A combination of FGFR4 inhibitors and bile acid scavengers.

Abstract

Pharmaceutical combinations comprising an FGFR4 inhibitor and a bile acid sequestrant are provided. The present invention provides the use of a pharmaceutical combination comprising an FGFR4 inhibitor, particularly a selective FGFR4 inhibitor, and a bile acid sequestrant in the treatment of cancer, and the use of the bile acid sequestrant to reduce or alleviate side effects associated with FGFR4 inhibitory therapy.

Description

[Technical Field]

[0001] The present invention relates to FGFR4 inhibitors, particularly selective FGFR4 inhibitors and bile acids. Pharmaceutical combinations including a sequestrant (bile acid sequestrant), the aforementioned pharmaceuticals in the treatment of cancer The use of combinations of drugs, as well as side effects during treatment with FGFR4 inhibitors, particularly liver problems. Regarding the use of bile acid scavenging agents to reduce or prevent enzyme elevation. [Background technology]

[0002] In recent years, progress has been made in the treatment of certain cancers, particularly those related to the FGFR4 pathway. For example, International Publication No. 2015059668 and International Publication No. 201 Pamphlet No. 4 / 011900 discusses FGFR, which can be used in the treatment of cancer, especially liver cancer. It lists four inhibitors.

[0003] Liver cancer, including hepatocellular carcinoma (HCC), is the fifth most common form of cancer worldwide. It is the second leading cause of cancer-related death. Surgical resection, liver transplant, or other local treatments, etc. Potential curative therapies for patients with early-stage HCC have a 50-70% survival rate at 5 years. This brings about... However, despite advances in diagnostic techniques and increased research, H Most cases of cystic carcinoma (CC) present with progressive, inoperable tumors. Sorafenib is used in HCC. It is the only approved drug in this regard, but the improvement in overall survival (OS) is slight, and tolerance is low. [Overview of the Initiative] [Problems that the invention aims to solve]

[0004] Therefore, an improved safety profile, an improved toxicity profile, and standard treatment. Compared to the previous method, improvements were observed in efficacy, patient tolerance, overall response rate, overall survival, and progression-free survival. Cancer treatments, including the treatment of HCC, that have one or more benefits, such as advantages for patients. It is necessary to provide this.

[0005] As with any cancer treatment, side effects associated with cancer treatment, such as treatment for HCC, can be mitigated. It is also the responsibility of the pharmaceutical industry to provide methods to reduce or decrease the risk. This provides solutions for managing side effects in a way that is optimal for patients, especially those suffering from HCC. This is still necessary. [Means for solving the problem]

[0006] The present inventors have found that bile acid scavenging agents such as cholestyramine can be used to selectively inhibit FGFR inhibitors. Side effects observed after administration include increased alanine aminotransferase (ALT) levels. We found ways to mitigate and reverse the effects.

[0007] Therefore, the present invention relates to FGFR4 inhibitors, particularly selective FGFR4 inhibitors. And by providing a pharmaceutical combination including a bile acid scavenger, several of the above needs can be met. To deal with it.

[0008] In another embodiment, the present invention relates to an FGFR4 inhibitor for use as a pharmaceutical agent. Preferably relating to a pharmaceutical combination comprising a selective FGFR4 inhibitor and a bile acid scavenger. do.

[0009] In another embodiment, the present invention relates to FG for use in the treatment of cancer, particularly liver cancer. The formulation includes an FR4 inhibitor, preferably a selective FGFR4 inhibitor, and a bile acid scavenger. Regarding pharmaceutical combinations.

[0010] In a further embodiment, the present invention reduces or reduces side effects associated with FGFR4 inhibitor therapy. Regarding the use of bile acid scavengers for prevention. FGFR inhibitor therapy is FGFR4 inhibitory. The addition of a bitter, preferably compound A, or a pharmaceutically acceptable salt thereof, such as citrate. Includes the given.

[0011] In a further embodiment, the present invention reduces or reduces side effects associated with FGFR4 inhibitor therapy. The use of bile acid scavengers for prevention, where the side effect is not diarrhea, and the use of such agents. .

[0012] In another embodiment, the present invention relates to the occurrence or severity of side effects associated with FGFR4 inhibitor therapy. A method to reduce the degree of FGFR4 inhibition, and effective in patients requiring FGFR4 inhibitory therapy. A certain amount of bile acid scavenger and a therapeutically effective amount of FGFR4 inhibitor, preferably selective FGF The present invention relates to a method comprising the step of administering a combination containing an R4 inhibitor.

[0013] In yet another embodiment, the present invention relates to a bile acid scavenger and an FGFR4 inhibitor. Regarding treatment regimens involving timed or sequential administration. [Brief explanation of the drawing]

[0014] [Figure 1]This graph shows the changes in serum ALT (alanine aminotransferase) levels in dogs administered simultaneously or sequentially with a bile acid scavenger (cholestyramine, abbreviated as CHO) and an FGFR4 inhibitor (N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide, compound A, abbreviated as Cpd A). [Figure 2] This graph shows the changes in miRNA122 levels in the serum of dogs administered cholestyramine (abbreviated as CHO) simultaneously or sequentially with an FGFR4 inhibitor (compound A, abbreviated as Cpd A). [Modes for carrying out the invention]

[0015] The present invention relates to an FGFR4 inhibitor, preferably a selective FGFR4 inhibitor, and This relates to pharmaceutical combinations containing bile acid scavengers.

[0016] In this specification, "pharmaceutical combination" refers to a combination that is not fixed. The term "combination without active ingredients" refers to the active ingredient, for example, an FGFR4 inhibitor (or selective FGFR4 inhibitors and bile acid scavengers can be used together without specific time restrictions. This means that the drugs are administered to the patient sequentially as separate entities, and such administration is performed on the patient. It provides therapeutically effective levels of the two compounds within the body.

[0017] In the following, "the pharmaceutical combination of the present invention" refers to an FGFR4 inhibitor, preferably This refers to a pharmaceutical combination containing selective FGFR4 inhibitors and bile acid scavengers. In embodiments, the pharmaceutical combination of the present invention optionally includes N-(5-) in citrate form. Cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7-formyl- 6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4-dihydro- This refers to 1,8-naphthyridine-1(2H)-carboxamide and cholestyramine.

[0018] As used herein, the term “active ingredient” means independently of each individual This refers to the other drugs in the combination, namely FGFR4 inhibitors and bile acid scavengers.

[0019] As used herein, the term "FGFR4" refers to CD334, JTK 2. This refers to fibroblast growth factor receptor 4, also known as TKF.

[0020] FGFR4 inhibitory therapy refers to treatment involving the use of FGFR4 inhibitors. One embodiment In this context, FGFR4 inhibitor therapy is a treatment for cancer. Preferably, FGF R4 inhibitor therapy is a treatment for liver cancer, including HCC.

[0021] When used herein, an FGFR4 inhibitor inhibits FGFR4. It is a compound. Preferably, the FRFR4 inhibitor is a selective FGFR4 inhibitor. For example, FGFR4 is selected by comparing it with FGFR1, FGFR2, and FGFR3. It is a compound that specifically inhibits FGFR4. FGFR4 inhibitors can be small or large molecules. Good. The FGFR4 inhibitor of the present invention is preferably a small molecule.

[0022] Therapies involving FGFR4 blocking antibodies are, for example, described in the patent application, International Publication No. 2009 / Pamphlet No. 009173, International Publication No. 2007 / 136893, International Pamphlet No. 2012 / 138975, International Publication No. 2010 / 026291 Brochure, International Publication No. 2008 / 052798, International Publication No. 2010 / Pamphlet No. 004204, International Publication No. 2014 / 105849, International Brochure No. 2014 / 165287 and International Publication No. 2016 / 023894 It is stated in the issue number of the pamphlet. International Publication No. 2014 / 144737, International Publication No. 2014 / 145909, International Publication No. 2014 / 011900 Pamphlet No. 2015 / 057963, International Publication No. 201 Pamphlet No. 5 / 057938, International Publication No. 2015 / 030021, International Publication No. 2015 / 107171, International Publication No. 2015 / 059668 Pamphlet No. 2016 / 064960, International Publication No. 201 Pamphlet No. 6 / 134320, International Publication No. 2016 / 134314, International Publication No. 2016 / 134294 also discusses low molecular weight FGFR4 inhibitors. This section describes the tar.

[0023] In one embodiment, the FGFR4 inhibitor used in the combination of the present invention is patent The application is International Publication No. 2009 / 009173, International Publication No. 2007 / 1 Pamphlet No. 36893, International Publication No. 2012 / 138975, International Publication Pamphlet No. 2010 / 026291, International Publication No. 2008 / 052798 Fret, International Publication No. 2010 / 004204, International Publication No. 2014 / 1 Pamphlet No. 05849, International Publication No. 2014 / 165287, International Publication Pamphlet No. 2016 / 023894, International Publication No. 2014 / 144737 Fret, International Publication No. 2014 / 145909 Pamphlet, International Publication No. 2014 / 0 Pamphlet No. 11900, International Publication No. 2015 / 057963, International Publication Pamphlet No. 2015 / 057938, International Publication No. 2015 / 030021 Fret, International Publication No. 2015 / 107171 Pamphlet, International Publication No. 2015 / 0 Pamphlet No. 59668, International Publication No. 2016 / 064960, International Publication Pamphlet No. 2016 / 134320, International Publication No. 2016 / 134314 As stated in either the fret or the brochure International Publication No. 2016 / 134294 It is one of the FGFR4 inhibitors.

[0024] In one embodiment, the FGFR4 inhibitor used in the combination of the present invention is free International Publication No. 2014 / 144737, regarding the form or pharmaceutically acceptable form of the salt. Lett, International Publication No. 2014 / 145909 Pamphlet, International Publication No. 2014 / 01 Pamphlet No. 1900, International Publication No. 2015 / 057963, International Publication Pamphlet No. 2015 / 057938, International Publication Pamphlet No. 2015 / 030021 Lett, International Publication No. 2015 / 107171 Pamphlet, International Publication No. 2015 / 05 Pamphlet No. 9668, International Publication No. 2016 / 064960, International Publication Pamphlet No. 2016 / 134320, International Publication Pamphlet No. 2016 / 134314 Lett, FGFR4 inhibitor as described in International Publication No. 2016 / 134294 It is one of the following.

[0025] In one embodiment, the FGFR4 inhibitor used in the combination of the present invention is free International Publication No. 2015059668 pamphlet on the form or pharmaceutically acceptable salt form of the product. It is a compound as defined in the .

[0026] Therefore, in one embodiment, FGF used in the pharmaceutical combination of the present invention R4 inhibitors are available in free form or in pharmaceutically acceptable salt form, according to formula (I)

