2Rb9, NRc9S(O)2NRc9Rd9, S(O)Rb9, S(O)NRc9Rd9, S (O)2Rb9, S(O)2NRc9Rd9, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl and C1-4 haloalkyl; wherein C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl and C1-4 haloalkyl are each optionally substituted with 1 or 2 R20 substituents independently selected from H, halo, CN, NO2, ORq, SRq, C(O)Rq, C(O)NRqRq, C(O)ORq, OC(O)Rq, OC(O)NRqRq, NRqRq, NRqC(O)Rq, NRqC(O)ORq, NRqC( O)NRqRq, NRqS(O)Rq, NRqS(O)2Rq, NRqS(O)2NRqRq, S(O)Rq, S(O)NRqRq, S(O)2Rq, S(O)2NRqRq, C1-4 alkyl , C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, and C1-4 haloalkyl, wherein each Rq is independently H or C1-4 alkyl.

[00121] each Ra9, Rc9 and Rd9 is independently selected from H and C1-4 alkyl;

[00122] each Rb9 is independently C1-4 alkyl; It is

[00123] the n subscript is 0, 1, 2 or 3.

[00124] In one aspect, the present invention provides a compound having formula (I):

[00125] or a pharmaceutically acceptable salt thereof, wherein:

[00126] ring A is C6-10 aryl or a 5- to 6-membered heteroaryl having carbon and 1 to 4 heteroatoms as ring members selected from O, N and S;

[00127] each R12 is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkylkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4 to 10 membered, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5 to 10 membered heteroaryl)-C1-4 alkyl-, (4 to 10 membered heterocycloalkyl) -C1-4-alkyl, CN, NO2, ORa, SRa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NRaRa, NRaORa, NRaC (O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(=NRa)Ra, C(=NRa)NRaRa, NRaC(=NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra and S(O)2NRaRa, where a is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-4-alkyl, C3-10-cycloalkyl-C1-4-alkyl, (5-membered heteroaryl) to 10-membered)-C 1-4 alkyl- and (4 to 10-membered heterocycloalkyl)-C 1-4 alkyl- are each optionally substituted with 1, 2, 3 or 4 independently selected Rb substituents;

[00128] or two adjacent R12 substituents on ring A, together with the atoms to which they are attached, form a 5- or 6-membered cycloalkyl ring, 5- or 6-membered heterocycloalkyl ring, phenyl or 5- to 6-membered heteroaryl ring, in that the heterocycloalkyl or heteroaryl has 1 to 2 heteroatoms as ring members selected from O, N and S;

[00129] Each Ra is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-aryl 10-C1-4-alkyl, C3-10-cycloalkyl-C1-4-alkyl, (5- to 10-membered heteroaryl)-C1-4-alkyl- and (4- to 10-membered heterocycloalkyl)-C1-4- alkyl-, in which is C1-6 alkyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-4-alkyl, C3-10 cycloalkyl-C1-alkyl -4-, (5- to 10-membered heteroaryl)-C 1-4 alkyl- and (4- to 10-membered heterocycloalkyl)- C 1-4 alkyl such as Ra are each optionally substituted by 1, 2, 3, 4 or 5 substituents Rd independently selected;

[00130] or any two Ra substituents attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 independently selected Rh substituents;

[00131] Each Rb is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, NO2, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC (O)Rc, OC(O)NRcRc, C(=NRc)NRcRc, NRcC(=NRc)NRcRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc , NRcS(O)2Rc, NRcS(O)2NRcRc, S(O)Rc, S(O)NRcRc, S(O)2Rc and S(O)2NRcRc;

[00132] each Rc is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5- to 10-membered heteroaryl)-C1-4 alkyl- and (4- to 10-membered heterocycloalkyl) to 10-membered)-C1-4-alkyl, wherein said C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C6-10-aryl, C3-10-cycloalkyl, 5- to 10-membered heteroaryl , 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5- to 10-membered heteroaryl)-C1-4 alkyl- and (C1-4-membered heterocycloalkyl) 4- to 10-membered)-C1-4 alkyl- are each optionally substituted by 1, 2, 3, 4 or 5 independently selected Rf substituents;

[00133] or any two Rc substituents attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted by 1, 2 or 3 independently selected Rh substituents, wherein the C1-6 alkyl, C3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-10 aryl or 5- to 6-membered heteroaryl as Rh is optionally substituted by 1, 2, or 3 independently selected Rj substituents;

[00134] each Rd is independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, CN, ORe, SRe, C(O)Re, C(O)NReRe, C(O)ORe, OC(O)Re , OC(O)NReRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, C(=NRe)NReRe, NReC(=NRe)NReRe, S(O)Re, S(O) )NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe and S(O)2NReRe;

[00135] each Rf is independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, CN, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg , OC(O)NRgRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg, C(=NRg)NRgRg, NRgC(=NRg)NRgRg, S(O)Rg, S(O) )NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg and S(O)2NRgRg;

[00136] each Rh is independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-10 aryl, 5- to 6-membered heteroaryl, C1-6 haloalkyl, halo, CN, ORi, SRi , C(O)Ri, C(O)NRiRi, C(O)ORi, OC(O)Ri, OC(O)NRiRi, NRiRi, NRiC(O)Ri, NRiC(O)NRiRi, NRiC(O)ORi , C(=NRi)NRiRi, NRiC(=NRi)NRiRi, S(O)Ri, S(O)NRiRi, S(O)2Ri, NRiS(O)2Ri, NRiS(O)2NRiRi, and S(O) 2NRiRi, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-10 aryl and 5- to 6-membered heteroaryl are optionally substituted by 1, 2 or 3 independently selected Rj substituents;

[00137] each Rj is independently selected from halo, C1-4 alkyl, haloC1-4 alkyl, CN, ORk, SRk, C(O)Rk, C(O)NRkRk, C(O)ORk, OC(O)Rk , OC(O)NRkRk, NRkRk, NRkC(O)Rk, NRkC(O)NRkRk, NRkC(O)ORi, C(=NRk)NRkRk, NRkC(=NRk)NRkRk, S(O)Rk, S(O) )NRkRk, S(O)2Rk, NRkS(O)2Rk, NRkS(O)2NRkRk and S(O)2NRkRk;

[00138] each Re, Rg, Ri or Rk is independently selected from H, C1-4 alkyl, C6-10 aryl, C1-4 haloalkyl, C2-4 alkenyl and C2-4 alkyl, wherein the C1- 4, C6-10 aryl, C2-4 alkenyl, or C2-4 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-4 alkyl, C1-alkoxy 4, C1-4 alkylthio, C1-4 alkylamino, di(C1-4 alkyl)amino, C1-4 haloalkyl and C1-4 haloalkoxy;

[00139] or any two Re substituents attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 independently selected Rh substituents;

[00140] or any two substituents Rg attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted by 1, 2 or 3 independently selected Rh substituents;

[00141] or any two Ri substituents attached to the same N atom, together with the N atom to which they are attached, form a 4, 5, 6 or 7 membered heterocycloalkyl group optionally substituted by 1, 2 or 3 independently selected Rh substituents;

[00142] X1 is -CR10R11- or -NR7-

[00143] X2 is N or CR6;

[00144] R1 is C1-3 alkyl or C1-3 haloalkyl;

[00145] R2 is H, halo, C1-3 alkyl, C1-3 haloalkyl, CN or C1-3 alkoxy;

[00146] R3 is H, halo, C1-3 alkyl, C1-3 haloalkyl, CN or C1-3 alkoxy;

[00147] R4 is C1-3 alkyl or C1-3 haloalkyl;

[00148] R5 is H, halo, C1-3 alkyl, C1-3 haloalkyl, CN or C1-3 alkoxy;

[00149] R6 and R7 are each independently selected from H, halo, CN, ORa4, SRa4, C(O)NRc4Rd4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O) ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, S(O)2NRc4Rd4, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, phenyl, C3-6 cycloalkyl, a 5- to 6-membered heteroaryl having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4- to 7-membered heterocycloalkyl having carbon and 1, 2 or 3 heteroatoms selected from N, O and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-6 cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups of R6 and R7 are each optionally substituted by 1, 2, or 3 substituents independently selected from R10A;

[00150] R10 and R11 are each independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkylkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, heteroaryl moiety from 5 to 10 members having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4- to 10-membered heterocycloalkyl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl groups of R10 and R11 are each one, optionally substituted with 1, 2 or 3 R10A;

[00151] Alternatively, R10 and R11, together with the carbon to which they are attached, form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group or a 4-, 5-, 6-, 7-, 8-, 9-membered heterocycloalkyl group or 10 members; wherein said 3, 4, 5, 6 or 7 membered cycloalkyl group and said 4, 5, 6, 7, 8, 9 or 10 membered heterocycloalkyl group are each optionally substituted by 1, 2, 3 or 4 R10A;

[00152] each R10A is independently selected from halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C (=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4 , S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, S(O)2NRc4Rd4, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, phenyl, C3-cycloalkyl 6, a 5- to 6-membered heteroaryl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4- to 7-membered heterocycloalkyl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-6 cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups of R10A are each optionally substituted by 1, 2, or 3 independently selected substituents of R19;

[00153] each Ra4, Rb4, Rc4 and Rd4 is independently selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkyl, C1-4 haloalkyl, phenyl, C3-6 cycloalkyl, a heteroaryl moiety of 5 to 6 membered having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4 to 7 membered heterocycloalkyl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N , O and S; wherein said C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, C3-6 cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups of Ra4, Rb4, Rc4 and Rd4 are each optionally substituted with 1, 2 or 3 substituents independently selected from R19;

[00154] Alternatively, Rc4 and Rd4, together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group that is optionally substituted by 1, 2, or 3 substituents independently selected from R19;

[00155] each Re4 is independently H or C1-4 alkyl;

[00156] each R19 is independently selected from halo, CN, NO2, ORa9, SRa9, C(O)Rb9, C(O)NRc9Rd9, C(O)ORa9, OC(O)Rb9, OC(O)NRc9Rd9, NRc9Rd9 , NRc9C(O)Rb9, NRc9C(O)ORa9, NRc9C(O)NRc9Rd9, NRc9S(O)Rb9, NRc9S(O)2Rb9, NRc9S(O)2NRc9Rd9, S(O)Rb9, S(O)NRc9Rd9, S (O)2Rb9, S(O)2NRc9Rd9, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl and C1-4 haloalkyl;

[00157] each Ra9, Rc9 and Rd9 is independently selected from H and C1-4 alkyl;

[00158] each Rb9 is independently C1-4 alkyl; It is

[00159] the n subscript is 0, 1, 2 or 3.

[00160] In some embodiments, R7 is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, phenyl, C3-6 cycloalkyl, a 5- to 6-membered heteroaryl having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4- to 7-membered heterocycloalkyl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-6 cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups of R6 are each optionally substituted by 1, 2, or 3 substituents independently selected from R10A.

[00161] In some embodiments, R7 is C1-6 alkyl, phenyl, benzyl, C3-6 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl-, 4- to 10-membered heterocycloalkyl, (4- to 10-membered heterocycloalkyl)- C1-4-alkyl, 5- to 10-membered heteroaryl, or (5- to 10-membered heteroaryl)-C1-4-alkyl, each of which is optionally substituted with 1, 2 or 3 independently selected R10A substituents; or two R10A substituents attached to adjacent ring atoms of the aryl or heteroaryl ring of R7, are optionally taken together with the atoms to which they are attached and form a fused C5-6 cycloalkyl ring or a fused 5-6 membered heterocycloalkyl ring having 1 to 2 heteroatoms as ring members independently selected from O, N and S, wherein the nitrogen and sulfur atoms are each optionally oxidized and the C5-6 cycloalkyl ring fused or heterocycloalkyl of 5 to 6 fused members is optionally replaced by 1 or 2 independently selected R19 groups.

[00162] R7 is C1-6 alkyl, cyclopropylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-fluorobenzyl, tetrahydrofuran-3-yl, (3-methylisoxazol-5-yl)methyl, (tetrahydro- 2H-pyran-4-yl)methyl, (5-cyclopropylisoxazol-3-yl)methyl, 5-methylisoxazol-3-yl)methyl, 4-fluorophenyl, (1-ethylpyrazol-4-yl)methyl, benzothiazol-6- yl, 1-methyl-5-oxopyrrolidin-3-yl, 1-acetylpiperidin-4-yl, 2,3-dihydro-1,4-benzodioxin-6-ylmethyl, 1-t-butoxycarbonylpiperidin-4-yl, 4- cyanophenyl, 4-pyrimidinyl, 2-pyrimidinyl, 5-pyrimidinyl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, (1,5-dimethylpyrazol-4-yl)methyl or (5-methyl-1, 3,4-oxadiazol-2-yl)methyl.

[00163] In some embodiments, R7 is C1-6 alkyl, cyclopropylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-fluorobenzyl, (3-methylisoxazol-5-yl)methyl, (5-cyclopropylisoxazol-3- yl)methyl, 4-fluorophenyl, (1-ethylpyrazol-4-yl)methyl, 1-acetylpiperidin-4-yl, 2,3-dihydro-1,4-benzodioxin-6-ylmethyl, 1-t-butoxycarbonylpiperidin -4-yl, 4-cyanophenyl, 4-pyrimidinyl, 2-pyrimidinyl, 5-pyrimidinyl, 1-methylpyrazol-3-yl, (1,5-dimethylpyrazol-4-yl)methyl or (5-methyl-1,3) ,4-oxadiazol-2-yl)methyl.

[00164] In some embodiments, R7 is C1-6 alkyl, cyclopropylmethyl, cyclopentyl, 4-fluorobenzyl, tetrahydrofuran-3-yl, (3-methylisoxazol-5-yl)methyl, (tetrahydro-2H- pyran-4-yl)methyl, (5-cyclopropylisoxazol-3-yl)methyl, 5-methylisoxazol-3-yl)methyl, 4-fluorophenyl, (1-ethylpyrazol-4-yl)methyl, benzothiazol-6-yl, 1-methyl-5-oxopyrrolidin-3-yl, 1-acetylpiperidin-4-yl, 2,3-dihydro-1,4-benzodioxin-6-ylmethyl, 4-cyanophenyl, 4-pyrimidinyl, (1.5 -dimethylpyrazol-4-yl)methyl or (5-methyl-1,3,4-oxadiazol-2-yl)methyl.

[00165] In some embodiments, R7 is methyl, isopropyl, pyridazin-4-yl, (2-methoxypyridin-4-yl)methyl, (6-methoxypyridin-3-yl)methyl, 3-cyanophenyl, pyrimidin-5-yl , isoquinolin-7-yl, 4-methylcarbamoylbenzyl, (5-ethylisoxazol-3-yl)methyl, pyrimidin-4-ylmethyl, 3-cyano-4-fluorophenyl, (5-ethyl-1,3,4-oxadiazol-2 -yl)methyl, (2-methylpyridin-4-yl)methyl, pyridin-4-ylmethyl, pyrazin-2-yl, 1-(methylsulfonyl)piperidin-4-yl, (1-methyl-1H-pyrazol-4- yl)methyl, 3,4-difluoro-benzyl, 2-cyano-5-pyridyl, 2-methylbenzo[d]oxazol-6-yl, 4-(1H-pyrazol-1-yl)phenyl, 3-cyano-5 -fluorophenyl, 5-cyano-2-pyridyl, oxazol-5-ylmethyl, 4-cyano-5-methoxyphenyl, (5-methyloxazol-2-yl)methyl, cyclopropyl, pyrimidin-5-ylmethyl, pyrazin-2- ylmethyl, pyridin-3-yl, 6-methylpyrazin-2-yl, pyridazin-3-ylmethyl, 3-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl, 1-cyanocyclopropyl, 2 -pyridyl, (5-isopropylisoxazol-3-yl)methyl, pyridin-2-ylmethyl, (2-methylthiazol-4-yl)methyl, (1-methyl-5-oxopyrrolidin-3-yl)methyl, 4-(cyanomethyl) )phenyl, 4-(methylsulfonyl)phenyl, 3-fluorophenyl, 1-methyl-1H-pyrazol-3-yl, (1,3-dimethyl-1H-pyrazol-4-yl)methyl, 3,4-difluorophenyl , 3,5-difluoro-phenyl, 4-methoxyphenyl, pyrimidin-2-yl, 5-ethylpyrazin-2-yl, 5-methylpyrazin-2-yl, (tetrahydrofuran-3-yl)methyl, 3-methoxyphenyl, 2-fluorophenyl, 3-(methylsulfamoyl)phenyl, 5-methoxypyrazin-2-yl, 4-(dimethylcarbamoyl)phenyl, 2-(1-methyl-1H-pyrazol-4-yl)ethyl, 5-methyl-1,3 ,4-oxadiazol-2-yl, (2-ethoxypyridin-4-yl)methyl, (1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl, (1-methyl-1H-benzo[ d][1,2,3]triazol-5-yl)methyl, 2-oxoindolin-5-yl, 2-methyl-3-oxoisoindolin-5-yl, (2-methylpyrimidin-4-yl)methyl, 1- (methylcarboxy)piperidin-4-yl, 4-(methoxycarbonylamino)phenyl, (1-cyclopropyl-1H-pyrazol-4-yl)methyl, (1-cyanomethyl-1H-pyrazol-4-yl)methyl, (1-cyclopropylmethyl) -1H-pyrazol-4-yl)methyl, (1-(2,2-difluoro-ethyl)-1H-pyrazol-4-yl)methyl, 1H-pyrazol-4-yl, 1-cyclopropyl-1H-pyrazol- 4-yl, 1-ethyl-1H-pyrazol-4-yl, 1-propyl-1H-pyrazol-4-yl, 1H-indazol-6-yl, 1H-indazol-5-yl, pyrimidin-4-yl, cyclobutyl, 3-pyridyl, 2-methoxyethyl, cyclopropylmethyl, ethyl, 4-cyanophenyl, (1-ethyl-1H-pyrazol-4-yl)methyl, (5-methyl-1,3,4-oxadiazol-2- yl)methyl or 1-methyl-1H-pyrazol-4-yl.

[00166] In some embodiments, the compounds of formula (I') or (I) have selective inhibitory activity on the FGFR4 enzyme or any mutant thereof with respect to other FGFR enzymes. In other embodiments, the compounds of formula (I') or (I) have selective inhibitory activity on the FGFR3 enzyme or any mutant thereof with respect to other FGFR enzymes. In other embodiments, compounds of formula (I') or (I) have dual selective inhibitory activity on both FGFR3 and FGFR4 enzymes or any mutant thereof.

[00167] In some embodiments of the compounds of formula (I') or (I), ring A is C6-10 aryl. In certain cases, ring A is phenyl. In one example, ring A is 1-naphthyl or 2-naphthyl.

[00168] In some embodiments of the compounds of formula (I') or (I), ring A is phenyl and two adjacent R12 substituents on the phenyl ring taken together with the carbon atoms to which they are attached form a 3 to cycloalkyl 7 members merged. In some cases, ring A is phenyl and two adjacent R12 substituents on the phenyl ring together with the carbon atoms to which they are attached form a fused cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[00169] In some embodiments of the compounds of formula (I') or (I), ring A is phenyl and two adjacent R12 substituents on the phenyl ring taken together with the carbon atoms to which they are attached form a fused 4- to 6-membered heterocycloalkyl. In some cases, ring A is phenyl and two adjacent R12 substituents on the phenyl ring together with the carbon atoms to which they are attached form a fused 2-oxetanyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 1,1-dioxotetrahydrothiophen-2-yl, 1,1-dioxotetrahydrothiophen-3-yl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4- tetrahydropyranyl, 3,6-dihydro-2H-pyranyl, 3,4-dihydro-2H-pyranyl, 1-azetidinyl, 2-azetidinyl, 3-azetidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-oxo-pyrrolidin-1-yl, 2-oxo-pyrrolidin-3-yl, 2-oxo-pyrrolidin-4-yl, 2-oxo-pyrrolidin-5-yl, 1-piperidinyl, 2-piperidinyl, 3- piperidinyl, 4-piperidinyl, 2-oxo-piperidin-1-yl, 2-oxo-piperidin-3-yl, 2-oxo-piperidin-4-yl, 2-oxo-piperidin-5-yl, 2-oxo- piperidin-6-yl, 1-piperazinyl, 2-piperazinyl, 4-morpholinyl, 3-morpholinyl or 2-morpholinyl.

[00170] In some embodiments of the compounds of formula (I') or (I), ring A is 5-membered heteroaryl. In some embodiments, ring A is a 5-membered heteroaryl selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiophenyl, thiazolyl, isoxazolyl, isothiazolyl, or furanyl. In some embodiments, the A ring is pyrazolyl or imidazolyl. In some embodiments, the A ring is pyrazolyl. In some embodiments, the A ring is 4-pyrazolyl.

[00171] In some embodiments of the compounds of formula (I') or (I), ring A is 5-membered heteroaryl selected from 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl , 4-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isoxazolyl, 4-isoxazolyl, 5 -isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-3-yl , 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-2-yl, l ,2,4-triazol-3-yl, 1,2,4-triazol-4-yl, 1,2,4-triazol-5-yl, 1-oxa-2,3-diazol-4-yl, 1 -oxa-2,3-diazol-5-yl, 1-oxa-2,4-diazol-3-yl, 1-oxa-2,4-diazol-5-yl, 1-oxa-2,5-diazole -3-yl, 1-oxa-2,5-diazol-4-yl, 1-thia-2,3-diazol-4-yl, 1-thia-2,3-diazol-5-yl, 1-thia - 2,4-diazol-3-yl, 1-thia-2,4-diazol-5-yl, 1-thia-2,5-diazol-3-yl, 1-thia-2,5-diazol-4 -yl, 1-tetrazolyl, 3-tetrazolyl, 1H-5-tetrazolyl, 3H-5-tetrazolyl, 2-furanyl, 3-furanyl, 2-thiopenyl and 3-thiophenyl.

[00172] In some embodiments of the compounds of formula (I') or (I), ring A is 6-membered heteroaryl. In certain embodiments, ring A is selected from pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl. In some embodiments of compounds of formula (I') or (I), ring A is 6-membered heteroaryl selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 1,2,3-triazin-4-yl, 1,2,3-triazin-5-yl, 1,3,5-triazin-2-yl, 1, 2,4-triazin-3-yl, 1,2,4-triazin-5-yl and 1,2,4-triazin-6-yl.

[00173] In some embodiments, the A ring is pyridyl. In other embodiments, ring A is 6-membered phenyl or heteroaryl. In other embodiments, ring A is phenyl or pyridyl.

[00174] In some embodiments, ring A is

[00175] each of which is optionally substituted with 1 or 2 R12 substituents as defined herein.

[00176] In some embodiments, ring A is

[00177] replaced by R12 as defined herein.

[00178] In some embodiments, ring A is

[00179] optionally replaced with R12.

[00180] In some embodiments, ring A is

[00181] In some embodiments, ring A is

[00182] optionally replaced with R12.

[00183] In some embodiments, ring A is

[00184] In some embodiments of the compounds of formula (I'), R13 is H, CN, NRc4Rd4, OR1 or -C(O)NHRe, wherein R1 is C1-3 alkyl or C1-3 haloalkyl and R14 is H, CN, NRc4Rd4, OR4 or -C(O)NHRg, wherein R 4 is C1-3 alkyl or C1-3 haloalkyl. In other embodiments, R13 is OR1 and R14 is OR4. In other embodiments, R13 is -C(O)NHRe and R14 is OR4. In other embodiments, R13 and R14 are each OCH3. In other embodiments, R13 is -C(O)NHRe and R14 is OR4. In some embodiments, R13 and R14 are each independently selected from C1-4 alkyl -NHC(O)- and OCH3. In one embodiment, R13 is -C(O)NHC1-6 alkyl and R14 is OR4. In another embodiment, R13 is -C(O)NHC1-6 alkyl and R14 is OCH3. In another embodiment, R13 is -C(O)NHCH3 and R14 is OCH3. In some embodiments, R13 is H and R14 is CN, NRc4Rd4, OR4 or -C(O)NHRg.

[00185] In some embodiments of the compounds of formula (I') or (I), R2 and R5 are each independently H, halo, C1-3 alkyl, C1-3 haloalkyl, CN or C1-3 alkoxy. In other embodiments, R2 and R5 are each independently halogen. In some cases, R2 and R5 are halogen. In a preferred embodiment, R2 and R5 are F.

[00186] In some embodiments of the compounds of formula (I') or (I), R1 and R4 are each independently C1-3 alkyl or C1-3 haloalkyl. In some cases, R1 and R4 are each independently C1-3 alkyl. In other cases, R1 and R4 are each independently methyl, ethyl, propyl, CF3, CF2H or CFH2. In a preferred embodiment, R1 and R4 are CH3.

[00187] In some embodiments of the compounds of formula (I') or (I), R3 is H, halo, C1-3 alkyl, C1-3 haloalkyl, CN or C1-3 alkoxy. In some cases, R3 is H, F, Cl, C1-3 alkyl, CF3, CF3O, CFH2, CHF2, OCFH2 or OCHF2. In a preferred embodiment, R3 is H.

[00188] In some embodiments of the compounds of formula (I') or (I), R10 and R11 are each independently C1-6 alkyl. In some cases, R10 and R11 are methyl. In some embodiments, R10 and R11, together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group, which is optionally substituted with 1 or 2 R10A groups regardless of whether -taught. In some cases, R 10 and R 11 taken together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, each of which is optionally substituted by 1 to 3 groups R10A. In a preferred embodiment, R 10 and R 11 together with the carbon atom to which they are attached form a cyclopropyl, optionally substituted with 1 or 2 independently selected C10A groups. In some embodiments, R10 and R11 are H. In certain embodiments, R10 and R11 are each independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; wherein the C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are each optionally substituted with 1, 2 or 3 substituents independently selected from R10A.

[00189] In some embodiments of the compounds of formula (I') or (I), R10 and R11, together with the carbon atom to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group, which is optionally replaced with 1 or 2 independently selected R10A groups. In some cases, R10 and R11 together with the carbon atom to which they are attached form 2-oxetanyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetra -hydropyranyl, 3,6-dihydro-2H-pyranyl, 3,4-dihydro-2H-pyranyl, 1-azetidinyl, 2-azetidinyl, 3-azetidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl , 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-piperazinyl, 2-piperazinyl, 4-morpholinyl, 3-morpholinyl or 2-morpholinyl, 1-azepanyl, 2-azepanyl, 3-azepanyl, 4 -azepanyl, 2-oxepanyl, 3-oxepanyl or 4-oxepanyl, each of which is optionally substituted with 1 or 2 independently selected R10A.

[00190] In some embodiments, R10A is halo, CN, C1-6 alkyl, C3-6 cycloalkyl, -C(O)Rb4, or -C(O)ORb4; or two R10A substituents attached to adjacent ring atoms of the aryl or heteroaryl ring of R7, are optionally taken together with the atoms to which they are attached and form a 5- to 6-membered heterocycloalkyl ring having 1 to 2 heteroatoms as members of the ring independently selected from O, N and S, in which the nitrogen and sulfur atoms are each optionally oxidized.

[00191] In some embodiments, R10A is F, Cl, CH3, C1-6 alkyl, CN, -C(O)C1-4 alkyl or -C(O)O C1-4 alkyl; or two R10A substituents attached to adjacent ring atoms of the aryl or heteroaryl ring of R7 are optionally taken together with the atoms to which they are attached to form a tetrahydrofuran, tetrahydropyran, 1,4-dioxane, morpholine, ring tetrahydrothiopyran or tetrahydrothiophene, each of which is optionally substituted by 1 or 2 R19 substituents.

[00192] In some embodiments, R10A is F, CH3, CN, -C(O)CH3 or cyclopropyl.

[00193] In some embodiments, R10 and R11, together with the carbon atom to which they are attached, form a cyclopropyl.

[00194] In some embodiments of the compounds of formula (I') or (I), X1 is -CR10R11- or -NR7-. In one embodiment, X1 is -CR10R11-. In another embodiment, X1 is -NR7-. In some cases, X1 is CH2 or NH.

[00195] In some embodiments of the compounds of formula (I') or (I), X1 is NR7, wherein R7 is C1-6 alkyl, phenyl, benzyl, C3-6 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl -, 4- to 10-membered heterocycloalkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, 5 to 10-membered heteroaryl, or (5 to 10-membered heteroaryl)-C 1-4 alkyl-, each of which being optionally substituted by 1, 2 or 3 independently selected R10A substituents; or two R10A substituents attached to adjacent ring atoms of the aryl or heteroaryl ring of R7, are taken together with the atoms to which they are attached and form a fused C5-6 cycloalkyl ring or a 5- to 6-membered heterocycloalkyl ring which has 1 to 2 heteroatoms as ring members independently selected from O, N and S, wherein the nitrogen and sulfur atoms are each optionally oxidized; and wherein one or two ring atoms in the 5- to 6-membered fused C5-6 cycloalkyl or fused heterocycloalkyl ring are optionally replaced by a carbonyl group, and the 5-6 fused C5-6 cycloalkyl or fused heterocycloalkyl ring members is optionally replaced with 1 or 2 independently selected R19 groups. In some cases, R10A is halo, CN, C1-6 alkyl, C3-6 cycloalkyl, -C(O)Rb4, or -C(O)ORb4; or two R10A substituents attached to adjacent ring atoms of the aryl or heteroaryl ring of R7, are taken together with the atoms to which they are attached and form a 5- to 6-membered heterocycloalkyl ring that has 1 to 2 heteroatoms as ring members independently selected from O, N and S, wherein the nitrogen and sulfur atoms are each optionally oxidized. In other cases, R10A is F, Cl, CH3, C1-6 alkyl, CN, -C(O)C1-4 alkyl or -C(O)O C1-4 alkyl; or two R10A substituents attached to adjacent ring atoms of the aryl or heteroaryl ring of R7 are taken together with the atoms to which they are attached to form a tetrahydrofuran, tetrahydropyran, 1,4-dioxane, morpholine, tetrahydropyran ring. -hydrothiopyran or tetrahydrothiophene, each of which is optionally substituted by 1 or 2 R19 substituents.

[00196] In some embodiments of the compounds of formula (I') or (I), X1 is NR7, where R7 is C1-6 alkyl, cyclopropylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-fluorobenzyl, (3 -methylisoxazol-5-yl)methyl, (5-cyclopropylisoxazol-3-yl)methyl, 4-fluorophenyl, (1-ethylpyrazol-4-yl)methyl, 1-acetylpiperidin-4-yl, 2,3-dihydro -1,4-benzodioxin-6-ylmethyl, 1-t-butoxycarbonylpiperidin-4-yl, 4-cyanophenyl, 4-pyrimidinyl, 2-pyrimidinyl, 5-pyrimidinyl, 1-methylpyrazol-3-yl, (1,5- dimethylpyrazol-4-yl)methyl or (5-methyl-1,3,4-oxadiazol-2-yl)methyl.

[00197] In some embodiments of the compounds of formula (I') or (I), X2 is N or CR6. In other embodiments, X2 is N or CH. In a preferred embodiment, X2 is N. In another embodiment, X2 is CH.

[00198] In some embodiments of the compounds of formula (I') or (i), each R12 is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, aryl C6-10, cycloalkyl, C3-10, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-4-alkyl, C3-10 cycloalkyl-C1-4-alkyl, (5-membered heteroaryl) to 10-membered)-C1-4-alkyl-, (4- to 10-membered heterocycloalkyl)-C1-4-alkyl-, CN, ORa, SRa, C(O)Ra, C(O)NRaRa, C(O) ORa, OC(O)Ra, OC(O)NRaRa, NRaRa, NRaORa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS( O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra and S(O)2NRaRa, where a is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl , C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4 alkyl-, (5 to 10-membered heteroaryl) 10-membered)-C1-4-alkyl, and (4- to 10-membered heterocycloalkyl)-C1-4-alkyl are each optionally substituted by 1, 2 or 3 Rb substituents.

[00199] In some embodiments, each R12 is independently selected from F, Cl, CN, CH3, CH2CH3, NH2, OCH3, - C(O)NH(C1-4 alkyl), NHC(O)CH3, NHS(O) 2CH3, NHS(O)2Ra, C(O)Ra, -CH2C(O)Ra, -CH2CH2Ra, morpholinosulfonyl, imidazolyl, 4-morpholinyl, (3-cyanopyrrolidin-1-yl)methyl, 2-cyanoprop-2-yl , 1-cyanocyclobutyl, 1-cyanocyclopropyl, benzyl, pyridylmethyl, 1,1-dioxothiolan-3-yl, 1-methylsulfonylazetidin-3-yl, 1-acetyl-3-(cyanomethyl)azetidin-3-yl and -CH2-( 4-morpholinyl), where Ra is 4-morpholinyl.

[00200] In some embodiments, each R12 is independently selected from F, Cl, CN, CH3, CH2CH3, NH2, -C(O)NH(C1-4 alkyl), NHC(O)CH3, NHS(O)2CH3, C(O)Ra, -CH2C(O)Ra, -CH2CH2Ra, morpholinesulfonyl, imidazolyl, 4-morpholinyl, (3-cyanopyrrolidin-1-yl)methyl, 2-cyanoprop-2-yl, 1-cyanocyclobutyl, pyridylmethyl , 1,1-dioxothiolan-3-yl, 1-acetyl-3-(cyanomethyl)azetidin-3-yl and -CH 2 -(4-morpholinyl), where Ra is 4-morpholinyl.

[00201] In some embodiments of the compounds of formula (I') or (I), each R12 is, independently, NH 2 , CH 3 , F, CN, 1-piperidinyl, 1-piperazinyl or 4-morpholinyl.

[00202] In some embodiments, each R12 is independently selected from -NH2, -NHOH, -NHRa, -NHRa, -NHC(O)Ra, -NHC(O)NHRa, -NHS(O)2Ra, -C(O)Ra, -S(O)2Ra, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-4 haloalkoxy, halo, CN, C3-6 cycloalkyl, phenyl-C1-4 alkyl, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-C 1-4 alkyl, 4- to 6-membered heterocycloalkyl, and (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl , C3-6 cycloalkyl, phenyl-C1-4 alkyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl and (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl- are optionally substituted by 1 to 3 Rb; and C1-6alkoxy or C1-4haloalkoxy is optionally substituted by 1 to 3 Rd.

[00203] In some embodiments, each R12 is independently F, Cl, CN, CH3, NH2, OCH3, NHS(O)2Ra, C(O)Ra, -CH2C(O)Ra, imidazoyl, 4-morpholinyl, -CH2-(4-morpholinyl), (3-cyanopyrrolidin-1-yl)methyl, 1-cycane-1-methyl-ethyl, 1-cyanocyclobutyl, 1-cyanocyclopropyl, benzyl, 1,1-dioxothiolan-3-yl, 1-methylsulfonylazetidin-3-yl, 1-acetyl-3-(cyanomethyl)azetidin-3-yl, and -CH 2 -(4-morpholinyl), where Ra is 4-morpholinyl.