[0027] [ka] [In the formula, V is selected from CH2, O, and CH(OH); W is selected from CH2, CH2CH2, and bond types; X is C(R X ) or N; Y is C(R Y ) or N; Z is either CH or N; If X is N, then Y and Z are not N; If Y is N, then X and Z are not N; If Z is N, then X and Y are not N; R X These are hydrogen, halogens, C1-C3 alkyl halogens, cyanoalkyl halogens, C1-C6 alkyl halogens, and hydroxylomers. Selected from roxy C1-C6 alkyl groups; R Y These are hydrogen, halogens, C1-C3 alkyl, C1-C6 alkoxy, and hydroxy C1 ~C3 alkoxy, NR Y1 R Y2 cyanoacrylate, C1-C3 alkoxy, C1-C3 alkoxy C1-C3 alkoxy-halo C1-C3 alkoxy, di(C1-C3 alkyl) amine C1-C6 alkoxy, O-(CH2) 0~1 -RY3 , CR Y6 R Y7 , S-C1~ C3 alkyl, optionally selected from halo C1-C6 alkoxy substituted with hydroxy selected; or R X and R Y together with the ring to which they are attached, optionally further contain one or two heteroatoms selected from N, O, or S to form a bicyclic aromatic ring system, this ring system is optionally substituted with C1-C3 alkyl; R R Y1 is hydrogen, R Y2 is C1-C6 alkyl; hydroxy C1-C6 alkyl; optionally hydroxy substituted halo C1-C6 alkyl; C1-C4 alkoxy C1-C6 alkyl; halo C1-C3 alkoxy C1-C6 alkyl; (CH2) 0~1 -R Y4 ; hydroxy substituted di(C1-C3 alkyl)amino C1-C6 alkyl; optionally hydroxy substituted by C1-C3 alkoxy bicyclic C5-C8 alkyl; S(O)2- phenyl substituted with CH(CH3)2; selected from C2-C3 alkyl sulfonic acid selected; or R Y1 and R Y2 together with the N atom to which they are attached, may contain an O atom to form a saturated or unsaturated non-aromatic 6-membered heterocyclic ring, this ring may be substituted by R Y5 with 1 or 2 substitutions; R Y3 is quinuclidinyl, at least one heteroatom selected from N, O or S A 4, 5, or 6-membered saturated heterocyclic ring containing offspring, or a 5 or 6-membered aromatic heterocyclic ring. Selected from, this saturated or aromatic heterocyclic ring is optionally a C1-C3 alkyl group It is replaced by a yobi / or oxo; R Y4 It contains 4, 5 heteroatoms, each containing at least one heteroatom selected from N, O, or S. It is a 6-membered saturated heterocyclic ring, and this ring is optionally substituted with a C1-C3 alkyl group. We are; R Y5 C1-C3 alkyl, hydroxy, di(C1-C3 alkyl)amino C1-C Selected independently from 3 alkyl groups, or Two R atoms bonded to the same carbon atom Y5 They are together with the carbon atoms to which they are bonded. This is a 5-membered saturated heteroatom containing at least one heteroatom selected from N, O, or S. It forms a cyclic ring, and this ring is substituted with one or more C1-C3 alkyl groups; R Y6 and R Y7 Together with the carbon atoms to which they are bonded, they form N, O, or S Forms a 6-membered saturated or unsaturated non-aromatic heterocyclic ring containing one heteroatom selected from the following: death; R 1 Hydrogen; halogen; C1-C3 alkyl; halo C1-C3 alkyl; hydroxy C 1-C3 alkyl; C3-C6 cycloalkyl; CH2NR 2 R 3 ;CH(CH3)NR 2 R 3 ;C1~C3 alkoxy C1~C3 alkyl;CH2CO2H;C(O)H;C1 ~C3 alkoxy; containing at least one heteroatom selected from N, O, or S. Alternatively, it is selected from a 6-membered saturated heterocyclic or aromatic heterocyclic ring, and this ring is optionally Independently from C1-C3 alkyl, halo-C1-C3 alkyl, oxetanyl, or oxo It is substituted with one or more of the selected elements; R 2 These are derived from C1-C3 alkyl and di(C1-C3 alkyl)amino C1-C3 alkyl groups. Selected; R 3 C1-C3 alkyl, C(O)C1-C3 alkyl, C(O)-CH2-OH, C(O)-CH2-O-CH3, C(O)-CH2-N(CH3)2, S(O)2CH3 Selected from; or R 2 and R 3 Together with the N atom to which they are bonded, they form N, N-oxide, O Alternatively, a saturated 5 or 6-membered polymer optionally containing one additional heteroatom selected from S. It forms a ring, and this ring is R 4 It is also acceptable if one or more substitutions are made; R 4 C1-C3 alkyl, di(C1-C3 alkyl)amino, C(O)CH3, hydr Selected independently from Roxy; or Two R atoms bonded to the same carbon atom 4 They are together with the carbon atoms to which they are bonded. and 4, 5 or It forms a 6-membered, non-aromatic heterocyclic ring; or Two R atoms bonded to the same ring atom 4 It forms an oxo group; R 5 [Selected from hydrogen or C1-C3 alkyl] It is a compound of [the compound].

[0028] As used herein, the term "C1-C6 alkyl" means carbon and It consists only of hydrogen atoms, is unsaturated, has 1 to 6 carbon atoms, and is a molecule formed by single bonds. This refers to the linear or branched hydrocarbon chain groups bonded to the remainder. 1~ "C4 alkyl" and The term "C" should be interpreted similarly. 1~ The term "C3 alkyl" is similarly interpreted. It should be explained. Examples of C1-C6 alkyl groups are not limited to these, but include methyl, e Tyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pteryl It contains 1,1-dimethylethyl(t-butyl) and 1,1-dimethylethyl(t-butyl).

[0029] As used herein, the term "hydroxy C1-C6 alkyl" means formula-R a -OH[wherein, R a This is C as defined above. 1~6 The alkyl group It refers to hydroxy C1-C6 alkyl groups, although examples are not limited to these. Tyl, 2-hydroxy-ethyl, 2-hydroxy-propyl, 3-hydroxy-propyl and contains 5-hydroxypentyl.

[0030] As used herein, the term "C3-C6 cycloalkyl" means 3- This refers to a saturated monocyclic hydrocarbon group consisting of six carbon atoms. Examples of C3-C6 cycloalkyl groups include cycloalkyl groups. Contains rhozpropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0031] As used herein, the term "C1-C6 alkoxy" refers to the formula -OR a [In the formula, R a This is C as outlined above. 1~The base is a C6 alkyl group. To point. "C 1~ The term "C3 alkoxy" should be interpreted similarly. C1-C6 Examples of alkoxys include, but are not limited to, methoxy, ethoxy, propoxy, and isopoxy. Contains lopoxy, butoxy, isobutoxy, pentoxy, and hexoxy.

[0032] In this specification, "C1-C4 alkoxy C1-C6 alkyl" is used as follows: The term is formula-R b -OR a [In the formula, R a R is a C1-C4 alkyl group, b teeth, This refers to a group that is a C1-C6 alkyl group as defined above. The term "C1-C6 alkyl" should be interpreted similarly. The oxygen atom is, In alkyl groups, any carbon atom can be bonded. C1-C4 alkoxy C1-C Examples of 6 alkyl groups include, but are not limited to, methoxymethyl, methoxyethyl, and . It contains toxicethyl, 1-ethoxypropyl, and 2-methoxybutyl.

[0033] "Halogen" or "halo" refers to bromo, chloro, fluoro, or iodine.

[0034] As used herein, "halogen C1-C6 alkyl" or "halo C1 The term "~C6 alkyl" is defined by one or more halo groups as defined above. This refers to the C1-C6 alkyl groups that have been replaced, as defined above. (Halogen C1-C6) Examples of alkyl groups are not limited to these, but include trifluoromethyl, difluoromethyl, and f Luoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl Lu-2-fluoroethyl, 3-bromo-2-fluoropropyl and 1-bromomethyl- Contains 2-bromoethyl.

[0035] As used herein, the term "halo C1-C3 alkoxy" means above Substituted by one or more halo groups as defined above, This refers to C1-C3 alkoxy compounds. Examples of halo-C1-C3 alkoxy compounds are not limited to these. However, it contains trifluoromethoxy, difluoromethoxy, and trifluoroethoxy.

[0036] As used herein, the term "hydroxy C1-C3 alkoxy" is used in this specification. This refers to the C1-C3 alkoxy group as defined above, and the hydrogen of the C1-C3 alkoxy group One of the atoms is replaced by an OH group. Examples of hydroxy C1-C3 alkoxys are , but not limited to, hydroxymethoxy and hydroxyethoxy compounds.

[0037] As used herein, "C1-C3 alkoxy C1-C3 alkoxy" The term refers to the C1-C3 alkoxy group as defined above, C 1~3 Alkoxy One of the hydrogen atoms in the group is replaced by a -O-C1~C3 alkyl group. Examples of 3-alkoxy C1-C3 alkoxys include, but are not limited to, methoxymethoxy. , contains ethoxymethoxy.

[0038] As used herein, "C1-C3 Alkyl Halo C1-C3 Alcohol The term "C" refers to the halo C1-C3 alkoxy group as defined above, and halo C1 One of the hydrogen atoms of the ~C3 alkoxy group is replaced by a -O-C1~C3 alkyl group. Examples of C1-C3 alkoxyhalo-halo-C1-C3 alkoxy are not limited to these. However, it contains methoxytrifluoropropyl oxy.

[0039] As used herein, "di(C1-C3 alkyl)amino C1-C6 alkyl" The term "kill" is derived from the formula -R a1 -N(R a2 )-R a2 [In the formula, R a1 is defined above These are C1-C6 alkyl groups, and each R a2 This is the same as defined above, and [The group is a C1-C3 alkyl group, which may be different.] It can bond to any carbon atom in the lukyl group. As described herein, "diC1~C The "3-alkylamino C1-C6 alkyl" group may be substituted with a hydroxyl group.

[0040] As used herein, "di(C1-C3 alkyl)amino C1-C6 alkyl" The term "coxy" is derived from formula -R a1 -N(R a2 )-R a2 [In the formula, R a1 This is defined above. These are C1-C6 alkoxy groups, and each R a2 The same as defined above. It refers to a group that is either a C1-C3 alkyl group or a different C1-C3 alkyl group.

[0041] When used herein, "one heteroatom selected from N, O, or S" The term "six-membered saturated heterocyclic ring containing piperidyl, tetrahydropyranil and Contains tetrahydrothiopyranil.

[0042] When used herein, "one heteroatom selected from N, O, or S" The term "six-membered unsaturated non-aromatic heterocyclic ring containing" is not limited to these, but includes tetra Contains hydropyridinyl, dihydropyranyl, and dihydrothiopyranyl.

[0043] When used herein, "at least one selected from N, O, or S" The term “4, 5, or 6-membered saturated heterocyclic ring containing a heteroatom” is not limited to these. However, examples include azetidinil, oxetanil, pyrrolidil, tetrahydrofuryl, and tetrahydrofuryl. Trahydrothienyl, piperidyl, piperazinyl, tetrahydropyranil, morpholinil Includes.

[0044] As used herein, the term "5-membered saturated heterocyclic ring" is not limited to this. It is not specified, but pyrrolidine is one example.

[0045] When used herein, R 2 and R 3 along with the N atom that binds them together In the embodiment relating to the formation of the aforementioned ring, "one additional ring selected from N, O, or S" The term "saturated 5- or 6-membered ring containing an optional heteroatom" is not limited to these. However, examples include pyrrolidine, oxazolidine, piperazine, morpholine, and thiomorpholine. It includes an N-ring.

[0046] When used herein, "at least one selected from N, O, or S" The term "four, five, or six-membered non-aromatic heterocyclic ring containing a heteroatom" is used herein to describe the odor. 4 containing at least one heteroatom selected from N, O, or S as defined by It includes a 5- or 6-membered saturated heterocyclic ring. This is also selected from N, O, or S. It comprises a 4, 5, or 6-membered unsaturated heterocyclic ring containing at least one heteroatom.

[0047] When used herein, "one or two selected from N, O, or S" The term "bicyclic aromatic ring system optionally containing further heteroatoms" is not limited to these. However, it contains imidazopyridine and isothiazolopyridine.

[0048] As used herein, the term "bicycloC5-C8 alkyl" means These, however, include bicyclo[2.1.1]hexyl and bicyclo[1.1.1]pentine. 5- This refers to a bicyclic hydrocarbon group containing eight carbon atoms.

[0049] When used herein, R Y , R X and R Y , R Y2 , R Y 3 , R Y4 The term "optionally replaced" as used in the explanation is a term that is not used in this context. , including non-substitutions or one or two substitutions.

[0050] When used herein, for example, R Y2 , two R Y5 Used in the explanation The term “substituted” as it is used includes one or two substitutions, preferably one substitution.

[0051] When used herein, substituent R 4 The term "2 or more" when referring to , including 2, 3, 4, 5, or 6. Preferably, this includes 2 or 3.

[0052] In one embodiment of the present invention, FGFR4 inhibitor used in the combination of the present invention Bitter, in the example of the patent application, International Publication No. 2015059668, As described, it is a compound in free form or in the form of a pharmaceutically acceptable salt.