[00204] In some embodiments, each R12 is independently F, Cl, CN, CH3, NH2, OCH3, NHS(O)2Ra, C(O)Ra, imidazoyl, 4-morpholinyl and -CH2-(4-morpholinyl), where Ra is 4-morpholinyl.

[00205] In some embodiments, R12 is H, methyl, ethyl, CN, cyanomethyl, 2-cyanoethyl, 1-cyanocyclobutyl, 3-morpholinopropyl, 1-(methylsulfonyl)pyrrolidin-3-yl, (1-(methylsulfonyl) piperidin-4-yl)ethyl, (4-methoxypiperidin-1-yl)ethyl, 2-morpholinoethyl, 2-morpholino-2-oxoethyl, dimethylamino, (3-methoxypyrrolidin-1-yl)ethyl, (1,1 -dioxide-1,2-thiazinan-3-yl)methyl, 1-methylpyrrolidin-3-yl, (dimethylamino)ethyl, 2-(piperidin-4-yl)ethyl, (1-(methylsulfonyl)azetidin-3-yl) )methyl, (1-acetylazetidin-3-yl)methyl, 1-acetylpyrrolidin-3-yl, (tetrahydro-2H-pyran-4-yl)methyl, ethylcarbamoyl, cyclopropylcarbamoyl, (2-hydroxyethyl)carbamoyl, propylcarbamoyl, iso-propylcarbamoyl, 1-cycanocyclopropyl, carbamoyl, morpholino, 1-cyanomethylpyrrolidin-1-yl or pyridin-3-ylmethyl.

[00206] In some embodiments, the subscript n is 0, 1, or 2. In some embodiments, the subscript n is 0. In some embodiments, the subscript n is 1. In another embodiment, the subscript n is 2. In another modality, the subscript n is 3.

[00207] In some modalities:

[00208] ring A is phenyl or a 6-membered heteroaryl ring;

[00209] R10 and R11 are C1-6 alkyl;

[00210] Alternatively, R10 and R11, together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6- or 7-membered cycloalkyl group, which is optionally substituted by 1 or 2 independently selected R10A groups.

[00211] each R12 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl C1-4-alkyl, C3-10-cycloalkyl-C1-4-alkyl, (5- to 10-membered heteroaryl)-C1-4-alkyl-, (4- to 10-membered heterocycloalkyl)-C1-4-alkyl, CN , NO2, ORa, C(O)Ra, C(O)NRaRa, C(O)ORa, NRaRa, NRaORa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, NRaS(O)2Ra , NRaS(O)2NRaRa, S(O)2Ra and S(O)2NRaRa , where a is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, heteroaryl 5- to 10-membered heterocycloalkyl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-4-alkyl, C3-10 cycloalkyl-C1-4-alkyl, (5- to 10-membered heteroaryl)-C1-4 alkyl- and (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl are each optionally substituted by 1 to 3 independently selected Rb substituents;

[00212] each Rb is independently selected from halo, C1-4 alkyl, haloC1-4 alkyl, CN, NO2, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC (O)Rc, OC(O)NRcRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S (O)Rc, S(O)NRcRc, S(O)2Rc and S(O)2NRcRc; It is

[00213] each R C is independently selected from H and C1-6 alkyl; It is

[00214] the n subscript is 0, 1, 2 or 3.

[00215] In some modalities:

[00216] X1 is CR10R11;

[00217] X2 is CH;

[00218] ring A is phenyl or a 6-membered heteroaryl ring;

[00219] R10 and R11 are C1-6 alkyl;

[00220] Alternatively, R10 and R11, together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6- or 7-membered cycloalkyl group, which is optionally substituted by 1 or 2 independently selected R10A groups.

[00221] each R12 is independently selected from halo, CN, NRaRa, NRaORa, NHC(O)Ra,

[00222] NHS(O)2Ra, C(O)Ra, S(O)2Ra, ORa, C1-6 alkyl, C1-6 haloalkyl, 5 to 6 membered heteroaryl and 4 to 6 membered heterocycloalkyl, in that said C1-6 alkyl, 5 to 6 membered heteroaryl or 4 to 6 membered heterocycloalkyl is optionally substituted with from 1 to 3 Rb;

[00223] each Rb is independently selected from halo, C1-4 alkyl, haloC1-4 alkyl, CN, NO2, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC (O)Rc, OC(O)NRcRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S (O)Rc, S(O)NRcRc, S(O)2Rc and S(O)2NRcRc;

[00224] each Rc is independently selected from H and C1-6 alkyl; It is

[00225] the n subscript is 0, 1, 2 or 3.

[00226] In some modalities:

[00227] X1 is CR10R11;

[00228] X2 is CH;

[00229] ring A is phenyl or pyridyl;

[00230] R10 and R11 are C1-6 alkyl;

[00231] alternatively, R10 and R11, together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6- or 7-membered cycloalkyl group, which is optionally substituted by 1 or 2 independently selected R10A groups;

[00232] each R12 is independently selected from halo, C1-6 alkyl, haloC1-6 alkyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl, (4- to 6-membered heterocycloalkyl)-C 1-2 alkyl -, CN, ORa, C(O)Ra, NRaRa, NRaS(O)2Ra and S(O)2Ra;

[00233] each Ra is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl; It is

[00234] the n subscript is 0, 1, 2 or 3.

[00235] In some embodiments, when ring A is a 5- to 6-membered heteroaryl ring, then ring A is connected by a carbon atom to the portion below the point indicated by the wavy line:

[00236] Subformulas

[00237] In some embodiments, the compounds of formula (I') or (I) have the subformula (Ia):

[00238] or a pharmaceutically acceptable salt thereof, in which the ring variables A, R1, R2, R3, R4, R5, R10, R11, R12, X2 and n are as defined in any embodiment of the compounds of formula (I ') or (I).

[00239] In some embodiments of the compounds of formula (Ia):

[00240] ring A is C6-10 aryl or a 5- to 6-membered heteroaryl having carbon and 1 to 4 heteroatoms as ring members selected from O, N and S;

[00241] each R12 is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4 to 10 membered, C6-10 aryl-C1-4 alkyl, C3-10 cycloalkyl -C1-4 alkyl -, (5 to 10 membered heteroaryl)-C1-4 alkyl-, (4 to 10 membered heterocycloalkyl)- C1-4- alkyl, CN, NO2, ORa, SRa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NRaRa, NRaORa, NRaC( O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(=NRa)Ra, C(=NRa)NRaRa, NRaC(=NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS (O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, and S(O)2NRaRa, where a is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6 aryl -10, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl - C1-4 alkyl-, C3-10 cycloalkyl -C1-4 alkyl-, (5 to 10-membered heteroaryl member)-C1-4alkyl-, and (4- to 10-membered heterocycloalkyl)-C1-4alkyl- are each optionally substituted with 1, 2, 3, or 4 Rb substituents independently selected from halo, C1-4alkyl, C1-4 haloalkyl, CN, NO2, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, C(=NRc)NRcRc, NRcC(=NRc)NRcRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S(O)Rc , S(O)NRcRc, S(O)2Rc and S(O)2NRcRc; or two adjacent R12 substituents on ring A, together with the atoms to which they are attached, form a 5- or 6-membered cycloalkyl ring, 5- or 6-membered heterocycloalkyl ring, 5- to 6-membered phenyl or heteroaryl ring, in which heterocycloalkyl or heteroaryl has 1 to 2 heteroatoms as ring members selected from O, N and S;

[00242] each Ra is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl -C1-4 alkyl-, (5- to 10-membered heteroaryl)-C1-4 alkyl- and (4- to 10-membered heterocycloalkyl) to 10-membered)-C1-4alkyl-, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C3-10cycloalkyl, 5- to 10-membered heteroaryl, heterocycloalkyl 4- to 10-membered aryl, C6-10-aryl-C1-4-alkyl, C3-10-cycloalkyl-C1-4-alkyl-, (5- to 10-membered heteroaryl)-C1-4-alkyl- and (4- to 10-membered heterocycloalkyl) 10-membered)-C1-4alkyl- is optionally substituted with 1, 2, 3, 4, or 5 Rd substituents independently selected from C1-4alkyl, C1-4haloalkyl, halo, CN, ORe, SRe, C(O) Re, C(O)NReRe, C(O)ORe, OC(O)Re, OC(O)NReRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, C(=NRe )NReRe, NReC(=NRe)NReRe, S(O)Re, S(O)NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe and S(O)2NReRe;

[00243] each Rc is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10-aryl-C1-4-alkyl, C3-10-cycloalkyl-C1-4-alkyl-, (5- to 10-membered heteroaryl)-C1-4-alkyl-, and (5- to 10-membered heterocycloalkyl)-C1-4-alkyl-, and 4 to 10-membered)-C1-4-alkyl, wherein said C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C6-10-aryl, C3-10-cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl -C1-4 alkyl-, C3-10 cycloalkyl -C1-4 alkyl-, (5- to 10-membered heteroaryl)-C1-4 alkyl-, and (4 to 10-membered heterocycloalkyl) 10-membered)-C1-4alkyl- is optionally substituted with 1, 2, 3, 4, or 5 Rf substituents independently selected from C1-4alkyl, C1-4haloalkyl, halo, CN, ORg, SRg, C(O) Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg, OC(O)NRgRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg, C(=NRg) )NRgRg, NRgC(=NRg)NRgRg, S(O)Rg, S(O)NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg and S(O)2NRgRg;

[00244] or any two Ra attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents Rh independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-10 aryl, 5- to 6-membered heteroaryl, C1-6 haloalkyl, halo, CN, ORi, SRi, C( O)Ri, C(O)NRiRi, C(O)ORi, OC(O)Ri, OC(O)NRiRi, NRiRi, NRiC(O)Ri, NRiC(O)NRiRi, NRiC(O)ORi, C( =NRi)NRiRi, NRiC(=NRi)NRiRi, S(O)Ri, S(O)NRiRi, S(O)2Ri, NRiS(O)2Ri, NRiS(O)2NRiRi and S(O)2NRiRi , where said C1-6 alkyl, C3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-10 aryl and 5- to 6-membered heteroaryl are optionally substituted by 1, 2, or 3 Rj substituents independently selected from halo, alkyl C1-4, C1-4 haloalkyl, CN, ORk, SRk, C(O)Rk, C(O)NRkRk, C(O)ORk, OC(O)Rk, OC(O)NRkRk, NRkRk, NRkC(O) )Rk, NRkC(O)NRkRk, NRkC(O)ORi, C(=NRk)NRkRk, NRkC(=NRk)NRkRk, S(O)Rk, S(O)NRkRk, S(O)2Rk, NRkS(O )2Rk, NRkS(O)2NRkRk and S(O)2NRkRk;

[00245] Any two Rc attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, or 3 Rh substituents independently selected;

[00246] any two Re substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 independently selected Rh substituents;

[00247] Any two Rg substituents attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, or 3 Rh substituents independently selected;

[00248] Any two Ri substituents attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted by 1, 2, or 3 Rh substituents independently selected;

[00249] each Re, Rg, Ri or Rk is independently selected from H, C1-4 alkyl, C6-10 aryl, C1-4 haloalkyl, C2-4 alkenyl and C2-4 alkyl, wherein the C1- 4, C6-10 aryl, C2-4 alkenyl or C2-4 alkynyl is optionally substituted by 1, 2 or 3 substituents independently selected from OH, CN, amino, halo, C1-4 alkyl, C1-4 alkoxy , C1-4 alkylthio, C1-4 alkylamino, di(C1-4 alkyl)amino, C1-4 haloalkyl and C1-4 haloalkoxy;

[00250] X2 is N or CR6;

[00251] R1 is C1-3 alkyl or C1-3 haloalkyl;

[00252] R2 is H, halo, C1-3 alkyl, C1-3 haloalkyl, CN or C1-3 alkoxy;

[00253] R3 is H, halo, C1-3 alkyl, C1-3 haloalkyl, CN or C1-3 alkoxy;

[00254] R4 is C1-3 alkyl or C1-3 haloalkyl;

[00255] R5 is H, halo, C1-3 alkyl, C1-3 haloalkyl, CN or C1-3 alkoxy;

[00256] R6 is H, halo, CN, ORa4, SRa4, C(O)NRc4Rd4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O) )Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, S(O)2NRc4Rd4, C1-6 alkyl, C2-6 alkenyl, al - C2-6 quinyl, C1-6 haloalkyl, phenyl, C3-6 cycloalkyl or a 5- to 6-membered heteroaryl having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a heterocycloalkyl- 4- to 7-membered la having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-6 cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups of R6 are each optionally substituted by 1, 2, or 3 substituents independently selected from R10A;

[00257] R10 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4- to 10-membered heterocycloalkyl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl groups of R10 are each one, optionally substituted with 1, 2, 3 or 4 R10A;

[00258] each R10A is independently selected from halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C (=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4 , S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, S(O)2NRc4Rd4, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, phenyl, C3-cycloalkyl 6, a 5- to 6-membered heteroaryl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4- to 7-membered heterocycloalkyl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-6 cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups of R10A are each optionally substituted by 1, 2, or 3 independently selected substituents from R19;

[00259] each Ra4, Rb4, Rc4 and Rd4 are independently selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkyl, C1-4 haloalkyl, phenyl, C3-6 cycloalkyl, a 5 to 5 heteroaryl moiety 6-membered having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4- to 7-membered heterocycloalkyl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein said C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, C3-6 cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups of Ra4, Rb4, Rc4 and Rd4 are each optionally substituted with 1, 2 or 3 substituents independently selected from R19;

[00260] Alternatively, Rc4 and Rd4, together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group that is optionally substituted by 1, 2, or 3 substituents independently selected from R19;

[00261] each Re4 is independently H or C1-4 alkyl;

[00262] R11 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C1-6 haloalkyl; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl are each optionally substituted with 1, 2 or 3 substituents independently selected from R19;

[00263] Alternatively, R10 and R11, together with the carbon to which they are attached, form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group or a 4-, 5-, 6-, 7-, 8-, 9-membered heterocycloalkyl group or 10 members; wherein said 3, 4, 5, 6 or 7 membered cycloalkyl group and said 4, 5, 6, 7, 8, 9 or 10 membered heterocycloalkyl group are each optionally substituted by 1, 2, 3 or 4 R10A;

[00264] each R19 is independently selected from halo, CN, NO2, ORa9, SRa9, C(O)Rb9, C(O)NRc9Rd9, C(O)ORa9, OC(O)Rb9, OC(O)NRc9Rd9, NRc9Rd9 , NRc9C(O)Rb9, NRc9C(O)ORa9, NRc9C(O)NRc9Rd9, NRc9S(O)Rb9, NRc9S(O)2Rb9, NRc9S(O)2NRc9Rd9, S(O)Rb9, S(O)NRc9Rd9, S (O)2Rb9, S(O)2NRc9Rd9, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl and C1-4 haloalkyl;

[00265] each Ra9, Rc9 and Rd9 is independently selected from H and C1-4 alkyl;

[00266] each Rb9 is independently C1-4 alkyl; It is

[00267] n as an integer is 0, 1, 2 or 3. In some embodiments, the compounds of formula (Ia) have selective inhibitory activity on the FGFR4 enzyme or any mutant thereof. In other embodiments, the compounds of formula (Ia) have selective inhibitory activity on the FGFR3 enzyme or any mutant thereof. In other embodiments, compounds of formula (Ia) have selective inhibitory activity on both FGFR3 and FGFR4 enzymes or any mutant thereof.

[00268] In some embodiments, the compounds of formula (I') or (I) have the subformula (Ib):

[00269] or a pharmaceutically acceptable salt thereof, wherein the ring variables A, R1, R2, R3, R4, R5, R7, R12, X2 and n are as defined in any embodiment of the compounds of formula (I') or (I). In some embodiments, R7 is H, halo, CN or C1-6 alkyl. In one embodiment, R7 is H or C1-6 alkyl.

[00270] In some embodiments, compounds of formula (I') or (I) have the subformula (Ic):

[00271] or a pharmaceutically acceptable salt thereof, wherein the variables R1, R2, R3, R4, R5, R10, R11, R12, X2 and n are as defined in any embodiment of the compounds of formula (I') or (I ).

[00272] In some modalities,

[00273] R2 is F or Cl;

[00274] R5 is F or Cl;

[00275] R10 is selected from C1-6 alkyl, C2-6 alkenyl, C1-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4- to 10-membered heterocycloalkyl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl groups of R10 are each one, optionally substituted with 1, 2, 3 or 4 R10A;

[00276] each R10A is independently selected from halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C (=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4 , S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, S(O)2NRc4Rd4 , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, phenyl, C3-cycloalkyl 6, a 5- to 6-membered heteroaryl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4- to 7-membered heterocycloalkyl moiety having carbon and 1, 2 or 3 heteroatoms independently selected among N, O and S; wherein said C1-6 alkyl, C26 alkenyl, C2-6 alkynyl, phenyl, C3-6 cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups of R10a are each optionally substituted by 1 , 2 or 3 substituents independently selected from R19;

[00277] each Ra4, Rb4, Rc4 and Rd4 is independently selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkyl, C1-4 haloalkyl, phenyl, C3-6 cycloalkyl, a heteroaryl moiety of 5 to 6 membered having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4 to 7 membered heterocycloalkyl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S ; wherein said C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, C3-6 cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups of Ra4, Rb4, Rc4 and Rd4 are each optionally substituted with 1, 2 or 3 substituents independently selected from R19;

[00278] Alternatively, Rc4 and Rd4, together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group that is optionally substituted by 1, 2, or 3 substituents independently selected from among R19;

[00279] Re4 is H or C1-4 alkyl;

[00280] R11 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C1-6 haloalkyl;

[00281] alternatively, R10 and R11, together with the carbon to which they are attached, form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group; wherein said 3, 4, 5, 6 or 7 membered cycloalkyl group and said 4, 5, 6 or 7 membered heterocycloalkyl group are each optionally substituted with 1, 2, 3 or 4 R10A;

[00282] each R19 is independently selected from halo, CN, NO2, ORa9, SRa9, C(O)Rb9, C(O)NRc9Rd9, C(O)ORa9, OC(O)Rb9, OC(O)NRc9Rd9, NRc9Rd9 , NRc9C(O)Rb9, NRc9C(O)ORa9, NRc9C(O)NRc9Rd9, NRc9S(O)Rb9, NRc9S(O)2Rb9, NRc9S(O)2NRc9Rd9, S(O)Rb9, S(O)NRc9Rd9, S (O)2Rb9, S(O)2NRc9Rd9, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl and C1-4 haloalkyl; wherein the C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl and C1-4 haloalkyl are each optionally substituted with 1 or 2 R20 substituents independently selected from H, halo, CN, NO2 , ORq, SRq, C(O)Rq, C(O)NRqRq, C(O)ORq, OC(O)Rq, OC(O)NRqRq, NRqRq, NRqC(O)Rq, NRqC(O)ORq, NRqC (O)NRqRq, NRqS(O)Rq, NRqS(O)2Rq, NRqS(O)2NRqRq, S(O)Rq, S(O)NRqRq, S(O)2Rq, S(O)2NRqRq, C14 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, and C1-4 haloalkyl, wherein each Rq is independently H or C1-4 alkyl.

[00283] each Ra9, Rc9 and Rd9 is independently selected from H and C1-4 alkyl; It is

[00284] each Rb9 is independently C1-4 alkyl;

[00285] In some embodiments, X2 is N.

[00286] In some arrangements, X2 is CR6.

[00287] In some embodiments, R6 is H, halo, CN, or C1-6 alkyl. In some embodiments, R6 is H.

[00288] In some embodiments, R6 is C1-6 alkyl. In some embodiments, R6 is methyl. In some embodiments, R6 is halo. In some embodiments, R6 is CN.

[00289] In some embodiments, R1 is C1-3 alkyl. In some embodiments, R1 is methyl.

[00290] In some embodiments, R2 is halo. In some embodiments, R2 is fluorine. In some embodiments, R2 is chlorine.

[00291] In some embodiments, R3 is H.

[00292] In some embodiments, R4 is C1-3 alkyl. In some embodiments, R4 is methyl.

[00293] In some embodiments, R5 is halo. In some embodiments, R5 is fluorine. In some embodiments, R5 is chlorine.

[00294] In some embodiments, R2 is fluorine and R5 is fluorine. In some embodiments, R2 is chlorine and R5 is chlorine.

[00295] In some embodiments, R1 is C1-3 alkyl; R2 is halo; R3 is H; R4 is C1-3 alkyl; and R5 is halo.

[00296] In some embodiments, R1 is C1-3 alkyl; R2 is F; R3 is H; R4 is C1-3 alkyl; and R5 is F.

[00297] In some embodiments, R1 is methyl; R2 is F; R3 is H; R4 is methyl; and R5 is F.

[00298] In some embodiments, R1 is C1-3 alkyl; R2 is Cl; R3 is H; R4 is C1-3 alkyl; and R5 is Cl.

[00299] In some embodiments, R1 is methyl; R2 is Cl; R3 is H; R4 is methyl; and R5 is Cl.

[00300] In some embodiments, R10 is C1-6 alkyl. In some embodiments, R10 is methyl.

[00301] In some embodiments, R11 is C1-6 alkyl. In some embodiments, R11 is methyl.

[00302] In some embodiments, R10 and R11 are each C1-6 alkyl; In some embodiments, R10 and R11 are each methyl.

[00303] In some embodiments, R10 and R11, together with the carbon to which they are attached, form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group. In some embodiments, R10 and R11, together with the carbon to which they are attached, form a 3-, 4-, 5-, or 6-membered cycloalkyl group. In some embodiments, R10 and R11, together with the carbon to which they are attached, form a 3-, 4-, or 5-membered cycloalkyl group.

[00304] In some embodiments, R10 and R11, together with the carbon to which they are attached, form a cyclopropyl group. In some embodiments, R10 and R11, together with the carbon to which they are attached, form a cyclobutyl group. In some embodiments, R10 and R11, together with the carbon to which they are attached, form a cyclopentyl group. In some embodiments, R10 and R11, together with the carbon to which they are attached, form a cyclohexyl group. In some embodiments, R10 and R11, together with the carbon to which they are attached, form a cycloheptyl group.

[00305] In some embodiments, R10 and R11 together with the carbon atom to which they are attached form a cyclopropyl group optionally substituted by 1 or 2 R10A. In some embodiments, R10 and R11 together with the carbon atom to which they are attached form a cyclobutyl group optionally substituted with 1 or 2 R10A. In some embodiments, R10 and R11 together with the carbon atom to which they are attached form a cyclopentyl group optionally substituted with 1 or 2 R10A. In some embodiments, R10 and R11 together with the carbon atom to which they are attached form a cyclohexyl group optionally substituted with 1 or 2 R10A.

[00306] In some embodiments, R10 and R11, together with the carbon to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group.

[00307] In some embodiments, R10 and R11 together with the carbon atom to which they are attached form a tetrahydropyranyl group, a tetrahydrofuranyl group, tetrahydrothiophene group, a pyrrolidinyl group or a piperidinyl group. In some embodiments, R10 and R11, together with the carbon to which they are attached, form a tetrahydropyranyl group. In some embodiments, R10 and R11 together with the carbon atom to which they are attached form a tetrahydropyranyl group optionally substituted with 1 or 2 R10A. In some embodiments, R10 and R11, together with the carbon to which they are attached, form a tetrahydrofuranyl group. In some embodiments, R10 and R11 together with the carbon atom to which they are attached form a tetrahydrofuranyl group optionally substituted by R10A. In some embodiments, R10 and R11, together with the carbon to which they are attached, form an azetidinyl group. In some embodiments, R10 and R11 together with the carbon atom to which they are attached form an azetidinyl group optionally substituted by R10A.

[00308] In some embodiments, compounds of formula (I'), (I) or (Ia) have the subformula (Id):

[00309] or a pharmaceutically acceptable salt thereof, wherein X2, R1, R2, R3, R4, R5, R10, R11, R12 and n are as defined in any embodiment of formula (I') or (I) as described in pre-sense invention.

[00310] In some embodiments, compounds of formula (I'), (I) or (Ia) have the subformula (Ie):

[00311] or a pharmaceutically acceptable salt thereof, wherein ring A, R2, R3, R5, R10, R11, R12, X2 and n are as defined in any embodiment of formula (I') or (I) as described in pre-sense invention.

[00312] In some embodiments, compounds of formula (I'), (I), (Ia) or (Ie) have the subformula (If):

[00313] or a pharmaceutically acceptable salt thereof, wherein the ring A, R3, R10, R11, R12, X2 and n are as defined in any embodiment of the compounds of formula (I') or (I) as described in the present invention .

[00314] In some embodiments, compounds of formula (I'), (I), (Ie) or (If) have the subformula (Ig):

[00315] or a pharmaceutically acceptable salt thereof, wherein ring A, R10, R11, X, R12 and n are as defined in any embodiment of the compounds of formula (I') or (I) as described herein invention. In some embodiments of the compounds of formula (Ie), X2 is N. In other embodiments, X is CH2. In one embodiment, ring A is phenyl. In another embodiment, ring A is 5-membered heteroaryl selected from 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4- imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-3-yl, 1,2,3-triazol-4-yl, 1, 2,3-triazol-5-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-2-yl, 1,2,4-triazol-3-yl, 1,2, 4-triazol-4-yl, 1,2,4-triazol-5-yl, 1-oxa-2,3-diazol-4-yl, 1-oxa-2,3-diazol-5-yl, 1- oxa-2,4-diazol-3-yl, 1-oxa-2,4-diazol-5-yl, 1-oxa-2,5-diazol-3-yl, 1-oxa-2,5-diazol- 4-yl, 1-thia-2,3-diazol-4-yl, 1-thia-2,3-diazol-5-yl, 1-thia-2,4-diazol-3-yl, 1-thia- 2,4-diazol-5-yl, 1-thia-2,5-diazol-3-yl, 1-thia-2,5-diazol-4-yl, 1-tetrazolyl, 3-tetrazolyl, 1H-5- tetrazolyl, 3H-5-tetrazolyl, 2-furanyl, 3-furanyl, 2-thiopenyl or 3-thiophenyl. In other embodiments, ring A is 2-pyridyl, 3-pyridyl or 4-pyridyl. In some embodiments of the compounds of formula (Ie), each R12 is independently selected from NH2, CH3, F, CN, 1-piperidinyl, methylcarbamoyl, 1-piperazinyl or 4-morpholinyl. In one embodiment, subscript n is 0. In one embodiment, subscript n is 1. In another embodiment, subscript n is 2. In another embodiment, subscript n is 3.

[00316] In some embodiments, compounds of formula (I') or (1) have the subformula (Ih):

[00317] The variables X., the ring A, R.2 and n are as defined in any embodiment of the compounds of formula (I') or (I), as described in the present invention. In certain cases, X1 is -CR.0R11- or -NR7- In some cases, X. is -CR.0R..-, where R.0 and R.. taken together form a C3-6 cycloalkyl ring. In one embodiment, R 11 and R 10 taken together form a cyclopropyl ring. In other cases, X1 is -NR7-. In one embodiment, R7 is C1-6 alkyl. In one embodiment, R7 is ethyl. In some cases, ring A is phenyl or 3-pyridyl. In one example, ring A is 4-pyrazolyl.

[00318] In some embodiments, the compounds of formula (I') have the subformula (Ih):

[00319] The variables R13, R14, X1, the ring A, R12 and n are as defined in any embodiment of the compounds of formula (I') or (I) as described in the present invention. In some cases, R13 is -C(O)NH C1-6 alkyl and R14 is OCH3. In certain cases, X1 is -CR10R11- or -NR7-. In some cases, X1 is -CR10R11-, where R10 and R11 taken together form a C3-6 cycloalkyl ring. In one embodiment, R11 and R10 taken together form a cyclopropyl ring. In other cases, X1 is -NR7-.

[00320] It is further understood that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. On the other hand, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.

[00321] Definitions

[00322] In various parts of the present specification, the substituents of the compounds of the present invention are presented in groups or in bands. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term "C1-6 alkyl" is specifically intended to individually denote methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl.

[00323] In various parts of this specification, various aryl, heteroaryl, cycloalkyl and heterocycloalkyl rings are described. Except where otherwise specified, these rings may be attached to the rest of the molecule on any ring member as allowed by valency. For example, the term "a pyridine ring" or "pyridinyl" can refer to a pyridin-2-yl, pyridin-3-yl or pyridin-4-yl ring.

[00324] The term "n-membered", where n is an integer, typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered and 1,2 heteroaryl ring, 3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[00325] For compounds of the invention in which a variable appears more than once, each variable can be a different portion selected regardless of the group defining the variable. For example, when a structure is described as having two R groups that are simultaneously present in the same compound, the two R groups may represent different independently selected moieties from the group defined for R.

[00326] As used herein, the phrase "optionally substituted" means substituted or not substituted.

[00327] As used herein, the term "substituted" means that a hydrogen atom is replaced by a different hydrogen group. It must be understood that substitution at a given atom is valence limited.

[00328] As used herein, the term "Ci-j," where i and j are integers, used in conjunction with a chemical group, designates a range of the number of carbon atoms in the chemical group with i-j defining the range. For example, C1-6 alkyl refers to an alkyl group that has 1, 2, 3, 4, 5 or 6 carbon atoms.

[00329] As used herein, the term "alkyl," employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight chain or branched. In some embodiments, the alkyl group contains 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methyl-1-butyl, 3- pentyl, n-hexyl, 1,2,2-trimethylpropyl and the like. In some embodiments, the alkyl group is methyl, ethyl or propyl.

[00330] As used herein, "alkenyl," used alone or in combination with other terms, refers to an alkyl group having one or more carbon-carbon double bonds. In some embodiments, the alkenyl moiety contains 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl and the like.

[00331] As used herein, "alkynyl," used alone or in combination with other terms, refers to an alkyl group having one or more carbon-carbon triple bonds. In some embodiments, the alkynyl moiety contains 2 to 6 or 2 to 4 carbon atoms. Exemplary alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like.

[00332] As used herein, "halo" or "halogen", used alone or in combination with other terms, includes fluorine, chlorine, bromine and iodine. In some embodiments, halo is F or Cl. In some embodiments, halo is F.

[00333] As used herein, the term "haloalkyl," used alone or in combination with other terms, refers to an alkyl group that has up to the full valence of substituents on the halogen atom, which may be the same or different. In some embodiments, the halogen atoms are fluorine atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4 or 1 to 3 carbon atoms. Exemplary haloalkyl groups include CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5 and the like.

[00334] As used herein, the term "alkoxy," used alone or in combination with other terms, refers to a group of the formula -O-alkyl. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (for example, n-propoxy and isopropoxy), t-butoxy, and the like. In some embodiments, alkoxy is methoxy.

[00335] As used herein, "haloalkoxy," used alone or in combination with other terms, refers to a group of the formula -O- (haloalkyl). In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. An example of a haloalkoxy group is -OCF3.

[00336] As used herein, "amino," used alone or in combination with other terms, refers to NH2.

[00337] As used herein, the term "alkylamino," used alone or in combination with other terms, refers to a group of the formula -NH(alkyl). In some embodiments, the alkylamino group has 1 to 6 or 1 to 4 carbon atoms. Exemplary alkylamino groups include methylamino, ethylamino, propylamino (e.g., n-propylamino and isopropylamino) and the like.

[00338] As used herein, the term "dialkylamino," used alone or in combination with other terms, refers to a group of the formula -N(alkyl)2. Examples of dialkylamino groups include dimethylamino, diethylamino, dipropylamino (e.g. di(n-propyl)amino, di(isopropyl)amino) and the like. In some embodiments, each alkyl group independently has 1 to 6 or 1 to 4 carbon atoms.

[00339] As used herein, the term "alkylthio," used alone or in combination with other terms, refers to a group of the formula-S-alkyl. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

[00340] As used herein, the term "cycloalkyl," used alone or in combination with other terms, refers to a non-aromatic cyclic hydrocarbon that includes cyclized alkyl and alkenyl groups. Cycloalkyl groups can include mono- or polycyclic ring systems (e.g., having 2, 3 or 4 fused, bridged or spiro rings). Also included in the definition of cycloalkyl are moieties which have one or more aromatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having a bond in common with) the cycloalkyl ring, e.g., benzo derivatives of ci - clopentane, cyclohexene, cyclohexane and the like, or pyrido derivatives of cyclopentane or cyclohexane. The ring-forming carbon atoms of a cycloalkyl group may be optionally substituted by oxo. Cycloalkyl groups also include cycloalkylidenes. The term "cycloalkyl" also includes bridgehead cycloalkyl groups (e.g., non-aromatic cyclic hydrocarbon moieties containing at least one bridgehead carbon, such as admantan-1-yl) and spirocycloalkyl groups (e.g., non-aromatic hydrocarbon moieties containing at least two rings fused to a single carbon atom, such as spiro[2.5]octane, and the like). In some embodiments, the cycloalkyl group has 3 to 10 ring members, 3 to 7 ring members, or 3 to 6 ring members. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is a monocyclic C3-7 cycloalkyl group. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, tetrahydronaphthalenyl, octahydronaphthalenyl, indanyl and similar. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[00341] As used herein, the term "heterocycloalkyl," employed alone or in combination with other terms, refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups or alkynylene as part of the ring structure, which has at least one ring member heteroatom selected independently from nitrogen, sulfur, oxygen and phosphorus. Heterocycloalkyl groups can include mono- or polycyclic ring systems (for example, having 2, 3 or 4 fused, bridged, or spiro rings). In some embodiments, the heterocycloalkyl group is a monocyclic or bicyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, sulfur and oxygen. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having a bond in common with) to the non-aromatic heterocycloalkyl ring, e.g., 1, 2,3,4-tetrahydro-quinoline and the like. Heterocycloalkyl groups can also include bridgehead heterocycloalkyl groups (for example, a heterocycloalkyl moiety containing at least one bridgehead atom, such as azaadmantan-1-yl and the like) and spiroheterocycloalkyl groups (for example, a heterocycloalkyl moiety containing at least two rings fused to a single atom, such as [1,4-dioxa-8-aza-spiro [4.5]decane-N-yl] and the like). In some embodiments, the heterocycloalkyl group has 3 to 10 ring-forming atoms, 4 to 10 ring-forming atoms, or 3 to 8 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or 2 heteroatoms. The carbon atoms or heteroatoms in the ring(s) of the heterocycloalkyl group can be oxidized to form a carbonyl, an N-oxide or a sulfonyl group (or other oxidized bond), or a nitrogen atom can be quaternized. In some embodiments, the heterocycloalkyl moiety is a monocyclic C2-7 heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is a morpholine ring, pyrrolidine ring, piperazine ring, piperidine ring, dihydropyran ring, tetrahydropyran ring, tetrahydropyridine ring, azetidine ring or tetrahydrofuran ring.