[0053] Therefore, in one embodiment, FGFR4 used in the combination of the present invention The inhibitor is available in free form or in the form of a pharmaceutically acceptable salt. 7-Formyl-N-(5-(trifluoromethyl)pyridine-2-yl)-3,4-di Hydro-1,8-naphthyrizine-1(2H)-carboxamide; N-(4,5-dichloropyridine-2-yl)-7-formyl-3,4-dihydro-1 ,8-Naphthyridine-1(2H)-Carboxamide; N-(5-cyanopyridine-2-yl)-7-formyl-3,4-dihydro-1,8- Naphthyridine-1(2H)-carboxamide; N-(5-chloropyridine-2-yl)-7-formyl-3,4-dihydro-1,8- Naphthyridine-1(2H)-carboxamide; 7-Formyl-N-(pyridine-2-yl)-3,4-dihydro-1,8-naphthilidi n-1(2H)-carboxamide; N-(4,5-dimethylpyridine-2-yl)-7-formyl-3,4-dihydro-1 ,8-Naphthyridine-1(2H)-Carboxamide; 7-Formyl-N-(5-methylpyridine-2-yl)-3,4-dihydro-1,8- Naphthyridine-1(2H)-carboxamide; N-(5-cyanopyrimidine-2-yl)-7-formyl-3,4-dihydro-1,8 -Naphthyridine-1(2H)-carboxamide; 6-Formyl-N-(5-methylpyridine-2-yl)-2H-pyrido[3,2-b] [1,4]Oxazine-4(3H)-carboxamide; 6-Chloro-N-(5-cyanopyridine-2-yl)-7-formyl-3,4-dihydr Ro-1,8-naphthirizine-1(2H)-carboxamide; 7-Formyl-N-(6-methoxypyrimidine-4-yl)-3,4-dihydro-1, 8-Naphthyridine-1(2H)-Carboxamide; N-(5-cyanopyrazine-2-yl)-7-formyl-3,4-dihydro-1,8- Naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-methoxypyridine-2-yl)-7-formyl-3,4-dihy Dro-1,8-naphthyrizine-1(2H)-carboxamide; 6-Formyl-N-(5-(trifluoromethyl)pyridine-2-yl)-2H-pyryl [3,2-b][1,4]oxazine-4(3H)-carboxamide; 6-Fluoro-7-formyl-N-(5-(trifluoromethyl)pyridine-2-yl) )-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyri Midine-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2 H)-Carboxamide; N-(4,5-dicyanopyridine-2-yl)-7-formyl-3,4-dihydro-1 ,8-Naphthyridine-1(2H)-Carboxamide; 7-Formyl-6-(hydroxymethyl)-N-(5-(trifluoromethyl)pyridin (n-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamyl Do; N-(5-cyano-4-ethoxypyridine-2-yl)-7-formyl-3,4-dihy Dro-1,8-naphthyrizine-1(2H)-carboxamide; 7-Formyl-6-methyl-N-(5-(trifluoromethyl)pyridine-2-yl) -3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyanopyridine-2-yl)-7-formyl-6-methyl-3,4-dihydr Ro-1,8-naphthirizine-1(2H)-carboxamide; 7-Formyl-N-(5-(1-hydroxypentyl)pyridine-2-yl)-3,4 -Dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(2-methoxyethoxy)pyridine-2-yl)-7-form ru-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(4-chloro-5-cyanopyridine-2-yl)-7-formyl-3,4-dihydr Ro-1,8-naphthirizine-1(2H)-carboxamide; N-(5-cyano-4-morpholinopyridine-2-yl)-7-formyl-3,4-di Hydro-1,8-naphthyrizine-1(2H)-carboxamide; N-(5-cyano-4-(4-hydroxy-4-methylpiperidine-1-yl)pyridin (n-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H) -Carboxamide; N-(5-cyanopyridine-2-yl)-7-formyl-6-(hydroxymethyl)- 3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(2-methyl-2,8-diazaspiro[4.5]decane-8- Iyl)pyridine-2-yl)7-formyl-3,4-dihydro-1,8-naphthyridine -1(2H)-carboxamide; N-(5-cyanopyridine-2-yl)-6-cyclopropyl-7-formyl-3,4 -Dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(3,6-dihydro-2H-pyran-4-yl)pyridine-2) -yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-cal Boxamide; N-(5-cyano-4-(tetrahydro-2H-pyran-4-yl)pyridine-2-yl) (L)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carbocyl Samido; N-(5-chloro-4-((tetrahydrofuran-3-yl)oxy)pyrimidine-2 -yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-cal Boxamide; N-(5-cyano-4-isopropoxypyridine-2-yl)-7-formyl-3,4 -Dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((tetrahydrofuran-2-yl)methoxy)pyridine-2 -yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-cal Boxamide; N-(5-cyano-4-(oxetan-2-ylmethoxy)pyridine-2-yl)-7 -Formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((tetrahydro-2H-pyran-2-yl)methoxy)pyri Zin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H )-Carboxamide; N-(5-cyanopyridine-2-yl)-6-(difluoromethyl)-7-formyl- 3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyridine-2-yl)- 7-Formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide ; N-(5-cyano-4-(2-methoxyethoxy)pyridine-2-yl)-7-form ru-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H) -Carboxamide; N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridine-2- Il)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carb Xamide; N-(5-cyano-4-(4-hydroxy-4-methylpiperidine-1-yl)pyridin (n-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8 -Naphthyridine-1(2H)-carboxamide; 7-Acetyl-N-(5-cyanopyridine-2-yl)-6-((dimethylamino)methylaminoyl) (Tyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((tetrahydrofuran-2-yl)methoxy)pyridine-2 -yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naph Tyrizine-1(2H)-carboxamide; N-(5-cyano-4-((tetrahydro-2H-pyran-2-yl)methoxy)pyri Zin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1, 8-Naphthyridine-1(2H)-Carboxamide; N-(5-cyano-4-(2-methyl-2,8-diazaspiro[4.5]decane-8- Iyl)pyridine-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihy Dro-1,8-naphthyrizine-1(2H)-carboxamide; N-(5-cyano-4-((1-methylpyrrolidine-3-yl)oxy)pyridine-2 -yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naph Tyrizine-1(2H)-carboxamide; N-(5-cyano-4-((1-methylpiperidine-4-yl)oxy)pyridine-2 -yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naph Tyrizine-1(2H)-carboxamide; N-(5-cyano-4-((1-methoxypropan-2-yl)oxy)pyridine-2 -yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naph Tyrizine-1(2H)-carboxamide; N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridine-2- (Iyl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyl Lysine-1(2H)-carboxamide; N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridine-2- Iyl)-6-((dimethylamino)methyl)-7-formyl-3,4-dihydro-1,8 -Naphthyridine-1(2H)-carboxamide; 2-(8-((5-cyanopyridine-2-yl)carbamoyl)-2-formyl-5, 6,7,8-Tetrahydro-1,8-naphthyridine-3-yl)acetic acid; N-(5-cyano-4-((tetrahydro-2H-pyran-4-yl)oxy)pyridyl (n-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8 -Naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((1-methylpyrrolidine-3-yl)oxy)pyridine-2 -yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naph Tyrizine-1(2H)-carboxamide; N-(5-cyano-4-(((tetrahydro-2H-pyran-3-yl)methyl)amide (no)pyridine-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihyde Ro-1,8-naphthirizine-1(2H)-carboxamide; N-(5-cyano-4-((tetrahydrofuran-3-yl)amino)pyridine-2- (Iyl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyl Lysine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxypropyl)amino)pyridine-2-yl)- 7-Formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxamide; N-(5-chloro-4-((1-methoxypropan-2-yl)oxy)pyrimidine- 2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-na Futilisine-1(2H)-carboxamide; N-(4-(4-chloro-2-hydroxybutoxy)-5-cyanopyridine-2-yl) )-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthilidi n-1(2H)-carboxamide; N-(5-cyano-4-(2-methoxyethoxy)pyridine-2-yl)-7-form Lu-6-(trifluoromethyl)-3,4-dihydro-1,8-naphthyridine-1(2H )-Carboxamide; N-(5-cyano-4-(2-methoxyethoxy)pyridine-2-yl)-6-cyclo Propyl-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-cal Boxamide; N-(5-cyano-4-(2-methoxyethoxy)pyridine-2-yl)-6-(diph Luoromethyl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H) -Carboxamide; N-(5-cyano-4-(2-methoxyethoxy)pyridine-2-yl)-6-((di Methylamino)methyl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1 (2H)-carboxamide; N-(5-cyano-4-((3(hydroxymethyl)bicyclo[2.2.1]hepta (-2-yl)amino)pyridine-2-yl)-7-formyl-6-(hydroxymethyl) )-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((tetrahydro-2H-pyran-4-yl)amino)pyrid (n-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8 -Naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(2-methoxyethoxy)pyridine-2-yl)-7-form Lu-6-(methoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)- Carboxamide; N-(5-cyanopyridine-2-yl)-7-formyl-6-((N-methylacetate Mido(methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxami Do; N-(5-chloro-4-((tetrahydrofuran-3-yl)oxy)pyrimidine-2 -yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naph Tyrizine-1(2H)-carboxamide; N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyrimidine-2 -yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naph Tyrizine-1(2H)-carboxamide; 7-Formyl-6-(hydroxymethyl)-N-(4-((tetrahydrofuran-3- Iyl)oxy)pyridine-2-yl)-3,4-dihydro-1,8-naphthyridine-1( 2H)-carboxamide; N-(5-chloro-4-((tetrahydrofuran-3-yl)oxy)pyridine-2- (Iyl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyl Lysine-1(2H)-carboxamide; N-(5-cyano-4-((1-methylpiperidine-3-yl)methoxy)pyridine- 2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-na Futilisine-1(2H)-carboxamide; N-(5-cyano-4-((1-methylpyrrolidine-2-yl)methoxy)pyridine- 2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-na Futilisine-1(2H)-carboxamide; N-(5-cyano-4-((1-methylpiperidine-2-yl)methoxy)pyridine- 2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-na Futilisine-1(2H)-carboxamide; N-(5-fluoropyridine-2-yl)-7-formyl-6-(hydroxymethyl) -3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyridine-2-yl)- 6-Holm- 13 C-yl-2H-pyrido[3,2-b][1,4]oxazine-4(3 H)-Carboxamide; N-(5-cyano-4-((1-methylpiperidine-4-yl)methoxy)pyridine- 2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-na Futilisine-1(2H)-carboxamide; N-(5-cyanopyridine-2-yl)-7-formyl-4-hydroxy-3,4-di Hydro-1,8-naphthyrizine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1 (2H)-carboxamide; N-(5-cyano-4-(2-((dimethylamino)methyl)morpholino)pyridine- 2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-na Futilisine-1(2H)-carboxamide; N-(5-cyano-4-(quinuclidin-3-yloxy)pyridine-2-yl)-7 -Formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1 (2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4 -Dihydro-1,8-naphthyridine-1(2H)-carboxamide; 7-Formyl-6-(hydroxymethyl)-N-(4-((2-methoxyethyl)amide (no)-5-(trifluoromethyl)pyridine-2-yl)-3,4-dihydro-1,8- Naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(4-((dimethylamino)methyl)-4-hydroxypiperine Zin-1-yl)pyridine-2-yl)-7-formyl-6-(hydroxymethyl)-3 ,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-hydroxy-2-methylpropyl)amino)pyridine -2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8- Naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((3-(dimethylamino)-2-hydroxy-2-methyl Ropyr(amino)pyridine-2-yl)-7-formyl-6-(hydroxymethyl)-3 ,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-fluoroethyl)amino)pyridine-2-yl)-7 -Formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1 (2H)-carboxamide; N-(5-cyano-4-(2,2,2-trifluoroethoxy)pyridine-2-yl) -7-Formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine -1(2H)-carboxamide; N-(5-cyano-4-isopropoxypyridine-2-yl)-7-formyl-6-( (4-methyl-2-oxopiperazine-1-yl)methyl)-3,4-dihydro-1,8 -Naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(isopropylamino)pyridine-2-yl)-7-formyl -6-((4-Methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro -1,8-naphthyridine-1(2H)-carboxamide; N-(5-Cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7 -formyl-6-((3-oxomorpholino)methyl)-3,4-dihydro-1,8-na phthyridine-1(2H)-carboxamide; N-(5-Cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7 -formyl-6-((3-hydroxy-2-oxopyrrolidin-1-yl)methyl)-3 ,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-Cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-formyl -6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihyd ro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-Cyano-4-ethylpyridin-2-yl)-6,7-diformyl-3,4- dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-Cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7 -formyl-6-((2-oxopiperazin-1-yl)methyl)-3,4-dihydro- 1,8-naphthyridine-1(2H)-carboxamide hydrochloride; N-(5-Cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2 -yl)-7-formyl-6-((4-methyl-2-oxooxazolidin-3-yl) methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-Cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7 -Formyl-6-((3-methyl-5-oxomorpholino)methyl)-3,4-dihydro -1,8-naphthyridine-1(2H)-carboxamide; 6-((4-acetylpiperazine-1-yl)methyl)-N-(5-cyano-4-iso) Propoxypyridine-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyl Zin-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(1-(N-methylacetamido)ethyl)-3,4-dihydro-1, 8-Naphthyridine-1(2H)-Carboxamide; N-(5-cyano-4-isopropoxypyridine-2-yl)-7-formyl-6-( (2-hydroxy-N-methylacetamide)methyl)-3,4-dihydro-1,8-na Futilisine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-6 -((N-(2-(dimethylamino)ethyl)acetamide)methyl)-7-formyl- 3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-6 -((N-(2-(dimethylamino)ethyl)methylsulfonamide)methyl)-7-H Lumil-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-isopropoxypyridine-2-yl)-6-((2-(dimeth (Luamino)-N-methylacetamido)methyl)-7-formyl-3,4-dihydro-1 ,8-Naphthyridine-1(2H)-Carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-((2-Methoxy-N-methylacetamido)methyl)-3,4-dimethyl Dro-1,8-naphthyrizine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-((3-oxothiomorpholino)methyl)-3,4-dihydro-1,8 -Naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-6 -((1,1-dioxide-3-oxothiomorpholino)methyl)-7-formyl-3, 4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(((4-methylmorpholin-2-yl)methyl)amino) Lysine-2-yl)-6-(difluoromethyl)-7-formyl-3,4-dihydro-1 ,8-Naphthyridine-1(2H)-Carboxamide; N-(5-cyano-4-((1,1,1-trifluoro-3-methoxypropane-2- Iyl)oxy)pyridine-2-yl)-6-(difluoromethyl)-7-formyl-3, 4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-(trifluoromethoxy)ethyl)amino)pyridine -2-yl)-7-formyl-6-((N-methylacetamide)methyl)-3,4-di Hydro-1,8-naphthyrizine-1(2H)-carboxamide; 6-(2-oxa-5-azaspiro[3,4]octan-5-ylmethyl)-N-(5 -Cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7-formyl -3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(4-((2-(tert-Butoxy)ethyl)amino)-5-cyanopyridin- 2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)me thyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-hydroxyethyl)amino)pyridin-2-yl)- 7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3, 4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(2-hydroxyethoxy)pyridin-2-yl)-7-for myl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dih dro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyanopyridin-2-yl)-2-formyl-7,8-dihydro-5H-py rido[2,3-b]azepin-9(6H)-carboxamide; N-(5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-2-for myl-7,8-dihydro-5H-pyrido[2,3-b]azepin-9(6H)-carboxy amide; N-(5-cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2 -yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)meth yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; 7-formyl-N-(1-isopropyl-1H-imidazo[4,5-c]pyridin-6 -yl)-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4- dihydro-1,8-naphthyridine-1(2H)-carboxamide; 7-Formyl-N-(1-isopropyl-1H-imidazo[4,5-c]pyridine-6) -yl)-6-((2-oxopyrrolidine-1-yl)methyl)-3,4-dihydro-1 ,8-Naphthyridine-1(2H)-Carboxamide; 4-((8-((5-cyano-4-((2-methoxyethyl)amino)pyridine-2- (Il)carbamoyl)-2-formyl-5,6,7,8-tetrahydro-1,8-naphthyl Lysine-3-yl(methyl)-1-methyl-3-oxopiperazine 1-oxide; N-(5-cyano-4-((2-oxopiperidine-4-yl)methoxy)pyridine- 2-yl)-7-formyl-6-((2-oxopyrrolidine-1-yl)methyl)-3, 4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(2-methoxyethoxy)pyridine-2-yl)-7-form 2-methyl-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3 ,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-isopropoxypyridine-2-yl)-7-formyl-2-methyl Tyl-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4-dimethyl Dro-1,8-naphthyrizine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-2-methyl-6-((4-methyl-2-oxopiperazine-1-yl)methyl (Lu)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-((3-hydroxy-4-methyl-2-oxopiperazine-1-yl) Methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-isopropoxypyridine-2-yl)-6-formyl-2,3 -dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide; 2-((5-cyano-2-(7-formyl-6-((4-methyl-2-oxopiperazi (-1-yl)methyl)-1,2,3,4-tetrahydro-1,8-naphthyridine-1- Carboxamide pyridine-4-yl amino ethyl hydrogen sulfide; N-(4-(Bicyclo[1.1.1]pentan-1-ylamino)-5-cyanopyridyl (-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazine-1-yl) )methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(thiophen-2-ylmethoxy)pyridine-2-yl)-7 -Formyl-6-((N-methylacetamido)methyl)-3,4-dihydro-1,8- Naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(isopropylthio)pyridine-2-yl)-7-formyl- 6-((N-methylacetamido)methyl)-3,4-dihydro-1,8-naphthyridine -1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-6 -((3,5-dimethylpiperazine-1-yl)methyl)-7-formyl-3,4-dimethyl Dro-1,8-naphthyrizine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-((3,3,4-trimethyl-2-oxopiperazine-1-yl)methyl (Lu)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; 6-amino-N-(5-cyanopyridine-2-yl)-7-formyl-3,4-dihydro Ro-1,8-naphthirizine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-1, 8-Naphthyridine-1(2H)-Carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-6 -(1,3-dimethyl-1H-pyrazole-4-yl)-7-formyl-3,4-dihydr Ro-1,8-naphthirizine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(1-methyl-1H-pyrazole-4-yl)-3,4-dihydro-1 ,8-Naphthyridine-1(2H)-Carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(2-methylthiazole-5-yl)-3,4-dihydro-1,8-na Futilisine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(thiophen-2-yl)-3,4-dihydro-1,8-naphthyridine -1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(1H-imidazole-1-yl)-3,4-dihydro-1,8-naph Tyrizine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(pyridine-3-yl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(1-methyl-1H-pyrazole-5-yl)-3,4-dihydro-1 ,8-Naphthyridine-1(2H)-Carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(3-methyl-1H-1,2,4-triazole-1-yl)-3,4 -Dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(3-methyl-2-oxopyrrolidine-1-yl)-3,4-dihydro -1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(3-oxomorpholino)-3,4-dihydro-1,8-naphthyridine -1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(2-oxoxazolidine-3-yl)-3,4-dihydro-1,8 -Naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-isopropoxypyridine-2-yl)-7-formyl-6-( Tetrahydrofuran-3-yl)-3,4-dihydro-1,8-naphthyridine-1(2H )-Carboxamide; N-(5-cyano-4-isopropoxypyridine-2-yl)-7-formyl-6-( Piperidine-4-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-cal Boxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(1-(oxetane-3-yl)piperidine-4-yl)-3,4-di Hydro-1,8-naphthyrizine-1(2H)-carboxamide; and N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-6 -(1-(2,2-difluoroethyl)piperidine-4-yl)-7-formyl-3,4 -Dihydro-1,8-naphthyridine-1(2H)-carboxamide A compound, selected from the group consisting of the following, in the form of a free form or a pharmaceutically acceptable salt. .

[0054] The patent application, International Publication No. 2015 / 059668, describes the combination of formula (I). The present invention describes the substance and methods for producing the specific compounds mentioned above. The dosage and treatment regimen can be determined by those skilled in the art.

[0055] In a preferred embodiment of the present invention, FGFR4 used in the combination of the present invention The inhibitor is N-(5-cyano-4-) in free form or in the form of a pharmaceutically acceptable salt. ((2-methoxyethyl)amino)pyridine-2-yl)-7-formyl-6-((4- Methyl-2-oxopiperazine-1-yl)methyl)3,4-dihydro-1,8-naph It is tyridine-1(2H)-carboxamide.

[0056] N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4 -Dihydro-1,8-naphthyridine-1(2H)-carboxamide is used herein. Also known as compound A (Cpd A). Compound A has an IC50 of 1.1 nM and FGFR4 It is a highly selective FGFR4 inhibitor that inhibits [the process]. In biochemical assays, At least 1000-fold selectivity was shown for the panel of 65 kinases, and also for 456 kinases. In a quinome-wide scan consisting of -ases, FGFR4 is the only target of compound A. (Porta et al, Abstract 2098, Proceedings: AACR Annual Meeting 2017; April) See 1-5, 2017). Compound A is also known as FGF401 and is progressive. It showed promising clinical activity in patients with HCC (Chan et al, Proceedings: AACR). See Annual Meeting 2017; April 1-5, 2017.

[0057] N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4 -Dihydro-1,8-naphthyridine-1(2H)-carboxamide is a patent application in the country This is specifically described in Example 83 of the International Publication Brochure No. 2015 / 059668. It has the following structure.

[0058] [ka]

[0059] In one embodiment of the present invention, the FGFR4 inhibitor is a free form of N-(5-shear No-4-((2-methoxyethyl)amino)pyridine-2-yl)-7-formyl-6- ((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4-dihydro-1, It is 8-naphthyridine-1(2H)-carboxamide.

[0060] In one embodiment, the FGFR4 inhibitor is in salt form, preferably patent application form. N-(5) salt form as described in Example 83 of International Publication No. 2015059668 -Cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7-formyl -6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4-dihydro It is -1,8-naphthirizine-1(2H)-carboxamide.

[0061] In one embodiment of the present invention, the FGFR4 inhibitor is N-(5) in citrate form. -Cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7-formyl -6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4-dihydro It is -1,8-naphthirizine-1(2H)-carboxamide.

[0062] The FGFR4 inhibitor of the combination of the present invention, namely N-(5-cyano-4-((2 -Methoxyethyl)amino)pyridine-2-yl)-7-formyl-6-((4-methyl -2-Oxopiperazine-1-yl)methyl)-3,4-dihydro-1,8-naphthilidi N-1(2H)-carboxamide is available in doses of approximately 25-200 mg, or approximately 50-150 mg. It may be administered in a therapeutically effective total daily dose (e.g., once daily). No-4-((2-methoxyethyl)amino)pyridine-2-yl)-7-formyl-6- ((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4-dihydro-1, Total daily dose of 8-naphthirizine-1(2H)-carboxamide (e.g., citrate form) The dosage may be 50 mg, 80 mg, 100 mg, 120 mg, or 150 mg. N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)- 7-Formyl-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3, 4-Dihydro-1,8-naphthyrizine-1(2H)-carboxamide is administered at a dose of up to 80 mg per day. Alternatively, it may be administered at a dose of 120 mg per day.

[0063] The dosage or administration of FGFR4 inhibitors as described herein refers to the amount of free base. This refers to the pharmacy of an FGFR4 inhibitor, for example, if the mentioned dosage is 80 mg. If an acceptable salt, such as its citrate, is used, a dose of 80 mg is appropriate for FGFR 4 inhibitor, namely N-(5-cyano-4-((2-methoxyethyl)amino) Lysine-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazine-1- Il(methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamyl This corresponds to the amount of free base in the dot matrix.

[0064] In a 4-week study of dogs administered compound A, no dose-dependent effect was observed in any dose group. Individual dogs showed increases in ALT and AST. The maximum increase was observed in ALT and AST. In contrast, these values ​​were 6 times and 2 times or less (compared to pre-medication values), and were present in the second week of the trial. In general, despite continuous medication for four weeks, transaminase levels remained low. No further increase was observed, which suggests that the effects of these pharmacologically mediated effects are not adequately addressed. The response level is indicated. Recovery was evident by the 8th day after discontinuation of compound A administration. Cholestyramine (CHO) and other bile acid scavenging agents increase compound A-mediated ALT levels in dogs. This reduced and reversed the effects, which is the increase in ALT observed after FGF401 administration. However, this suggests that it may be secondary to an increase in bile acids.

[0065] Based on these observations and examples, despite the risk of lack of effectiveness, bile acid capture is still possible. Side effects can be reversed and managed by administering drugs simultaneously or sequentially, such as compound A. Selective FGFR4 inhibitors are effective in patients with cancer, particularly liver cancer and HCC. It is predicted that this will provide effective treatment options.

[0066] The FGFR4 inhibitor used in the present invention is for proliferative disorders, such as cancer, particularly Liver cancer, breast cancer, glioblastoma, prostate cancer, rhabdomyosarcoma, stomach cancer, ovarian cancer, lung cancer, It can be used to treat colon cancer, and more specifically, liver cancer.

[0067] As used herein, “liver cancer” also means hepatocellular carcinoma (HCC).

[0068] The FGFR4 inhibitor is the FGFR4 inhibitor and one or more drugs As an independent pharmaceutical composition containing a scientifically acceptable carrier, the pharmaceutically acceptable combination of the present invention It can be used.

[0069] Similarly, bile acid scavengers are bile acid scavengers and one or more pharmaceutically acceptable drugs. It can be used in the pharmaceutical combination of the present invention as an independent pharmaceutical composition containing a carrier.