[00342] As used herein, the term "aryl," employed alone or in combination with other terms, refers to a monocyclic or polycyclic aromatic hydrocarbon moiety (e.g., having 2 fused rings) as, but not limited to phenyl, 1-naphthyl, 2-naphthyl and the like. In some embodiments, aryl groups have 6 to 10 carbon atoms or 6 carbon atoms. In some embodiments, the aryl group is a monocyclic or bicyclic group. In some embodiments, the aryl group is phenyl or naphthyl.

[00343] As used herein, the term "heteroaryl", used alone or in combination with other terms, refers to a monocyclic or polycyclic aromatic hydrocarbon moiety (e.g., having 2 or 3 fused rings), which has one or more ring member heteroatoms independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl group is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur and oxygen. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyrrolyl, azolyl, quinolinyl, isoquinolinyl, benzisoxazolyl, imidazo [1,2-b] thiazolyl or the like. The carbon atoms or heteroatoms in the ring(s) of the heteroaryl group can be oxidized to form a carbonyl, an N-oxide, or a sulfonyl group (or other oxidized bond), or a nitrogen atom can be quaternized, as long as the aromatic nature of the ring is preserved. In one embodiment, the heteroaryl group is a 5- to 10-membered heteroaryl group. In another embodiment, the heteroaryl group is a 5- to 6-membered heteroaryl group.

[00344] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended, except where otherwise noted. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolving racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like may also be present in the compounds described herein, and all of these stable isomers are contemplated in the present invention. The cis and trans geometric isomers of the compound of the present invention are described and can be isolated as a mixture of isomers or as separate isomeric forms.

[00345] The resolution of racemic mixtures of compounds can be performed by any method known in the art. An exemplary method includes fractional recrystallization using a chiral resolving acid which is an optically active salt forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids. Other suitable resolving agents for fractional crystallization methods include the stereoisomerically pure forms of methylbenzylamine (e.g., the S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane and the like.

[00346] Resolution of racemic mixtures can also be performed by elution on a column packed with an optically active resolving agent (eg, dinitrobenzoylphenylglycine). The proper eluting solvent composition can be determined by one skilled in the art.

[00347] The compounds of the invention also include tautomeric forms. The tautomeric forms result from the exchange of a single bond for an adjacent double bond along with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers that are isomeric protonation states with the same empirical formula and net charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and ring forms where a proton can occupy two or more positions in a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. The tautomeric forms can be in equilibrium or sterically locked into one form by suitable substitution.

[00348] The compounds of the invention also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include atoms that have the same atomic number but different mass numbers. For example, hydrogen isotopes include tritium and deuterium.

[00349] The term, "compound," as used herein, is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures shown.

[00350] All compounds and their pharmaceutically acceptable salts can be found together with other substances such as water and solvents (for example, in the form of hydrates and solvates) or can be isolated.

[00351] In some embodiments, compounds of the invention or their salts are substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation may include, for example, a composition enriched in the compounds of the invention. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 95% at least about 97%, or at least about 99%, by weight of the compounds of the invention, or salt thereof. Methods for isolating the compounds and their salts are routine in the art.

[00352] The expression "pharmaceutically acceptable" is used in the present invention to refer to compounds, materials, compositions, and/or dosage forms that are, within the scope of good medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable risk/benefit ratio.

[00353] The invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by converting an existing acidic or basic moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkaline or organic salts of acid residues, such as carboxylic acids; and the like. Pharmaceutically acceptable salts of the present invention include the non-toxic salts of the parent compound formed, for example, from non-toxic organic or inorganic acids. Pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. In general, these salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, alcohols (eg, methanol, ethanol, isopropanol, or butanol) or acetonitrile (ACN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., USA, 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein, by reference, in its entirety.

[00354] The following abbreviations may be used in the present invention: AcOH (acetic acid); Ac2O (acetic anhydride); here (aqueous); atm. (atmosphere(s)); Boc (t-butoxycarbonyl); br (wide); Cbz (carboxybenzyl); calc. (calculated); d (doublet); dd (doublet of doublets); DCM (dichloromethane); DEAD (diethyl azodicarboxylate); DIAD (N,N',-diisopropyl azidodicarboxylate); DIPEA (N,N-diisopropylethylamine); DMF (N,N-dimethylformamide); Et (ethyl); EtOAc (ethyl acetate); g (gram(s)); h (hour(s)); HATU (N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate); HCl (hydrochloric acid); HPLC (high performance liquid chromatography); Hz (Hertz); J (coupling constant); LCMS (Liquid Chromatography Coupled to Mass Spectrometry); m (multiplet); M (molar); m CPBA (3-chloroperoxybenzoic acid); MgSO4 (magnesium sulfate); MS (mass spectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); mG (milligram(s)); min (minute(s)); mL (milliliter(s)); mmol (millimolar(s)); N (normal); NaHCO3 (sodium bicarbonate); NaOH (sodium hydroxide); Na2SO4 (sodium sulfate); NH4Cl (ammonium chloride); NH4OH (ammonium hydroxide); nM (nanomolar); NMR (nuclear magnetic resonance spectroscopy); OTf (trifluoromethanesulfonate); Pd (palladium); Ph (phenyl); pM (picomolar); PMB (para-methoxybenzyl), POCl3 (phosphoryl chloride); RP-HPLC (Reversed Phase High Performance Liquid Chromatography); s (singlet); t (triplet or tertiary); TBS (tert-butyldimethylsilyl); tert (tertiary); tt (triplet of triplets); t-Bu (tert-butyl); TFA (trifluoroacetic acid); THF (tetrahydrofuran); μg (microgram(s)); μl (microliter(s)); µm (micromolar); wt % (weight percentage).

[00355] As used herein, the term "cell" refers to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in cell culture. In some embodiments, an in vivo cell is a cell that lives in an organism such as a mammal.

[00356] As used herein, the term "contacting" refers to bringing together the indicated portions in an in vitro system or an in vivo system. For example, "contacting" the FGFR4 enzyme with a compound of the invention includes administering a compound of the present invention to an individual or patient, such as a human, who has FGFR, as well as, for example, introducing a compound of the invention. invention in a sample containing a cellular or purified preparation containing the FGFR4 enzyme.

[00357] As used herein, the term "individual" or "patient," used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs , cattle, sheep, horses or primates and, most preferably, humans.

[00358] As used herein, the expression "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that generates the biological or medicinal response in a tissue, system, animal, individual or human being by a researcher, veterinarian , doctor or other clinician.

[00359] As used herein, the term "treat" or "treatment" refers to 1) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but who does not yet experience or display the pathology or symptomatology of the disease; 2) inhibit the disease; for example, inhibiting a disease, condition, or disorder in an individual who is experiencing or exhibiting the pathology or symptomatology of the disease, condition, or disorder (i.e., stopping further development of the symptomatology and/or pathology), or 3) ameliorating the disease ; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (ie, reversing the pathology and/or symptomatology).

[00360] Summary

[00361] The compounds of the invention, including their salts, can be prepared using known techniques of organic synthesis and according to several possible synthetic routes.

[00362] The reactions to prepare the compounds of the invention can be carried out in suitable solvents that can be readily selected by one skilled in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reagents), intermediates or products at the temperatures at which the reactions are carried out, for example, temperatures ranging from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or in a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the person skilled in the art.

[00363] The preparation of the compounds of the invention may involve protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999), which is incorporated in its entirety herein by reference.

[00364] The reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g. 1H or 13C), infrared spectroscopy, spectrophotometry (e.g. UV-visible) or mass spectrometry, or by chroma - chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.

[00365] The expressions, "ambient temperature," "ambient temperature," and "t.a. (r.t)", as used herein, are understood in the art, and generally refer to a temperature, for example, to a reaction temperature, which is approximately the temperature of the environment in which the reaction is carried out, for example, a temperature of about 20°C to about 30°C.

[00366] The compounds presented in the present invention can be prepared by a person skilled in the art, according to preparation routes known in the literature. Examples of the synthetic methods for preparing the compounds of the invention are provided in the schemes below. scheme 1

[00367] The synthesis of compound 4 is described in Scheme 1. Ester 1 can be reduced to the corresponding aldehyde 2 using DIBAL-H. Reductive amination on this aldehyde with aniline 3 can produce dichloropyridine 4.

[00368] Scheme 2

[00369] Dichloropyrimidine 8 can be prepared by the methods described in scheme 2. The treatment of 5-(hydroxymethyl)pyrimidine-2,4(1H,3H)-dione with POCl3 can generate trichloride 6, which can be converted into Iodide 7 using NaI. Compound 7 can be coupled with aniline 3 in the presence of a base such as iPr2NEt, Cs2CO3 or NaI to obtain dichloropyrimidine 8. Scheme 3

[00370] The synthesis of compound 13 is described in Scheme 3. Compound 9 can be treated with ethyl 3-chloro-3-oxopropanoate and NaH in THF to provide amide 10. Lactam 11 can be prepared by treating compound 10 with a strong base, such as NaH or Cs2CO3 in DMF, and followed by an acid, such as HCl-mediated decarboxylation, α-substituted lactam 12 can be obtained by treating compound 11 with a base, such as NaH or Cs2CO3 in DMF or acetonitrile, followed by the addition of halides R10X and/or R11 (X is halo, like Cl, Bro, or I). Chloride 12 can be converted to compound 13, where M is a boronic acid, boronic ester, or suitably substituted metal (e.g., M is B(OH)2, Sn(Bu)3, or ZnBr), under standard Suzuki conditions {for example, in the presence of a palladium catalyst, such as, but not limited to, [1,1'-bis(dicyclohexylphosphine)ferrocene]dichloropalladium(II) and a bicarbonate or carbonate base}, or conditions Standard Stille conditions [e.g., in the presence of a palladium catalyst, such as, but not limited to, Pd(dba)2] or standard Negishi conditions [e.g., in the presence of a palladium catalyst, such as, but not cis (triphenylphosphine)palladium(0)]. scheme 4

[00371] Compound 16 can be synthesized according to the procedure shown in scheme 4. Therefore, compound 9 is first treated with triphosgene in the presence of a base such as pyridine, and then with amine R7NH2 in the presence of another base ( eg DIPEA) to provide a urea compound 14. Upon treatment with a suitable base (e.g. Cs2CO3), cyclization of 14 occurs to generate cyclic urea 15, which can then be converted to compound 16, where M is a boronic acid, boronic ester, or suitably substituted metal (for example, M is B(OH)2, Sn(Bu)3, or ZnBr). The coupling reaction to generate 16 can occur under standard Suzuki conditions (e.g., in the presence of a palladium catalyst such as, but not limited to, [1,1'-bis(dicyclohexylphosphino)ferrocene]dichloro palladium (II) and a bicarbonate or carbonate base}, or standard Stille conditions [e.g., in the presence of a palladium catalyst, such as, but not limited to, Pd(dba)2] or standard Negishi conditions [e.g. , in the presence of a palladium catalyst, such as, but not limited to, tetracis(triphenylphosphine)palladium(0)].

[00372] Scheme 5

[00373] Compound 21 can be prepared according to the synthetic procedures described in Scheme 5. Reductive amination of aldehyde 18 with aniline 17 can provide compound 19. Compound 19 is treated with triphosgene in the presence of a base such as triethylamine to produce urea 20. Compound 20 can then be converted to compound 21, where M is a boronic acid, boronic ester, or suitably substituted metal (eg, M is B(OH)2, Sn(Bu )3 or ZnBr). The coupling reaction to generate 21 can occur under standard Suzuki conditions (e.g., in the presence of a palladium catalyst such as, but not limited to, [1,1'-bis(dicyclohexylphosphino)ferrocene]dichloro palladium (II) and a bicarbonate or carbonate base}, or standard Stille conditions [e.g., in the presence of a palladium catalyst, such as, but not limited to, Pd(dba)2] or standard Negishi conditions [e.g. , in the presence of a palladium catalyst, such as, but not limited to, tetracis(triphenylphosphine)palladium(0)].

[00374] Scheme 6

[00375] Compound 21 can be synthesized using an alternative procedure shown in scheme 6. Ester 1 can be reduced to the corresponding aldehyde 2 using DIBAL-H. Reductive amination of this aldehyde with aniline 17 can produce compound 22. Compound 22 is then converted to 23, where M is a boronic acid, boronic ester, or suitably substituted metal (for example, M is B(OH )2, Sn(Bu)3 or ZnBr). The coupling reaction to generate 23 can occur under standard Suzuki conditions (e.g., in the presence of a palladium catalyst such as, but not limited to, [1,1'-bis(dicyclohexylphosphino)ferrocene]dichloro palladium (II) and a bicarbonate or carbonate base}, or standard Stille conditions [e.g., in the presence of a palladium catalyst, such as, but not limited to, Pd(dba)2] or standard Negishi conditions [e.g. , in the presence of a palladium catalyst such as, but not limited to, tetracis(triphenylphosphine)palladium(0)]. Compound 23 may undergo Buchwald coupling with amine R7NH2 under standard conditions (e.g., in the presence of a palladium catalyst, for example, but not limited to (2'-aminobiphenyl-2-yl)(chlorine) [ dicyclohexyl(2',6'-diisopropoxybiphenyl-2-yl)phosphoranyl] palladium and a base such as, but not limited to, cesium carbonate or sodium tert-butoxide} then cyclized with triphosgene in the presence of a base such as triethylamine to provide compound 21.

[00376] Methods of use

[00377] The compounds of the present invention can inhibit the activity of the FGFR enzyme. For example, compounds of the description can be used to selectively inhibit the activity of a FGFR3 and/or FGFR4 enzyme in a cell or in an individual or patient in need of inhibition of the enzyme by administering an inhibitory amount of a compound of the invention to the cell, individual or patient.

[00378] In some embodiments, compounds of the invention are selective for the FGFR4 enzyme over one or more of FGFR1, FGFR2 and/or FGFR3. In some embodiments, compounds of the invention have selective inhibitory activity for the FGFR4 enzyme over FGFR1, FGFR2 and FGFR3. In some embodiments, compounds of the invention are selective for the FGFR4 enzyme over VEGFR2. In some embodiments, the selectivity is 2 times or more, 3 times or more, 5 times or more, 10 times or more, 25 times or more, 50 times or more, or 100 times or more.

[00379] In some embodiments, compounds of the invention have selective inhibitory activity for the FGFR3 enzyme towards one or more of FGFR1 and/or FGFR2, and/or FGFR4. In some embodiments, compounds of the invention are selective for the FGFR3 enzyme over FGFR1 and FGFR2. In certain embodiments, compounds of the invention are selective for the FGFR3 enzyme over FGFR1. In certain embodiments, compounds of the invention are selective for the FGFR3 enzyme over FGFR4. In some embodiments, compounds of the invention are selective for the FGFR3 enzyme over VEGFR2. In some embodiments, the selectivity of the compounds of the present disclosure for FGFR3 over FGFR1 and/or FGFR2 and/or FGFR4 is 2-fold or greater, 3-fold or greater, 5-fold or greater, 10-fold or greater, 25 times or more, 50 times or more, or 100 times or more.

[00380] As selective inhibitors of FGFR3 and/or FGFR4, the compounds of the invention are useful in the treatment of various diseases associated with abnormal activity or expression of FGFR3 and/or FGFR4 enzyme, or FGFR ligands. Compounds that inhibit FGFR will be useful in providing a means of preventing tumor growth or inducing apoptosis in tumors, particularly by inhibiting angiogenesis. It is therefore anticipated that the compounds will be useful in the treatment or prevention of proliferative disorders such as cancer. In particular, tumors with mutants of receptor tyrosine kinase activation or upregulation of receptor tyrosine kinases may be particularly sensitive to inhibitors.

[00381] In certain embodiments, the activity of FGFR4, or a mutant thereof, is irreversibly inhibited. In certain embodiments, the activity of FGFR4, or a mutant thereof, is irreversibly inhibited by covalent modification of Cys 552 of FGFR4.

[00382] In certain embodiments, the invention provides a method of treating a FGFR4-mediated disorder in a patient in need thereof, comprising the step of administering to said patient an effective amount of a compound according to the invention -tion, or a pharmaceutically acceptable composition thereof.

[00383] As selective inhibitors of FGFR3, the compounds of the invention are useful in the treatment of various diseases associated with abnormal activity or expression of FGFR3 enzyme or FGFR ligands.

[00384] In certain embodiments, the invention provides a method of treating a FGFR3-mediated disorder in a patient in need thereof, comprising the step of administering to said patient an effective amount of a compound according to the invention, or a pharmaceutically acceptable composition thereof.

[00385] In certain embodiments, compounds of the invention are useful in treating cancer. Exemplary cancers include bladder cancer, breast cancer, cervical cancer, colorectal cancer, small bowel cancer, colon cancer, rectal cancer, anal cancer, endometrial cancer, gastric cancer, head and neck cancer (e.g., larynx, hypopharynx, nasopharynx, oropharynx, lips, and mouth), kidney cancer, liver cancer (eg, hepatocellular carcinoma, cholangiocellular carcinoma), lung cancer (eg, adenocarcinoma, small cell lung carcinoma and non-small cell lung, parvicellular and non-parvicellular carcinoma, bronchial carcinoma, bronchial adenoma, pleuropulmonary blastoma), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gallbladder cancer , pancreatic cancer (eg, exocrine pancreatic carcinoma), stomach cancer, thyroid cancer, parathyroid cancer, skin cancer (eg, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer) and brain cancer (eg, astrocytoma, medulloblastoma, ependymoma, neuroectodermal tumors, and pineal tumors).

[00386] Additional examples of cancer types include hematopoietic malignancies such as leukemia or lymphoma, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, cutaneous T-cell lymphoma, acute myeloid leukemia, lymphoma, Hodgkin's and non-Hodgkin's form, myeloproliferative neoplasms (eg, polycythemia vera, essential thrombocythemia, and primary myelofibrosis), Waldenstrom's macroglobulinemia, hairy cell lymphoma, chronic myeloid lymphoma, acute lymphoblastic lymphoma, AIDS-related lymphomas, and Burkitt's lymphoma .

[00387] Other cancers treatable with the compounds of the invention include eye tumors, glioblastoma, melanoma, rhabdosarcoma, lymphosarcoma, and osteosarcoma. Compounds of the invention may also be useful in inhibiting tumor metastasis.

[00388] In some embodiments, the present invention provides a method for treating hepatocellular carcinoma in a patient in need thereof, comprising the step of administering to a patient a compound of Formula (I') or (I ), or a compound as set out in the present invention or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of formula (I') or (I) or a compound as described in the present invention.

[00389] In some embodiments, the present invention provides a method for treating rhabdomyosarcoma, esophageal carcinoma, breast cancer, or head or neck cancer in a patient in need of such treatment, comprising the step of administering to the patient a compound of formula (I') or (I) or a compound as described herein, or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of formula (I') or (I) or of a compound as described in the present invention.

[00390] In some embodiments, the present invention provides a method for treating cancer, in which the cancer is selected from hepatocellular cancer, breast cancer, bladder cancer, colorectal cancer, melanoma, mesothelioma, lung cancer, prostate cancer , pancreatic cancer, testicular cancer, thyroid cancer, squamous cell carcinoma, glioblastoma, neuroblastoma, uterine cancer and rhabdosarcoma.

[00391] In addition to oncogenic neoplasms, the compounds of the invention are useful in the treatment of bone complications and chondrocyte disorders including, but not limited to, acrondroplasia, hypochondroplasia, dwarfism, thanatophoric dysplasia (TD) (clinical forms of TD and TD II), Apert syndrome, Crouzon syndrome, Jack-son-Weiss syndrome, Beare-Stevenson cutis gyrate syndrome, Pfeiffer syndrome, and craniosynostosis syndromes. In some embodiments, the present invention features a method of treating a patient suffering from a skeletal and chondrocyte disorder including, but not limited to, acrondroplasia, hypochondroplasia, dwarfism, thanatophoric dysplasia (TD) (clinical forms of TD and TD II ), Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrate syndrome, Pfeiffer syndrome, and craniosynostosis syndromes. The method includes administering to the patient in need thereof an effective amount of a compound of Formula (I') or (I) or a compound as described herein, or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of formula (I') or (I) or a compound as described in the present invention.

[00392] The compounds of the invention may also be useful in the treatment of hypophosphatemic disorders, for example, X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, and tumor-induced osteomalacia. In some embodiments, the present invention features a method of treating a patient suffering from a hypophosphatemic disorder including, but not limited to, X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, and induced osteomalacia. by tumour. The method includes administering to the patient in need thereof an effective amount of a compound of Formula (I') or (I) or a compound as described herein, or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of formula (I') or (I) or a compound as described in the present invention.

[00393] The compounds of the invention may further be useful in the treatment of fibrotic diseases, for example, when a symptom of the disease or disorder is characterized by fibrosis. Examples of fibrotic diseases include liver cirrhosis, glomerulonephritis, pulmonary fibrosis, systemic fibrosis, rheumatoid arthritis, and wound healing.

[00394] Combination therapy

[00395] One or more pharmaceutical agents or additional treatment methods such as, for example, antiviral agents, chemotherapeutic agents or other anti-cancer agents, immune system enhancers, immunosuppressants, radiation, anti-tumor and anti-tumor vaccines viral therapy, cytokine therapy (e.g. IL2, GM-CSF, etc.), and/or tyrosine kinase inhibitors may be used in combination with the compounds of formula (I') or (I) or a compound as described here for the treatment of diseases, disorders, or conditions associated with FGFR. The agents can be combined with the present compounds in a single dosage form or the agents can be administered simultaneously or sequentially as separate dosage forms.

[00396] Suitable antiviral agents contemplated for use in combination with the compounds of the present invention may comprise nucleoside and nucleotide analogue reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors and other antiviral drugs.

[00397] Exemplary NRTIs include zidovudine (AZT); di-danosine (DDL); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-10652 emitricitabine [(-)-FTC]; beta-L-FD4 (also called beta-L-D4C and called beta-L-2',3'-dicleoxy-5-fluoro-cytidene); DAPD, ((-)-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA). Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviridine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721 AG-1549 MKC-442 (1-(ethoxymethyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H) pyrimidinedione); and (+)-calanolide A (NSC-675451) and B. Typical suitable protease inhibitors include sa-quinavir ((Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir (BMS-234475); DMP-450 BMS-2322623 ABT-378 and AG-1 549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, and pentafuside and Yissum project No. 11607.

[00398] Agents suitable for use in combination with the compounds of the present invention for the treatment of cancer include chemotherapeutic agents, targeted cancer therapies, immunotherapies or radiotherapy. The compounds of the present invention can be effective in combination with antihormonal agents in the treatment of breast cancer and other tumors. Suitable examples are anti-estrogen agents including, but not limited to, tamoxifen and toremifene, aromatase inhibitors, including, but not limited to, letrozole, anastrozole, and exemestane, adrenocorticosteroids, and (e.g., prednisone), progestins (eg, megastrol acetate), and estrogen receptor antagonists (eg, fulvestrant). Antihormonal agents used to treat prostate and other cancers can also be combined with the compounds of the present invention. These include antiandrogens, including but not limited to flutamide, bicalutamide, nilutamide, and luteinizing hormone-releasing hormone (LHRH) analogues, including leuprolide, goserelin, triptorelin, and histrelin, LHRH antagonists (e.g., degarelix), androgen receptor blockers (eg enzalutamide) and agents that inhibit androgen production (eg abiraterone).

[00399] The compounds of the present invention can be combined with or in sequence with other agents against membrane receptor kinases, especially for patients who have developed primary or acquired resistance to the therapeutic target. Such therapeutic agents include inhibitors or antibodies against EGFR, Her2, VEGFR, c-Met, Ret, IGFR1, or Flt-3 and or against cancer-associated fusion protein kinases such as Bcr-Abl and EML4-Alk. EGFR inhibitors include gefitinib and erlotinib and EGFR/Her2 inhibitors include but are not limited to dacomitinib, afatinib, lapitinib and neratinib. Antibodies against EGFR include, but are not limited to, cetuximab, panitumumab, and necitumumab. c-Met inhibitors can be used in combination with FGFR inhibitors. These include onartumzumab, tivantnib, and INC-280. Agents against Abl (or Bcr-Abl) include imatinib, dasatinib, nilotinib, and ponatinib and those against Alk (or EML4-Alk) include crizotinib.

[00400] Inhibitors of angiogenesis may be effective in some tumors in combination with FGFR inhibitors. These include antibodies against VEGF or VEGFR or VEGFR kinase inhibitors. Antibodies or other therapeutic proteins against VEGF include bevacizumab and aflibercept. VEGFR kinase inhibitors and other anti-angiogenesis inhibitors include, but are not limited to, sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, and vandetanib.

[00401] Activation of intracellular signaling pathways is frequent in cancer, and agents that target components of these pathways have been combined with receptor targeting agents to improve efficacy and reduce resistance. Examples of agents that can be combined with the compounds of the present invention include inhibitors of the PI3K-AKT-mTOR pathway, inhibitors of the Raf-MAPK pathway, inhibitors of the JAK-STAT pathway, and inhibitors of chaperone proteins and progression. of the cell cycle.

[00402] Anti-PI3 kinase agents include but are not limited to topilaralisib, idelalisib, buparlisib. mTOR inhibitors such as rapamycin, sirolimus, temsirolimus, and everolimus can be combined with FGFR inhibitors. Other suitable examples include, but are not limited to, vemurafenib and dabrafenib (Raf inhibitors) and trametinib, selumetinib and GDC-0973 (MEK inhibitors). Inhibitors of one or more JAKs (eg, ruxolitinib, baricitinib, tofacitinib), Hsp90 (eg, tanespimycin), cyclin-dependent kinases (eg, palbociclib), HDACs (eg, panobistat), PARP ( eg olaparib), and proteasomes (e.g. bortezomib, carfilzomib) can also be combined with the compounds of the present invention. In some embodiments, the JAK inhibitor is selective for JAK1 over JAK2 and JAK3.

[00403] Other agents suitable for use in combination with the compounds of the present invention include chemotherapy combinations such as platinum-based duos used in lung cancer and other solid tumors (cisplatin or carboplatin plus gemcitabine; cisplatin or carboplatin plus docetaxel; cisplatin or carboplatin plus paclitaxel; cisplatin or carboplatin plus pemetrexed) or gemcitabine plus particles bound to paclitaxel (Abraxane®).

[00404] Chemotherapeutic agents or other suitable anti-cancer agents include, for example, alkylating agents (including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes) such as uracil mustard, chlormethine, cyclophosphamide (Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobromane, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[00405] Other agents suitable for use in combination with the compounds of the present invention include: dacarbazine (DTIC), optionally, along with other chemotherapy drugs such as carmustine (BCNU) and cisplatin; the "Dartmouth regimen," which consists of DTIC, BCNU, cisplatin, and tamoxifen; the combination of cisplatin, vinblastine, and DTIC; or temozolomide. The compounds according to the invention can also be combined with immunotherapy drugs, including cytokines such as interferon alpha, interleukin 2, tumor necrosis factor (TNF).

[00406] Chemotherapeutic agents or other suitable anti-cancer agents include, for example, antimetabolites (including, without limitation, folic acid antagonists, pyrimidine analogues, purine analogues and adenosine deaminase inhibitors) such as methotrexate, 5-fluorouracil, floxuridine , cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine.

[00407] Chemotherapeutic agents or other suitable anti-cancer agents also include, for example, certain natural products and their derivatives (for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins) such as vinblastine, vincristine , vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, Ara-C, paclitaxel (TAXOL™), mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide, and teniposide .

[00408] Other cytotoxic agents include navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, and dloxafine.

[00409] Cytotoxic agents such as epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes such as cisplatin and carboplatin; biological response modifiers; growth inhibitors; anti-hormonal therapeutic agents; leucoverine; tegafur; and hematopoietic growth factors.

[00410] Other anti-cancer agent(s) include therapeutic antibodies such as trastuzumab (Herceptin), antibodies to costimulatory molecules such as CTLA-4, 4-1BB PD-1, or antibodies against cytokines ( IL-10, TGF-β, etc).

[00411] Other anticancer agents also include those that block immune cell migration, such as antagonists of chemokine receptors, including CCR2 and CCR4.

[00412] Other anticancer agents also include those that enhance the immune system, such as adjuvants or adoptive T-cell transfer.

[00413] Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses.

[00414] Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. Furthermore, its administration is described in the standard literature. For example, the administration of many of the chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), which description is incorporated herein by reference. as if it were presented in its entirety.

[00415] Pharmaceutical Formulations and Dosage Forms

[00416] When used as pharmaceuticals, the compounds of the invention can be administered in the form of pharmaceutical compositions, which refers to a combination of a compound of the invention, or its pharmaceutically acceptable salt, and at least one vehicle pharmaceutically acceptable. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending on whether local or systemic treatment is desired and on the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including intranasal, vaginal, and rectal application), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal, and transdermal), ocular, oral or parenteral. Methods for ocular delivery may include topical administration (eye drops), subconjunctival, periocular, or intravitreal injection, or introduction by balloon catheter or ophthalmic implants surgically placed in the conjunctival sac. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial administration, for example, intrathecal or intraventricular. Parenteral administration can be in the form of a single bolus dose or can be, for example, by a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oil bases, thickeners and the like may be necessary or desirable.

[00417] This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of the above invention in combination with one or more pharmaceutically acceptable carriers. In making the compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed within such a vehicle in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Accordingly, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example , up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[00418] When preparing a formulation, the active compound can be ground to provide the proper particle size before combining with the other ingredients. If the active compound is substantially insoluble, it can be ground to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, for example about 40 mesh.

[00419] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservative agents such as methyl and propyl hydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide rapid, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.

[00420] The compositions may be formulated in unit dose form, each dosage containing from about 5 to about 100 mg, more usually from about 10 mg to about 30 mg, of the active ingredient. The term "unit dose forms" refers to physically distinct units suitable as unitary dosages for human and other mammalian patients, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[00421] The active compound can be effective over a wide range of dosages and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of compound actually administered will generally be determined by a physician in accordance with the relevant circumstances, including the condition being treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[00422] To prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When such preformulation compositions are called homogeneous, the active ingredient is evenly dispersed throughout the composition so that the composition can be readily subdivided into equally effective dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dose forms of the type described above containing, for example, 0.1 mg to about 500 mg of the active ingredient of the present invention.

[00423] The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form that obtains the advantage of prolonged action. For example, the tablet or pill may comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and allows the internal component to pass intact through the duodenum, or even to be released in a delayed manner. A variety of materials can be used in such enteric layers or coatings, such materials including numerous polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

[00424] The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions with edible oils such as seed oil cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[00425] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the compositions are administered by the oral or nasal airway for local or systemic effect. The compositions can be nebulized by the use of inert gases. Nebulized solutions can be aspirated directly from the nebulizer device or the nebulizer device can be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices that deliver the formulation in a suitable form.

[00426] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of administration such as prophylaxis or therapy, the condition of the patient, the manner of administration, and the like. In therapeutic applications, the compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the condition being treated as well as the judgment of the treating physician, depending on such factors as the severity of the disease, the age, weight and general condition of the patient, and the like.

[00427] The compositions administered to a patient may be in the form of the pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or they can be sterile filtered. The aqueous solutions can be packaged for use as they are, or they can be lyophilized, the lyophilized preparation being combined with a sterile aqueous vehicle prior to administration. The pH of the compound preparations will typically be from 3 to 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that the use of certain of the above mentioned excipients, vehicles, or stabilizers -acted will result in the formation of pharmaceutical salts.

[00428] The therapeutic dosage of the compounds of the present invention may vary according, for example, to the specific use for which the treatment is made, the form of administration of the compound, the health and condition of the patient, and the judgment of the physician prescriber. The proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending on several factors including dosage, chemical characteristics (eg, hydrophobicity), and route of administration. For example, the compounds of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% weight by volume of the compound for parenteral administration. Some typical dosage ranges are from about 1 µg/kg to about 1 g/kg of body weight per day. In some embodiments, the dosage range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day. Dosage will likely depend on such variables as the type and extent of progression of the disease or disorder, the general health status of the specific patient, the relative biological efficacy of the selected compound, the formulation of the excipient, and its route of administration. dog. Effective dosages can be extrapolated from these dose-response curves derived from animal model or in vitro test systems.

[00429] The compounds of the invention may also be formulated in combination with one or more additional active ingredients which may include any pharmaceutical agent such as antiviral agents, vaccines, antibodies, immune enhancers, immune suppressants, anti-inflammatory agents and the like.

[00430] Marked Compounds and Test Methods

[00431] Another aspect of the present invention relates to a fluorescent dye, spin marker, heavy metal or radiolabeled compounds of the invention that would be useful not only in imaging, but also in assays, in in vitro and in vivo, to localize and quantify the FGFR enzyme in tissue samples, including humans, and to identify FGFR enzyme binders by inhibiting the binding of a labeled compound. Accordingly, the present invention includes FGFR enzyme assays that contain these labeled compounds.

[00432] The present invention further includes the isotopically labeled compounds of the invention. An "isotopically" or "radiolabeled" compound is a compound of the invention where one or more atoms are replaced or exchanged with an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature ( i.e. naturally occurring). Suitable radionuclides that can be incorporated into the compounds of the present invention include, but are not limited to, 2H (also written as D for deuterium), 3H (also written as T for tritium), 11C, 13C, 14C, 13N , 15N, 15O, 17O, 18O, 18F, 35S, 36Cl, 82Br, 75Br, 76Br, 77Br, 123I, 124I, 125I and 131I. The radionuclide that is incorporated into the present radiolabeled compounds will depend on the specific application of that radiolabelled compound. For example, for in vitro FGFR enzyme labeling assays and competition assays, compounds incorporating 3H, 14C, 82Br, 125I, 131I, or 35S will generally be most useful. For ap cations and reaming 11C, 18F, 125I, 123I, 124I, 131I, 75Br, 76Br or 77Br will generally be most useful.

[00433] It is understood that a "radio-labeled" or "labelled" compound is a compound that has incorporated at least one radionuclide. In some embodiments, the radionuclide is selected from the group consisting of 3H, 14C, 125I, 35S and 82Br.

[00434] Synthetic methods for incorporating radioisotopes into organic compounds are applicable to the compounds of the invention and are well known in the art.

[00435] A radiolabeled compound of the invention can be used in a screening assay to identify/evaluate the compounds. In general terms, an identified or newly synthesized compound (i.e., test compound) can be evaluated for its ability to reduce the binding of the radiolabeled compound of the invention to the FGFR4 enzyme. Consequently, the ability of a test compound to compete with the radiolabeled compound for binding to the FGFR4 enzyme directly correlates with its binding affinity.

[00436] Kits

[00437] The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of diseases or disorders associated with FGFR, obesity, diabetes and other diseases referred to herein, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective use of a compound of the invention. These kits may further include, if desired, one or more of the various components of conventional pharmaceutical kits, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those versed in the technique. Instructions, such as package inserts or labels, indicating the amounts of the components to be administered, instructions for administration, and/or instructions for mixing the components, may also be included in the kit.