[0070] As used herein, the term “pharmaceutically acceptable carrier” means as used by those skilled in the art. As is well known, all kinds of solvents, dispersions, coatings, surfactants, oxidation Inhibitory agents, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption retarders, salts, preservatives, drugs Stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavorings, dyes, etc., and combinations thereof. Includes combinations (for example, Remington The Science and Practice of Pharmacy, 22 nd Ed. Pha (See rmaceutical Press, 2013, pp. 1049-1070). Any conventional carrier becomes active Unless otherwise specified, its use in therapeutic or pharmaceutical compositions is intended.

[0071] The terms "therapeutic effective amount" or "therapeutic effective level" of the compound combination of the present invention are defined as follows: The biological or medical response of the target, such as reduction or inhibition of enzyme or protein activity. To alleviate harm or symptoms, reduce a condition, slow or inhibit disease progression, or prevent disease, etc. This refers to the amount of the compound in the combination of the present invention that induces the effect.

[0072] For example, when referring to an FGFR4 inhibitor in one non-limited embodiment: The term "therapeutic effective dose" means that when administered to a subject, (1)(i) FGFR4 (ii) mediated by, or related to FGFR4 activity, or (iii) FGF A condition, disorder, or disease characterized by R4 activity (normal or abnormal) (2) FGFR (4) Reduce or inhibit the activity of (3) FGFR4, or reduce or inhibit the expression of FGFR4. This refers to the amount of FGFR4 inhibitor compound that is effective in doing so. In this context, the term "therapeutic effective dose" refers to cells or tissues or non-cellular biological materials or When administered to a culture medium, it at least partially reduces or inhibits FGFR4 activity. This refers to the amount of FGFR4 inhibitor compound that is effective against it.

[0073] In another, non-limited embodiment, when referring to a bile acid scavenger, the term "therapeutic effective dose" is used. The term refers to a condition in which, when administered to the target population, the side effects associated with FGFR4 inhibitor therapy are at least The amount of bile acid scavenging agent that is effective in partially alleviating, inhibiting, preventing and / or improving This refers to FGFR inhibitor therapy, which involves FGFR4 inhibitors, preferably compound A, or so This includes the administration of a pharmaceutically acceptable salt, such as citrate.

[0074] As used herein, the terms "subject" or "patient" refer to a human being. The subjects or patients are those with proliferative disorders as described herein, such as cancer, particularly liver cancer, breast cancer. Glioblastoma, prostate cancer, rhabdomyosarcoma, stomach cancer, ovarian cancer, lung cancer, colon cancer, more Physically, he has liver cancer, including HCC.

[0075] Bile acid scavenging agents are used clinically, for example, for conditions related to bile acid malabsorption, such as diarrhea. It is an ion exchange resin. A review of the clinical use of bile acid scavengers is by Scaldaferri. This was described by F. et al. in Intern Emerg Med (2013) 8:205-210.

[0076] Bile acid scavengers function by combining with bile components to prevent reabsorption from the gastrointestinal tract. This has the ability to interfere with the enterohepatic circulation of bile acids. An example of a bile acid scavenger is Cholesti. Contains lamin, cholecevelam, cholecevelam hydrochloride, colestipol, or sevelamer. In a preferred embodiment of the present invention, the bile acid scavenger is cholestyramine.

[0077] Bile acid scavengers may be used to treat bile acid-induced diarrhea. However, This invention is the first to provide an FGFR4 inhibitor comprising, preferably, a selective FGFR4 inhibitor. - When administered concurrently with other drugs, side effects associated with FGFR4 inhibitor therapy, such as increased liver enzymes, may occur. The use of bile acid scavengers to reduce or prevent [unclear] is provided.

[0078] Bile acid scavengers such as cholestyramine can be taken at a daily dose of 4 to 24 g. The recommended dosage schedule for acid scavengers is a maximum of 1 to 4 doses per day, but 1 to 6 doses per day is also possible. It may be administered orally. Cholestyramine is usually in the form of a suspension mixed with water or other liquids. It is administered as a liquid.

[0079] In another embodiment, the present invention relates to a pharmaceutical combination of the present invention for use as a pharmaceutical. do.

[0080] In another embodiment, the present invention relates to the treatment of diseases that can be treated by inhibiting FGFR4. The present invention relates to a pharmaceutical combination for use. In another embodiment, the present invention relates to The present invention relates to a pharmaceutical combination for use in the treatment of [unclear]. In one embodiment, Cancers include liver cancer, breast cancer, glioblastoma, prostate cancer, rhabdomyosarcoma, stomach cancer, ovarian cancer, The cancer is selected from lung cancer and colon cancer. In a preferred embodiment, the cancer is liver cancer. .

[0081] As a further embodiment, the present invention relates to the use of the pharmaceutical combination of the present invention in therapeutic treatment. In a further embodiment, the treatment is for a disease that can be treated by inhibiting FGFR4. It is a treatment. In another embodiment, the disease is cancer. In yet another embodiment, The diseases include liver cancer, breast cancer, glioblastoma, prostate cancer, rhabdomyosarcoma, stomach cancer, ovarian cancer, The disease is selected from lung cancer and colon cancer. In a preferred embodiment, the disease is liver cancer. .

[0082] In another embodiment, the present invention treats diseases treated by FGFR4 inhibition. The present invention relates to a method comprising the administration of the pharmaceutical combination of the present invention. Further embodiments In this invention, the present invention relates to a method for treating a disease treated by inhibiting FGFR4, and F The pharmaceutical method of the present invention comprises the simultaneous or sequential administration of a GFR4 inhibitor and a bile acid scavenger. This relates to a method including the administration of a combination of substances.

[0083] Another aspect of the present invention involves using a bile acid scavenger in combination with an FGFR4 inhibitor, and More FGFR4 inhibitory therapies, for example, compound A or a pharmaceutically acceptable salt thereof, for example, que The discovery that side effects associated with the administration of sodium chloride can be reduced or prevented. Related to.

[0084] Therefore, in one embodiment, the present invention addresses side effects associated with FGFR4 inhibitor therapy. Regarding the use of bile acid scavengers to reduce or prevent FGFR. FGFR inhibitor therapy is used for FGF R4 inhibitor, preferably compound A, or a pharmaceutically acceptable salt thereof, e.g., quae This includes the administration of sodium chloride.

[0085] In one important embodiment of the present invention, side effects associated with FGFR4 inhibitor therapy include diarrhea. Not included.

[0086] In another embodiment, the present invention aims to reduce side effects associated with FGFR4 inhibitor therapy or A bile acid scavenger for preventive use that does not have diarrhea as a side effect. Regarding this, FGFR inhibitory therapy involves FGFR4 inhibitors, preferably compound A, or This includes the administration of a pharmaceutically acceptable salt, such as citrate.

[0087] In one embodiment, the bile acid scavenger is cholestyramine. In one embodiment, FGFR4 inhibitor therapy can be administered in free form or in the form of pharmaceutically acceptable salts, particularly citrate forms. N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)- 7-Formyl-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3, This includes the use of 4-dihydro-1,8-naphthyrizine-1(2H)-carboxamide.

[0088] In another embodiment, the present invention reduces or reduces side effects associated with FGFR4 inhibitor therapy. A method for prevention involves administering a bile acid scavenger to a patient undergoing FGFR4 inhibitor therapy. Regarding methods including steps.

[0089] In another embodiment, the present invention relates to the occurrence of side effects associated with FGFR4 inhibitor therapy or A method for reducing the severity of the condition, comprising FGFR4 inhibitors and bile acid scavengers. Combined therapies, including simultaneous or sequential administration, are administered to patients requiring FGFR4 inhibitor therapy. Regarding the method, including the steps.

[0090] Side effects associated with FGFR4 inhibitor therapy include those associated with FGFR4 inhibitors, such as compound A. or side effects that may be observed during treatment with a pharmaceutically acceptable salt, such as citrate. That is the case.

[0091] In one embodiment, a side effect associated with FGFR4 inhibitory therapy is elevated liver enzymes.

[0092] Liver enzymes, such as alanine aminotransaminase (ALT) and aspartate Minotransferase (AST) is detected in the serum, plasma, or blood of the subject. This may indicate hepatitis and / or liver damage. Elevated liver enzymes are a serious side effect. Some symptoms of the rise include fatigue, abdominal pain with jaundice, and swelling.

[0093] In relation to FGFR4 inhibitor therapy, the serum, plasma, or blood of the subject during FGFR4 inhibitor therapy. Elevated liver enzyme levels can result in the treatment having to be discontinued.

[0094] In another embodiment, a side effect associated with FGFR4 inhibitor therapy is elevated ALT levels. In another embodiment, a side effect associated with FGFR4 inhibitor therapy is elevated AST. In this embodiment, side effects associated with FGFR4 inhibitory therapy include elevated miRNA122 levels. be.

[0095] As used herein, the term ALT refers to serum glutamate pyruvate Alanine aminotransaminase, also known as transaminase (SGPT), To point.

[0096] As used herein, the term AST means serum glutamate oxalovinegar Aspartate aminotransferase, also known as acid transaminase (SGOT), It refers to the enzyme.

[0097] As used herein, the term “elevated liver enzymes” means “elevated liver enzymes” in the art. Liver enzymes in the serum, plasma, or blood of the subject, as measured by known standard tests. This refers to an increase compared to the normal value. For example, the normal value of ALT in blood is per liter. The value is between 7 and 55 units. Therefore, in one embodiment of the present invention, an increase in ALT is associated with blood This means that more than 55 units per liter are detected in the liquid. In this case, the elevated ALT level was more than 2-3 times the upper limit of the normal level, i.e., approximately 110-16. It is more than 5 units / liter.

[0098] Typically, the normal AST range is between 10 and 40 units per liter. Therefore, in one embodiment of the present invention, an increase in AST is defined as 40 units per liter of blood. This means that a value exceeding the normal range is detected. In one embodiment of the present invention, the elevated AST is positive This is more than 2 to 3 times the upper limit of normal levels, or approximately 80 to 120 units / liter.

[0099] In one embodiment, the present invention relates to the ALT level of patients receiving FGFR4 inhibitor therapy. A method for reducing the amount to less than 55 units per liter of serum, plasma, or blood in a person. The patient has an ALT level greater than 55 units per liter of serum, plasma, or blood. The method involves administering to the patient a pharmaceutical combination including an FGFR4 inhibitor and a bile acid scavenger. The present invention relates to a method that includes the step of administering a substance.

[0100] In another embodiment, the present invention relates to AST levels in patients receiving FGFR4 inhibitor treatment. A method to reduce the amount to less than 40 units per liter of serum, plasma, or blood in the patient. Furthermore, the patient has an AST level of more than 40 units per liter of serum, plasma, or blood. The method involves administering to the patient a pharmaceutical combination including an FGFR4 inhibitor and a bile acid scavenger. The present invention relates to a method including the step of administering a substance.

[0101] As used herein, it is also abbreviated as miR122, and micro-RNA12 miRNA122, also known as 2, is a microRN that is highly expressed in the liver. A is considered a biomarker for liver injury. In one study, several Several animals tend to show a decrease in miR122 levels after simultaneous treatment with cholestyramine. Compared to their respective controls, the results showed a slight to moderate increase in miR122. (See Figure 2.)

[0102] Therefore, in one embodiment, the present invention relates to patients receiving FGFR4 inhibitor therapy. A method for reducing the level of miR122 in the patient, wherein the patient has an FGFR4 inhibitor The present invention relates to a method comprising the step of administering a pharmaceutical combination including a tar and a bile acid scavenger.

[0103] Therefore, the present invention allows for the continuation of beneficial treatment with an FGFR4 inhibitor, This offers the possibility of reducing or reversing side effects associated with the treatment.

[0104] In another embodiment, the present invention relates to the occurrence or severity of elevated liver enzymes during FGFR4 inhibitor therapy. A method for reducing the severity of the symptoms, comprising a therapeutically effective dose of FGFR4 inhibitor and treatment Combinations including simultaneous or sequential administration of effective doses of bile acid scavengers are necessary for FGFR4 inhibitor therapy. The step includes administering the drug to the target subject, and also includes the occurrence of elevated liver enzymes during FGFR4 inhibitor therapy. This concerns methods for reducing the severity of the condition.

[0105] In another embodiment, the present invention relates to the regeneration of liver enzymes in the serum of a subject during FGFR4 inhibitor therapy. A method to lower BELL, which is effective in lowering liver enzyme levels in the target group. The present invention relates to a method comprising the step of administering a certain amount of bile acid scavenger.

[0106] In another embodiment, the present invention relates to miRNA1 in subjects undergoing FGFR4 inhibitor therapy. A method to reduce the level of 22, and to reduce the level of miRNA122 in the target. The present invention relates to a method that includes the step of administering a bile acid scavenger in an effective amount to induce diarrhea.