[00438] The invention will be described in more detail by way of specific examples. The following examples are offered for illustrative purposes and are not intended to limit the invention in any way. One skilled in the art will readily recognize a variety of non-critical parameters that can be changed or modified to produce essentially the same results. The example compounds were found to be inhibitors of one or more FGFRs as described later herein.

[00439] Examples

[00440] Experimental procedures for the compounds of the invention are provided below. Preparatory LC-MS purifications of some of the prepared compounds were done on Waters directed mass fractionation systems. The basic configuration of the equipment, the protocols and the control software for the operation of these systems have been described in detail in the literature. See, for example, "Two-Pump At Column Dilution Configuration for Pre parative LC-MS", K. Blom, J. Combi. Chem., 4, 295 (2002); "Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification", K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003); and "Preparative LC-MS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874-883 (2004). The separated compounds are typically subjected to mass spectrometry and analytical liquid chromatography (LCMS) to verify purity, under the following conditions: Instrument; Agilent 1100 Series, LC/MSD, column: Waters Sunfire™ C18 5 µm particle size, 2.1 X 5.0 mm, buffers: mobile phase A: 0.025% TFA in water and mobile phase B: acetonitrile; gradient from 2% to 80% B in 3 minutes with a flow rate of 2.0 mL/minute.

[00441] Some of the prepared compounds were also separated on a preparative scale by reversed phase high performance liquid chromatography (RP-HPLC) with an MS detector or flash chromatography (silica gel) as indicated in the examples. The preparative reverse phase high performance liquid chromatography (RP-HPLC) column conditions are as follows:

[00442] Purifications at pH = 2: Waters Sunfire™ C18 particle size 5 μm, column 19 X 100 mm, eluting with mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobile phase B: acetonide trail; the flow rate was 30 mL/minute, the separation gradient was optimized for each compound using the compound-specific method optimization protocol as described in the literature [see "Preparative LCMS Purification: Improved Compound Specific Method Optimization", K Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)]. Typically, the flow rate used with the 30 x 100 mm column is 60 mL/minute.

[00443] Purifications at pH = 10: Waters XBridge C18 particle size 5 μm, column 19 X 100 mm, eluting with mobile phase A: 0.15% NH 4OH in water and mobile phase B: acetonitrile; the flow rate was 30 mL/minute, the separation gradient was optimized for each compound using the compound-specific method optimization protocol as described in the literature [see "Preparative LCMS Purification: Improved Compound Specific Method Optimization", K Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874883 (2004)]. Typically, the flow rate used with the 30 x 100 mm column is 60 mL/minute.

[00444] Example 1

[00445] 6'-(5-amino-2-methylphenyl)-2'-(2,6-difluoro-3,5-dimethoxyphenyl)-1'H-spiro[cyclopropane-1,4'-[2,7 ]naphthyridin]-3'(2'H)-one

[00446] Step 1: 4,6-dichloronicotinaldehyde

[00447] To a stirred solution of 2,4-dichloro-5-carbethoxypyridine (10.0 g, 45.4 mmol) in methylene chloride (100.0 mL), diisobutylaluminum hydride in methylene chloride (50.0 mL, 1.0 M, 50.0 mmol) was added dropwise at -78 °C. After 2 hours, the reaction was quenched with saturated Rochelle's salt solution. After stirring for 12 hours, the aqueous solution was extracted with DCM (3 x 150 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to yield the crude aldehyde (7.51 g, 42.9 mmol), which was used directly in the next step without further purification. LC-MS calculated for C6H4Cl2NO [M+H]+ m/z: 176.0; found 176.0.

[00448] Step 2: N-[(4,6-dichloropyridin-3-yl)methyl]-2,6-difluoro-3,5-dimethoxyaniline

[00449] To a stirred solution of 2,6-difluoro-3,5-dimethoxyaniline (9.03 g, 47.7 mmol), sodium triacetoxyborohydride (38.0 g, 180 mmol) in methylene chloride (60 mL )/trifluoroacetic acid (30 mL), 4,6-dichloronicotinaldehyde (8.00 g, 45.5 mmol) was added in small portions at room temperature. After 1 hour, the volatiles were removed in vacuo and saturated aqueous NaHCO 3 (200 mL) was added. The resulting mixture was extracted with DCM (3 x 150 mL). The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified on silica gel (eluting with 0 to 0-40% EtOAc in hexanes) to provide the desired product (15.0 g). LC-MS calculated for C14H13Cl2F2N2O2 [M+H]+ m/z: 349.0. found 349.1.

[00450] Step 3: Ethyl 3-[[(4,6-dichloropyridin-3-yl)methyl](2,6-difluoro-3,5-dimethoxyphenyl)amino]-3-oxopropanoate

[00451] To a stirred solution of N-[(4,6-dichloropyridin-3-yl)methyl]-2,6-difluoro-3,5-dimethoxyaniline (3.50 g, 10.0 mmol) in tetra- hydrofuran (20 mL), NaH (60% w/w in mineral oil, 421 mg, 10.5 mmol) was added at room temperature. After 10 minutes, ethyl malonyl chloride (1.92 mL, 15.0 mmol) was added dropwise. After an additional 1 hour, the reaction was quenched with saturated aqueous NH4Cl, and extracted with DCM (3 x 100 mL). The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified on silica gel (eluting with 0 to 0-35% EtOAc in hexanes) to provide the desired product (4.20 g, 9.1 mmol). LC-MS calculated for C19H19Cl2F2N2O5 [M+H]+ m/z: 463.1. found 463.1.

[00452] Step 4: 6-chloro-2-(2,6-difluoro-3,5-dimethoxyphenyl)-3-oxo-1,2,3,4-tetrahydro-2,7-naphthyridine-4- ethyl carboxylate

[00453] To a stirred solution of ethyl 3-[[(4,6-dichloropyridin-3-yl)methyl](2,6-difluoro-3,5-dimethoxyphenyl)amino]-3-oxopropanoate (1.50 g, 3.24 mmol) in DMF (15 mL), NaH (60% w/w in mineral oil, 337 mg, 8.42 mmol) was added at room temperature. The resulting mixture was then heated to 110°C. After 5 hours, the reaction was cooled to room temperature, and saturated aqueous NH4Cl (50 mL) was added to form a precipitate. After filtration, the solid was dried in vacuo to give the crude cyclized product (0.95 g, 2.23 mmol). LC-MS calculated for C19H18ClF2N2O5 [M+H]+ m/z: 427.1; found 427.0.

[00454] Step 5: 6-chloro-2-(2,6-difluoro-3,5-dimethoxy-phenyl)-1,2-dihydro-2,7-naphthyridin-3(4H)-one

[00455] To a stirred solution of 6-chloro-2-(2,6-difluoro-3,5-dimethoxyphenyl)-3-oxo-1,2,3,4-tetrahydro-2,7-naphthyridine- Ethyl 4-carboxylate (0.95 g, 2.23 mmol) in 1,4-dioxane (5 mL), hydrogen chloride (4.0 M in dioxane, 2 mL, 8 mmol) was added at room temperature. environment. The resulting mixture was heated to 100°C. After 4 hours, the reaction was cooled to room temperature, quenched with saturated aqueous NaHCO 3 , and extracted with DCM (3 x 100 mL). The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified on silica gel (eluting with 0 to 0-30% EtOAc in DCM) to provide the desired product (0.75 g, 2.12 mmol). LC-MS calculated for C16H14ClF2N2O3 [M+H]+ m/z: 355.1; found 355.1.

[00456] Step 6: 6'-chloro-2'-(2,6-difluoro-3,5-dimethoxyphenyl)-1',2'-dihydro-3'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-3'-one

[00457] To a stirred solution of 6-chloro-2-(2,6-difluoro-3,5-dimethoxy-phenyl)-1,4-dihydro-2,7-naphthyridin-3-(2H) -one (1.50 g, 4.23 mmol) in DMF (10 mL), cesium carbonate (3.03 g, 9.30 mmol) and 1-bromo-2-chloro-ethane (701 µL, 8, 46 mmol) were added sequentially at room temperature. After 5 hours, the reaction was quenched with saturated aqueous NH 4 Cl, and extracted with DCM (3 x 75 mL). The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified on silica gel (eluting with 0 to 0-50% EtOAc in hexanes) to provide the desired product (1.20 g, 3.15 mmol). LC-MS calculated for C18H16ClF2N2O3 [M+H]+ m/z: 381.1; found 381.1.

[00458] Step 7: 6'-(5-amino-2-methylphenyl)-2'-(2,6-difluoro-3,5-dimethoxyphenyl)-1'H-spiro[cyclopropane-1,4'-[ 2,7]naphthyridin]-3'(2'H)-one

[00459] A mixture of 6'-chloro-2'-(2,6-difluoro-3,5-dimethoxyphenyl)-1',2'-dihydro-3'H-spiro[cyclopropane-1,4' - [2.7]naphtridin]-3'-one (30.0 mg, 0.0788 mmol), (5-amino-2-methylphenyl)boronic acid (17.8 mg, 0.118 mmol), sodium carbonate (18, 4 mg, 0.173 mmol), and [1,1'-bis(dicyclohexylphosphine)ferrocene] dichloro palladium(II) (3.0 mg, 0.0039 mmol) in tert-butyl alcohol (3.0 mL)/ Water (3.0 mL) was stirred and heated to 90°C. After 2 hours, the reaction mixture was quenched with saturated aqueous NH 4 Cl, and extracted with methylene chloride. The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The crude product was purified on prep-HPLC (pH=2, acetonitrile / water + TFA) to obtain the desired product (22 mg) as its TFA salt. LC-MS calculated for C25H24F2N3O3 [M+H]+m/z: 452.2; found 452.2.

[00460] Example 2

[00461] 6'-(5-amino-4-fluoro-2-methylphenyl)-2'-(2,6-difluoro-3,5-dimethoxyphenyl)-1'H-spiro[cyclopropane-1,4'- [2,7]naphthyridin]-3'(2'H)-one

[00462] This compound was prepared using procedures analogous to those for example 1, step 7, with 2-fluoro-4-methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)aniline replacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated for C25H23F3N3o3 [M+H]+ m/z: 470.2; Found: 470.2.

[00463] Example 3:

[00464] 4-amino-2-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane- 1,4'-[2,7]naphthyridine]-6'-yl)benzonitrile

[00465] This compound was prepared using procedures analogous to those for example 1, step 7, with 4-amino-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl) benzonitrile replacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated for C25H21F2N4O3 [M+H]+ m/z: 463.2 Found: 463.2.

[00466] Example 4

[00467] 6'-(5-aminopyridin-3-yl)-2'-(2,6-difluoro-3,5-dimethoxyphenyl)-1'H-spiro[cyclopropane-1,4'-[2,7 ]naphthyridin]-3'(2'H)-one

[00468] Step 1: N-(5-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro-1'H-spiro[ cyclopropane-1,4'-[2,7]naphthyridin]-6'-yl)pyridin-3-yl)acetamide;

[00469] This compound was prepared using procedures analogous to those for example 1, step 7, with N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )pyridin-3-yl]acetamide replacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated for C25H23F2N4O4 [M+H]+ m/z: 481.2; Found: 481.2.

[00470] Step 2: 6'-(5-aminopyridin-3-yl)-2'-(2,6-difluoro-3,5-dimethoxyphenyl)-1'H-spiro[cyclopropane-1,4'-[ 2,7]naphthyridin]-3'(2'H)-one

[00471] To a stirred solution of N-{5-[2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro-1'H- spiro[cyclopropane-1,4'-[2.7]naphthyridin]-6'-yl]pyridin-3-yl}acetamide (0.048 g, 0.10 mmol) in ethanol (3.0 mL), potassium hydroxide (2.0 M in water, 0.15 mL, 0.30 mmol) was added at room temperature. The resulting mixture was heated at 60°C overnight. The reaction was quenched with saturated aqueous NH 4 Cl, and the volatiles were removed under reduced pressure. The residue was dissolved in methylene chloride and washed with saturated aqueous NH 4 Cl. The organic layer was dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The crude product was purified on prep-HPLC (pH=2, acetonitrile / water + TFA) to give the desired product (26 mg) as its TFA salt, LCMS calculated for C23H21F2N4O3 (M+H)+ m/z : 439.2; Found: 439.2.

[00472] Example 5

[00473] 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(5-fluoropyridin-3-yl)-1'H-spiro[cyclopropane-1,4'-[2,7 ]naphthyridin]-3'(2'H)-one

[00474] This compound was prepared using procedures analogous to those for example 1, step 7, with (5-fluoropyridin-3-yl) boronic acid replacing (5-amino-2-methylphenyl) boronic acid. LCMS calculated for C23H19F3N3O3 [M+H]+ m/z: 442.1: Found: 442.2.

[00475] Example 6

[00476] 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(5-morpholinopyridin-3-yl)-1'H-spiro[cyclopropane-1,4'-[2,7 ]naphthyridin]-3'(2'H)-one

[00477] This compound was prepared using procedures analogous to those for example 1, step 7, with 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )pyridin-3-yl]morpholine replacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated for C27H27F2N4O4 [M+H]+ m/z: 509.2; Found: 509.2.

[00478] Example 7:

[00479] 6'-(5-amino-2-methylpyridin-3-yl)-2'-(2,6-difluoro-3,5-dimethoxyphenyl)-1'H-spiro[cyclopropane-1,4'- [2,7]naphthyridin]-3'(2'H)-one

[00480] Step 1: 6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine

[00481] A stirred mixture of 5-bromo-6-methylpyridin-3-amine (0.100 g, 0.535 mmol), 4,4,5,5,4',4',5',5'-octamethyl-[2.2 ']bi[[1,3,2]dioxaborolanil] (0.136 g, 0.535 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (42 mg, 0.051 mmol), and potassium acetate (0.150 g, 1.53 mmol) in 1,4-dioxane (5.0 mL) was heated to 110 °C. After 2 hours, the reaction was quenched with saturated aqueous NH 4 Cl, and extracted with DCM (3 x 30 mL). The organic layers were combined, dried over Na2SO4 and concentrated. The crude product was used directly in the next step without further purification.

[00482] Step 2: 6'-(5-amino-2-methylpyridin-3-yl)-2'-(2,6-difluoro-3,5-dimethoxyphenyl)-1'H-spiro[cyclopropane-1, 4'-[2,7]naphthyridin]-3'(2'H)-one

[00483] This compound was prepared using procedures analogous to those for example 1, step 7, with 6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridin-3-amine replacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated for C24H23F2N4O3 [M+H]+ m/z: 453.2; Found: 453.2.

[00484] Example 8:

[00485] 5-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro-1'Hespiro[cyclopropane-1,4'-[ 2,7]naphthyridine]-6'-yl)nicotinonitrile

[00486] This compound was prepared using procedures analogous to those for example 7, steps 1 to 2, with 5-bromonicotinonitrile replacing 5-bromo-6-methylpyridin-3-amine in step 1. LCMS calculated for C24H19F2N4O3 [ M+H]+ m/z: 449.1; Found: 449.1.

[00487] Example 9:

[00488] 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(pyridin-3-yl)-1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin ]-3'(2'H)-one

[00489] This compound was prepared using procedures analogous to those for example 1, step 7, with pyridin-3-ylboronic acid replacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated for C23H20F2N3O3 [M+H]+ m/z: 424.2; Found: 424.2.

[00490] Example 10:

[00491] 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(5-methoxypyridin-3-yl)-1'Hespiro[cyclopropane-1,4'-[2,7]naphthyridin ]-3'(2'H)-one

[00492] This compound was prepared using procedures analogous to those for example 1, step 7, with 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl)pyridine replacing 5-amino-2-methylphenyl boronic acid. LCMS calculated for C24H22F2N3O3 [M+H]+ m/z: 454.2; Found: 454.1.

[00493] Example 11

[00494] 6'-(5-chloropyridin-3-yl)-2'-(2,6-difluoro-3,5-dimethoxyphenyl)-1'Hespiro[cyclopropane-1,4'-[2,7]naphthyridin ]-3'(2'H)-one

[00495] This compound was prepared using procedures analogous to those for example 1, step 7, with 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl)pyridine replacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated for C23H19ClF2N3O3 [M+H]+ m/z: 458.1; Found: 458.1.

[00496] Example 12:

[00497] 6'-(5-(1H-imidazol-1-yl)pyridin-3-yl)-2'-(2,6-difluoro-3,5-dimethoxyphenyl)-1'H-spiro[cyclopropane- 1,4'-[2,7]naphthyridin]-3'(2'H)-one

[00498] This compound was prepared using procedures analogous to those for example 1, step 7, with 3-(1H-imidazol-1-yl)-5-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolane-2-yl)pyridine replacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated for C26H22F2N5O3 [M+H]+ m/z: 490.2; Found: 490.1.

[00499] Example 13

[00500] 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(5-(morpholine-4-carbonyl)pyridin-3-yl)-1'H-spiro[cyclopropane-1, 4'-[2,7]naphthyridin]-3'(2'H)-one

[00501] This compound was prepared using procedures analogous to those for example 1, step 7, with morpholino (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) pyridin-3-yl)methanone replacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated for C28H27F2N4O5 [M+H]+ m/z: 537.2; Found: 537.2.

[00502] Example 14

[00503] 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(5-(morpholinosulfonyl)pyridin-3-yl)-1'H-spiro[cyclopropane-1,4'- [ 2,7]naphthyridin]-3'(2'H)-one

[00504] This compound was prepared using procedures analogous to those for example 1, step 7, with 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )pyridin-3-ylsulfonyl]morpholine replacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated for C27H27F2N4O6 [M+H]+ m/z: 573.2; Found: 573.2.

[00505] Example 15

[00506] N-(5-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1 ,4'-[2,7]naphthyridine]-6'-yl)pyridin-3-yl)methanesulfonamide

[00507] This compound was prepared using procedures analogous to those for example 1, step 7, with N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl ) pyridin-3-yl)methanesulfonamide replacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated for C24H23F2N4O5 [M+H]+ m/z: 517.1; Found: 517.1.

[00508] Example 16

[00509] 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(5-(morpholinomethyl)pyridin-3-yl)-1'H-spiro[cyclopropane-1,4'-[ 2,7]naphthyridin]-3'(2'H)-one

[00510] Step 1: 5-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1 ,4'-[2,7]naphthyridine]-6'-yl)nicotinaldehyde

[00511] This compound was prepared using procedures analogous to those for example 1, step 7, with N5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolano-2-yl)nicotinaldehyde replacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated for C24H20F2N3O4 [M+H]+ m/z: 452.1; Found: 452.1.

[00512] Step 2: 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(5-(morpholinomethyl)pyridin-3-yl)-1'H-spiro[cyclopropane-1,4 '-[2,7]naphthyridin]-3'(2'H)-one

[00513] To a stirred solution of 5-[2'-(2,6-difluoro-3,5-dimethoxy-phenyl)-3'-oxo-2',3'-dihydro-1'H-spiro [cyclopropane-1,4'-[2.7]naphthyridin]-6'-yl]nicotinaldehyde (20 mg, 0.04 mmol) and morpholine (7.7 µL, 0.088 mmol) in methylene chloride (5.0 mL) , acetic acid (0.198 mL, 3.49 mmol) was added at room temperature. After 15 minutes, sodium triacetoxyborohydride (18.7 mg, 0.0884 mmol) was added. After a further 1 hour, the volatiles were removed and the residue was purified on prep-HPLC (pH=2, acetonitrile/water + TFA) to obtain the desired product (10 mg) as its TFA salt. LCMS calculated for C28H29F2N4O4 [M+H]+ m/z: 523.2; Found: 523.2.

[00514] Example 17

[00515] 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-phenyl-1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-3'(2 'H)-one

[00516] This compound was prepared using procedures analogous to those for example 1, step 7, with phenylboronic acid replacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated for C24H21F2N2O3 [M+H]+ m/z: 423.2; Found: 423.1.

[00517] Example 18

[00518] 5-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-6'-yl)-N-methylpicolinamide

[00519] This compound was prepared using procedures analogous to those for example 1, step 7, with N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl)picolinamide replacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated for C25H23F2N4O4 [M+H]+ m/z: 481.2; Found: 481.1.

[00520] Example 19

[00521] 4-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-6'-yl)-N-methylbenzamide

[00522] This compound was prepared using procedures analogous to those for example 1, step 7, with 4-(methylcarbamoyl)phenylboronic acid replacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated for C26H24F2N3O4 [M+H]+ m/z: 480.2; Found: 480.2.

[00523] Example 20

[00524] 5-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridine]-6'-yl)picolinonitrile

[00525] This compound was prepared using procedures analogous to those for example 1, step 7, with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) picolinonitrile replacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated for C24H19F2N4O3 [M+H]+ m/z: 449.1; Found: 449.1.

[00526] Example 21

[00527] 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(1,3-dimethyl-1H-pyrazol-4-yl)-1',2'-dihydro-3 'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-3'-one;

[00528] This compound was prepared using procedures analogous to those for example 1, step 7, with 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-pyrazole replacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated for C23H23F2N4O3 [M+H]+ m/z: 441.2; Found: 441.2. 1H NMR (500 MHz, dmso) δ 8.36 (s, 1H), 8.22 (s, 1H), 7.06 (t, J = 8.0 Hz, 1H), 7.03 (s, 1H ), 4.92 (s, 2H), 3.89 (s, 6H), 3.78 (s, 3H), 2.40 (s, 3H), 1.71-1.73 (m, 2H) , 1.55-1.57 (m, 2H).

[00529] Example 22

[00530] 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-phenyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00531] Step 1: 7-chloro-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H) -one

[00532] To a solution of triphosgene (344 mg, 1.16 mmol) in CH 2 Cl 2 (12 mL, 190 mmol) at 0 °C was first added pyridine (0.250 mL, 3.09 mmol). The mixture was then stirred at 0°C for 10 minutes, and a solution of N-[(4,6-dichloropyridin-3-yl)methyl]-2,6-difluoro-3,5-dimethoxy aniline was added (900 mg, 2.58 mmol) in CH 2 Cl 2 (8.0 mL). The reaction mixture was stirred at 0 °C for 1 h and tylamine was added in THF (2.0 M, 6.4 mL, 13 mmol), followed by N,N-diisopropylethylamine (920 μL, 5.3 mmol ). The resulting mixture was then warmed to room temperature, stirred overnight, quenched with saturated NaHCO 3 (aq) solution, and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4 and concentrated to yield the crude intermediate which was used directly in the next step.

[00533] The crude intermediate obtained from the previous step was first dissolved in DMF (20 mL), and Cs2CO3 was added (1.70 g, 5.2 mmol). The reaction mixture was then stirred at 95°C for 5 hours to completion, cooled to room temperature, quenched with water, and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, and concentrated. The resulting material was purified by column chromatography (25% to 55% EtOAc in hexanes) to provide the product as a pale yellow solid. LC-MS calculated for C17H17ClF2N3O3 [M+H]+ m/z: 384.1; found 384.1.

[00534] Step 2: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-phenyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H) -one

[00535] A mixture of 7-chloro-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H) -one (35.0 mg, 0.0912 mmol), sodium carbonate (19.3 mg, 0.18 mmol), phenylboronic acid (16.7 mg, 0.14 mmol), and Pd-127 (6, 9 mg, 0.0091 mmol) in tert-butyl alcohol (1.0 mL) and water (1.0 mL) was first degassed with nitrogen and then stirred at 90°C for 3 hours. The resulting mixture was then cooled to room temperature, diluted with water and extracted with EtOAc (3 x 1.5 mL). The combined organic layers were dried over Na2SO4, and concentrated. The resulting material was purified by preparative LC/MS at pH 2 (MeCN/TFA water) to provide the product as a white solid (TFA salt). LC/MS calculated for C23H22F2N3O3 [M+H]+m/z: 426.2; found 426.1.

[00536] Example 23

[00537] 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(pyridin-3-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2 (1H)-one

[00538] This compound was prepared using procedures analogous to those for example 22, step 2, with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine replacing phenylboronic acid. LC/MS calculated for C22H21F2N4O3 [M+H]+m/z: 427.2; Found: 427.1.

[00539] Example 24

[00540] 5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7- yl)-N-methylpicolinamide

[00541] This compound was prepared using procedures analogous to those for example 21, step 2, with N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)picolinamide replacing phenyl boronic acid. LC/MS calculated for C24H24F2N5O4 [M+H]+m/z: 484.2; Found: 484.1.

[00542] Example 25

[00543] (S)-1-(4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4] ,3-d]pyrimidin-7-yl)benzyl)pyrrolidine-3-carbonitrile

[00544] This compound was prepared using procedures analogous to those for example 22, step 2, with (S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)benzyl)pyrrolidine-3-carbonitrile replacing phenylboronic acid. LC/MS calculated for C29H30F2N5O3 [M+H]+m/z: 534.2; Found: 534.2.

[00545] Example 26

[00546] 2-(5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d ]pyrimidin-7-yl)pyridin-2-yl)-2-methylpropanenitrile

[00547] This compound was prepared using procedures analogous to those for example 22, step 2, with 2-methyl 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyridin-2-yl)propanenitrile replacing phenylboronic acid. LC/MS calculated for C26H26F2N5O3 [M+H]+m/z: 494.2; Found: 494.2.

[00548] Example 27:

[00549] 1-(5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d ]pyrimidin-7-yl)pyridin-2-yl)cyclobutanecarbonitrile

[00550] This compound was prepared using procedures analogous to those for example 22, step 2, with 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) pyridin-2-yl)cyclobutanecarbonitrile replacing phenylboronic acid. LC/MS calculated for C27H26F2N5O3 [M+H]+m/z: 506.2; Found: 506.2. 1H NMR (600 MHz, DMSO) δ 9.34 - 9.32 (m, 1H), 8.55 (dd, J = 8.2, 2.4 Hz, 1H), 8.46 (s, 1H) , 7.78 - 7.74 (m, 1H), 7.70 (s, 1H), 7.07 (t, J = 8.1 Hz, 1H), 4.85 (s, 2H), 4, 06 (q, J = 6.8 Hz, 2H), 3.91 (s, 6H), 2.87 - 2.80 (m, 2H), 2.79 - 2.73 (m, 2H), 2 .35 - 2.26 (m, 1H), 2.13 - 2.05 (m, 1H), 1.23 (t, J = 7.0 Hz, 3H).

[00551] Example 28

[00552] 3-(7-(6-(1-cyanocyclobutyl)pyridin-3-yl)-1-ethyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H) )-yl)-2-fluoro-5-methoxy-N-methylbenzamide

[00553] Step 1: 3-bromo-2-fluoro-5-iodobenzoic acid

[00554] To a mixture of 3-bromo-2-fluorobenzoic acid (1.50 g, 6.85 mmol) in sulfuric acid (5.0 mL) at 0°C, was added n-iodosuccinimide (1.62 g, 7.19 mmol) in portions. The resulting mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was then quenched with cold water, and the precipitate was collected by filtration, washed with cold water, and dried under vacuum to provide the product as a white solid, which was used directly in the next step (2.36 g , 91%). LC-MS calculated for C7H4BrFIO2 [M+H]+ m/z: 344.8; found 344.7.

[00555] Step 2: 3-bromo-2-fluoro-5-hydroxybenzoic acid

[00556] A mixture of 3-bromo-2-fluoro-5-iodobenzoic acid (2.15 g, 6.23 mmol), copper(I) oxide (130 mg, 0.94 mmol), and NaOH (1 .25 g, 31.2 mmol) in water (20 mL) was stirred at 100 °C overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate was acidified with 2M HCl (aq) to pH~1, and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated to give the product as a yellow solid, which was used directly in the next step (1.41 g, 96%). LC-MS calculated for C7H5BrFO3 [M+H]+ m/z: 234.9; found 234.9.

[00557] Step 3: Methyl 3-bromo-2-fluoro-5-methoxybenzoate

[00558] To a solution of 3-bromo-2-fluoro-5-hydroxybenzoic acid (4.88 g, 20.8 mmol) in N,N-dimethylformamide (20 mL) at room temperature was first added K2CO3 (8 .60 g, 62.3 mmol), followed by MeI (2.84 mL, 45.6 mmol). The reaction mixture was stirred for 1 hour at 80°C, cooled to room temperature, quenched with water, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude material was then purified using column chromatography (0% to 30% EtO-Ac in hexanes) to provide the product as a yellow solid (4.87 g, 89%). LC-MS calculated for C9H9BrFO3 [M+H]+ m/z: 263.0; found 263.0.

[00559] Step 4: 3-bromo-2-fluoro-5-methoxy-N-methylbenzamide

[00560] To a mixture of methyl 3-bromo-2-fluoro-5-methoxybenzoate (200 mg, 0.76 mmol) in methanol (7.5 mL)/water (2.5 mL) at room temperature To room temperature NaOH (152 mg, 3.80 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, and 1.0M HCl in water (4.56 mL, 4.56 mmol) was added. The resulting mixture was extracted with EtOAc, and the combined organic layers were dried over Na2SO4, filtered, and concentrated to give a carboxylic acid intermediate, which was used directly in the next step.

[00561] The carboxylic acid resulting from the previous step was dissolved in CH2Cl2 (7.5 mL), and the BOP reagent (404 mg, 0.912 mmol), 2.0 M methylamine in THF (1.52 mL, 3, 04 mmol), and Et3N (0.424 mL, 3.04 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 3 hours before being quenched with water, and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified using column chromatography (0% to 50% EtOAc in hexanes) to provide the product as a white solid. LC-MS calculated for C9H10BrFNO2 [M+H]+ m/z: 262.0; found 262.0.

[00562] Step 5: 3-amino-2-fluoro-5-methoxy-N-methylbenzamide

[00563] A mixture of 3-bromo-2-fluoro-5-methoxy-N-methylbenzamide (205 mg, 0.78 mmol), benzophenone imine (157 μL, 0.94 mmol), (9,9-dimethyl- 9H-xanthene-4,5-diyl)bis(diphenylphosphine) (45 mg, 0.078 mmol), tris(dibenzylidene acetone) dipalladium(0) (36 mg, 0.039 mmol), and Cs2CO3 (381 mg, 1.17 mmol) in 1,4-dioxane (3.0 mL) was purged with nitrogen, and stirred at 95°C for 24 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified using column chromatography (25% to 55% EtOAc in hexanes) to provide the imine intermediate, which was used directly in the next step.

[00564] The imine intermediate obtained from the previous step was dissolved in THF (3.0 mL), and 1.0 M HCl in water (1.0 mL, 1.0 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, neutralized with saturated NaHCO 3 solution and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified using column chromatography (0% to 10% MeOH in CH 2 Cl 2 ) to provide the product as a yellow solid (132 mg, 85% over two steps). LC-MS calculated for C9H12FN2O2 [M+H]+ m/z: 199.1; found 199.1.

[00565] Step 6: 3-({[6-chloro-4-(ethylamino)pyridin-3-yl]methyl}amino)-2-fluoro-5-methoxy-N-methylbenzamide

[00566] To a solution of 3-amino-2-fluoro-5-methoxy-N-methylbenzamide (132 mg, 0.66 mmol), and 6-chloro-4-(ethylamino)nicotinaldehyde (147 mg, 0 .80 mmol) in CH 2 Cl 2 (3.0 mL) at room temperature was first added trifluoroacetic acid (1.0 mL). The resulting mixture was stirred at room temperature for 15 minutes. NaBH(OAc) 3 (211 mg, 1.00 mmol) was added in four portions over a 2 hour period. The reaction mixture was then stirred at room temperature for a further 1 hour before being quenched with saturated NaHCO 3 solution and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude material was purified using column chromatography (0% to 60% EtOAc in hexanes) to provide the product as a yellow solid (171 mg, 70%). LC-MS calculated for C17H21ClFN4O2 [M+H]+ m/z: 367.1; found 367.1.

[00567] Step 7: 3-(7-chloro-1-ethyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)-2-fluoro-5 -methoxy-N-methylbenzamide

[00568] To a solution of 3-({[6-chloro-4-(ethylamino)pyridin-3-yl]methyl}amino)-2-fluoro-5-methoxy-N-methylbenzamide (131 mg, 0.36 mmol) in THF (5.0 mL) at room temperature was added Et3N (200 µL, 1.4 mmol), followed by triphosgene (85 mg, 0.28 mmol) in THF (1.0 mL). The reaction mixture was stirred at room temperature for 2 hours. 1.0 M NaOH in water (1.4 mL, 1.4 mmol) was then added and the resulting mixture was stirred for an additional hour before being extracted with EtOAc. The combined organic layers were dried over -Na 2 SO 4 , filtered and concentrated. The residue was purified by column chromatography (0-50% EtOAc in hexanes) to provide the product as a colorless oil (137 mg, 98%). LC-MS calculated for C18H19ClFN4O3 [M+H]+ m/z: 393.1; found 393.1.

[00569] Step 8: 3-(7-(6-(1-cyanocyclobutyl)pyridin-3-yl)-1-ethyl-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin- 3(4H)-yl)-2-fluoro-5-methoxy-N-methylbenzamide

[00570] A mixture of 3-(7-chloro-1-ethyl 2-oxo-1,4-dihydropyrido [4,3-D] pyrimidin-3-(2H)-yl)-2-fluoro-5 -methoxy-N-methylbenzamide (20 mg, 0.051 mmol), [1.1'-bis(dicyclohexylphosphino)ferrocene]dichloropalladium(II) (7.7 mg, 0.010 mmol), Na2CO3 (11 mg, 0.10 mmol), and 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]cyclobutanecarbonitrile (22 mg, 0.076 mmol) in water (1 .0 mL)/t-BuOH (1.0 mL) was purged with nitrogen, and stirred for 3 hours at 100°C. The reaction mixture was cooled to room temperature, and extracted with EtOAc. The combined organic layers were concentrated, and purified on preparative HPLC (pH=2, acetonitrile/water + TFA) to provide the product as a white solid (TFA salt). LC-MS calculated for C28H28FN6O3 [M+H]+ m/z: 515.2; found 515.2. 1H NMR (400 MHz, DMSO) δ 9.34 (d, J = 1.7 Hz, 1H), 8.56 (dd, J = 8.3, 2.3 Hz, 1H), 8.45 (s , 1H), 8.27 (s, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.67 (s, 1H), 7.26 (dd, J = 5.9, 3.2 Hz, 1H), 7.07 (dd, J = 4.9, 3.3 Hz, 1H), 4.87 (s, 3H), 4.05 (q, J = 6.7 Hz, 2H), 3.79 (s, 3H), 2.89 - 2.66 (m, 6H), 2.35 - 2.21 (m, 1H), 2.09 (ddd, J = 20.4, 9.0, 5.4 Hz, 1H), 1.23 (t, J = 6.9 Hz, 3H).