[0107] Bile acid scavengers are marketed as single drugs, and therefore their dosage and administration are not fully understood. The form shall be as described in the package insert of the bile acid scavenger, unless otherwise specified herein. You can follow the information provided.

[0108] The optimal dosage of each combination of components for use as a pharmaceutical according to the present invention is known. The method may be experimentally determined for each subject using the method, but is not limited to the method, for the disease. Stage of progression; age, weight, overall health, sex, and diet of the subject; time and route of administration; if It also depends on various factors, including other medications the individual is taking.

[0109] The frequency of medication varies depending on the compound used and the specific condition being treated or prevented. It may be affected. Generally, it is preferable to use the minimum dosage sufficient to provide effective treatment. The subject is generally an appropriate applicator for the condition to be treated or prevented, which is well known to those skilled in the art. The effectiveness of treatment can be monitored using the CE. The subject is also generally in the art. Using routinely used tests, the effectiveness in reducing or preventing elevated liver enzymes was investigated. This can be monitored.

[0110] Therefore, in another embodiment, the present invention relates to FGFR4 inhibitors and bile acid scavenging. The present invention relates to a treatment regimen that includes the simultaneous or sequential administration of drugs. In one embodiment, FGFR 4. Inhibitors are defined by the formula as described in International Publication No. 2015059668 ( It is a compound of I). In a preferred embodiment, the FGFR4 inhibitor is in a free form. or in the form of a pharmaceutically acceptable salt N-(5-cyano-4-((2-methoxyethyl) Amino)pyridine-2-yl)-7-formyl-6-((4-methyl-2-oxopiper Zin-1-yl(methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)- It is ruboxamide.

[0111] In one embodiment, the bile acid scavenger used in the therapeutic regimen of the present invention is It's styramine.

[0112] In another embodiment, the treatment regimen is for the treatment of a disease that can be treated by FGFR4 inhibition. This is a treatment regimen for the following conditions. In one embodiment, the diseases treated are liver cancer, breast cancer, glioblastoma. The cancers selected are cell carcinoma, prostate cancer, rhabdomyosarcoma, stomach cancer, ovarian cancer, lung cancer, and colon cancer. In a preferred embodiment, the disease is liver cancer.

[0113] Various embodiments of the present invention are described below. The features specified in each embodiment are as follows. To provide further embodiments of the invention, it may be combined with other specified features. This is recognized.

[0114] Embodiment 1. A pharmaceutical combination comprising an FGFR4 inhibitor and a bile acid scavenger.

[0115] Embodiment 2. The FGFR4 inhibitor is in free form or in the form of a pharmaceutically acceptable salt. Equation (I)

[0116] [ka] [In the formula, V is selected from CH2, O, and CH(OH); W is selected from CH2, CH2CH2, and bond types; X is C(R X ) or N; Y is C(R Y ) or N; Z is either CH or N; If X is N, then Y and Z are not N; If Y is N, then X and Z are not N; If Z is N, then X and Y are not N; R X These are hydrogen, halogens, C1-C3 alkyl halogens, cyanoalkyl halogens, C1-C6 alkyl halogens, and hydroxylomers. Selected from roxy C1-C6 alkyl groups; R Y These are hydrogen, halogens, C1-C3 alkyl, C1-C6 alkoxy, and hydroxy C1 ~C3 alkoxy, NR Y1 R Y2 cyanoacrylate, C1-C3 alkoxy, C1-C3 alkoxy C1-C3 alkoxy-halo C1-C3 alkoxy, di(C1-C3 alkyl) amine C1-C6 alkoxy, O-(CH2)0~1 -R Y3 、CR Y6 R Y7 、S-C1~ C3 alkyl, optionally selected from halo C1-C6 alkoxy substituted with hydroxy selected; or R X and R Y together with the ring to which they are attached, optionally further contain one or two heteroatoms selected from N, O, or S to form a bicyclic aromatic ring system, and this ring system is optionally substituted with C1-C3 alkyl; R is hydrogen, Y1 R is C1-C6 alkyl; hydroxy C1-C6 alkyl; optionally halo C1-C6 alkyl substituted with hydroxy Y2 ; C1-C4 alkoxy C1-C6 alkyl; halo C1-C3 alkoxy C1-C6 alkyl; (CH2) -R 0~1 ; hydroxy Y4 substituted di(C1-C3 alkyl)amino C1-C6 alkyl; optionally bicyclic C5-C8 alkyl substituted with hydroxy C1-C3 alkyl; S(O)2- substituted phenyl with CH(CH3)2; selected from C2-C3 alkylsulfonic acid selected; or R and R together with the N atom to which they are attached, may contain an O atom to form a saturated or unsaturated non-aromatic 6-membered heterocyclic ring, and this ring may be mono- Y1 or disubstituted by R Y2 as well; R Y5 is quinuclidinyl, at least one heteroatom selected from N, O or S selected; R Y3 is selected from N, O or S A 4, 5, or 6-membered saturated heterocyclic ring containing offspring, or a 5 or 6-membered aromatic heterocyclic ring. Selected from, this saturated or aromatic heterocyclic ring is optionally a C1-C3 alkyl group It is replaced by a yobi / or oxo; R Y4 It contains 4, 5 heteroatoms, each containing at least one heteroatom selected from N, O, or S. It is a 6-membered saturated heterocyclic ring, and this ring is optionally substituted with a C1-C3 alkyl group. We are; R Y5 C1-C3 alkyl, hydroxy, di(C1-C3 alkyl)amino C1-C Selected independently from 3 alkyl groups, or Two R atoms bonded to the same carbon atom Y5 They are together with the carbon atoms to which they are bonded. This is a 5-membered saturated heteroatom containing at least one heteroatom selected from N, O, or S. It forms a cyclic ring, and this ring is substituted with one or more C1-C3 alkyl groups; R Y6 and R Y7 Together with the carbon atoms to which they are bonded, they form N, O, or S Forms a 6-membered saturated or unsaturated non-aromatic heterocyclic ring containing one heteroatom selected from the following: death; R 1 Hydrogen; halogen; C1-C3 alkyl; halo C1-C3 alkyl; hydroxy C 1-C3 alkyl; C3-C6 cycloalkyl; CH2NR 2 R 3 ;CH(CH3)NR 2 R 3 ;C1~C3 alkoxy C1~C3 alkyl;CH2CO2H;C(O)H;C1 ~C3 alkoxy; containing at least one heteroatom selected from N, O, or S. Alternatively, it is selected from a 6-membered saturated heterocyclic or aromatic heterocyclic ring, and this ring is optionally Independently from C1-C3 alkyl, halo-C1-C3 alkyl, oxetanyl, or oxo It is substituted with one or more of the selected elements; R 2 These are derived from C1-C3 alkyl and di(C1-C3 alkyl)amino C1-C3 alkyl groups. Selected; R 3 C1-C3 alkyl, C(O)C1-C3 alkyl, C(O)-CH2-OH, C(O)-CH2-O-CH3, C(O)-CH2-N(CH3)2, S(O)2CH3 Selected from; or R 2 and R 3 Together with the N atom to which they are bonded, they form N, N-oxide, O Alternatively, a saturated 5 or 6-membered polymer optionally containing one additional heteroatom selected from S. It forms a ring, and this ring is R 4 It is also acceptable if one or more substitutions are made; R 4 C1-C3 alkyl, di(C1-C3 alkyl)amino, C(O)CH3, hydr Selected independently from Roxy; or Two R atoms bonded to the same carbon atom 4 They are together with the carbon atoms to which they are bonded. and 4, 5 or It forms a 6-membered, non-aromatic heterocyclic ring; or Two R atoms bonded to the same ring atom 4 It forms an oxo group; R 5 [Selected from hydrogen or C1-C3 alkyl] A pharmaceutically acceptable combination according to Embodiment 1, which is a compound of the above.