[00571] Example 29

[00572] 1-(cyclopropylmethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrido [4,3-d]pyrimidin-2(1H)-one

[00573] Step 1: N-{[4-chloro-6-(1,3-dimethyl-1H-pyrazol-4-yl) pyridin-3-yl]methyl}-2,6-difluoro-3,5- dimethoxyaniline

[00574] N-[(4,6-dichloropyridin-3-yl)methyl]-2,6-difluoro-3,5-dimethoxyaniline (1.58 g, 4.52 mmol), 1,3-dimethyl-4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.00 g, 4.52 mmol), tetracis(triphenylphosphine)palladium(0) (520 mg, 0.45 mmol) and potassium carbonate (2.50 g, 18.1 mmol) in a flask were dissolved in a mixture of water (7.1 mL) and 1,4-dioxane (20 mL). The reaction mixture was then stirred at 120°C overnight. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated. The residue was purified on silica gel (50 to 100% ethyl acetate in hexanes) to provide the desired product (1.55 g, 31.6 mmol). LC-MS calculated for C19H19ClF2N4O2 [M+H]+ m/z: 409.1, found 409.1.

[00575] Step 2: N-(cyclopropylmethyl)-5-((2,6-difluoro-3,5-dimethoxyphenylamino)methyl)-2-(1, 3-dimethyl-1H-pyrazol-4-yl)pyridin- 4-amine

[00576] Conditions A:

[00577] A solution of N-{[4-chloro-6-(1,3-dimethyl-1H-pyrazol-4-yl) pyridin-3-yl]methyl}-2,6-difluoro-3,5- dimethoxyaniline (50.0 mg, 0.122 mmol), (2'-aminobiphenyl-2-yl)(chloro)[dicyclohexyl (2',6'-diisopropoxybiphenyl-2-yl) phosphoranyl] palladium (10 mg, 0. 01 mmol), sodium tert-butoxide (21 mg, 0.22 mmol), and cyclopropyl methylamine (15.6 µL, 0.183 mmol) in 1,4-dioxane (700 µL) was heated at 90°C for 2 hours . The reaction mixture was diluted with dichloromethane and filtered through a pad of celite. The filtrate was concentrated and the residue used directly in the next step. LC/MS calculated for C23H28F2N5O2 [M+H]+ m/z: 444.2, found 444.2.

[00578] Conditions B:

[00579] A solution of N-{[4-chloro-6-(1,3-dimethyl-1H-pyrazol-4-yl) pyridin-3-yl]methyl}-2,6-difluoro-3,5- dimethoxyaniline (50.0 mg, 0.122 mmol), (2'-aminobiphenyl-2-yl)(chloro)[dicyclohexyl (2',6'-diisopropoxybiphenyl-2-yl) phosphoranyl] palladium (10 mg, 0. 01 mmol), cesium carbonate (71 mg, 0.366 mmol), and cyclopropylmethylamine (15.6 µL, 0.183 mmol) in tert-butanol (800 µL) was heated at 100°C overnight. The reaction mixture was diluted with dichloromethane and filtered through a pad of celite. The filtrate was concentrated and the residue used directly in the next step.

[00580] Step 3: 1-(cyclopropylmethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4- dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00581] The crude residue from the previous step was dissolved in tetrahydrofuran (1.5 mL). Triethylamine (68.2 µL, 0.489 mmol) was added and the mixture cooled to 0°C. Triphosgene (36.3 mg, 0.122 mmol) was added in one portion and the reaction mixture stirred at room temperature for 1 hour, then quenched with 1N Na-OH and stirred for a further 1 hour at room temperature. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate and concentrated. The crude product was purified on prep-HPLC (pH=2, acetonitrile / water + TFA) to obtain the desired product (22 mg) as its TFA salt. LC/MS calculated for C24H26F2N5O3 [M+H]+ m/z: 470.2, found 470.2.

[00582] Example 30

[00583] 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-propyl-3,4-dihydropyrido[4 ,3-d]pyrimidin-2(1H)-one

[00584] This compound was prepared using procedures analogous to those for example 29, step 2 (condition A) and step 3, with n-propylamine replacing cyclopropylmethylamine in step 2. LCMS calculated for C23H26F2N5O3 [M+H]+ m/z: 458.2; Found: 458.2.

[00585] Example 31

[00586] 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-((5-methylisoxazol-3-yl)methyl )-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00587] This compound was prepared using procedures analogous to those for example 29, step 2 (condition B) and step 3, with 1-(5-methylisoxazol-3-yl)methanamine replacing cyclopropylmethylamine in step 2 LCMS calculated for C25H25F2N6O4 [M+H]+ m/z: 511.2; Found: 511.1. 1H NMR (500 MHz, DMSO) δ 8.36 (s, 1H), 8.17 (s, 1H), 7.26 (s, 1H), 7.09 (t, J = 8.2 Hz, 1H ), 6.13 (m, 1H), 5.23 (s, 2H), 4.87 (s, 2H), 3.90 (s, 6H), 3.82 (s, 3H), 2.36 (s, 3H), 2.32 (s, 3H).

[00588] Example 32

[00589] 1-cyclopentyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4 ,3-d]pyrimidin-2(1H)-one

[00590] This compound was prepared using procedures analogous to those for example 29, step 2 (condition A) and step 3, with cyclopentylamine replacing cyclopropylmethylamine in step 2. LCMS calculated for C25H28F2N5O3 [M+H]+ m/ z: 484.2; Found: 484.2.

[00591] Example 33

[00592] 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(tetrahydrofuran-3-yl)-3 ,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00593] This compound was prepared using procedures analogous to those for example 29, step 2 (condition A) and step 3, with tetrahydrofuran-3-amine (HCl salt) replacing cyclopropylmethylamine in step 2 LCMS calculated for C24H26F2N5O4 [M+H]+ m/z: 486.2; Found: 486.2.

[00594] Example 34

[00595] 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(4-fluorobenzyl)-3,4-di -hydropyrido[4,3-d]pyrimidin-2(1H)-one

[00596] This compound was prepared using procedures analogous to those for example 29, step 2 (condition A) and step 3, with 4-fluorobenzyl replacing cyclopropylmethylamine in step 2. LCMS calculated for C27H25F3N5O3 [M+H]+ m/z: 524.2; Found: 524.1.

[00597] Example 35

[00598] 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-((3-methylisoxazol-5-yl)methyl )-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00599] This compound was prepared using procedures analogous to those for example 29, step 2 (condition B) and step 3, with 1-(3-methylisoxazol-5-yl)methanamine replacing cyclopropylmethylamine in step 2 LCMS calculated for C25H25F2N6O4 [M+H]+ m/z: 511.2; Found: 511.2.

[00600] Example 36

[00601] 1-((5-cyclopropylisoxazol-3-yl)methyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl )-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one;

[00602] This compound was prepared using procedures analogous to those for example 29, step 2 (condition B) and step 3, with 1-(5-cyclopropylisoxazol-3-yl)methanamine replacing cyclopropylmethylamine in step 2 LCMS calculated for C27H27F2N6α4 [M+H]+ m/z: 537.2; Found: 537.2.

[00603] Example 37

[00604] 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-((tetrahydro-2H-pyran-4 -yl)methyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00605] This compound was prepared using procedures analogous to those for example 29, step 2 (condition A) and step 3, with 1-(tetrahydro-2H-pyran-4-yl)methanamine replacing cyclopropyl- lmethylamine in step 2. LCMS calculated for C26H30F2N5O4 [M+H]+ m/z: 514.2; Found: 514.2.

[00606] Example 38

[00607] 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-7-( 1,3-dimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00608] This compound was prepared using procedures analogous to those for example 29, step 2 and step 3 (condition B), with 1-(3,4-dihydro-2H-chromen-6-yl) methanamine substituting cyclopropylmethylamine in step 2. LCMS calculated for C29H28F2N5O5 [M+H]+ m/z: 564.2; Found: 564.2.

[00609] Example 39

[00610] 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-((1-ethyl-1H-pyrazol-4 -yl)methyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00611] This compound was prepared using procedures analogous to those for example 29, step 2 (condition B) and step 3, with 1-(1-ethyl-1H-pyrazol-4-yl) methanamine replacing cyclopropylmethyl tylamine in step 2. LCMS calculated for C26H28F2N7O3 [M+H]+ m/z: 524.2; Found: 524.1. 1H NMR (600 MHz, DMSO) δ 8.39 (s, 1H), 8.25 (s, 1H), 7.73 (s, 1H), 7.45 (s, 1H), 7.32 (s , 1H), 7.11 (t, J = 8.2 Hz, 1H), 5.08 (s, 2H), 4.90 (s, 2H), 4.08 (q, J = 7.2 Hz , 2H), 3.93 (s, 6H), 3.86 (s, 3H), 2.29 (s, 3H), 1.31 (t, J = 7.3 Hz, 3H).

[00612] Example 40

[00613] 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(4-fluorophenyl)-3,4-di -hydropyrido[4,3-d]pyrimidin-2(1H)-one

[00614] This compound was prepared using procedures analogous to those for example 29, step 2 (condition A) and step 3, 4-fluoroaniline replacing cyclopropylmethylamine in step 2. LCMS calculated for C26H23F3N5O3 [M+H]+ m/z: 510.2; Found: 510.1. 1H NMR (600 MHz, DMSO) δ 8.43 (s, 1H), 8.04 (s, 1H), 7.55 - 7.49 (m, 2H), 7.46 - 7.40 (m, 2H), 7.09 (t, J = 8.1 Hz, 1H), 6.28 (s, 1H), 4.99 (s, 2H), 3.91 (s, 6H), 3.77 ( s, 3H), 2.11 (s, 3H).

[00615] Example 41

[00616] 1-(1,3-benzothiazol-6-yl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl) -3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00617] This compound was prepared using procedures analogous to those for example 29, step 2 (condition B) and step 3, with 1,3-benzothiazol-6-amine replacing cyclopropylmethylamine in step 2. LCMS calculated for C27H23F2N6O3 [M+H]+ m/z: 549.1; Found: 549.1.

[00618] Example 42

[00619] 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1-methyl-5-oxopyrrolidin-3- yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00620] This compound was prepared using procedures analogous to those for example 29, step 2 (condition B) and step 3, with 4-amino-1-methylpyrrolidin-2-one replacing cyclopropylmethylamine in step 2. LCMS calculated for C25H27F2N6O4 [M+H]+ m/z: 513.2; Found: 513.2.

[00621] Example 43

[00622] 1-(1-acetylpiperidin-4-yl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-3 ,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00623] Step 1: 4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3,4 tert-Butyl-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)piperidine-1-carboxylate

[00624] This compound was prepared using procedures analogous to those for example 29, step 2 (condition B) and step 3, with 4-amino-1-methylpyrrolidin-2-one replacing cyclopropylmethylamine in step 2. LCMS calculated for C30H37F2N6O5 [M+H]+ m/z: 599.3; Found: 599.2.

[00625] Step 2: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(piperidin-4-yl)- 3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00626] To the crude residue from step 1 was added methanol (1 mL) and 4.0 M HCl in 1,4-dioxane (1 mL). The reaction mixture was stirred at room temperature for 1 hour and then concentrated. The crude product was purified on prep-HPLC (pH=2, acetonitrile / water + TFA) to obtain the desired product (24 mg) as its bis-TFA salt. LCMS calculated for C25H29F2N6O3 [M+H]+ m/z: 499.2; Found: 499.2.

[00627] Step 3: 1-(1-acetylpiperidin-4-yl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl )-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00628] The product of step 2 (9.8 mg, 0.0135 mmol) was dissolved in methylene chloride (200 μL) and pyridine (5.5 μL, 0.0675 mmol) was added, followed by acetyl chloride (2.9 µL, 0.0405 mmol). The mixture was stirred at room temperature overnight, then purified by preparative HPLC (pH=2, acetonitrile/water + TFA) to obtain the desired product (5 mg) as its TFA salt. LCMS calculated for C27H31F2N6O4 [M+H]+ m/z: 541.2; Found: 541.2.

[00629] Example 44:

[00630] 4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3,4-di- hydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzonitrile;

[00631] This compound was prepared using procedures analogous to those for example 29, step 2 (condition A) and step 3, with 4-aminobenzonitrile replacing cyclopropylmethylamine in step 2. LCMS calculated for C27H23F2N6O3 [M+ H]+ m/z: 517.2; Found: 517.1. 1H NMR (600 MHz, DMSO) δ 8.45 (s, 1H), 8.09 (d, J = 4.7 Hz, 2H), 8.03 (s, 1H), 7.72 (d, J = 4.7 Hz, 2H), 7.10 (t, J = 8.2 Hz, 1H), 6.29 (s, 1H), 5.00 (s, 2H), 3.91 (s, 6H ), 3.77 (s, 3H), 2.14 (s, 3H).

[00632] Example 45

[00633] 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-pyrimidin-4-yl-3,4-di -hydropyrido[4,3-d]pyrimidin-2(1H)-one

[00634] This compound was prepared using procedures analogous to those for example 29, step 2 (condition A) and step 3, with 5-aminopyrimidine replacing cyclopropylmethylamine in step 2. LCMS calculated for C24H22F2N7O3 [M+H] + m/z: 494.2; Found: 494.1. 1H NMR (600 MHz, DMSO) δ 9.32 (d, J = 0.9 Hz, 1H), 9.09 (d, J = 5.4 Hz, 1H), 8.46 (s, 1H), 8.07 (s, 1H), 7.85 (dd, J = 5.3, 1.3 Hz, 1H), 7.10 (t, J = 8.2 Hz, 1H), 6.70 (s , 1H), 4.98 (s, 2H), 3.91 (s, 6H), 3.76 (s, 3H), 2.24 (s, 3H).

[00635] Example 46

[00636] 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-[(5-methyl-1,3,4 -oxadiazol-2-yl)methyl]-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00637] This compound was prepared using procedures analogous to those for example 29, step 2 (condition B) and step 3, with 1-(5-methyl-1,3,4-oxadiazol-2-yl) methanamine substituting cyclopropylmethylamine in step 2 LCMS calculated for C24H24F2N7O4 [M+H]+ m/z: 512.2; Found: 512.2. 1H NMR (600 MHz, DMSO) δ 8.40 (s, 1H), 8.19 (s, 1H), 7.38 (s, 1H), 7.10 (t, J = 8.1 Hz, 1H ), 5.45 (s, 2H), 4.89 (s, 2H), 3.90 (s, 6H), 3.83 (s, 3H), 2.48 (s, 3H), 2.36 (s, 3H).

[00638] Example 47

[00639] 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1-methyl-1H-pyrazol-4- yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00640] This compound was prepared using procedures analogous to those for example 29, step 2 (condition B) and step 3, with 1-methyl-1H-pyrazol-4-amine replacing cyclopropylmethylamine in step 2. Calculated LCMS for C24H24F2N7O3 [M+H]+ m/z: 496.2; Found: 496.2. 1H NMR (600 MHz, DMSO) δ 8.46 (s, 1H), 8.14 (s, 1H), 8.03 (s, 1H), 7.61 (d, J = 0.7 Hz, 1H ), 7.10 (t, J = 8.1 Hz, 1H), 6.70 (s, 1H), 4.97 (s, 2H), 3.92 (s, 3H), 3.92 (s , 6H), 3.81 (s, 3H), 2.22 (s, 3H).

[00641] Example 48

[00642] 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-[(1,5-dimethyl-1H-pyrazole) -4-yl)methyl]-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00643] This compound was prepared using procedures similar to those for example 29, step 2 (condition B) and step 3, with 1-(1,5-dimethyl-1H-pyrazol-4-yl) methanamine replacing the cyclopropylmethylamine in step 2. LCMS calculated for C26H28F2N7O3 [M+H]+ m/z: 524.2; Found: 524.2. 1H NMR (600 MHz, DMSO) δ 8.37 (s, 1H), 8.23 (s, 1H), 7.28 (s, 1H), 7.26 (s, 1H), 7.10 (t , J = 8.2 Hz, 1H), 5.08 (s, 2H), 4.86 (s, 2H), 3.92 (s, 6H), 3.85 (s, 3H), 3.68 (s, 3H), 2.28 (s, 3H), 2.25 (s, 3H).

[00644] Example 49

[00645] 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-3,4 -dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00646] Step 1: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[ 4,3-d]pyrimidin-2(1H)-one

[00647] This compound was prepared using procedures analogous to those for example 22, step 2, with 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-pyrazole replacing phenylboronic acid. LCMS calculated for C21H21F2N5o3 [M+H]+ m/z: 430.2; Found: 430.2.

[00648] Step 2: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)- 3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00649] A mixture of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1H-pyrazol-4-yl)-3, 4-dihydropyrido [ 4.3-D]pyrimidin-2(1H)-one (170.0 mg, 0.3959 mmol), cesium carbonate (520.0 mg, 1.6 mmol), and 2-(4-morpholine)ethyl hydrochloride bromide (164.0 mg, 0.712 mmol) in acetonitrile (5.0 mL) was stirred and heated at 90°C for 12 hours. The resulting mixture was then cooled to room temperature, diluted with water and extracted with EtOAc (3 x 15 mL). The combined organic layers were dried over Na2SO4, and concentrated. The resulting material was purified by preparative LC/MS at pH 2 (MeCN/TFA water) to provide the product as a white solid (TFA salt). LC/MS calculated for C27H33F2N6O4 [M+H]+m/z: 543.2; found 543.2. 1H NMR (500 MHz, dmso) δ 8.42 (s, 1H), 8.36 (s, 1H), 7.23 (s, 1H), 7.07 (t, J = 8.2 Hz, 1H ), 4.80 (s, 2H), 4.55 (t, J = 6.6 Hz, 2H), 3.99 (q, J = 7.0 Hz, 2H), 3.89 (s, 6H ), 3.64 (t, J = 6.6 Hz, 2H), 2.47 (s, 3H), 1.22 (t, J = 7.0 Hz, 3H). Note: The signals for the 8 protons in morpholine were very broad and hidden at baseline.

[00650] Example 50

[00651] 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)-3 ,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00652] Step 1: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[ 4,3-d]pyrimidin-2(1H)-one

[00653] This compound was prepared using procedures analogous to those for example 22, step 2, with 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-pyrazole replacing phenylboronic acid. LCMS calculated for C21H22F2N5O3 [M+H]+ m/z: 430.2; Found: 430.2.

[00654] Step 2: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl )-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00655] A mixture of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1H-pyrazol-4-yl)-3, 4-dihydropyrido[ 4,3-D]pyrimidin-2(1H)-one (20.0 mg, 0.0466 mmol), cesium carbonate (61.3 mg, 0.1883 mmol), and 3-(bromomethyl)pyridine hydrobromide (21.2 mg, 0.0838 mmol) in acetonitrile (0.6 mL) was stirred and heated at 90°C for 12 hours. The resulting mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3 x 2 mL). The combined organic layers were dried over Na2SO4, and concentrated. The resulting material was purified by preparative LC/MS at pH 2 (MeCN/TFA water) to provide the product as a white solid (TFA salt). LC/MS calculated for C27H26F2N6O3 [M+H]+m/z: 521.2; found 521.2.

[00656] Example 51

[00657] 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1-(2-morpholino-2-oxoethyl)-1H-pyrazol-4-yl) -3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00658] Step 1: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[ 4,3-d]pyrimidin-2(1H)-one

[00659] This compound was prepared using procedures analogous to those for example 22, step 2, with 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-pyrazole replacing phenylboronic acid. LCMS calculated for C21H22F2N5O3 [M+H]+ m/z: 430.2; Found: 430.2.

[00660] Step 2: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1-(2-morpholino-2-oxoethyl)-1H-pyrazole-4 -yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00661] A mixture of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1H-pyrazol-4-yl)-3, 4-dihydropyrido [ 4,3-D]pyrimidin-2-one (1H) (20.0 mg, 0.0466 mmol), cesium carbonate (61.3 mg, 0.1883 mmol), and 2-chloro-1-morpholinoethanone (13, 7 mg, 0.0838 mmol) in acetonitrile (0.6 mL) was stirred and heated at 90 °C for 12 hours. The resulting mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3 x 2 mL). The combined organic layers were dried over Na2SO4, and concentrated. The resulting material was purified by preparative LC/MS at pH 2 (MeCN/TFA water) to provide the product as a white solid (TFA salt). LC/MS calculated for C27H31F2N6O5 [M+H]+m/z: 557.2; found 557.2.

[00662] Example 52

[00663] 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(3-methyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1'H-spiro [cyclopropane-1,4'-[2,7]naphthyridin]-3'(2'H)-one

[00664] Step 1: 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(3-methyl-1H-pyrazol-4-yl)-1'H-spiro[cyclopropane-1, 4'-[2,7]naphthyridin]-3'(2'H)-one

[00665] This compound was prepared using procedures analogous to those for example 1, step 7, with 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-pyrazole replacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated for C22H21F2N4O3 [M+H]+ m/z: 427.1; Found: 427.1.

[00666] Step 2: 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(3-methyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1' H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-3'(2'H)-one

[00667] A mixture of 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(3-methyl-1H-pyrazol-4-yl)-1'H-spiro[cyclopropane-1, 4'-[2,7]naphthyridin]-3'(2'H)-one (17.0 mg, 0.0399 mmol), cesium carbonate (40.0 mg, 0.1 mmol), and sodium hydrochloride 2-(4-morpholine)ethyl bromide (23.0 mg, 0.1 mmol) in acetonitrile (0.5 mL) was stirred and heated at a temperature of 90°C for 12 hours. The resulting mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3 x 2 mL). The combined organic layers were dried over Na2SO4, and concentrated. The resulting material was purified by preparative LC/MS at pH 2 (MeCN/TFA water) to provide the product as a white solid (TFA salt). LC/MS calculated for C28H31F2N5O4 [M+H]+m/z: 540.2; found 540.2. 1H NMR (400 MHz, DMSO) δ 8.41 (s, 1H), 8.36 (s, 1H), 7.14 - 6.98 (m, 2H), 4.94 (s, 2H), 4 .49 (t, J = 6.4 Hz, 2H), 3.89 (s, 6H), 3.73 - 3.49 (m, 2H), 2.45 (s, 3H), 1.86 - 1.64 (m, 2H), 1.56 (q, J = 3.9 Hz, 2H).

[00668] Example 53

[00669] 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(1-ethyl-1H-imidazol-4-yl)-1'H-spiro[cyclopropane-1,4'- [2,7]naphthyridin]-3'(2'H)-one

[00670] This compound was prepared using procedures analogous to those for example 1, step 7, with 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-imidazole replacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated for C23H23F2N4O3 [M+H]+ m/z: 441.2; Found: 441.2.

[00671] Example 54

[00672] 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-[1-(1,1-dioxidotetrahydro-3-thienyl)-3-methyl-1H-pyrazole-4- yl]-1',2'-dihydro-3'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-3'-one

[00673] Step 1: 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(3-methyl-1H-pyrazol-4-yl)-1'H-spiro[cyclopropane-1, 4'-[2,7]naphthyridin]-3'(2'H)-one

[00674] This compound was prepared using procedures analogous to those for example 1, step 7, with 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-pyrazole replacing (5-amino-2-methylphenyl)boronic acid. LCMS calculated for C22H21F2N4O3 [M+H]+ m/z: 427.1; Found: 427.1.

[00675] Step 2: 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-[1-(1,1-dioxidotetrahydro-3-thienyl)-3-methyl-1H-pyrazole -4-yl]-1',2'-dihydro-3'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-3'-one

[00676] A mixture of 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(3-methyl-1H-pyrazol-4-yl)-1'H-spiro[cyclopropane-1, 4'-[2,7]naphthyridin]-3'(2'H)-one (20.0 mg, 0.0469 mmol), cesium carbonate (40.0 mg, 0.1 mmol), and 1, 3-Bromotetrahydrothiophene 1-dioxide (23.0 mg, 0.12 mmol) in acetonitrile (0.6 mL) was stirred and heated at 90°C for 12 h. The resulting mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3 x 2 mL). The combined organic layers were dried over Na2SO4, and concentrated. The resulting material was purified by preparative LC/MS at pH 2 (MeCN/TFA water) to provide the product as a white solid (TFA salt). LC/MS calculated for C26H27F2N4O5 [M+H]+m/z: 545.2; found 545.2.

[00677] Example 55

[00678] 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(1-(1-(methylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-3'(2'H)-one

[00679] Step 1: tert 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl) azetidine-1-carboxylate -butyl

[00680] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (19.4 mg, 0.10 mmol), cesium carbonate (49.0 mg, 0.15 mmol), and tert-butyl 3-iodoazetidine-1-carboxylate (31.0 mg, 0.11 mmol) in acetonitrile (0.5 mL) was stirred and heated to a temperature 90°C for 12 hours. The resulting mixture was cooled to room temperature, and the reaction was quenched with saturated aqueous NH 4 Cl, and extracted with DCM (3 x 2 mL). The organic layers were combined, dried over Na2SO4 and concentrated. The crude product was used directly in the next step without further purification.

[00681] Step 2: 3-(4-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro-1'H-spiro[ tert-butyl cyclopropane-1,4'-[2,7]naphthyridine]-6'-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate

[00682] This compound was prepared using procedures analogous to those for example 1, step 7, with 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl tert-butyl )-1H-pyrazol-1-yl)azetidine-1-carboxylate replacing (5-amino-2-methylphenyl)boronic acid. The crude product was used directly in the next step without further purification.

[00683] Step 3: 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(1-(1-(methylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl) -1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-3'(2'H)-one

[00684] 3-(4-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro-1'H-spiro [cyclopropane-1 tert-butyl ,4'-[2.7]naphthyridine]-6'-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate was dissolved in a solution of hydrogen chloride, 4.0 M in dioxane (1 ml), and the resulting mixture was stirred at room temperature for 1 hour. The crude reaction mixture was concentrated, then dissolved in DCM (0.6 mL). After cooling to 0°C, triethylamine (0.023 mL, 0.16 mmol) and methanesulfonyl chloride (0.010 mL, 0.129 mmol) were slowly added into the reaction mixture. The resulting solution was stirred at room temperature for 1 hour. The reaction was quenched with aqueous NaHCO 3 (2 mL) and extracted with EtOAc (3 x 2 mL). The combined organic layers were dried over Na2SO4, and concentrated. The resulting material was purified by preparative LC/MS at pH 2 (MeCN/TFA water) to provide the product as a white solid (TFA salt). LC/MS calculated for C25H26F2N4O5 [M+H]+m/z: 545.2; found 545.2.

[00685] Example 56

[00686] 2-(1-acetyl-3-(4-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-6'-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile

[00687] Step 1: 3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl) azetidine tert-butyl-1-carboxylate

[00688] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (19.4 mg, 0.10 mmol), 1.8 -diazabicyclo[5.4.0]undec-7-ene (0.0313 mL, 0.209 mmol), and tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (19.4 mg, 0.10 mmol) in acetonitrile (0.5 ml) was stirred at room temperature for 12 hours. The resulting mixture was quenched with saturated aqueous NaHCO 4 and extracted with dichloromethylene (3x 2 mL). The organic layers were combined, dried over Na2SO4 and concentrated. The crude product was used directly in the next step without further purification.

[00689] Step 2: 3-(cyanomethyl)-3-(4-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro- tert-Butyl 1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-6'-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate

[00690] This compound was prepared using procedures analogous to those for example 1, step 7, with 3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2 tert-butyl-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate replacing (5-amino-2-methylphenyl)boronic acid. The crude product was used directly in the next step without further purification.

[00691] Step 3: 2-(1-acetyl-3-(4-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro -1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-6'-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile

[00692] 3-(cyanomethyl)-3-(4-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro-1'H tert-butyl spiro [cyclopropane-1,4'-[2,7]naphthyridine]-6'-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate was dissolved in hydrogen chloride solution, 4, 0 M in dioxane (1 ml), and the resulting mixture was stirred at room temperature for 1 hour. The crude reaction mixture was concentrated, then dissolved in DCM (0.6 mL). After cooling to 0°C, triethylamine (0.015 mL, 0.11 mmol) and acetyl chloride (0.010 mL, 0.140 mmol) were slowly added into the reaction mixture. The resulting solution was stirred at room temperature for 1 hour. The reaction was quenched with aqueous NaHCO 3 (2 mL) and extracted with EtOAc (3 x 2 mL). The combined organic layers were dried over Na2SO4, and concentrated. The resulting material was purified by preparative LC/MS at pH 2 (MeCN/TFA water) to provide the product as a white solid (TFA salt). LC/MS calculated for C28H27F2N6O4 [M+H]+m/z: 549.2; found 549.2.

[00693] Table 5. The compounds in Table 5 were prepared analogously to example 29 using the appropriate amine building block and using method A or B as noted in step 2 below. Table 5.

[00694] Example 122

[00695] 4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3,4-di- methyl hydropyrido[4,3-d]pyrimidin-1(2H)-yl)piperidine-1-carboxylate

[00696] Step 1. Preparation of 4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3 tert-Butyl ,4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)piperidine-1-carboxylate

[00697] This compound was prepared using procedures analogous to those for example 29, step 2 (condition B) and step 3, with tert-butyl 4-aminopiperidine-1-carboxylate replacing 4-aminomethyl pyridine in step 2 LCMS calculated for C30H37F2N6O5 [M+H]+ m/z: 599.1; Found: 599.1.

[00698] Step 2: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(piperidin-4-yl)- 3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00699] To the crude residue from step 1 above was added methanol (1 mL) and 4.0 M HCl and 1,4-dioxane (1 mL) and the reaction mixture was stirred at room temperature for 1 h, then concentrated. The crude product was purified on prep-HPLC (pH=2, acetonitrile / water + TFA) to obtain the desired product (24 mg) as its bis-TFA salt. LCMS calculated for C25H29F2N6O3 [M+H]+ m/z: 499.2; Found: 499.1.

[00700] Step 3. Preparation of 4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3 Methyl ,4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)piperidine-1-carboxylate

[00701] To a solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-piperidin-4-yl-3 ,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (7.00 mg, 0.0140 mmol) in tetrahydrofuran (500 µL) was added N,N-diisopropylethylamine (9 .78 µL, 0.0562 mmol) and methyl chloroformate (1.63 µL, 0.0211 mmol). The reaction mixture was stirred overnight and then diluted with methanol and purified directly by reverse phase HPLC (pH=2, acetonitrile/water + TFA) to provide the desired product as the corresponding TFA salt. LCMS calculated for C27H31F2N6O5 [M+H]+ m/z: 557.2, found 557.2.

[00702] Example 123

[00703] -(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3,4-dihydropyrido methyl [4,3-d]pyrimidin-1(2H)-yl)phenylcarbamate;

[00704] Step 1: 4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3,4 tert-butyl-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenylcarbamate

[00705] This compound was prepared using procedures analogous to those for example 29, step 2 (condition B) and step 3, with tert-butyl 4-aminophenylcarbamate replacing 4-aminomethyl pyridine in step 2. LCMS calculated for C31H33F2N6O5 [M+H]+ m/z: 607.2; Found: 607.2

[00706] Step 2. Preparation of 1-(4-aminophenyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)- 3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00707] To the crude residue from step 1 above was added methanol (1 mL) and 4.0 M HCl and 1,4-dioxane (1 mL) and the reaction mixture was stirred at room temperature for 1 h, then concentrated. The crude product was purified by column chromatography (0-10% methanol in dichloromethane). LCMS calculated for C26H25F2N6O3 [M+H]+ m/z: 507.2; Found: 507.2.

[00708] Step 3. Preparation of 4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3 Methyl ,4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenylcarbamate

[00709] To a solution of 1-(4-aminophenyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1, 3-dimethyl-1H-pyrazol-4-yl)-3 ,4-Dihydropyrido[4,3-D]pyrimidin-2-(1H)-one (7.00 mg, 0.0140 mmol) in tetrahydrofuran (500 µL) was added N,N-diisopropylethylamine ( 9.78 µL, 0.0562 mmol) and methyl chloroformate (1.63 µL, 0.0211 mmol). The reaction mixture was stirred overnight and then diluted with methanol and purified directly by reverse phase HPLC (pH=2, acetonitrile/water + TFA) to provide the desired product as the corresponding TFA salt. LC/MS calculated for C28H27F2N6O5 [M+H]+ m/z: 565.2, found 565.2.

[00710] Example 124

[00711] 1-((1-cyclopropyl-1H-pyrazol-4-yl)methyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazole -4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00712] Step 1. Preparation of (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methanamine

[00713] To a solution of ethyl 1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxylate (500 mg, 2 mmol) in tetrahydrofuran (2 mL) was added tetrahydrofuran 2.0M lithium hydroaluminate in tetrahydrofuran (1.11 mL, 2.22 mmol) and the mixture was stirred at room temperature for 2 h, then quenched by adding 20 µL of water, 20 µL of a 15% aqueous NaOH solution, then an additional 60 µL of water. After stirring for an additional 1 hour, the reaction mixture was filtered through a pad of celite and concentrated.

[00714] To the above residue in methylene chloride (10 mL) was added triethylamine (644 μL, 4.62 mmol) and the mixture cooled to 0°C. Methanesulfonyl chloride (143 µL, 1.85 mmol) was added dropwise and the mixture was stirred at room temperature for 30 min, then cooled again to 0 degrees and quenched by carefully adding 2 mL of water. The mixture was washed with brine and the aqueous layer extracted with more methylene chloride. The combined organic layers were dried over sodium sulfate and concentrated.

[00715] The residue was dissolved in N,N-dimethylformamide (10 mL) and sodium azide (180 mg, 2.77 mmol) was added. The mixture was stirred overnight at room temperature, then quenched to 0° by adding 1.5 mL of water. The mixture was diluted with diethyl ether and the layers separated. The organic layer was then washed with water and brine, then dried over sodium sulfate and concentrated.

[00716] The residue was dissolved in 1,4-dioxane (1.5 mL) and resin-bound triphenylphosphine (924 mg, 2.77 mmol) was added. The mixture was stirred for 1 hour, then a 4:1 mixture of dioxane: water (1.5 mL total) was added and the mixture was stirred at room temperature overnight. The resin was filtered off and the filtrate was concentrated to yield the desired compound, which was used without further purification in the next step. LC-MS calculated for C10H22N3OSi [M+H]+ m/z: 228.2, found 228.2.

[00717] Step 2. Preparation of 1-((1H-pyrazol-4-yl)methyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H- pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00718] To a mixture of N-{[4-chloro-6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl]methyl}-2,6-difluoro-3,5 -dimethoxyaniline (50 mg, 0.1 mmol), 1-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)methanamine (41.7 mg, 0.183 mmol), (2 '-aminobiphenyl-2-yl)(chloro)[cyclohexyl(2',6'-diisopropoxybiphenyl-2-yl)phosphoranyl]palladium (9.5 mg, 0.012 mmol) and cesium carbonate (120 mg, 0.367 mmol) ) tert-butyl alcohol (2 mL) was added and the reaction vessel was evacuated and backfilled with nitrogen three times. The mixture was then stirred at 100°C overnight, at which point the LCMS showed complete conversion. The reaction mixture was diluted with dichloromethane and filtered through a celite pad. The filtrate was concentrated.