[0117] Embodiment 3. The FGFR4 inhibitor is in free form or in the form of a pharmaceutically acceptable salt. of 7-Formyl-N-(5-(trifluoromethyl)pyridine-2-yl)-3,4-di Hydro-1,8-naphthyrizine-1(2H)-carboxamide; N-(4,5-dichloropyridine-2-yl)-7-formyl-3,4-dihydro-1 ,8-Naphthyridine-1(2H)-Carboxamide; N-(5-cyanopyridine-2-yl)-7-formyl-3,4-dihydro-1,8- Naphthyridine-1(2H)-carboxamide; N-(5-chloropyridine-2-yl)-7-formyl-3,4-dihydro-1,8- Naphthyridine-1(2H)-carboxamide; 7-Formyl-N-(pyridine-2-yl)-3,4-dihydro-1,8-naphthilidi n-1(2H)-carboxamide; N-(4,5-dimethylpyridine-2-yl)-7-formyl-3,4-dihydro-1 ,8-Naphthyridine-1(2H)-Carboxamide; 7-Formyl-N-(5-methylpyridine-2-yl)-3,4-dihydro-1,8- Naphthyridine-1(2H)-carboxamide; N-(5-cyanopyrimidine-2-yl)-7-formyl-3,4-dihydro-1,8 -Naphthyridine-1(2H)-carboxamide; 6-Formyl-N-(5-methylpyridine-2-yl)-2H-pyrido[3,2-b] [1,4]Oxazine-4(3H)-carboxamide; 6-Chloro-N-(5-cyanopyridine-2-yl)-7-formyl-3,4-dihydr Ro-1,8-naphthirizine-1(2H)-carboxamide; 7-Formyl-N-(6-methoxypyrimidine-4-yl)-3,4-dihydro-1, 8-Naphthyridine-1(2H)-Carboxamide; N-(5-cyanopyrazine-2-yl)-7-formyl-3,4-dihydro-1,8- Naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-methoxypyridine-2-yl)-7-formyl-3,4-dihy Dro-1,8-naphthyrizine-1(2H)-carboxamide; 6-Formyl-N-(5-(trifluoromethyl)pyridine-2-yl)-2H-pyryl [3,2-b][1,4]oxazine-4(3H)-carboxamide; 6-Fluoro-7-formyl-N-(5-(trifluoromethyl)pyridine-2-yl) )-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyri Midine-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2 H)-Carboxamide; N-(4,5-dicyanopyridine-2-yl)-7-formyl-3,4-dihydro-1 ,8-Naphthyridine-1(2H)-Carboxamide; 7-Formyl-6-(hydroxymethyl)-N-(5-(trifluoromethyl)pyridin (n-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamyl Do; N-(5-cyano-4-ethoxypyridine-2-yl)-7-formyl-3,4-dihy Dro-1,8-naphthyrizine-1(2H)-carboxamide; 7-Formyl-6-methyl-N-(5-(trifluoromethyl)pyridine-2-yl) -3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyanopyridine-2-yl)-7-formyl-6-methyl-3,4-dihydr Ro-1,8-naphthirizine-1(2H)-carboxamide; 7-Formyl-N-(5-(1-hydroxypentyl)pyridine-2-yl)-3,4 -Dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(2-methoxyethoxy)pyridine-2-yl)-7-form ru-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(4-chloro-5-cyanopyridine-2-yl)-7-formyl-3,4-dihydr Ro-1,8-naphthirizine-1(2H)-carboxamide; N-(5-cyano-4-morpholinopyridine-2-yl)-7-formyl-3,4-di Hydro-1,8-naphthyrizine-1(2H)-carboxamide; N-(5-cyano-4-(4-hydroxy-4-methylpiperidine-1-yl)pyridin (n-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H) -Carboxamide; N-(5-cyanopyridine-2-yl)-7-formyl-6-(hydroxymethyl)- 3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(2-methyl-2,8-diazaspiro[4.5]decane-8- Iyl)pyridine-2-yl)7-formyl-3,4-dihydro-1,8-naphthyridine -1(2H)-carboxamide; N-(5-cyanopyridine-2-yl)-6-cyclopropyl-7-formyl-3,4 -Dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(3,6-dihydro-2H-pyran-4-yl)pyridine-2) -yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-cal Boxamide; N-(5-cyano-4-(tetrahydro-2H-pyran-4-yl)pyridine-2-yl) (L)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carbocyl Samido; N-(5-chloro-4-((tetrahydrofuran-3-yl)oxy)pyrimidine-2 -yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-cal Boxamide; N-(5-cyano-4-isopropoxypyridine-2-yl)-7-formyl-3,4 -Dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((tetrahydrofuran-2-yl)methoxy)pyridine-2 -yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-cal Boxamide; N-(5-cyano-4-(oxetan-2-ylmethoxy)pyridine-2-yl)-7 -Formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((tetrahydro-2H-pyran-2-yl)methoxy)pyri Zin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H )-Carboxamide; N-(5-cyanopyridine-2-yl)-6-(difluoromethyl)-7-formyl- 3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyridine-2-yl)- 7-Formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide ; N-(5-cyano-4-(2-methoxyethoxy)pyridine-2-yl)-7-form ru-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H) -Carboxamide; N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridine-2- Il)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carb Xamide; N-(5-cyano-4-(4-hydroxy-4-methylpiperidine-1-yl)pyridin (n-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8 -Naphthyridine-1(2H)-carboxamide; 7-Acetyl-N-(5-cyanopyridine-2-yl)-6-((dimethylamino)methylaminoyl) (Tyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((tetrahydrofuran-2-yl)methoxy)pyridine-2 -yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naph Tyrizine-1(2H)-carboxamide; N-(5-cyano-4-((tetrahydro-2H-pyran-2-yl)methoxy)pyri Zin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1, 8-Naphthyridine-1(2H)-Carboxamide; N-(5-cyano-4-(2-methyl-2,8-diazaspiro[4.5]decane-8- Iyl)pyridine-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihy Dro-1,8-naphthyrizine-1(2H)-carboxamide; N-(5-cyano-4-((1-methylpyrrolidine-3-yl)oxy)pyridine-2 -yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naph Tyrizine-1(2H)-carboxamide; N-(5-cyano-4-((1-methylpiperidine-4-yl)oxy)pyridine-2 -yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naph Tyrizine-1(2H)-carboxamide; N-(5-cyano-4-((1-methoxypropan-2-yl)oxy)pyridine-2 -yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naph Tyrizine-1(2H)-carboxamide; N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridine-2- (Iyl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyl Lysine-1(2H)-carboxamide; N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridine-2- Iyl)-6-((dimethylamino)methyl)-7-formyl-3,4-dihydro-1,8 -Naphthyridine-1(2H)-carboxamide; 2-(8-((5-cyanopyridine-2-yl)carbamoyl)-2-formyl-5, 6,7,8-Tetrahydro-1,8-naphthyridine-3-yl)acetic acid; N-(5-cyano-4-((tetrahydro-2H-pyran-4-yl)oxy)pyridyl (n-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8 -Naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((1-methylpyrrolidine-3-yl)oxy)pyridine-2 -yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naph Tyrizine-1(2H)-carboxamide; N-(5-cyano-4-(((tetrahydro-2H-pyran-3-yl)methyl)amide (no)pyridine-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihyde Ro-1,8-naphthirizine-1(2H)-carboxamide; N-(5-cyano-4-((tetrahydrofuran-3-yl)amino)pyridine-2- (Iyl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyl Lysine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxypropyl)amino)pyridine-2-yl)- 7-Formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxamide; N-(5-chloro-4-((1-methoxypropan-2-yl)oxy)pyrimidine- 2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-na Futilisine-1(2H)-carboxamide; N-(4-(4-chloro-2-hydroxybutoxy)-5-cyanopyridine-2-yl) )-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthilidi n-1(2H)-carboxamide; N-(5-cyano-4-(2-methoxyethoxy)pyridine-2-yl)-7-form Lu-6-(trifluoromethyl)-3,4-dihydro-1,8-naphthyridine-1(2H )-Carboxamide; N-(5-cyano-4-(2-methoxyethoxy)pyridine-2-yl)-6-cyclo Propyl-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-cal Boxamide; N-(5-cyano-4-(2-methoxyethoxy)pyridine-2-yl)-6-(diph Luoromethyl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H) -Carboxamide; N-(5-cyano-4-(2-methoxyethoxy)pyridine-2-yl)-6-((di Methylamino)methyl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1 (2H)-carboxamide; N-(5-cyano-4-((3(hydroxymethyl)bicyclo[2.2.1]hepta (-2-yl)amino)pyridine-2-yl)-7-formyl-6-(hydroxymethyl) )-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((tetrahydro-2H-pyran-4-yl)amino)pyrid (n-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8 -Naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(2-methoxyethoxy)pyridine-2-yl)-7-form Lu-6-(methoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)- Carboxamide; N-(5-cyanopyridine-2-yl)-7-formyl-6-((N-methylacetate Mido(methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxami Do; N-(5-chloro-4-((tetrahydrofuran-3-yl)oxy)pyrimidine-2 -yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naph Tyrizine-1(2H)-carboxamide; N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyrimidine-2 -yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naph Tyrizine-1(2H)-carboxamide; 7-Formyl-6-(hydroxymethyl)-N-(4-((tetrahydrofuran-3- Iyl)oxy)pyridine-2-yl)-3,4-dihydro-1,8-naphthyridine-1( 2H)-carboxamide; N-(5-chloro-4-((tetrahydrofuran-3-yl)oxy)pyridine-2- (Iyl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyl Lysine-1(2H)-carboxamide; N-(5-cyano-4-((1-methylpiperidine-3-yl)methoxy)pyridine- 2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-na Futilisine-1(2H)-carboxamide; N-(5-cyano-4-((1-methylpyrrolidine-2-yl)methoxy)pyridine- 2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-na Futilisine-1(2H)-carboxamide; N-(5-cyano-4-((1-methylpiperidine-2-yl)methoxy)pyridine- 2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-na Futilisine-1(2H)-carboxamide; N-(5-fluoropyridine-2-yl)-7-formyl-6-(hydroxymethyl) -3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyridine-2-yl)- 6-Holm- 13 C-yl-2H-pyrido[3,2-b][1,4]oxazine-4(3 H)-Carboxamide; N-(5-cyano-4-((1-methylpiperidine-4-yl)methoxy)pyridine- 2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-na Futilisine-1(2H)-carboxamide; N-(5-cyanopyridine-2-yl)-7-formyl-4-hydroxy-3,4-di Hydro-1,8-naphthyrizine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1 (2H)-carboxamide; N-(5-cyano-4-(2-((dimethylamino)methyl)morpholino)pyridine- 2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-na Futilisine-1(2H)-carboxamide; N-(5-cyano-4-(quinuclidin-3-yloxy)pyridine-2-yl)-7 -Formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1 (2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4 -Dihydro-1,8-naphthyridine-1(2H)-carboxamide; 7-Formyl-6-(hydroxymethyl)-N-(4-((2-methoxyethyl)amide (no)-5-(trifluoromethyl)pyridine-2-yl)-3,4-dihydro-1,8- Naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(4-((dimethylamino)methyl)-4-hydroxypiperine Zin-1-yl)pyridine-2-yl)-7-formyl-6-(hydroxymethyl)-3 ,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-hydroxy-2-methylpropyl)amino)pyridine -2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8- Naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((3-(dimethylamino)-2-hydroxy-2-methyl Ropyr(amino)pyridine-2-yl)-7-formyl-6-(hydroxymethyl)-3 ,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-fluoroethyl)amino)pyridine-2-yl)-7 -Formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1 (2H)-carboxamide; N-(5-cyano-4-(2,2,2-trifluoroethoxy)pyridine-2-yl) -7-Formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine -1(2H)-carboxamide; N-(5-cyano-4-isopropoxypyridine-2-yl)-7-formyl-6-( (4-methyl-2-oxopiperazine-1-yl)methyl)-3,4-dihydro-1,8 -Naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(isopropylamino)pyridine-2-yl)-7-formyl -6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4-dihydro -1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-((3-oxomorpholino)methyl)-3,4-dihydro-1,8-na Futilisine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-((3-hydroxy-2-oxopyrrolidine-1-yl)methyl)-3 ,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(2-methoxyethoxy)pyridine-2-yl)-7-form Ru-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4-dihydr Ro-1,8-naphthirizine-1(2H)-carboxamide; N-(5-cyano-4-ethylpyridine-2-yl)-6,7-diformyl-3,4- Dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-((2-oxopiperazine-1-yl)methyl)-3,4-dihydro- 1,8-Naphthyrizine-1(2H)-Carboxamide hydrochloride; N-(5-cyano-4-((1-methoxypropan-2-yl)oxy)pyridine-2 -yl)-7-formyl-6-((4-methyl-2-oxoxazolidine-3-yl) Methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-((3-methyl-5-oxomorpholino)methyl)-3,4-dihydro -1,8-naphthyridine-1(2H)-carboxamide; 6-((4-acetylpiperazine-1-yl)methyl)-N-(5-cyano-4-iso) Propoxypyridine-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyl Zin-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(1-(N-methylacetamido)ethyl)-3,4-dihydro-1, 8-Naphthyridine-1(2H)-Carboxamide; N-(5-cyano-4-isopropoxypyridine-2-yl)-7-formyl-6-( (2-hydroxy-N-methylacetamide)methyl)-3,4-dihydro-1,8-na Futilisine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-6 -((N-(2-(dimethylamino)ethyl)acetamide)methyl)-7-formyl- 3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-6 -((N-(2-(dimethylamino)ethyl)methylsulfonamide)methyl)-7-H Lumil-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-isopropoxypyridine-2-yl)-6-((2-(dimeth (Luamino)-N-methylacetamido)methyl)-7-formyl-3,4-dihydro-1 ,8-Naphthyridine-1(2H)-Carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-((2-Methoxy-N-methylacetamido)methyl)-3,4-dimethyl Dro-1,8-naphthyrizine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-((3-oxothiomorpholino)methyl)-3,4-dihydro-1,8 -Naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-6 -((1,1-dioxide-3-oxothiomorpholino)methyl)-7-formyl-3, 4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(((4-methylmorpholin-2-yl)methyl)amino) Lysine-2-yl)-6-(difluoromethyl)-7-formyl-3,4-dihydro-1 ,8-Naphthyridine-1(2H)-Carboxamide; N-(5-cyano-4-((1,1,1-trifluoro-3-methoxypropane-2- Iyl)oxy)pyridine-2-yl)-6-(difluoromethyl)-7-formyl-3, 4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-(trifluoromethoxy)ethyl)amino)pyridine -2-yl)-7-formyl-6-((N-methylacetamide)methyl)-3,4-di Hydro-1,8-naphthyrizine-1(2H)-carboxamide; 6-(2-oxa-5-azaspiro[3,4]octan-5-ylmethyl)-N-(5 -Cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7-formyl -3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(4-((2-(tert-butoxy)ethyl)amino)-5-cyanopyridine- 2-yl)-7-formyl-6-((4-methyl-2-oxopiperazine-1-yl) (Tyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-hydroxyethyl)amino)pyridine-2-yl)- 7-Formyl-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3, 4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(2-hydroxyethoxy)pyridine-2-yl)-7-hol Mil-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4-dimethyl Dro-1,8-naphthyrizine-1(2H)-carboxamide; N-(5-cyanopyridine-2-yl)-2-formyl-7,8-dihydro-5H-pyridine Lido[2,3-b]azepine-9(6H)-carboxamide; N-(5-cyano-4-(2-methoxyethoxy)pyridine-2-yl)-2-form Ru-7,8-dihydro-5H-pyrido[2,3-b]azepine-9(6H)-carboxate Mido; N-(5-cyano-4-((1-methoxypropan-2-yl)oxy)pyridine-2 -yl)-7-formyl-6-((4-methyl-2-oxopiperazine-1-yl)meth (Lu)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; 7-Formyl-N-(1-isopropyl-1H-imidazo[4,5-c]pyridine-6) -yl)-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4- Dihydro-1,8-naphthyridine-1(2H)-carboxamide; 7-Formyl-N-(1-isopropyl-1H-imidazo[4,5-c]pyridine-6) -yl)-6-((2-oxopyrrolidine-1-yl)methyl)-3,4-dihydro-1 ,8-Naphthyridine-1(2H)-Carboxamide; 4-((8-((5-cyano-4-((2-methoxyethyl)amino)pyridine-2- (Il)carbamoyl)-2-formyl-5,6,7,8-tetrahydro-1,8-naphthyl Lysine-3-yl(methyl)-1-methyl-3-oxopiperazine 1-oxide; N-(5-cyano-4-((2-oxopiperidine-4-yl)methoxy)pyridine- 2-yl)-7-formyl-6-((2-oxopyrrolidine-1-yl)methyl)-3, 4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(2-methoxyethoxy)pyridine-2-yl)-7-form 2-methyl-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3 ,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-isopropoxypyridine-2-yl)-7-formyl-2-methyl Tyl-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4-dimethyl Dro-1,8-naphthyrizine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-2-methyl-6-((4-methyl-2-oxopiperazine-1-yl)methyl (Lu)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-((3-hydroxy-4-methyl-2-oxopiperazine-1-yl) Methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-isopropoxypyridine-2-yl)-6-formyl-2,3 -dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide; 2-((5-cyano-2-(7-formyl-6-((4-methyl-2-oxopiperazi (-1-yl)methyl)-1,2,3,4-tetrahydro-1,8-naphthyridine-1- Carboxamide pyridine-4-yl amino ethyl hydrogen sulfide; N-(4-(Bicyclo[1.1.1]pentan-1-ylamino)-5-cyanopyridyl (-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazine-1-yl) )methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(thiophen-2-ylmethoxy)pyridine-2-yl)-7 -Formyl-6-((N-methylacetamido)methyl)-3,4-dihydro-1,8- Naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(isopropylthio)pyridine-2-yl)-7-formyl- 6-((N-methylacetamido)methyl)-3,4-dihydro-1,8-naphthyridine -1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-6 -((3,5-dimethylpiperazine-1-yl)methyl)-7-formyl-3,4-dimethyl Dro-1,8-naphthyrizine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-((3,3,4-trimethyl-2-oxopiperazine-1-yl)methyl (Lu)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; 6-amino-N-(5-cyanopyridine-2-yl)-7-formyl-3,4-dihydro Ro-1,8-naphthirizine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-1, 8-Naphthyridine-1(2H)-Carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-6 -(1,3-dimethyl-1H-pyrazole-4-yl)-7-formyl-3,4-dihydr Ro-1,8-naphthirizine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(1-methyl-1H-pyrazole-4-yl)-3,4-dihydro-1 ,8-Naphthyridine-1(2H)-Carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(2-methylthiazole-5-yl)-3,4-dihydro-1,8-na Futilisine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(thiophen-2-yl)-3,4-dihydro-1,8-naphthyridine -1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(1H-imidazole-1-yl)-3,4-dihydro-1,8-naph Tyrizine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(pyridine-3-yl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(1-methyl-1H-pyrazole-5-yl)-3,4-dihydro-1 ,8-Naphthyridine-1(2H)-Carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(3-methyl-1H-1,2,4-triazole-1-yl)-3,4 -Dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(3-methyl-2-oxopyrrolidine-1-yl)-3,4-dihydro -1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(3-oxomorpholino)-3,4-dihydro-1,8-naphthyridine -1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(2-oxoxazolidine-3-yl)-3,4-dihydro-1,8 -Naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-isopropoxypyridine-2-yl)-7-formyl-6-( Tetrahydrofuran-3-yl)-3,4-dihydro-1,8-naphthyridine-1(2H )-Carboxamide; N-(5-cyano-4-isopropoxypyridine-2-yl)-7-formyl-6-( Piperidine-4-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-cal Boxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(1-(oxetane-3-yl)piperidine-4-yl)-3,4-di Hydro-1,8-naphthyrizine-1(2H)-carboxamide; and N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-6 -(1-(2,2-difluoroethyl)piperidine-4-yl)-7-formyl-3,4 -Dihydro-1,8-naphthyridine-1(2H)-carboxamide A pharmaceutical combination according to Embodiment 1 or 2, selected from the above.