[00719] The residue was dissolved in tetrahydrofuran (2.2 mL) and triethylamine (68.2 μL, 0.489 mmol) was added. After cooling to 0 °C, triphosgene (36.3 mg, 0.122 mmol) was added in one portion and the reaction mixture was allowed to stir at room temperature for 1 h, then quenched by the addition of NaOH. 1N and stirred for an additional 1 hour. The mixture was then extracted with ethyl acetate and the organic layer was dried over sodium sulfate and concentrated.

[00720] The residue was dissolved in trifluoroacetic acid (1.0 ml) and stirred at room temperature for 1 h. LCMS analysis showed complete conversion to the desired product. The mixture was concentrated, then purified by column chromatography (50-100% ethyl acetate in hexanes) to provide the desired product as a brown powder. LC/MS calculated for C24H24F2N7O3 [M+H]+ m/z: 496.2, found 496.2.

[00721] Step 3. Preparation of 1-((1-cyclopropyl-1H-pyrazol-4-yl)methyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3- dimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00722] A mixture of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1 (1H-pyrazol-4-ylmethyl) -3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (10 mg, 0.02 mmol), cyclopropylboronic acid (6.93 mg, 0.0807 mmol), sodium carbonate (8.56 mg, 0.0807 mmol), copper(II) diacetate (7.33 mg, 0.0404 mmol) and 2,2'-bipyridine (6.30 mg, 0.0404 mmol) was dissolved in 1,2-dichloroethane (200 µL) and the mixture was heated at 95°C overnight. The mixture was diluted with methanol and purified directly by reverse phase HPLC (pH=2, acetonitrile/water + TFA) to provide the desired product as a white solid. LC/MS calculated for C27H28F2N7O3 [M+H]+ m/z: 536.2, found 536.2.

[00723] Example 125

[00724] 2-(4-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3, 4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)methyl)-1H-pyrazol-1-yl)acetonitrile

[00725] To a solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1H-pyrazol-4- ylmethyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (Example 124, step 2; 17 mg, 0.034 mmol) in N,N-dimethylformamide (500 µL) at 0°C °C sodium hydride (4.12 mg, 0.172 mmol) was added and the mixture was stirred at 0 °C for 10 minutes. Bromoacetonitrile (23.9 µL, 0.343 mmol) was then added and the reaction mixture stirred for 1 h at room temperature. The reaction mixture was then diluted with methanol and purified directly by reverse phase HPLC (pH=2, acetonitrile/water + TFA) to provide the desired product as the corresponding TFA salt. LC/MS calculated for C26H25F2N8O3 [M+H]+ m/z: 535.2, found 535.2.

[00726] Example 126

[00727] 1-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H -pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00728] This compound was prepared using procedures analogous to those for example 125, with cyclopropylmethyl bromide replacing bromoacetonitrile. LCMS calculated for C28H30F2N7O3 [M+H]+ m/z: 550.2; Found: 550.2.

[00729] Example 127

[00730] 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-((1-((tetrahydrofuran-2 -yl)methyl)-1H-pyrazol-4-yl)methyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00731] This compound was prepared using procedures analogous to those for example 125, with 2-(bromomethyl)tetrahydrofuran replacing bromoacetonitrile. LCMS calculated for C29H32F2N7O4 [M+H]+ m/z: 580.2; Found: 580.2.

[00732] Example 128

[00733] 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)methyl)-7-(1,3 -dimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00734] This compound was prepared using procedures analogous to those for example 125, with 2-bromo-1,1-difluoroethane replacing bromoacetonitrile. LCMS calculated for C26H26F4N7O3 [M+H]+ m/z: 560.2; Found: 560.2.

[00735] Example 129

[00736] 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1H-pyrazol-4-yl)-3 ,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00737] Step 1. Preparation of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-amine

[00738] To a 0 degree 4 solution of 4-nitro-1H-pyrazole (250 mg, 2.2 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (60% by weight in mineral oil, 63.7 mg, 2.65 mmol) and the reaction mixture was stirred for 10 minutes at this temperature. [β-(Trimethylsilyl)ethoxy]methyl chloride (430 µL, 2.43 mmol) was then added dropwise and the reaction mixture was stirred for a further 1 h at room temperature. The reaction mixture was quenched with brine and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by column chromatography (10-80% ethyl acetate in hexanes) to provide the protected nitropyrazole intermediate.

[00739] The residue was dissolved in ethyl acetate (2.5 mL) and 10% palladium on carbon (240 mg, 0.11 mmol) was added. The reaction vessel was evacuated and filled with hydrogen gas (0.1 MPa (1 atm)) and the reaction mixture was stirred for 2 h at room temperature. The mixture was filtered through a pad of celite and concentrated. The residue was used without further purification in the next step. LCMS calculated for C9H20N3OSi [M+H]+ m/z: 214.1; Found: 214.2.

[00740] Step 2. Preparation of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1H-pyrazol-4 -yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00741] To a mixture of N-{[4-chloro-6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl]methyl}-2,6-difluoro-3,5 -dimethoxyaniline (50 mg, 0.1 mmol), 1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-amine (39.1 mg, 0.183 mmol), RuPhos Pd G2 (9.5 mg, 0.012 mmol) and cesium carbonate (120 mg, 0.367 mmol) tert-butyl alcohol (2 mL) was added and the reaction vessel was evacuated and backfilled three times with nitrogen. The mixture was stirred at 100 degrees overnight. The reaction mixture was diluted with dichloromethane and filtered through a celite pad. The filtrate was concentrated.

[00742] The residue was dissolved in tetrahydrofuran (2.2 mL) and triethylamine (68.2 μL, 0.489 mmol) was added. After cooling to 0 °C, triphosgene (36.3 mg, 0.122 mmol) was added in one portion and the reaction mixture was allowed to stir at room temperature for 1 h, then quenched by the addition of NaOH. 1N and stirred for an additional 1 hour. The mixture was then extracted with ethyl acetate and the organic layer was dried over sodium sulfate and concentrated. The residue was purified by column chromatography (0-15% methanol in dichloromethane) to provide the desired product as a light brown solid. This solid was further purified by reverse phase HPLC (pH=2, acetonitrile/water + TFA) to provide the desired product as the corresponding TFA salt. LCMS calculated for C23H22F2N7O3 [M+H]+ m/z: 482.2; Found: 482.2.

[00743] Example 130

[00744] 1-(1-cyclopropyl-1H-pyrazol-4-yl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4- yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one;

[00745] This compound was prepared using procedures analogous to those for Example 124, step 3 with the product of Example 129 serving as the starting material. LCMS calculated for C26H26F2N7O3 [M+H]+ m/z: 522.2; Found: 522.2.

[00746] Example 131

[00747] 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1-ethyl-1H-pyrazol-4- yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00748] This compound was prepared using procedures analogous to those for example 125 with 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazole-4- yl)-1-(1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-D]pyrimidin-2(1H)-one (Example 129) replacing 3-(2,6-difluoro -3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1H-pyrazol-4-ylmethyl)-3,4-dihydropyrido[4,3- d] pyrimidin-2(1H)-one and ethyl iodide replacing bromoacetonitrile. LCMS calculated for C25H26F2N7O3 [M+H]+ m/z: 510.2; Found: 510.2.

[00749] Example 132

[00750] 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1-propyl-1H-pyrazol-4- yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00751] This compound was prepared using procedures analogous to those for example 131, with propyl iodide replacing ethyl iodide. LCMS calculated for C26H28F2N7O3 [M+H]+ m/z: 524.2; Found: 524.2.

[00752] Example 133

[00753] 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1H-indazol-6-yl)-3 ,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00754] Step 1. Preparation of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-amine.

[00755] To a solution of 5-nitroindazole (250 mg, 1.5 mmol) in tetrahydrofuran (10 mL) at 0 °C was added sodium hydride (60% suspension in mineral oil, 67 mg, 1.7 mmol) and the mixture was stirred for 10 minutes at 0°C. [β-(Trimethylsilyl)ethoxy]methyl chloride (320 µL, 1.8 mmol) was then added dropwise and the reaction mixture warmed to room temperature and stirred for 1 h, at which point LCMS confirmed conversion complete. The reaction mixture was quenched with water and diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted with additional ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The above residue was purified by column (0-35% ethyl acetate in hexanes) to provide the desired intermediate.

[00756] The above residue was dissolved in ethyl acetate (10 mL) and 10% palladium on carbon (0.16 g, 0.15 mmol) was added. The reaction was then placed under hydrogen balloon pressure and stirred overnight and then filtered and concentrated to provide the desired product, which was purified by column chromatography (0-20% methanol in dichloromethane). LCMS calculated for C13H22N3OSi [M+H]+ m/z: 264.2; Found: 264.2.

[00757] Step 2. Preparation of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1H-indazol-6 -yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00758] This compound was prepared using procedures analogous to those for example 29, step 2 (condition B) and step 3, with the product of step 1 replacing cyclopropylmethylamine in step 2. LCMS calculated for C27H24F2N7O3 [M+H ]+ m/z: 532.2; Found: 532.2.

[00759] Example 134

[00760] 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1H-indazol-5-yl)-3 ,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00761] This compound was prepared using procedures analogous to those for example 133 4-nitroimidazole replacing 5-nitroimidazole. LCMS calculated for C27H24F2N7O3 [M+H]+ m/z: 532.2; Found: 532.2.

[00762] Example 135

[00763] 1-(5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-(pyrimidin-4-yl)-1,2,3,4-tetrahydropyrido [4,3-d]pyrimidin-7-yl)pyridin-2-yl)cyclobutanecarbonitrile

[00764] Step 1. Preparation of 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)cyclobutanecarbonitrile.

[00765] A mixture of 1-(6-bromopyridin-3-yl)cyclobutanecarbonitrile (500 mg, 2 mmol), 4,4,5,5,4',4',5',5'-octamethyl-[2 ,2']bi[[1,3,2]dioxaborolanil] (802 mg, 3.16 mmol), potassium acetate (621 mg, 6.33 mmol), and [1,1'-bis(diphenylphosphino)ferrocene ] dichloropalladium(II) (92 mg, 0.13 mmol) in 1,4-dioxane (8 mL) was first purged with nitrogen gas and then stirred overnight at 90°C. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, filtered through a celite pad, and concentrated. The crude material was then purified by column chromatography (0% to 30% EtOAc in hexanes) to provide the product as a yellow solid. LC-MS calculated for C10H12BN2O2 [M+H for boronic acid]+ m/z: 203.1; Found: 203.1.

[00766] Step 2. Preparation of 1-(4-chloro-5-((2,6-difluoro-3,5-dimethoxyphenylamino)methyl)-2,3'-bipyridin-6'-yl)cyclobutanecarbonitrile.

[00767] A mixture of N-[(4,6-dichloropyridin-3-yl)methyl]-2,6-difluoro-3,5-dimethoxyaniline (400 mg, 1 mmol), 1-[5-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]cyclobutanecarbonitrile (330 mg, 1.2 mmol), tetracis(triphenylphosphine)palladium(0) (120 mg, 0 .10 mmol) and potassium carbonate (580 mg, 4.2 mmol) was dissolved in a mixture of 1,4-dioxane (5 mL) and water (1 mL). the reaction flask was unloaded and refilled with nitrogen and then heated to 120 degrees for 2 h, at which point LCMS showed almost complete conversion. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by column chromatography (0-30% ethyl acetate in hexanes) to provide the desired product as a pale yellow solid. LCMS calculated for C24H22ClF2N4O2 [M+H]+ m/z: 471.1; Found: 471.1.

[00768] Step 3. Preparation of 1-(5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-(pyrimidin-4-yl)-1,2,3, 4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)pyridin-2-yl)cyclobutanecarbonitrile

[00769] A mixture of 1-(4-chloro-5-{[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}-2,3'-bipyridin-6'-yl)cyclobutanecarbonitrile (30 0 mg, 0.0637 mmol), pyrimidin-4-amine (9.09 mg, 0.0956 mmol), RuPhos Pd G2 (4.9 mg, 0.0064 mmol) and cesium carbonate (62.3 mg , 0.191 mmol) was dissolved in tert-butyl alcohol (0.6 mL) and the reaction flask was drained and refilled with nitrogen three times. The reaction was then stirred at 95 degrees overnight. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate and then diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted with additional ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated.

[00770] The residue was dissolved in tetrahydrofuran (0.75 mL) and triethylamine (25.8 mg, 0.255 mmol) was added. After cooling to 0°C, triphosgene (18.9 mg, 0.0637 mmol) was added and the mixture was stirred at room temperature for 1 h, then diluted with methanol and purified using reverse-phase HPLC (pH = 2 , acetonitrile/water +TFA) to provide the desired product as the corresponding TFA salt. LCMS calculated for C29H24F2N7O3 [M+H]+ m/z: 556.2; Found: 556.2.

[00771] Example 136

[00772] 1-(5-(1-cyclobutyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d ]pyrimidin-7-yl)pyridin-2-yl)cyclobutanecarbonitrile

[00773] This compound was prepared using procedures analogous to those for example 135, step 3 with cyclobutylamine replacing pyrimidin-4-amine. LCMS calculated for C29H28F2N5O3 [M+H]+ m/z: 532.2; Found: 532.2.

[00774] Example 137

[00775] 1-(5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-(pyridin-2-yl)-1,2,3,4-tetrahydropyrido [4,3-d]pyrimidin-7-yl)pyridin-2-yl)cyclobutanecarbonitrile

[00776] This compound was prepared using procedures analogous to those for example 135, step 3 with 2-aminopyridine replacing pyrimidin-4-amine. LCMS calculated for C30H25F2N6O3 [M+H]+ m/z: 555.2; Found: 555.2.

[00777] Example 138

[00778] 1-(5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-(pyridin-3-yl)-1,2,3,4-tetrahydropyrido [4,3-d]pyrimidin-7-yl)pyridin-2-yl)cyclobutanecarbonitrile

[00779] This compound was prepared using procedures analogous to those for example 135, step 3 with 3-aminopyridine replacing pyrimidin-4-amine. LCMS calculated for C30H25F2N6O3 [M+H]+ m/z: 555.2; Found: 555.2.

[00780] Example 139

[00781] 1-(5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-methoxyethyl)-2-oxo-1,2,3,4-tetrahydropyrido[4 ,3-d]pyrimidin-7-yl)pyridin-2-yl)cyclobutanecarbonitrile

[00782] This compound was prepared using procedures analogous to those for example 135, step 3 with 2-methoxyethylamine replacing pyrimidin-4-amine. LCMS calculated for C28H28F2N5O4 [M+H]+ m/z: 536.2; Found: 536.2.

[00783] Example 140

[00784] oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)pyridin-2-yl)cyclobutanecarbonitrile

[00785] This compound was prepared using procedures analogous to those for example 135, step 3 with cyclopropylmethylamine replacing pyrimidin-4-amine. LCMS calculated for C29H28F2N5O3 [M+H]+ m/z: 532.2; Found: 532.2.

[00786] Example 141

[00787] 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(1-methyl-1H-pyrazol-3-yl)-3,4-dihydropyrido[4,3 -d]pyrimidin-2(1H)-one

[00788] Step 1. Preparation of N-((4-chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-2,6-difluoro-3,5- dimethoxyaniline.

[00789] This compound was prepared using procedures analogous to those for example 135, step 2 with 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-1H-pyrazole replacing 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)cyclobutanecarbonitrile. LCMS calculated for C18H18ClF2N4O2 [M+H]+ m/z: 395.1; Found: 395.1.

[00790] Step 2. Preparation of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(1-methyl-1H-pyrazol-3-yl)-3,4-di- hydropyrido[4,3-d]pyrimidin-2(1H)-one

[00791] This compound was prepared using procedures analogous to those for example 135, step 3 with N-((4-chloro-6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl )methyl)-2,6-difluoro-3,5-dimethoxyaniline (step 1) replacing 1-(4-chloro-5-((2,6-difluoro-3,5-dimethoxyphenylamino)methyl)-2,3 '-bipyridin-6'-yl)cyclobutanecarbonitrile and ethylamine replacing pyrimidin-4-amine. LCMS calculated for C21H22F2N5O3 [M+H]+ m/z: 430.2; Found: 430.2.

[00792] Example 142

[00793] 4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1-methyl-1H-pyrazol-3-yl)-2-oxo-3,4-dihydropyrido[ 4,3-d]pyrimidin-1(2H)-yl)benzonitrile

[00794] This compound was prepared using procedures analogous to those for example 141, step 2 with 4-amino benzonitrile replacing ethylamine. LCMS calculated for C26H21F2N6O3 [M+H]+ m/z: 503.2; Found: 503.2.

[00795] Example 143

[00796] 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-((1-ethyl-1H-pyrazol-4-yl)methyl)-7-(1-methyl-1H-pyrazol-3 -yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00797] This compound was prepared using procedures analogous to those for example 141, step 2 with (1-ethyl-1H-pyrazol-4-yl)methanamine replacing ethylamine. LCMS calculated for C25H26F2N7O3 [M+H]+ m/z: 510.2; Found: 510.2.

[00798] Example 144

[00799] 4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1-methyl-1H-pyrazol-4-yl)-2-oxo-3,4-dihydropyrido[ 4,3-d]pyrimidin-1(2H)-yl)benzonitrile

[00800] Step 1. Preparation of N-((4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2,6-difluoro-3,5- dimethoxyaniline.

[00801] This compound was prepared using procedures analogous to those for example 135, step 2 with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-1H-pyrazole replacing 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)cyclobutanecarbonitrile. LCMS calculated for C18H18ClF2N4O2 [M+H]+ m/z: 395.1; Found: 395.1.

[00802] Step 2. Preparation of 4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1-methyl-1H-pyrazol-4-yl)-2-oxo-3,4 -dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzonitrile

[00803] This compound was prepared using procedures analogous to those for example 135, step 3 with 4-aminobenzonitrile replacing pyrimidin-4-amine. LCMS calculated for C26H21F2N6O3 [M+H]+ m/z: 503.2; Found: 503.2.

[00804] Example 145

[00805] 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-((1-ethyl-1H-pyrazol-4-yl)methyl)-7-(1-methyl-1H-pyrazol-4 -yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[00806] This compound was prepared using procedures analogous to those for example 144, step 2 with (1-ethyl-1H-pyrazol-4-yl)methanamine replacing 4-aminobenzonitrile. LCMS calculated for C25H26F2N7O3 [M+H]+ m/z: 510.2; Found: 510.2.

Tabela 7. Os compostos na tabela 7 foram preparados de acordo com os protocolos sintéticos descritos no esquema 4 e no exemplo 22, usando os materiais de partida adequados.

[00807] Table 6. The compounds in Table 6 were prepared according to the synthetic protocols described in Scheme 3 and Example 1, using the appropriate starting materials.

Table 7. The compounds in Table 7 were prepared according to the synthetic protocols described in Scheme 4 and Example 22, using the appropriate starting materials.

[00808] Example 171

[00809] 5-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridine]-6'-yl)-1H-pyrazole-4-carbonitrile

[00810] Step 1: 5-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1 ,4'-[2,7]naphthyridin]-6'-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbonitrile

[00811] 6'-chloro-2'-(2,6-difluoro-3,5-dimethoxyphenyl)-1',2'-dihydro-3'H-spiro[cyclopropane-1,4'-[2 ,7]naphthyridin]-3'-one (0.507 g, 1.33 mmol), 1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile (0.342 g, 1.53 mmol) , palladium acetate (29.9 mg, 0.133 mmol), trimethylacetic acid (34.0 mg, 0.333 mmol), potassium carbonate (0.552 g, 4.00 mmol), and di-1-adamantyl(butyl)phosphine (71 .6 mg, 0.200 mmol) were mixed in N,N-dimethylformamide (2.67 mL) and 1,4-dioxane (2.67 mL). The mixture was heated at 130 °C for 1.5 h. The crude product was diluted with DCM, and filtered through Celite. The filtrate was concentrated. The residue was purified by silica gel chromatography (35-60% EtOAc/Hex) to provide 760 mg of the desired coupling product (not 100% pure). Rf = 0.41 (50% EtOAc/Hex). LC/MS calculated for C28H32F2N5O4Si [M+H]+ m/z: 568.2; found: 568.2.

[00812] Step 2: 5-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1 ,4'-[2,7]naphthyridine]-6'-yl)-1H-pyrazole-4-carbonitrile

[00813] Trifluoroacetic acid (0.464 mL, 6.02 mmol) was added to the solution of 5-[2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3 '-dihydro-1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-6'-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole -4-carbonitrile (171 mg, 0.301 mmol) in DCM. The mixture was stirred at room temperature for 15 h. The resulting mixture was concentrated and NH4OH in MeOH was added. The mixture was stirred at room temperature for 30 min. The crude product was diluted with water and extracted with DCM. The organic phase was concentrated. The residue was purified by silica gel chromatography (4-10% MeOH/DCM) to provide 49.0 mg of product. LC/MS calculated for C22H18F2N5O3 [M+H]+ m/z: 438.1; found: 438.2.

[00814] Example 172

[00815] 3-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridine]-6'-yl)-1-methyl-1H-pyrazole-4-carbonitrile

[00816] Cesium carbonate (13.1 mg, 0.0402 mmol) was added to the solution of 5-[2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2', 3'-dihydro-1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-6'-yl]-1H-pyrazole-4-carbonitrile (Example 171: 8.8 mg, 0.020 mmol) in N,N-dimethylformamide (150 µL), followed by methyl iodide (7.14 mg, 0.0503 mmol). The mixture was stirred at room temperature overnight. The crude product was diluted with DCM and filtered. The filtrate was concentrated. The residue was diluted with MeOH and purified by preparative LC/MS to pH 2 (MeCN/TFA water) to give the product as a white solid (TFA salt). LC/MS calculated for C23H20F2N5O3 [M+H]+ m/z: 452.2; found: 452.2.

[00817] Example 173

[00818] 3-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-6'-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazole-4-carbonitrile

[00819] Cesium carbonate (10.4 mg, 0.0320 mmol) was added to the solution of 5-[2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2', 3'-dihydro-1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-6'-yl]-1H-pyrazole-4-carbonitrile (Example 171: 7.0 mg, 0.016 mmol) and 4-(bromomethyl)tetrahydro-2H-pyran (7.16 mg, 0.0400 mmol) in N,N-dimethylformamide (120 µL). The mixture was stirred at room temperature overnight. The crude product was diluted with DCM and filtered. The filtrate was concentrated. The residue was diluted with MeOH and purified by preparative LC/MS to pH 2 (MeCN/TFA water) to give the product as a white solid (TFA salt). LC/MS calculated for C28H28F2N5O4 [M+H]+ m/z: 536.2; found: 536.1.

[00820] Example 174

[00821] 1-(cyanomethyl)-3-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro-1'H-spiro[ cyclopropane-1,4'-[2,7]naphthyridine]-6'-yl)-1H-pyrazole-4-carbonitrile

[00822] Cesium carbonate (10.4 mg, 0.0320 mmol) was added to the solution of 5-[2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2', 3'-dihydro-1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-6'-yl]-1H-pyrazole-4-carbonitrile (Example 171: 7.0 mg, 0.016 mmol) and bromoacetonitrile (4.80 mg, 0.0400 mmol) in N,N-dimethylformamide (120 µL). The mixture was stirred at 40 °C for 2 h. The crude product was diluted with DCM and filtered. The filtrate was concentrated. The residue was diluted with MeOH and purified by preparative LC/MS to pH 2 (MeCN/TFA water) to give the product as a white solid (TFA salt). LC/MS calculated for C24H19F2N6O3 [M+H]+ m/z: 477.1; found: 477.2.

[00823] Example 175

[00824] 5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin- 7-yl)-N-ethylpicolinamide

[00825] Step 1: 5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3- d]pyrimidin-7-yl)-N-picolinic;

[00826] This compound was prepared using procedures analogous to those for example 22, step 2, with 6-(methoxycarbonyl)pyridin-3-ylboronic acid replacing phenyl boronic acid. LC/MS calculated for C23H21F2N4O5 [M+H]+m/z: 471.1; Found: 471.2.

[00827] Step 2: 5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d ]pyrimidin-7-yl)-N-ethylpicolinamide

[00828] To a mixture of 5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3) acid -d]pyrimidin-7-yl)picolinic acid (10 mg, 0.021 mmol) from the previous step, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (11 mg, 0.025 mmol), and Et3N (15 μL, 0.11 mmol) ) in DMF (1.5 mL) at room temperature, EtNH 2 (2.0 M in THF, 53 µL, 0.11 mmol) was added. The reaction mixture was stirred at room temperature overnight, diluted with MeOH, and purified directly via preparative LC/MS to pH 2 (MeCN/TFA water) to provide the desired product as a white solid ( TFA salt). LC/MS calculated for C25H26F2N5O4 [M+H]+m/z: 498.2; Found: 498.2. 1H NMR (600 MHz, DMSO) δ 9.32 (dd, J = 2.2, 0.7 Hz, 1H), 8.87 (t, J = 6.0 Hz, 1H), 8.67 (dd , J = 8.2, 2.2 Hz, 1H), 8.46 (s, 1H), 8.15 (dd, J = 8.2, 0.7 Hz, 1H), 7.72 (s, 1H), 7.07 (t, J = 8.1 Hz, 1H), 4.84 (s, 2H), 4.07 (q, J = 7.0 Hz, 2H), 3.90 (s, 6H), 3.42 - 3.32 (m, 2H), 1.23 (t, J = 7.0 Hz, 3H), 1.15 (t, J = 7.2 Hz, 3H).

[00829] Example 176

[00830] N-cyclopropyl-5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3- d]pyrimidin-7-yl)picolinamide

[00831] This compound was prepared using procedures analogous to those for example 175, step 2, with cyclopropylamine replacing EtNH2 (2.0 M in THF). LC/MS calculated for C26H26F2N5O4 [M+H]+m/z: 510.2; Found: 510.2.

[00832] Example 177

[00833] 5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin- 7-yl)-N-(2-hydroxyethyl)picolinamide

[00834] This compound was prepared using procedures analogous to those for example 175, step 2, with ethanolamine replacing EtNH2 (2.0 M in THF). LC/MS calculated for C25H26F2N5O5 [M+H]+m/z: 514.2; Found: 514.2.

[00835] Example 178

[00836] 5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7 -yl)-N-isopropylpicolinamide

[00837] This compound was prepared using procedures analogous to those for example 175, step 2, with 2-propanamine replacing EtNH2 (2.0 M in THF). LC/MS calculated for C26H28F2N5O4 [M+H]+m/z: 512.2; Found: 512.2.

[00838] Example 179

[00839] 5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7- yl)-N-propylpicolinamide

[00840] This compound was prepared using procedures analogous to those for example 175, step 2, with 1-propanamine replacing EtNH2 (2.0 M in THF). LC/MS calculated for C26H28F2N5O4 [M+H]+m/z: 512.2; Found: 512.2.

[00841] Example 180

[00842] 2-(4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d ]pyrimidin-7-yl)phenyl)acetonitrile

[00843] This compound was prepared using procedures analogous to those for example 22, step 2, with 4-(cyanomethyl)phenylboronic acid replacing phenylboronic acid. LC/MS calculated for C25H23F2N4O3 [M+H]+m/z: 465.2; Found: 465.1.

[00844] Example 181

[00845] 1-(4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d ]pyrimidin-7-yl)phenyl)cyclobutanecarbonitrile

[00846] This compound was prepared using procedures analogous to those for example 22, step 2, with 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )phenyl)cyclobutanecarbonitrile replacing phenylboronic acid. LC/MS calculated for C28H27F2N4O3 [M+H]+m/z: 505.2; Found: 505.2.

[00847] Example 182

[00848] 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(6-morpholinopyridin-3-yl)-3,4-dihydropyrido[4,3-d]pyrimidin -2(1H)-one

[00849] This compound was prepared using procedures analogous to those for example 22, step 2, with 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )pyridin-2-yl)morpholine replacing phenylboronic acid. LC/MS calculated for C26H28F2N5O4 [M+H]+m/z: 512.2; Found: 512.2.

[00850] Example 183

[00851] 1-(4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d ]pyrimidin-7-yl)phenyl)cyclopropanecarbonitrile

[00852] This compound was prepared using procedures analogous to those for example 22, step 2, with 4-(1-cyanocyclopropyl)phenylboronic acid replacing phenylboronic acid. LC/MS calculated for C27H25F2N4O3 [M+H]+m/z: 491.2; Found: 491.2.

[00853] Example 184

[00854] 5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7- yl)picolinamide

[00855] Step 1: 5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d ]pyrimidin-7-yl)picolinonitrile

[00856] This compound was prepared using procedures analogous to those for example 22, step 2, with 5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )picolinonitrile replacing phenylboronic acid LC/MS calculated for C23H20F2N5O3 [M+H]+ m/z: 452.2 Found: 452.1.

[00857] Step 2: 5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d ]pyrimidin-7-yl)picolinamide

[00858] A mixture of 5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d ]pyrimidin-7-yl)picolinonitrile (94 mg, 0.21 mmol) in NaOH (1.0 M in H 2 O) solution (1.20 mL) and ethanol (3.6 mL) was stirred at 80 °C of one day to another. The reaction mixture was cooled to room temperature, quenched with HCl solution (12.0 M in H2O, 120 µL), and concentrated. The crude material was then purified by preparative LC/MS at pH 2 (MeCN/TFA water) to provide the desired product as a white solid (TFA salt). LC/MS calculated for C23H22F2N5O4 [M+H]+ m/z: 470.2; Found: 470.1.

[00859] Example 185

[00860] 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(pyridin-4-yl)-1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin ]-3'(2'H)-one

[00861] This compound was prepared using procedures analogous to those for example 1, step 7, with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine replacing (5-amino-2-methylphenyl)boronic acid. LC/MS calculated for C23H20F2N3O3 [M+H]+ m/z: 424.1; Found: 424.2.

[00862] Example 186

[00863] 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(1-methyl-1H-pyrazol-4-yl)-1',2'-dihydro-3'H -spiro[cyclopropane-1,4'-[2,7]naphthyridin]-3'-one

[00864] This compound was prepared using procedures analogous to those for example 1, step 7, with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-pyrazole replacing (5-amino-2-methylphenyl)boronic acid. LC/MS calculated for C22H21F2N4O3 [M+H]+m/z: 427.2; Found: 427.1.

[00865] Example 187

[00866] 1-(5-{3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-2- oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl}pyridin-2-yl)cyclobutanecarbonitrile

[00867] This compound was prepared using procedures analogous to those for example 135, step 3 with 1-(5-methyl-1,3,4-oxadiazol-2-yl)methanamine replacing pyrimidin-4-amine. LCMS calculated for C29H26F2N7O4 [M+H]+ m/z: 574.2; Found: 574.2.

[00868] Example 188

[00869] 1-{5-[3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1,2,3 ,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl]pyridin-2-yl}cyclobutanecarbonitrile

[00870] This compound was prepared using procedures analogous to those for example 135, step 3 with 1-methyl-1H-pyrazol-4-amine replacing pyrimidin-4-amine. LCMS calculated for C29H26F2N7O3 [M+H]+ m/z: 558.2. Found: 558.1.

[00871] Example A

[00872] Enzymatic assay for FGFR

[00873] The inhibitory potency of the exemplified compounds was measured in an enzymatic assay that measures peptide phosphorylation using FRET measurements to detect product formation. Inhibitors were serially diluted in DMSO and a volume of 0.5 µL was transferred to the wells of a 384-well plate. For FGFR3, a 10 µL volume of FGFR3 enzyme (Millipore) diluted in assay buffer (50 mM HEPES, 10 mM MgCl2, 1 mM EGTA, 0.01% Tween-20, 5 mM DTT, pH 7.5) was added to the plate and pre-incubated for a time between 5 to 10 minutes and up to 4 hours. Appropriate controls (enzyme control and enzyme without inhibitor) were included in the plate. The assay was initiated by adding a 10 µL solution containing biotinylated EQEDEPEGDYFEWLE peptide substrate (SEQ ID NO: 1) and ATP (500 nM and 140 µM final concentrations, respectively) in assay buffer to the wells. The plate was incubated at 25°C for 1 h. Reactions were terminated by adding 10 µL/well of cooling solution (50 mM Tris, 150 mM NaCl, 0.5 mg/mL BSA, pH 7.8; 30 mM EDTA with Perkin Elmer Lance reagents at 3, 75 nM Eu PY20 antibody and 180 nM APC-streptavidin). The plate was allowed to equilibrate for ~1 h before scanning the wells in a PheraStar plate reader (BMG Labtech).

[00874] FGFR1, FGFR2, and FGFR4 are measured under equivalent conditions with the following changes in enzyme and ATP concentrations: FGFR1, 0.02 nM and 210 μM, respectively, FGFR2, 0.01 nM and 100 μM, respectively, and FGFR4, 0.04 nM and 600 µM, respectively. Enzymes were purchased from Millipore or Invitrogen.

[00875] The GraphPad prism3 program was used to analyze the data. IC50 values were derived by fitting the data to the equation for a sigmoidal dose-response with a variable angular coefficient. Y=bottom + (top-bottom)/(1+10A((LogIC50-X)*HillSlope)) where X is the logarithm of the concentration and Y is the response. Compounds with an IC50 of 1 µM or less are considered active.

[00876] It was observed that the compounds of the invention are selective inhibitors of FGFR3 and/or FGFR4, according to the enzymatic assays for FGFR. Compounds of formula (I') and (I) and all compounds described here have been tested and show an IC50 less than 1 μM.

Tabela 2

Tabela 2A

[00877] Table 1 provides the IC50 data for the compounds of the invention tested in the enzyme assay for FGFR after dilution in assay buffer, added to the plate and pre-incubated for 4 hours. The symbol: "+" indicates an IC50 less than 10 nM; "++" indicates an IC50 greater than or equal to 10 nM but less than 30 nM; "+++" indicates an IC50 greater than or equal to 30 nM but less than 200 nM; and "++++" indicates an IC50 greater than or equal to 200 nM. Table 2 provides IC50 ratios showing selectivity for FGFR4. Table 2A provides IC50 ratios showing the FGFR3 selectivity of the compounds. Table 1

Table 2

Table 2A

Tabela 4

[00878] Table 3 provides the IC50 data for the compounds of the invention tested in the enzyme assay for FGFR after dilution in assay buffer, added to the plate and pre-incubated for 5 to 10 minutes. The symbol: "+" indicates an IC50 less than 10 nM; "++" indicates an IC50 greater than or equal to 10 nM but less than 30 nM; "+++" indicates an IC50 greater than or equal to 30 nM but less than 200 nM; and "++++" indicates an IC50 greater than or equal to 200 nM. Table 4 provides the ratios of IC50 data showing selectivity for FGFR4. Table 3

Table 4

[00879] Example B

[00880] Cellular and in vivo FGFR4 assays

[00881] The FGFR4 inhibitory activity of the example compounds in cells, tissues, and/or animals can be demonstrated according to one or more assays or models described in the art as, for example, in French et al. "Targeting FGFR4 Inihibits Hepatocellular Carcinoma in Preclinical Mouse Models," PLoS ONE, May 2012, Vol. 7, number 5, e36713, which is incorporated in its entirety herein by reference.

Example C Cell Based FGFR Phosphorylation Assays

[00882] The inhibitory effect of compounds on FGFR phosphorylation in relevant cell lines (cancer cell lines Ba/F3-FGFR3, KMS-11, RT112, KatoIII, H-1581 and HUVEC cell line) can be evaluated using specific immunoassays for FGFR phosphorylation. Cells are starved in medium low in serum (0.5%) and without FGF1 for 4 to 18 h depending on the cell line then treated with various concentrations of individual inhibitors for 1 to 4 hours. For some cell lines, such as Ba/F3-FGFR3 and KMS-11, cells are stimulated with heparin (20 μg/mL) and FGF1 (10 ng/mL) for 10 min. Whole cell protein extracts are prepared by incubation in lysis buffer with protease and phosphatase inhibitors [50 mM HEPES (pH 7.5), 150 mM NaCl, 1.5 mM MgCl<+lower>2</lower>, 10% glycerol, 1% Triton X-100, 1 mM sodium orthovanadate, 1 mM sodium fluoride, aprotinin (2 μg/mL), leupeptin (2 μg/mL), pepstatin A (2 μg/mL), and phenylmethylsulfonyl fluoride (1 mM)] at 4°C. Protein extracts are cleared of cell debris by centrifugation at 14,000 x g for 10 minutes and quantified using BCA (bicinchoninic acid) microplate assay reagent (Thermo Scientific).

[00883] FGFR receptor phosphorylation in protein extracts was determined using immunoassays including western blotting, enzyme-linked immunoassay (ELISA) or microbead-based immunoassays (Luminex). For the detection of phosphorylated FGFR2, a commercial ELISA kit designated DuoSet IC Human Phospho-FGF R2α ELISA assay (R&D Systems, Minneapolis, MN) can be used. For the assay, KatoIII cells are plated in Iscove's medium supplemented with 0.2% FBS (50,000 cells/well/per 100 µL) in 96-well, flat-bottom treated tissue culture plates (Corning, Corning, NY, USA), in the presence or absence of a range of test compound concentrations and incubated for 4 hours at 37°C, 5% CO2. The assay is stopped with the addition of 200 µL of ice-cold PBS and centrifugation. Washed cells are lysed in cell lysis buffer (Cell Signaling, #9803) with protease inhibitor (Calbiochem, #535140) and PMSF (Sigma, #P7626) for 30 min on wet ice. Cell lysates were frozen at -80°C before testing an aliquot with the ELISA assay kit designated DuoSet IC Human Phospho-FGF R2α. The GraphPad prism3 program was used to analyze the data. IC50 values were derived by fitting the data to the equation for a sigmoidal dose-response with a variable slope.

[00884] For the detection of phosphorylated FGFR3, a microbead-based immunoassay was developed. A mouse anti-human FGFR3 mAb (R&D Systems, Catalog No. MAB7661) was conjugated to Luminex MAGplex microspheres, microsphere region 20 and used as the capture antibody. RT-112 cells were seeded into multi-well tissue culture plates and grown to 70% confluency. Cells were washed with PBS and starved in RPMI + 0.5% FBS for 18 h. Cells were treated with 10 μL of 10X concentrations of serially diluted compounds for 1 hour at 37°C, 5% CO 2 before stimulation with 10 ng/mL of human FGF1 and 20 μg/mL of heparin for 10 min. . Cells were washed with ice-cold PBS and lysed with cell extraction buffer (Invitrogen) and centrifuged. Clarified supernatants were frozen at -80°C until analysis.

[00885] For the assay, cell lysates are diluted 1:10 in assay diluent and incubated with microbeads bound to capture antibody in a 96-well filter plate for 2 hours at room temperature on a plate shaker. Plates are washed three times using vacuum tubing and incubated with polyclonal rabbit anti-phospho-FGF antibody R1-4 (Y653/Y654) (R&D Systems catalog # AF3285) for 1 hour at room temperature with agitation. Plates are washed three times. Diluted reporter antibody, goat anti-rabbit RPE-conjugated antibody (Invitrogen Catalog No. LHB0002) is added and incubated for 30 minutes with shaking. Plates are washed three times. Capsules are suspended in wash buffer with shaking at room temperature for 5 minutes and then read on a Luminex 200 instrument set to count 50 events per sample, port settings 7500-13500. Data are expressed as mean fluorescence intensity (MFI). The MFI of the compound-treated samples is divided by the MFI values of the DMSO controls to determine percent inhibition, and the IC50 values are calculated using the GraphPad Prism program. Compounds with an IC50 of 1 µM or less are considered active.

[00886] Various modifications of the invention, in addition to those described herein, will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patents, patent applications, and publications, cited in this application is incorporated herein by reference in its entirety.

Claims (58)

1. Compound, characterized by the fact that it has formula (I'):

or a pharmaceutically acceptable salt thereof, wherein: ring A is a C6-10 aryl or a 5- to 10-membered heteroaryl having carbon and 1 to 4 heteroatoms as ring members selected from O, N, and S, in that N and S are each optionally oxidized; each R12 is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl member, C6-10 aryl-C1-4-alkyl, C3-10 cycloalkyl-C1-4-alkyl, (5- to 10-membered heteroaryl)-C1-4-alkyl, (4- to 10-membered heterocycloalkyl)-C1-alkyl -4-, CN, NO2, ORa, SRa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NRaRa, NRaORa, NRaC(O) Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(=NRa)Ra, C(=NRa)NRaRa, NRaC(=NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O) )2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra and S(O)2NRaRa, where a is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-4-alkyl, C3-10-cycloalkyl-C1-4-alkyl, (5- to 10-membered heteroaryl)- C1-4alkyl- and (4- to 10-membered heterocycloalkyl)-C1-4alkyl- are each optionally substituted by 1, 2, 3 or 4 independently selected Rb substituents; or two adjacent R12 substituents on ring A, together with the atoms to which they are attached, form a fused 5- or 6-membered cycloalkyl ring, 5- or 6-membered heterocycloalkyl ring, 5- to 6-membered phenyl or heteroaryl ring, in which the heterocycloalkyl or heteroaryl has 1 to 2 heteroatoms as ring members selected from O, N and S; each Ra is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-alkyl C1-4-, C3-10 cycloalkyl-C1-4 alkyl-, (5- to 10-membered heteroaryl)-C1-4 alkyl- and (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, wherein the alkyl C1-6, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-4-alkyl, C3-10 cycloalkyl-C1-4-alkyl, (5- to 10-membered heteroaryl)-C 1-4 alkyl- and (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl- of Ra are each optionally substituted by 1, 2, 3, 4, or 5 substituents Rd independently selected; or any two Ra substituents attached to the same N atom together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 independently selected Rh substituents; each Rb is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-alkyl C1-4-, C3-10 cycloalkyl-C1-4 alkyl-, (5- to 10-membered heteroaryl)-C1-4 alkyl- and (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO2, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, C(=NRc)NRcRc, NRcC(=NRc)NRcRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S(O)Rc, S(O)NRcRc, S( O)2Rc and S(O)2NRcRc; wherein is C1-6 alkyl, C26 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-4-alkyl , C3-10 cycloalkyl-C1-4 alkyl-, (5- to 10-membered heteroaryl)-C14-alkyl- and (4- to 10-membered heterocycloalkyl)-C1-4 alkyl Rb are each optionally substituted by 1, 2 , 3, 4 or 5 independently selected Rf substituents; each Rc is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl member, C6-10 aryl-C1-4-alkyl, C3-10 cycloalkyl-C1-4-alkyl-, (5- to 10-membered heteroaryl)-C1-4-alkyl- and (4- to 10-membered heterocycloalkyl)-C1-alkyl -4-, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6- aryl 10-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5- to 10-membered heteroaryl)-C1-4-alkyl- and (4- to 10-membered heterocycloalkyl)-C1-4 alkyl of Rc are , each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rf substituents; or any two Rc substituents attached to the same N atom together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 independently selected Rh substituents; each Rd is independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, CN, ORe, SRe, C(O)Re, C(O)NReRe, C(O)ORe, OC(O)Re, OC( O)NReRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, C(=NRe)NReRe, NReC(=NRe)NReRe, S(O)Re, S(O)NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe and S(O)2NReRe; each Rf is independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, CN, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg, OC( O)NRgRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg, C(=NRg)NRgRg, NRgC(=NRg)NRgRg, S(O)Rg, S(O)NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg and S(O)2NRgRg; each Rh is independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-10 aryl, 5- to 6-membered heteroaryl, C1-6 haloalkyl, halo, CN, ORi, SRi, i ii ii ii ii ii C(O)R, C(O)NRR, C(O)OR, OC(O)R, OC(O)NRR, NRR, NRC(O)R, i ii iii ii ii ii i NRC (O)NRR, NRC(O)OR, C(=NR)NRR, NRC(=NR)NRR, S(O)R, S(O)NRiRi, S(O)2Ri, NRiS(O)2Ri, NRiS (O)2NRiRi and S(O)2NRiRi, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-10 aryl and 5- to 6-membered heteroaryl of Rh are optionally substituted by 1 , 2, or 3 independently selected substituents Rj; each Rf is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, ORk, SRk, C(O)Rk, C(O)NRkRk, C(O)ORk, OC(O)Rk, OC( O)NRkRk, NRkRk, NRkC(O)Rk, NRkC(O)NRkRk, NRkC(O)ORi, C(=NRk)NRkRk, NRkC(=NRk)NRkRk, S(O)Rk, S(O)NRkRk, S(O)2Rk, NRkS(O)2Rk, NRkS(O)2NRkRk and S(O)2NRkRk; each Re, Rg, Ri or Rk is independently selected from H, C1-4 alkyl, C6-10 aryl, C1-4 haloalkyl, C2-4 alkenyl and C2-4 alkyl, wherein the C1-4 alkyl, C6-aryl 10, C2-4 alkenyl or C2-4 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1 alkylamino -4, di(C1-4alkyl)amino, haloC1-4alkyl and haloC1-4alkoxy; or any two Re substituents attached to the same N atom together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 independently selected Rh substituents; or any two Rg substituents attached to the same N atom together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 independently selected Rh substituents; or any two Ri substituents attached to the same N atom together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 independently selected Rh substituents; X1 is -CR10R11- or -NR7- X2 is N or CR6; R13 is H, CN, NRc4Rd4, OR1 or -C(O)NHRe, wherein R1 is C1-3 alkyl or C1-3 haloalkyl; R2 is H, halo, C1-3 alkyl, C1-3 haloalkyl, CN or C1-3 alkoxy; R3 is H, halo, C1-3 alkyl, C1-3 haloalkyl, CN or C1-3 alkoxy; R14 is H, CN, NRc4Rd4, OR4 or -C(O)NHRg, wherein R4 is C1-3 alkyl or C1-3 haloalkyl; R5 is H, halo, C1-3 alkyl, C1-3 haloalkyl, CN or C1-3 alkoxy; R6 is selected from H, halo, CN, ORa4, SRa4, C(O)NRc4Rd4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S( O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, S(O)2NRc4Rd4, C1-6 alkyl, C2-6 alkenyl, C2-6 alkyl, C1-6 haloalkyl, phenyl, C3-6 cycloalkyl, a 5- to 6-membered heteroaryl having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4- to 7-membered heterocycloalkyl members having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-6 cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups of R6 are each optionally substituted by 1, 2, or 3 substituents independently selected from R10A; R7 is selected from H, C(O)NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, S(O)2NRc4Rd4, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl , C1-6 haloalkyl, phenyl, C3-6 cycloalkyl, 5- to 10-membered heteroaryl having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, 4- to 10-membered heterocycloalkyl having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5- to 10-membered heteroaryl)-C1-4 alkyl- and (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-; wherein said groups are C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-6 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl -, C3-10 cycloalkyl-C1-4 alkyl-, (5- to 10-membered heteroaryl)-C1-4 alkyl-, and (4- to 10-membered heterocycloalkyl)-C1-4 alkyl- of R7 are each optionally substituted with 1, 2 or 3 substituents independently selected from R10A; or two R10A substituents attached to adjacent ring atoms of the aryl or heteroaryl ring of R7, together with the atoms to which they are attached, form a fused C5-6 cycloalkyl ring or a 5- to 6-membered heterocycloalkyl ring having 1 to 2 heteroatoms as ring members independently selected from O, N and S, wherein the nitrogen and sulfur atoms are each optionally oxidized and the fused C5-6 cycloalkyl or fused 5- to 6-membered heterocycloalkyl ring is optionally replaced by 1 or 2 independently selected R19 groups; R10 and R11 are each independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4- to 10-membered heterocycloalkyl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl groups of R10 and R11 are each one, optionally substituted with 1, 2 or 3 R10A; alternatively, R10 and R11 together with the carbon atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group or a 4-, 5-, 6-, 7-, 8-, 9-, or 7-membered heterocycloalkyl group. 10 members; wherein said 3, 4, 5, 6 or 7 membered cycloalkyl group and said 4, 5, 6, 7, 8, 9 or 10 membered heterocycloalkyl group are each optionally substituted with 1, 2, 3 or 4 R10A; each R10A is independently selected from halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(=NRe4) )NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S( O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, S(O)2NRc4Rd4, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C16 haloalkyl, phenyl, C3-6 cycloalkyl, one heteroaryl moiety 5- to 6-membered heterocycloalkyl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4- to 7-membered heterocycloalkyl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-6 cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups of R10A are each optionally substituted by 1, 2, or 3 substituents independently selected from R19; each Ra4, Rb4, Rc4 and Rd4 is independently selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, phenyl, C3-6 cycloalkyl, a 5- to 6-membered heteroaryl moiety that has carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4- to 7-membered heterocycloalkyl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein said C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, C36 cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups of Ra4, Rb4, Rc4 and Rd4 are each , optionally substituted with 1, 2 or 3 substituents independently selected from R19; alternatively, Rc4 and Rd4, together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group which is optionally substituted by 1, 2, or 3 substituents independently selected from R19; each Re4 is independently H or C1-4 alkyl; each R19 is independently selected from halo, CN, NO2, ORa9, SRa9, C(O)Rb9, C(O)NRc9Rd9, C(O)ORa9, OC(O)Rb9, OC(O)NRc9Rd9, NRc9Rd9, NRc9C(O)Rb9, NRc9C(O)ORa9, NRc9C(O)NRc9Rd9, NRc9S(O)Rb9, NRc9S(O)2Rb9, NRc9S(O)2NRc9Rd9, S(O)Rb9, S(O)NRc9Rd9, S( O)2Rb9, S(O)2NRc9Rd9, C1-4 alkyl, C24 alkenyl, C2-4 alkylkynyl, C3-6-cycloalkyl, 4- to 6-membered heterocycloalkyl and C1-4 haloalkyl, wherein the C1-4 alkyl groups, C2-4 alkenyl, C2-4 alkynyl, C3-6-cycloalkyl, 4- to 6-membered heterocycloalkyl and C1-4 haloalkyl of R19 are each optionally further substituted with 1 or 2 R20 substituents independently selected from H, halo, CN, NO2, ORq, SRq, C(O)Rq, C(O)NRqRq, C(O)ORq, OC(O)Rq, OC(O)NRqRq, NRqRq, NRqC(O)Rq, NRqC(O) ORq, NRqC(O)NRqRq, NRqS(O)Rq, NRqS(O)2Rq, NRqS(O)2NRqRq, S(O)Rq, S(O)NRqRq, S(O)2Rq, S(O)2NRqRq, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl and C1-4 haloalkyl, wherein each Rq is independently H or C1-4 alkyl; each Ra9, Rc9 and Rd9 is independently selected from H and C1-4 alkyl; each Rb9 is independently C1-4 alkyl; eon subscript is 0, 1, 2 or 3. 2. Compound, characterized by the fact that it has formula (I'):

or a pharmaceutically acceptable salt thereof, wherein: ring A is a C6-10 aryl or a 5- to 10-membered heteroaryl having carbon and 1 to 4 heteroatoms as ring members selected from O, N, and S, wherein N and S are each optionally oxidized; each R12 is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl member, C6-10 aryl-C1-4-alkyl, C3-10 cycloalkyl-C1-4-alkyl, (5- to 10-membered heteroaryl)-C1-4-alkyl, (4- to 10-membered heterocycloalkyl)-C1-alkyl -4-, CN, NO2, ORa, SRa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NRaRa, NRaORa, NRaC(O) Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(=NRa)Ra, C(=NRa)NRaRa, NRaC(=NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O) )2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra and S(O)2NRaRa, where a is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-4-alkyl, C3-10-cycloalkyl-C1-4-alkyl, (5- to 10-membered heteroaryl)- C1-4alkyl- and (4- to 10-membered heterocycloalkyl)-C1-4alkyl- are each optionally substituted by 1, 2, 3 or 4 independently selected Rb substituents; or two adjacent R12 substituents on ring A, together with the atoms to which they are attached, form a fused 5- or 6-membered cycloalkyl ring, 5- or 6-membered heterocycloalkyl ring, 5- to 6-membered phenyl or heteroaryl ring, in which the heterocycloalkyl or heteroaryl has 1 to 2 heteroatoms as ring members selected from O, N and S; each Ra is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-alkyl C1-4-, C3-10 cycloalkyl-C1-4 alkyl-, (5- to 10-membered heteroaryl)-C1-4 alkyl- and (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, wherein the alkyl C1-6, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-4-alkyl, C3-10 cycloalkyl-C1-4-alkyl, (5- to 10-membered heteroaryl)-C 1-4 alkyl- and (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl- of Ra are each optionally substituted by 1, 2, 3, 4, or 5 substituents Rd independently selected; or any two Ra substituents attached to the same N atom together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 independently selected Rh substituents; each Rb is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl alkyl C1-4-, C3-10 cycloalkyl-C1-4 alkyl-, (5- to 10-membered heteroaryl)-C1-4 alkyl- and (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO2, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, C(=NRc)NRcRc, NRcC(=NRc)NRcRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S(O)Rc, S(O)NRcRc, S( O)2Rc and S(O)2NRcRc; wherein is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-alkyl 4-, C3-10 cycloalkyl-C1-4 alkyl-, (5- to 10-membered heteroaryl)-C1-4 alkyl- and (4- to 10-membered heterocycloalkyl)-C1-4 alkyl of Rb are each optionally substituted with 1, 2, 3, 4 or 5 independently selected Rf substituents; each Rc is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl member, C6-10 aryl-C1-4-alkyl, C3-10 cycloalkyl-C1-4-alkyl-, (5- to 10-membered heteroaryl)-C1-4-alkyl- and (4- to 10-membered heterocycloalkyl)-C1-alkyl -4-, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6- aryl 10-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5- to 10-membered heteroaryl)-C1-4-alkyl- and (4- to 10-membered heterocycloalkyl)-C1-4 alkyl of Rc are , each optionally substituted with 1, 2, 3, 4, or 5 independently selected Rf substituents; or any two Rc substituents attached to the same N atom together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 independently selected Rh substituents; each Rd is independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, CN, ORe, SRe, C(O)Re, C(O)NReRe, C(O)ORe, OC(O)Re, OC( O)NReRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, C(=NRe)NReRe, NReC(=NRe)NReRe, S(O)Re, S(O)NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe and S(O)2NReRe; each Rf is independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, CN, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg, OC( O)NRgRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg, C(=NRg)NRgRg, NRgC(=NRg)NRgRg, S(O)Rg, S(O)NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg and S(O)2NRgRg; each Rh is independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-10 aryl, 5- to 6-membered heteroaryl, C1-6 haloalkyl, halo, CN, ORi, SRi, i ii ii ii ii ii C(O)R, C(O)NRR, C(O)OR, OC(O)R, OC(O)NRR, NRR, NRC(O)R, i ii iii ii ii ii i NRC (O)NRR, NRC(O)OR, C(=NR)NRR, NRC(=NR)NRR, S(O)R, S(O)NRiRi, S(O)2Ri, NRiS(O)2Ri, NRiS (O)2NRiRi and S(O)2NRiRi, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-10 aryl and 5- to 6-membered heteroaryl of Rh are optionally substituted by 1 , 2, or 3 independently selected substituents Rj; each Rj is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, ORk, SRk, C(O)Rk, C(O)NRkRk, C(O)ORk, OC(O)Rk, OC( O)NRkRk, NRkRk, NRkC(O)Rk, NRkC(O)NRkRk, NRkC(O)ORi, C(=NRk)NRkRk, NRkC(=NRk)NRkRk, S(O)Rk, S(O)NRkRk, S(O)2Rk, NRkS(O)2Rk, NRkS(O)2NRkRk and S(O)2NRkRk; each Re, Rg, Ri or Rk is independently selected from H, C1-4 alkyl, C6-10 aryl, C1-4 haloalkyl, C2-4 alkenyl and C2-4 alkyl, wherein the C1-4 alkyl, C6-aryl 10, C2-4 alkenyl or C2-4 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1 alkylamino -4, di(C1-4alkyl)amino, haloC1-4alkyl and haloC1-4alkoxy; or any two Re substituents attached to the same N atom together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 independently selected Rh substituents; or any two Rg substituents attached to the same N atom together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 independently selected Rh substituents; or any two Ri substituents attached to the same N atom together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 independently selected Rh substituents; X1 is -CR10R11- or -NR7- X2 is N or CR6; R13 is H, CN, NRc4Rd4, OR1 or -C(O)NHRe, wherein R1 is C1-3 alkyl or C1-3 haloalkyl; R2 and R5 are halogen; R3 is H, halo, C1-3 alkyl, C1-3 haloalkyl, CN or C1-3 alkoxy; R14 is H, CN, NRc4Rd4, OR4 or -C(O)NHRg, wherein R4 is C1-3 alkyl or C1-3 haloalkyl; R6 is selected from H, halo, CN, ORa4, SRa4, C(O)NRc4Rd4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S( O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, S(O)2NRc4Rd4, C1-6 alkyl, C26 alkenyl, C2 alkynyl -6, C1-6 haloalkyl, phenyl, C3-6 cycloalkyl, a 5- to 6-membered heteroaryl having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4- to 7-membered heterocycloalkyl having has carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-6 cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups of R6 are each optionally substituted by 1, 2, or 3 substituents independently selected from R10A; R7 is selected from H, C(O)NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, S(O)2NRc4Rd4, C1-6 alkyl, C2-6 alkenyl, C2 alkynyl -6, C1-6 haloalkyl, phenyl, C3-6 cycloalkyl, 5- to 10-membered heteroaryl having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, 4- to 10-membered heterocycloalkyl having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5- to 10-membered heteroaryl)-C1-4 alkyl - and (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-; wherein said groups are C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-6 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl -, C3-10 cycloalkyl-C1-4 alkyl-, (5- to 10-membered heteroaryl)-C1-4 alkyl-, and (4- to 10-membered heterocycloalkyl)-C1-4 alkyl- of R7 are each optionally substituted with 1, 2 or 3 substituents independently selected from R10A; or two R10A substituents attached to adjacent ring atoms of the aryl or heteroaryl ring of R7, together with the atoms to which they are attached, form a fused C5-6 cycloalkyl ring or a 5- to 6-membered heterocycloalkyl ring having 1 to 2 heteroatoms as ring members independently selected from O, N and S, wherein the nitrogen and sulfur atoms are each optionally oxidized and the fused C5-6 cycloalkyl or fused 5- to 6-membered heterocycloalkyl ring is optionally replaced by 1 or 2 independently selected R19 groups; R10 and R11 are each independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, a heteroaryl moiety of 5 to 10 members having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4- to 10-membered heterocycloalkyl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C610 aryl, C3-10 cycloalkyl, 5 to 10 membered heteroaryl and 4 to 10 membered heterocycloalkyl groups of R10 and R11 are each optionally substituted with 1, 2 or 3 R10A; alternatively, R10 and R11 together with the carbon atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group or a 4-, 5-, 6-, 7-, 8-, 9-, or 7-membered heterocycloalkyl group. 10 members; wherein said 3, 4, 5, 6 or 7 membered cycloalkyl group and said 4, 5, 6, 7, 8, 9 or 10 membered heterocycloalkyl group are each optionally substituted with 1, 2, 3 or 4 R10A; each R10A is independently selected from halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(=NRe4) )NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S( O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, S(O)2NRc4Rd4, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C16 haloalkyl, phenyl, C3-6 cycloalkyl, one heteroaryl moiety 5- to 6-membered heterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatoms independently selected from N, O, and S, and a 4- to 7-membered heterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatoms independently selected from N, O and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-6 cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups of R10A are each optionally substituted by 1, 2, or 3 substituents independently selected from R19; each Ra4, Rb4, Rc4 and Rd4 is independently selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, phenyl, C3-6 cycloalkyl, a 5- to 6-membered heteroaryl moiety that has carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4- to 7-membered heterocycloalkyl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein said C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, C36 cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups of Ra4, Rb4, Rc4 and Rd4 are each , optionally substituted with 1, 2 or 3 substituents independently selected from R19; alternatively, Rc4 and Rd4, together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group which is optionally substituted by 1, 2, or 3 substituents independently selected from R19; each Re4 is independently H or C1-4 alkyl; each R19 is independently selected from halo, CN, NO2, ORa9, SRa9, C(O)Rb9, C(O)NRc9Rd9, C(O)ORa9, OC(O)Rb9, OC(O)NRc9Rd9, NRc9Rd9, NRc9C(O)Rb9, NRc9C(O)ORa9, NRc9C(O)NRc9Rd9, NRc9S(O)Rb9, NRc9S(O)2Rb9, NRc9S(O)2NRc9Rd9, S(O)Rb9, S(O)NRc9Rd9, S( O)2Rb9, S(O)2NRc9Rd9, C1-4 alkyl, C2-4 alkenyl, C2-4 alkylkynyl, C3-6 cycloalkyl-, and C1-4 haloalkyl, wherein a is C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, and C1-4 haloalkyl of R19 are each further optionally substituted with 1 or 2 R20 substituents independently selected from H, halo, CN, NO2, ORq, SRq, C(O )Rq, C(O)NRqRq, C(O)ORq, OC(O)Rq, OC(O)NRqRq, NRqRq, NRqC(O)Rq, NRqC(O)ORq, NRqC(O)NRqRq, NRqS(O) )Rq, NRqS(O)2Rq, NRqS(O)2NRqRq, S(O)Rq, S(O)NRqRq, S(O)2Rq, S(O)2NRqRq, C1-4 alkyl, C2-4 alkenyl, alkynyl C2-4, C3-6 cycloalkyl and C1-4 haloalkyl, wherein each Rq is independently H or C1-4 alkyl; each Ra9, Rc9 and Rd9 is independently selected from H and C1-4 alkyl; each Rb9 is independently C1-4 alkyl; eon subscript is 0, 1, 2 or 3. 3. Compound, according to claim 1 or 2, characterized in that it has formula (I):

or a pharmaceutically acceptable salt thereof, wherein: ring A is C6-10 aryl or a 5- to 6-membered heteroaryl having carbon and 1 to 4 heteroatoms as ring members selected from O, N and S; each R12 is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl member, C6-10 aryl-C1-4-alkyl, C3-10 cycloalkyl-C1-4-alkyl, (5- to 10-membered heteroaryl)-C1-4-alkyl, (4- to 10-membered heterocycloalkyl)-C1-alkyl -4-, CN, NO2, ORa, SRa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NRaRa, NRaORa, NRaC(O) Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(=NRa)Ra, C(=NRa)NRaRa, NRaC(=NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O) )2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra and S(O)2NRaRa, where a is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-4-alkyl, C3-10-cycloalkyl-C1-4-alkyl, (5- to 10-membered heteroaryl)- C1-4-alkyl and (4- to 10-membered heterocycloalkyl)-C1-4-alkyl are each optionally substituted by 1, 2, 3 or 4 independently selected Rb substituents; or two adjacent R12 substituents on ring A, together with the atoms to which they are attached, form a fused 5- or 6-membered cycloalkyl ring, 5- or 6-membered heterocycloalkyl ring, 5- to 6-membered phenyl or heteroaryl ring, in which the heterocycloalkyl or heteroaryl has 1 to 2 heteroatoms as ring members selected from O, N and S; each Ra is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-alkyl C1-4-, C3-10-cycloalkyl-C1-4-alkyl, (5- to 10-membered heteroaryl)-C1-4-alkyl- and (4- to 10-membered heterocycloalkyl)-C1-4-alkyl-, wherein C1-alkyl 6, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-4-alkyl, C3-10-cycloalkyl-C1-4-alkyl, (heteroaryl 5- to 10-membered)-C 1-4 alkyl- and (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl such as Ra are each optionally substituted by 1, 2, 3, 4 or 5 independently selected Rd substituents; or any two Ra substituents attached to the same N atom together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 independently selected Rh substituents; each Rb is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, NO2, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O) Rc, OC(O)NRcRc, C(=NRc)NRcRc, NRcC(=NRc)NRcRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc, NRcS( O)2Rc, NRcS(O)2NRcRc, S(O)Rc, S(O)NRcRc, S(O)2Rc and S(O)2NRcRc; each Rc is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl member, C6-10 aryl-C1-4-alkyl, C3-10 cycloalkyl-C1-4-alkyl-, (5- to 10-membered heteroaryl)-C1-4-alkyl- and (4- to 10-membered heterocycloalkyl)-C1-alkyl -4-, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6- aryl 10-C1-4alkyl-, C3-10cycloalkyl-C1-4alkyl-, (5- to 10-membered heteroaryl)-C14-alkyl- and (4- to 10-membered heterocycloalkyl)-C1-4-alkyl-are each , optionally substituted with 1, 2, 3, 4 or 5 independently selected Rf substituents; or any two Rc substituents attached to the same N atom together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 independently selected Rh substituents; each Rd is independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, CN, ORe, SRe, C(O)Re, C(O)NReRe, C(O)ORe, OC(O)Re, OC( O)NReRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, C(=NRe)NReRe, NReC(=NRe)NReRe, S(O)Re, S(O)NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe and S(O)2NReRe; each Rf is independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, CN, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg, OC( O)NRgRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg, C(=NRg)NRgRg, NRgC(=NRg)NRgRg, S(O)Rg, S(O)NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg and S(O)2NRgRg; each Rh is independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-10 aryl, 5- to 6-membered heteroaryl, C1-6 haloalkyl, halo, CN, ORi, SRi, i ii ii ii ii ii C(O)R, C(O)NRR, C(O)OR, OC(O)R, OC(O)NRR, NRR, NRC(O)R, i ii iii ii ii ii i NRC (O)NRR, NRC(O)OR, C(=NR)NRR, NRC(=NR)NRR, S(O)R, S(O)NRiRi, S(O)2Ri, NRiS(O)2Ri, NRiS (O)2NRiRi, and S(O)2NRiRi, wherein said C1-6 alkyl, C3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C6-10 aryl and 5- to 6-membered heteroaryl are optionally substituted by 1, 2 or 3 independently selected Rj substituents; each Rj is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, ORk, SRk, C(O)Rk, C(O)NRkRk, C(O)ORk, OC(O)Rk, OC( O)NRkRk, NRkRk, NRkC(O)Rk, NRkC(O)NRkRk, NRkC(O)ORi, C(=NRk)NRkRk, NRkC(=NRk)NRkRk, S(O)Rk, S(O)NRkRk, S(O)2Rk, NRkS(O)2Rk, NRkS(O)2NRkRk and S(O)2NRkRk; each Re, Rg, Ri or Rk is independently selected from H, C1-4 alkyl, C6-10 aryl, C1-4 haloalkyl, C2-4 alkenyl and C2-4 alkyl, wherein the C1-4 alkyl, C6-aryl 10, C2-4 alkenyl or C2-4 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1 alkylamino -4, di(C1-4alkyl)amino, haloC1-4alkyl and haloC1-4alkoxy; or any two Re substituents attached to the same N atom together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 independently selected Rh substituents; or any two Rg substituents attached to the same N atom together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 independently selected Rh substituents; or any two Ri substituents attached to the same N atom together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted by 1, 2 or 3 independently selected Rh substituents; X1 is -CR10R11- or -NR7- X2 is N or CR6; R1 is C1-3 alkyl or C1-3 haloalkyl; R2 and R5 are halogen; R3 is H, halo, C1-3 alkyl, C1-3 haloalkyl, CN or C1-3 alkoxy; R4 is C1-3 alkyl or C1-3 haloalkyl; R6 is selected from H, halo, CN, ORa4, SRa4, C(O)NRc4Rd4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S( O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, S(O)2NRc4Rd4, C1-6 alkyl, C26 alkenyl, C2 alkynyl -6, C1-6 haloalkyl, phenyl, C3-6 cycloalkyl, a 5- to 6-membered heteroaryl having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4- to 7-membered heterocycloalkyl having has carbon and 1, 2 or 3 heteroatoms selected from N, O and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-6 cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups of R6 are each optionally substituted by 1, 2, or 3 substituents independently selected from R10A; R7 is selected from H, C(O)NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, S(O)2NRc4Rd4, C1-6 alkyl, C2-6 alkenyl, C2 alkynyl -6, C1-6 haloalkyl, phenyl, C3-6 cycloalkyl, 5- to 6-membered heteroaryl having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4- to 7-membered heterocycloalkyl moiety which has carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-6 cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups of R7 are each optionally substituted by 1, 2 or 3 substituents independently selected from R10A; R10 and R11 are each independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4- to 10-membered heterocycloalkyl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl groups of R10 and R11 are each one, optionally substituted with 1, 2 or 3 R10A; alternatively, R10 and R11 together with the carbon atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group or a 4-, 5-, 6-, 7-, 8-, 9-, or 7-membered heterocycloalkyl group. 10 members; wherein said 3, 4, 5, 6 or 7 membered cycloalkyl group and said 4, 5, 6, 7, 8, 9 or 10 membered heterocycloalkyl group are each optionally substituted with 1, 2, 3 or 4 R10A; each R10A is independently selected from halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(=NRe4) )NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S( O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, S(O)2NRc4Rd4, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C16 haloalkyl, phenyl, C3-6 cycloalkyl, one heteroaryl moiety 5- to 6-membered heterocycloalkyl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4- to 7-membered heterocycloalkyl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-6 cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups of R10A are each optionally substituted by 1, 2, or 3 substituents independently selected from R19; each Ra4, Rb4, Rc4 and Rd4 is independently selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, phenyl, C3-6 cycloalkyl, a 5- to 6-membered heteroaryl moiety that has carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 4- to 7-membered heterocycloalkyl moiety having carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein said C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, C36 cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups of Ra4, Rb4, Rc4 and Rd4 are each , optionally substituted with 1, 2 or 3 substituents independently selected from R19; alternatively, Rc4 and Rd4, together with the nitrogen atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group which is optionally substituted by 1, 2, or 3 substituents independently selected from R19; each Re4 is independently H or C1-4 alkyl; each R19 is independently selected from halo, CN, NO2, ORa9, SRa9, C(O)Rb9, C(O)NRc9Rd9, C(O)ORa9, OC(O)Rb9, OC(O)NRc9Rd9, NRc9Rd9, NRc9C( O)Rb9, NRc9C(O)ORa9, NRc9C(O)NRc9Rd9, NRc9S(O)Rb9, NRc9S(O)2Rb9, NRc9S(O)2NRc9Rd9, S(O)Rb9, S(O)NRc9Rd9, S(O) 2Rb9, S(O)2NRc9Rd9, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl and C1-4 haloalkyl; each Ra9, Rc9 and Rd9 is independently selected from H and C1-4 alkyl; each Rb9 is independently C1-4 alkyl; eon subscript is 0, 1, 2 or 3. 4. Compound according to any one of claims 1 to 3, characterized in that it has formula (Ia):

or a pharmaceutically acceptable salt thereof. 5. Compound according to any one of claims 1 to 3, characterized in that it has the formula (Ib):

or a pharmaceutically acceptable salt thereof. 6. Compound according to any one of claims 1 to 3, characterized in that it has the formula (Ic):

or a pharmaceutically acceptable salt thereof. 7. Compound according to any one of claims 1 to 3, characterized in that it has the formula (Id):

or a pharmaceutically acceptable salt thereof. 8. Compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, characterized in that ring A is C6-10 aryl. 9. Compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, characterized in that ring A is phenyl. Compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, characterized in that ring A is 5-membered heteroaryl. 11. Compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, characterized in that ring A is a 5-membered heteroaryl selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiophenyl, thiazolyl, isoxazolyl, isothiazolyl and furanyl. Compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, characterized in that ring A is 6-membered heteroaryl. 13. Compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, characterized in that ring A is a 6-membered heteroaryl selected from pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl. 14. Compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, characterized in that ring A is pyridyl. 15. Compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, characterized in that ring A is 6-membered phenyl or heteroaryl. 16. Compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, characterized in that ring A is phenyl or pyridyl. 17. Compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, characterized in that ring A is 4-pyrazolyl. 18. Compound, according to any one of claims 1 to 5, or a pharmaceutically acceptable salt of the yn-same, characterized in that the ring A is

19. Compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, characterized in that R2 and R5 are F. 20. Compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, characterized in that R1 and R4 are each C1-3 alkyl. 21. Compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, characterized in that R1 and R4 are each methyl. 22. Compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, characterized in that R10 and R11 are each C1-6 alkyl. 23. Compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, characterized in that R10 and R11 are methyl. 24. Compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, characterized in that R10 and R11 together with the carbon atom to which they are attached form a cycloalkyl group of 3, 4, 5, 6 or 7 members, which is optionally replaced by 1 or 2 independently selected R10A groups. 25. Compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, characterized in that R10 and R11 together with the carbon atom to which they are attached form a cyclopropyl, optionally substituted by 1 or 2 independently selected R10A groups. 26. Compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, characterized in that R10 and R11 together with the carbon atom to which they are attached form a cyclopropyl. 27. Compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, characterized in that R10 and R11 together with the carbon atom to which they are attached form a heterocycloalkyl group of 4, 5, 6 or 7 members, which is optionally replaced by 1 or 2 independently selected R10A groups. 28. Compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, characterized in that X2 is N or CH. 29. Compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, characterized in that X2 is CH. 30. Compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, characterized in that each R12 is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2 alkynyl -6, C1-6 haloalkyl, C6-10 aryl, cycloalkyl, C3-10, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-4-alkyl, C3-10 cycloalkyl-alkyl C1-4-, (5- to 10-membered heteroaryl)-C1-4-alkyl-, (4- to 10-membered heterocycloalkyl)-C1-4-alkyl-, CN, ORa, SRa, C(O)Ra, C(O )NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NRaRa, NRaORa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, NRaS(O)Ra, NRaS (O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra and S(O)2NRaRa, wherein a is C1-6 alkyl, C2-6 alkenyl, C2 alkynyl -6, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-4-alkyl, C3-10-cycloalkyl-C1-4-alkyl, ( (5- to 10-membered heteroaryl)-C 1-4 alkyl-, and (4- to 10-membered heteroaryl)-C 1-4 alkyl- are each optionally substituted by 1, 2 or 3 Rb substituents. 31. Compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, characterized in that each R12 is independently selected from -NH2, -NHOH, -NHORa, -NHRa, -NHC( O)Ra, -NHC(O)NHRa, -NHS(O)2Ra, -C(O)Ra, -S(O)2Ra, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-haloalkoxy 4, halo, CN, C3-6 cycloalkyl, phenyl-C1-4 alkyl, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-C1-4 alkyl, 4- to 6-membered heterocycloalkyl and (4- to 10-membered heterocycloalkyl) member)-C1-4-alkyl, where a is C1-6-alkyl, C3-6-cycloalkyl, phenyl-C1-4-alkyl, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl-C1-4-alkyl, C-1-4 heterocycloalkyl 4- to 6-membered and (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl- are optionally substituted by 1 to 3 Rb; and C1-6alkoxy or C1-4haloalkoxy is optionally substituted by 1 to 3 Rd. 32. Compound, according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, characterized in that each R12 is independently selected from F, Cl, CN, CH3, CH2CH3, NH2, OCH3, -C (O)NH(C1-4 alkyl), NHC(O)CH3, NHS(O)2CH3, NHS(O)2Ra, C(O)Ra, -CH2C(O)Ra, -CH2CH2Ra, morpholinosulfonyl, imidazolyl, 4 -morpholinyl, (3-cyanopyrrolidin-1-yl)methyl, 2-cyanoprop-2-yl, 1-cyanocyclobutyl, 1-cyanocyclopropyl, benzyl, pyridylmethyl, 1,1-dioxothiolan-3-yl, 1-methylsulfonylazetidin-3- yl, 1-acetyl-3-(cyanomethyl)azetidin-3-yl and -CH 2 -(4-morpholinyl), where Ra is 4-morpholinyl. 33. Compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, characterized in that each R12 is independently NH2, CH3, F, CN, 1-piperidinyl, 1-piperazinyl or 4- morpholinil. 34. Compound according to any one of claims 1 and 6 to 33, characterized in that R13 and R14 are each independently selected from among C1-4 alkyl-NHC(O)- and OCH3. 35. Compound, according to any one of claims 1 to 3, 5 and 8 to 34, or a pharmaceutically acceptable salt thereof, characterized in that R7 is C1-6 alkyl, phenyl, benzyl, C3-6 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl-, 4- to 10-membered heterocycloalkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, 5- to 10-membered heteroaryl, or (5- to 10-membered heteroaryl)-alkyl C1-4-, each of which is optionally substituted with 1, 2 or 3 independently selected R10A substituents; or two R10A substituents attached to adjacent ring atoms of the aryl or heteroaryl ring of R7, are optionally taken together with the atoms to which they are attached and form a fused C5-6 cycloalkyl ring or a fused 5-6 membered heterocycloalkyl ring having 1 to 2 heteroatoms as ring members independently selected from O, N and S, wherein the nitrogen and sulfur atoms are each optionally oxidized and the C5-6 cycloalkyl ring fused or the 5- to 6-membered heterocycloalkyl ring fused is optionally replaced by 1 or 2 independently selected R19 groups. 36. Compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, characterized in that R10A is halo, CN, C1-6 alkyl, C3-6 cycloalkyl, -C(O)Rb4 or -C(O)ORb4; or two R10A substituents attached to adjacent ring atoms of the aryl or heteroaryl ring of R7, are optionally taken together with the atoms to which they are attached and form a 5- to 6-membered heterocycloalkyl ring having 1 to 2 heteroatoms as members of the ring independently selected from O, N and S, in which the nitrogen and sulfur atoms are each optionally oxidized. 37. Compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, characterized in that R10A is F, Cl, CH3, C1-6 alkyl, CN, -C(O)C1- alkyl 4 or alkyl -C(O)OC1-4; or two R10A substituents attached to adjacent ring atoms of the aryl or heteroaryl ring of R7 are optionally taken together with the atoms to which they are attached to form a tetrahydrofuran, tetrahydropyran, 1,4-dioxane, morpholine, ring tetrahydrothiopyran or tetrahydrothiophene, each of which is optionally substituted by 1 or 2 R19 substituents. 38. Compound according to any one of claims 1 to 3, 5 and 8 to 37, or a pharmaceutically acceptable salt thereof, characterized in that R7 is C1-6 alkyl, cyclopropylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclo- hexyl, 4-fluorobenzyl, tetrahydrofuran-3-yl, (3-methylisoxazol-5-yl)methyl, (tetrahydro-2H-pyran-4-yl)methyl, (5-cyclopropylisoxazol-3-yl)methyl , 5-methylisoxazol-3-yl)methyl, 4-fluorophenyl, (1-ethylpyrazol-4-yl)methyl, benzothiazol-6-yl, 1-methyl-5-oxopyrrolidin-3-yl, 1-acetylpiperidin-4- yl, 2,3-dihydro-1,4-benzodioxin-6-ylmethyl, 1-t-butoxycarbonylpiperidin-4-yl, 4-cyanophenyl, 4-pyrimidinyl, 2-pyrimidinyl, 5-pyrimidinyl, 1-methylpyrazol- 3-yl, 1-methylpyrazol-4-yl, (1,5-dimethylpyrazol-4-yl)methyl, or (5-methyl-1,3,4-oxadiazol-2-yl)methyl. 39. Compound according to any one of claims 1 to 3, 5 and 8 to 37, or a pharmaceutically acceptable salt thereof, characterized in that R7 is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, phenyl, C3-6 cycloalkyl, a 5-6 membered heteroaryl with carbon and 1, 2 or 3 heteroatoms independently selected from N, O and S, and a heterocycloalkyl moiety of 4 -7 members with carbon and 1, 2, or 3 heteroatoms independently selected from N, O and S; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-6 cycloalkyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl groups of R7 are each optionally substituted with 1, 2 or 3 substituents independently selected from R10A. 40. Compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, characterized in that R3 is H. 41. Compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, characterized in that the subscript n is 0, 1 or 2. 42. Compound according to any one of claims 1 to 5, characterized in that: ring A is phenyl or a 6-membered heteroaryl ring; R10 and R11 are C1-6 alkyl; alternatively, R10 and R11, together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6- or 7-membered cycloalkyl group, which is optionally substituted by 1 or 2 independently selected R10A groups. each R12 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C6-10 aryl-C1-alkyl 4-, C3-10 cycloalkyl-C1-4 alkyl-, (5- to 10-membered heteroaryl)-C1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO2, ORa, C(O)Ra, C(O)NRaRa, C(O)ORa, NRaRa, NRaORa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, NRaS(O)2Ra, NRaS(O) 2NRaRa, S(O)2Ra and S(O)2NRaRa, wherein a is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, heterocycloalkyl 4- to 10-membered aryl-C1-4-alkyl-, C3-10-cycloalkyl-C1-4-alkyl-, (5- to 10-membered heteroaryl)-C1-4-alkyl- and (4- to 10-membered heterocycloalkyl) )-C1-4 alkyl are each optionally substituted by 1 to 3 independently selected Rb substituents; each Rb is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, NO2, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O) Rc, OC(O)NRcRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S(O) Rc, S(O)NRcRc, S(O)2Rc and S(O)2NRcRc; each Rc is independently selected from H and C1-6 alkyl; and the subscript n is 0, 1, 2 or 3. 43. Compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, characterized in that X1 is CR10R11; X2 is CH; ring A is phenyl or a 6-membered heteroaryl ring; R10 and R11 are C1-6 alkyl; alternatively, R10 and R11, together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6- or 7-membered cycloalkyl group, which is optionally substituted by 1 or 2 independently selected R10A groups. each R12 is independently selected from halo, CN, NRaRa, NRaORa, NHC(O)Ra, NHS(O)2Ra, C(O)Ra, S(O)2Ra, ORa, C1-6 alkyl, C1-6 haloalkyl, 5 to 6 membered heteroaryl and 4 to 6 membered heterocycloalkyl, wherein said C1-6 alkyl, 5 to 6 membered heteroaryl or 4 to 6 membered heterocycloalkyl is optionally substituted with from 1 to 3 Rb; each Rb is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, NO2, ORc, SRc, C(O)Rc, C(O)NRcRc, c c cc cc c c c c C(O)OR , OC(O)R , OC(O)NR R , NR R , NR C(O)R , NR C(O)OR , c cc c c c c c cc c NR C(O)NR R , NR S(O)R , NR S(O)2R , NR S(O)2NR R , S(O)R , S(O)NRcRc, S(O)2Rc and S(O)2NRcRc; each Rc is independently selected from H and C1-6 alkyl; and the n subscript is 0, 1, 2 or 3. 44. Compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, characterized in that X1 is CR10R11; X2 is CH; ring A is phenyl or pyridyl; R10 and R11 are C1-6 alkyl; alternatively, R10 and R11, together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6- or 7-membered cycloalkyl group, which is optionally substituted by 1 or 2 independently selected R10A groups. each R12 is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl, (4- to 6-membered heterocycloalkyl)-C 1-2 alkyl-, CN, ORa , C(O)Ra, NRaRa, NRaS(O)2Ra and S(O)2Ra; each Ra is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl; and the n subscript is 0, 1, 2 or 3. 45. Compound, according to claim 1, characterized in that the compound is selected from: 6'-(5-amino-2-methylphenyl)-2'-(2,6-difluoro-3,5-dimethoxyphenyl) )-1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-3'(2'H)-one; 6'-(5-amino-4-fluoro-2-methylphenyl)-2'-(2,6-difluoro-3,5-dimethoxyphenyl)-1'H-spiro[cyclopropane-1,4'-[2, 7]naphthyridin]-3'(2'H)-one; 4-amino-2-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4 '-[2,7]naphthyridine]-6'-yl)benzonitrile; 6'-(5-aminopyridin-3-yl)-2'-(2,6-difluoro-3,5-dimethoxyphenyl)-1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin] -3'(2'H)-one; 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(5-fluoropyridin-3-yl)-1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin] -3'(2'H)-one; 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(5-morpholinopyridin-3-yl)-1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin] -3'(2'H)-one; 6'-(5-amino-2-methylpyridin-3-yl)-2'-(2,6-difluoro-3,5-dimethoxyphenyl)-1'H-spiro[cyclopropane-1,4'-[2, 7]naphthyridin]-3'(2'H)-one; 5-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-[2 ,7]naphthyridine]-6'-yl)nicotinonitrile; 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(pyridin-3-yl)-1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-3 '(2'H)-one; 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(5-methoxypyridin-3-yl)-1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin] -3'(2'H)-one; 6'-(5-chloropyridin-3-yl)-2'-(2,6-difluoro-3,5-dimethoxyphenyl)-1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin] -3'(2'H)-one; 6'-(5-(1H-imidazol-1-yl)pyridin-3-yl)-2'-(2,6-difluoro-3,5-dimethoxyphenyl)-1'H-spiro[cyclopropane-1,4 '-[2,7]naphthyridin]-3'(2'H)-one; 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(5-(morpholine-4-carbonyl)pyridin-3-yl)-1'H-spiro[cyclopropane-1,4'- [2,7]naphthyridin]-3'(2'H)-one; 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(5-(morpholinosulfonyl)pyridin-3-yl)-1'H-spiro[cyclopropane-1,4'-[2,7 ]naphthyridin]-3'(2'H)-one; N-(5-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4' -[2,7]naphthyridine]-6'-yl)pyridin-3-yl)methanesulfonamide; and 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(5-(morpholinomethyl)pyridin-3-yl)-1'H-spiro[cyclopropane-1,4'-[2, 7]naphthyridin]-3'(2'H)-one, or a pharmaceutically acceptable salt thereof. 46. Compound according to claim 1, characterized in that the compound is selected from: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(pyridin-3-yl )-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl )-N-methylpicolinamide; (S)-1-(4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3- d]pyrimidin-7-yl)benzyl)pyrrolidine-3-carbonitrile; 2-(5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin- 7-yl)pyridin-2-yl)-2-methylpropanenitrile; 1-(5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin- 7-yl)pyridin-2-yl)cyclobutanecarbonitrile; 1-(cyclopropylmethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4, 3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-propyl-3,4-dihydropyrido[4,3- d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-((5-methylisoxazol-3-yl)methyl)-3 ,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 1-cyclopentyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3- d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(tetrahydrofuran-3-yl)-3,4- dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(4-fluorobenzyl)-3,4-dihydropyrido[ 4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-((3-methylisoxazol-5-yl)methyl)-3 ,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 1-((5-cyclopropylisoxazol-3-yl)methyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-3 ,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-((tetrahydro-2H-pyran-4-yl) methyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-7-(1,3 -dimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-((1-ethyl-1H-pyrazol-4-yl) methyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(4-fluorophenyl)-3,4-dihydropyrido[ 4,3-d]pyrimidin-2(1H)-one; 1-(1,3-benzothiazol-6-yl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-3, 4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1-methyl-5-oxopyrrolidin-3-yl)- 3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 1-(1-Acetylpiperidin-4-yl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4- dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3,4-dihydropyrido[4 ,3-d]pyrimidin-1(2H)-yl)benzonitrile; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-pyrimidin-4-yl-3,4-dihydropyrido[ 4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-[(5-methyl-1,3,4-oxadiazol- 2-yl)methyl]-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1-methyl-1H-pyrazol-4-yl)- 3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-[(1,5-dimethyl-1H-pyrazol-4- yl)methyl]-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-3,4-di- hydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)-3,4- dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(3-methyl-1-(2-morpholino-2-oxoethyl)-1H-pyrazol-4-yl)-3, 4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(3-methyl-1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1'H-spiro[cyclopropane- 1,4'-[2,7]naphthyridin]-3'(2'H)-one; 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(1-ethyl-1H-imidazol-4-yl)-1'H-spiro[cyclopropane-1,4'-[2, 7]naphthyridin]-3'(2'H)-one; 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-[1-(1,1-dioxidotetrahydro-3-thienyl)-3-methyl-1H-pyrazol-4-yl]- 1',2'-dihydro-3'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-3'-one; 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(1-(1-(methylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-1'H-spiro [cyclopropane-1,4'-[2,7]naphthyridin]-3'(2'H)-one; and 2-(1-acetyl-3-(4-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro-1'H- spiro[cyclopropane-1,4'-[2,7]naphthyridin]-6'-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile; or a pharmaceutically acceptable salt thereof. 47. Compound, according to claim 1, characterized in that the compound is selected from: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazole -4-yl)-1-(pyridazin-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-((2-methoxypyridin-4-yl)methyl)-3 ,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-((6-methoxypyridin-3-yl)methyl)-3 ,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3,4-dihydropyrido[4 ,3-d]pyrimidin-1(2H)-yl)benzonitrile; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(pyrimidin-5-yl)-3,4-di- hydropyrido[4,3-d]pyrimidin-2(1H)-one; 4-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3,4-dihydropyrido[ 4,3-d]pyrimidin-1(2H)-yl)methyl)-N-methylbenzamide; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(isoquinolin-7-yl)-3,4-di- hydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-((5-ethylisoxazol-3-yl)methyl)-3 ,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(pyrimidin-4-ylmethyl)-3,4-di- hydropyrido[4,3-d]pyrimidin-2(1H)-one; 5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3,4-dihydropyrido[4 ,3-d]pyrimidin-1(2H)-yl)-2-fluorobenzonitrile; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-((5-ethyl-1,3,4-oxadiazol- 2-yl)methyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-((2-methylpyridin-4-yl)methyl)-3 ,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(pyridin-4-ylmethyl)-3,4-di- hydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(pyrazin-2-yl)-3,4-di- hydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1-(methylsulfonyl)piperidin-4-yl)-3 ,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-((1-methyl-1H-pyrazol-4-yl) methyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(3,4-difluorobenzyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4-di- hydropyrido[4,3-d]pyrimidin-2(1H)-one; 5-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3,4-dihydropyrido[ 4,3-d]pyrimidin-1(2H)-yl)methyl)picolinonitrile; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(2-methylbenzo[d]oxazol-6-yl)- 3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methyl-3,4-dihydropyrido[4,3- d]pyrimidin-2(1H)-one; 1-(4-(1H-pyrazol-1-yl)phenyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl) -3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3,4-dihydropyrido[4 ,3-d]pyrimidin-1(2H)-yl)-5-fluorobenzonitrile; 6-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3,4-dihydropyrido[4 ,3-d]pyrimidin-1(2H)-yl)nicotinonitrile; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(oxazol-5-ylmethyl)-3,4-di- hydropyrido[4,3-d]pyrimidin-2(1H)-one; 4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3,4-dihydropyrido[4 ,3-d]pyrimidin-1(2H)-yl)-2-methoxybenzonitrile; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-((5-methyloxazol-2-yl)methyl)-3 ,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 1-cyclopropyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3- d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(pyrimidin-5-ylmethyl)-3,4-di- hydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(pyrazin-2-ylmethyl)-3,4-di- hydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(pyridin-3-yl)-3,4-di- hydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(6-methylpyrazin-2-yl)-3,4- dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(pyridazin-3-ylmethyl)-3,4-di- hydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(3-(1-methyl-1H-1,2, 3-triazol-5-yl)phenyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-isopropyl-3,4-dihydropyrido[4,3- d]pyrimidin-2(1H)-one; 1-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3,4-dihydropyrido[4 ,3-d]pyrimidin-1(2H)-yl)cyclopropanecarbonitrile; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(pyridin-2-yl)-3,4-di- hydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-((5-isopropylisoxazol-3-yl)methyl)-3 ,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(pyridin-2-ylmethyl)-3,4-di- hydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-((2-methylthiazol-4-yl)methyl)-3 ,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-((1-methyl-5-oxopyrrolidin-3-yl) methyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 2-(4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3,4-di- hydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetonitrile; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(4-(methylsulfonyl)phenyl)-3,4-di -hydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(3-fluorophenyl)-3,4-dihydropyrido[ 4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1-methyl-1H-pyrazol-3-yl)- 3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-((1,3-dimethyl-1H-pyrazol-4- yl)methyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(3,4-difluorophenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4-di- hydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(3,5-difluorophenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4-di- hydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(4-methoxyphenyl)-3,4-dihydropyrido[ 4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(pyrimidin-2-yl)-3,4-di- hydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(5-ethylpyrazin-2-yl)-3,4- dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(5-methylpyrazin-2-yl)-3,4- dihydropyrido[4,3-d]pyrimidin-2(1H)-one; (R)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-((tetrahydrofuran-3-yl) methyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(3-methoxyphenyl)-3,4-dihydropyrido[ 4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(2-fluorophenyl)-3,4-dihydropyrido[ 4,3-d]pyrimidin-2(1H)-one; 3-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3,4-dihydropyrido[4 ,3-d]pyrimidin-1(2H)-yl)-N-methylbenzenesulfonamide; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(5-methoxypyrazin-2-yl)-3,4- dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3,4-dihydropyrido[4 ,3-d]pyrimidin-1(2H)-yl)-N,N-dimethylbenzamide; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(2-(1-methyl-1H-pyrazol-4- yl)ethyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(4-(5-methyl-1,3,4- oxadiazol-2-yl)phenyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-((2-ethoxypyridin-4-yl)methyl)-3 ,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-((1-methyl-2-oxo-1,2- dihydropyridin-4-yl)methyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-((1-methyl-1H-benzo[d][1 ,2,3]triazol-5-yl)methyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(2-oxoindolin-5-yl)-3,4- dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(2-methyl-3-oxoisoindolin-5-yl)- 3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-((2-methylpyrimidin-4-yl)methyl)-3 ,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3,4-dihydropyrido[4 methyl ,3-d]pyrimidin-1(2H)-yl)piperidine-1-carboxylate; 4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3,4-dihydropyrido[4 methyl ,3-d]pyrimidin-1(2H)-yl)phenylcarbamate; 1-((1-cyclopropyl-1H-pyrazol-4-yl)methyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4- yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 2-(4-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-2-oxo-3,4-di -hydropyrido[4,3-d]pyrimidin-1(2H)-yl)methyl)-1H-pyrazol-1-yl)acetonitrile; 1-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol- 4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-((1-((tetrahydrofuran-2-yl) methyl)-1H-pyrazol-4-yl)methyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)methyl)-7-(1,3-dimethyl- 1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1H-pyrazol-4-yl)-3,4- dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 1-(1-cyclopropyl-1H-pyrazol-4-yl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)- 3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1-ethyl-1H-pyrazol-4-yl)- 3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1-propyl-1H-pyrazol-4-yl)- 3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1H-indazol-6-yl)-3,4- dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-(1H-indazol-5-yl)-3,4- dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 1-(5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-(pyrimidin-4-yl)-1,2,3,4-tetrahydropyrido[4, 3-d]pyrimidin-7-yl)pyridin-2-yl)cyclobutanecarbonitrile; 1-(5-(1-cyclobutyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin- 7-yl)pyridin-2-yl)cyclobutanecarbonitrile; 1-(5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-(pyridin-2-yl)-1,2,3,4-tetrahydropyrido[4, 3-d]pyrimidin-7-yl)pyridin-2-yl)cyclobutanecarbonitrile; 1-(5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-(pyridin-3-yl)-1,2,3,4-tetrahydropyrido[4, 3-d]pyrimidin-7-yl)pyridin-2-yl)cyclobutanecarbonitrile; 1-(5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-methoxyethyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3- d]pyrimidin-7-yl)pyridin-2-yl)cyclobutanecarbonitrile; 1-(5-(1-(cyclopropylmethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d] pyrimidin-7-yl)pyridin-2-yl)cyclobutanecarbonitrile; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(1-methyl-1H-pyrazol-3-yl)-3,4-dihydropyrido[4,3-d] pyrimidin-2(1H)-one; 4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1-methyl-1H-pyrazol-3-yl)-2-oxo-3,4-dihydropyrido[4,3 -d]pyrimidin-1(2H)-yl)benzonitrile; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-((1-ethyl-1H-pyrazol-4-yl)methyl)-7-(1-methyl-1H-pyrazol-3-yl) -3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1-methyl-1H-pyrazol-4-yl)-2-oxo-3,4-dihydropyrido[4,3 -d]pyrimidin-1(2H)-yl)benzonitrile; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-((1-ethyl-1H-pyrazol-4-yl)methyl)-7-(1-methyl-1H-pyrazol-4-yl) -3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one; 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(3-methyl-1-(3-morpholinopropyl)-1H-pyrazol-4-yl)-1'H-spiro[cyclopropane- 1,4'-[2,7]naphthyridin]-3'(2'H)-one; 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(1-(1-(methylsulfonyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1'H-spiro [cyclopropane-1,4'-[2,7]naphthyridin]-3'(2'H)-one; 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(1-(2-(1-(methylsulfonyl)piperidin-4-yl)ethyl)-1H-pyrazol-4-yl)- 1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-3'(2'H)-one; 1-(4-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4' -[2,7]naphthyridin]-6'-yl)-5-methyl-1H-pyrazol-1-yl)cyclobutanecarbonitrile; 6'-(1-(1-acetylpyrrolidin-3-yl)-1H-pyrazol-4-yl)-2'-(2,6-difluoro-3,5-dimethoxyphenyl)-1'H-spiro[cyclopropane- 1,4'-[2,7]naphthyridin]-3'(2'H)-one; 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(1-(3-morpholinopropyl)-1H-pyrazol-4-yl)-1'H-spiro[cyclopropane-1,4' -[2,7]naphthyridin]-3'(2'H)-one; 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(1-(2-(4-methoxypiperidin-1-yl)ethyl)-1H-pyrazol-4-yl)-1'H -spiro[cyclopropane-1,4'-[2,7]naphthyridin]-3'(2'H)-one; 2-(4-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4' -[2,7]naphthyridin]-6'-yl)-3-methyl-1H-pyrazol-1-yl)acetonitrile; 2-(3-(4-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1 ,4'-[2,7]naphthyridin]-6'-yl)-3-methyl-1H-pyrazol-1-yl)pyrrolidin-1-yl)acetonitrile; 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(3-methyl-1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)-1'H-spiro[ cyclopropane-1,4'-[2,7]naphthyridin]-3'(2'H)-one; 3-(4-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4' -[2,7]naphthyridin]-6'-yl)-3-methyl-1H-pyrazol-1-yl)propanenitrile; 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1'H-spiro[cyclopropane-1,4' -[2,7]naphthyridin]-3'(2'H)-one; 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-1'H-spiro[cyclopropane-1,4' -[2,7]naphthyridin]-3'(2'H)-one; 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(3-methyl-1-(2-morpholino-2-oxoethyl)-1H-pyrazol-4-yl)-1'H- spiro[cyclopropane-1,4'-[2,7]naphthyridin]-3'(2'H)-one; 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(2-(dimethylamino)thiazol-4-yl)-1'H-spiro[cyclopropane-1,4'-[2,7 ]naphthyridin]-3'(2'H)-one; 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(1-(2-(3-methoxypyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)-1'H -spiro[cyclopropane-1,4'-[2,7]naphthyridin]-3'(2'H)-one; 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-{1-[(1,1-dioxide-1,2-thiazinan-3-yl)methyl]-1H-pyrazol-4- yl}-1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-3'(2'H)-one; 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(3-methyl-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)-1'H- spiro[cyclopropane-1,4'-[2,7]naphthyridin]-3'(2'H)-one; 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)-1'H-spiro [cyclopropane-1,4'-[2,7]naphthyridin]-3'(2'H)-one; 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(3-methyl-1-(2-(piperidin-4-yl)ethyl)-1H-pyrazol-4-yl)-1 'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-3'(2'H)-one; 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(1-((1-(methylsulfonyl)azetidin-3-yl)methyl)-1H-pyrazol-4-yl)-1' H- spiro[cyclopropane-1,4'-[2,7]naphthyridin]-3'(2'H)-one; 6'-(1-((1-acetylazetidin-3-yl)methyl)-1H-pyrazol-4-yl)-2'-(2,6-difluoro-3,5-dimethoxyphenyl)-1'H-spiro [cyclopropane-1,4'-[2,7]naphthyridin]-3'(2'H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4, 3-d]pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydropyrido[4,3-d] pyrimidin-2(1H)-one; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazol-4-yl)-1-ethyl-3,4-dihydropyrido[4,3- d]pyrimidin-2(1H)-one; 5-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-[2 ,7]naphthyridin]-6'-yl)-1H-pyrazole-4-carbonitrile; 3-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-[2 ,7]naphthyridin]-6'-yl)-1-methyl-1H-pyrazole-4-carbonitrile; 3-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-[2 ,7]naphthyridin]-6'-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazole-4-carbonitrile; 1-(cyanomethyl)-3-(2'-(2,6-difluoro-3,5-dimethoxyphenyl)-3'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1 ,4'-[2,7]naphthyridine]-6'-yl)-1H-pyrazole-4-carbonitrile; 5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl )-N-ethylpicolinamide; N-cyclopropyl-5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin -7-yl)picolinamide; 5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl )-N-(2-hydroxyethyl)picolinamide; 5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl )-N-isopropylpicolinamide; 5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl )-N-propylpicolinamide; 2-(4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin- 7-yl)phenyl)acetonitrile; 1-(4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin- 7-yl)phenyl)cyclobutanecarbonitrile; 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(6-morpholinopyridin-3-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2( 1H)-one; 1-(4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin- 7-yl)phenyl)cyclopropanecarbonitrile; 5-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl )picolinamide; 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(pyridin-4-yl)-1'H-spiro[cyclopropane-1,4'-[2,7]naphthyridin]-3 '(2'H)-one; 2'-(2,6-difluoro-3,5-dimethoxyphenyl)-6'-(1-methyl-1H-pyrazol-4-yl)-1',2'-dihydro-3'H-spiro[ cyclopropane-1,4'-[2,7]naphthyridin]-3'-one; 1-(5-{3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-2-oxo-1 ,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl}pyridin-2-yl)cyclobutanecarbonitrile; and 1-{5-[3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1,2,3,4 -tetrahydropyrido[4,3-d]pyrimidin-7-yl]pyridin-2-yl}cyclobutanecarbonitrile; or a pharmaceutically acceptable salt thereof. 48. Compound according to claim 1, characterized in that the compound is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazole-4- yl)-1-(pyridazin-4-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one, or a pharmaceutically acceptable salt thereof. 49. Compound according to claim 1, characterized in that the compound is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazole-4- yl)-1-pyrimidin-4-yl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one, or a pharmaceutically acceptable salt thereof. 50. Compound according to claim 1, characterized in that the compound is 4-(3-(2,6-difluoro-3,5-dimethoxyphenyl)-7-(1,3-dimethyl-1H-pyrazole -4-yl)-2-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. 51. Pharmaceutical composition, characterized in that it comprises a compound as defined in any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle or excipient. 52. Use of a compound as defined in any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, or a composition as defined in claim 51, characterized in that it is for the preparation of a composition or medicine to treat cancer in a patient. 53. Use, according to claim 52, characterized in that said cancer is selected from hepatocellular cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer , kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, leukemia adult T-cell, B-cell lymphoma, acute myeloid leukemia, Hodgkin's or non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, hairy cell lymphoma, Burkitt's lymphoma, glioblastoma, melanoma and rhabdosarcoma. 54. Use, according to claim 52, characterized in that said cancer is selected from hepatocellular cancer, breast cancer, bladder cancer, colorectal cancer, melanoma, mesothelioma, lung cancer, prostate cancer, pancreatic cancer , testicular cancer, thyroid cancer, squamous cell carcinoma, glioblastoma, neuroblastoma, uterine cancer and rhabdosarcoma. 55. Use of a compound as defined in any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, or a composition as defined in claim 51, characterized in that it is for the preparation of a composition or medicine for the treatment of a myeloproliferative disorder in a patient, wherein said myeloproliferative disorder is selected from polycythemia vera, essential thrombocythemia and primary myelofibrosis. 56. Use of a compound as defined in any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, or a composition as defined in claim 51, characterized in that it is for the preparation of a composition or medicine to treat a disorder chondrocyte or skeletal disorder in a patient, wherein said chondrocyte or skeletal disorder is selected from acrondroplasia, hypochondroplasia, dwarfism, thanatophoric dysplasia (TD), Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome, cutis gyrata syndrome of Beare-Stevenson syndrome, Pfeiffer syndrome and craniosynostosis syndrome. 57. Use of a compound as defined in any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, or a composition as defined in claim 51, characterized in that it is for the preparation of a composition or medicine for the treatment of a hypophosphatemic disorder in a patient. 58. Use according to claim 57, characterized by the fact that said hypophosphatemic disorder is X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets or tumor-induced osteomalacia.