[0118] Embodiment 4. The FGFR4 inhibitor is in free form or in the form of a pharmaceutically acceptable salt. N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4 Embodiment 1 is -dihydro-1,8-naphthyridine-1(2H)-carboxamide A pharmaceutical combination as described in any of the three items above.

[0119] Embodiment 5. The FGFR4 inhibitor is in the citrate form N-(5-cyano-4-( (2-methoxyethyl)amino)pyridine-2-yl)-7-formyl-6-((4-Me) Tyl-2-oxopiperazine-1-yl)methyl)3,4-dihydro-1,8-naphthyl Lysine-1(2H)-carboxamide, the pharmaceutical according to any one of Embodiments 1 to 4 A combination of things.

[0120] Embodiment 6. The bile acid scavenger is cholestyramine, choleceveram, choleceveram hydrochloride, Pharmaceuticals according to any of the above embodiments, selected from colestipol or sevelamer A combination of things.

[0121] Embodiment 7. The pharmaceutical combination according to Embodiment 6, wherein the bile acid scavenger is cholestyramine. A scam.

[0122] Embodiment 8. Pharmaceutical use according to any one of Embodiments 1 to 7 for use as a medicine A combination of items.

[0123] Embodiment 9. The pharmaceutical combination according to Embodiment 8 for use in the treatment of cancer.

[0124] Embodiment 10. Liver cancer, breast cancer, glioblastoma, prostate cancer, rhabdomyosarcoma, stomach cancer, egg Pharmaceutical combination according to Embodiment 8 for use in the treatment of tumor, lung, and colon cancer. A scam.

[0125] Embodiment 11. The pharmaceutical combination according to Embodiment 8 for use in the treatment of liver cancer. A scam.

[0126] Embodiment 12. Use in reducing or preventing side effects associated with FGFR4 inhibitor therapy. A bile acid scavenger for this purpose.

[0127] Embodiment 13. Side effects are detected in the serum, plasma, or blood of a subject receiving FGFR4 inhibitor therapy. A bile acid scavenger for use according to Embodiment 12, comprising an increase in liver enzymes in the liquid.

[0128] Embodiment 14. The liver enzyme is alanine aminotransferase (ALT). A bile acid scavenger for use as described in Form 13.

[0129] Embodiment 15. The liver enzyme is aspartate aminotransferase (AST). , a bile acid scavenger for use as described in Embodiment 13.

[0130] Embodiment 16. Side effects include miRNA1 in subjects receiving FGFR4 inhibitor therapy. A bile acid scavenger for use according to Embodiment 12, including an increase of 22.

[0131] Embodiment 17. Cholestyramine, choleceveram, choleceveram hydrochloride, cholestipol Or selected from sevelamer, for use as described in any of embodiments 12 to 16 A bile acid scavenger.

[0132] Embodiment 18. Cholestyramine, for bile acid scavenging, for use as described in Embodiment 17. medicine.

[0133] Embodiment 19. Reducing the occurrence or severity of side effects associated with FGFR4 inhibitor therapy. Drugs containing bile acid scavengers and FGFR4 inhibitors for use in the method for A chemical combination wherein the above method provides the aforementioned pharmaceutical to a subject requiring FGFR4 inhibitory therapy. A pharmaceutical combination comprising the step of administering the combination of substances simultaneously or sequentially.

[0134] Embodiment 20. The bile acid scavenger is cholestyramine, choleceveram, choleceveram hydrochloride. , selected from Colestipol or Sevelamer, for use as described in Embodiment 19 A combination of pharmaceutical substances.

[0135] Embodiment 21. The use described in Embodiment 19, wherein the bile acid scavenger is cholestyramine. A pharmaceutical combination for that purpose.

[0136] Embodiment 22. The FGFR4 inhibitor is in free form or in the form of a pharmaceutically acceptable salt. The expression of state (I)

[0137] [ka] [In the formula, V is selected from CH2, O, and CH(OH); W is selected from CH2, CH2CH2, and bond types; X is C(R X ) or N; Y is C(R Y ) or N; Z is either CH or N; If X is N, then Y and Z are not N; If Y is N, then X and Z are not N; If Z is N, then X and Y are not N; R X These are hydrogen, halogens, C1-C3 alkyl halogens, cyanoalkyl halogens, C1-C6 alkyl halogens, and hydroxylomers. Selected from roxy C1-C6 alkyl groups; R Y These are hydrogen, halogens, C1-C3 alkyl, C1-C6 alkoxy, and hydroxy C1 ~C3 alkoxy, NR Y1 R Y2 cyanoacrylate, C1-C3 alkoxy, C1-C3 alkoxy C1-C3 alkoxy-halo C1-C3 alkoxy, di(C1-C3 alkyl) amine C1-C6 alkoxy, O-(CH2) 0~1 -R Y3 , CR Y6 R Y7 , S-C1~ Select from C3 alkyl groups and optionally hydroxylated halo-C1 to C6 alkoxy groups. Selected; or R X and R Y Together with the ring to which they are bonded, they are selected from N, O, or S. It forms a bicyclic aromatic ring system that optionally includes one or two additional heteroatoms. This ring system is optionally substituted with C1-C3 alkyl groups; R Y1 It is hydrogen, R Y2 C1-C6 alkyl; hydroxy C1-C6 alkyl; hydroxy (optional) Halo-C1~C6 alkyl; C1~C4 alkoxy-C1~C6 alkyl; substituted with Halo C1-C3 alkoxy C1-C6 alkyl; (CH2) 0~1 -R Y4 ; hydroxy Di(C1~C3 alkyl)aminoC1~C6 alkyl substituted with; hyphens are optional. BicycloC5-C8 alkyl substituted with roxyC1-C3 alkyl; S(O)2- Phenyl(CH3)2-substituted; selected from C2-C3 alkylsulfonic acids. re; or R Y1 and R Y2 These, together with the N atoms to which they are bonded, even include O atoms. It forms a good saturated or unsaturated non-aromatic 6-membered heterocyclic ring, and this ring is R Y5 Therefore, 1 Alternatively, two substitutions may be made; R Y3 is at least one heterogen selected from quinuclidinyl, N, O, or S. A 4, 5, or 6-membered saturated heterocyclic ring containing offspring, or a 5 or 6-membered aromatic heterocyclic ring. Selected from, this saturated or aromatic heterocyclic ring is optionally a C1-C3 alkyl group It is replaced by a yobi / or oxo; R Y4 It contains 4, 5 heteroatoms, each containing at least one heteroatom selected from N, O, or S. It is a 6-membered saturated heterocyclic ring, and this ring is optionally substituted with a C1-C3 alkyl group. We are; R Y5 C1-C3 alkyl, hydroxy, di(C1-C3 alkyl)amino C1-C Selected independently from 3 alkyl groups, or Two R atoms bonded to the same carbon atom Y5 They are together with the carbon atoms to which they are bonded. This is a 5-membered saturated heteroatom containing at least one heteroatom selected from N, O, or S. It forms a cyclic ring, and this ring is substituted with one or more C1-C3 alkyl groups; R Y6 and R Y7 Together with the carbon atoms to which they are bonded, they form N, O, or S Forms a 6-membered saturated or unsaturated non-aromatic heterocyclic ring containing one heteroatom selected from the following: death; R 1 Hydrogen; halogen; C1-C3 alkyl; halo C1-C3 alkyl; hydroxy C 1-C3 alkyl; C3-C6 cycloalkyl; CH2NR 2 R 3 ;CH(CH3)NR 2 R 3 ;C1~C3 alkoxy C1~C3 alkyl;CH2CO2H;C(O)H;C1 ~C3 alkoxy; containing at least one heteroatom selected from N, O, or S. Alternatively, it is selected from a 6-membered saturated heterocyclic or aromatic heterocyclic ring, and this ring is optionally Independently from C1-C3 alkyl, halo-C1-C3 alkyl, oxetanyl, or oxo It is substituted with one or more of the selected elements; R 2 These are derived from C1-C3 alkyl and di(C1-C3 alkyl)amino C1-C3 alkyl groups. Selected; R 3 C1-C3 alkyl, C(O)C1-C3 alkyl, C(O)-CH2-OH, C(O)-CH2-O-CH3, C(O)-CH2-N(CH3)2, S(O)2CH3 Selected from; or R 2 and R 3 Together with the N atom to which they are bonded, they form N, N-oxide, O Alternatively, a saturated 5 or 6-membered polymer optionally containing one additional heteroatom selected from S. It forms a ring, and this ring is R 4 It is also acceptable if one or more substitutions are made; R 4 C1-C3 alkyl, di(C1-C3 alkyl)amino, C(O)CH3, hydr Selected independently from Roxy; or Two R atoms bonded to the same carbon atom 4 They are together with the carbon atoms to which they are bonded. and 4, 5 or It forms a 6-membered, non-aromatic heterocyclic ring; or Two R atoms bonded to the same ring atom 4 It forms an oxo group; R 5 [Selected from hydrogen or C1-C3 alkyl] A compound of which is a pharmaceutically acceptable combination for use as described in any of embodiments 19 to 21. .

[0138] Embodiment 23. The FGFR4 inhibitor is in free form or in the form of a pharmaceutically acceptable salt. state 7-Formyl-N-(5-(trifluoromethyl)pyridine-2-yl)-3,4-di Hydro-1,8-naphthyrizine-1(2H)-carboxamide; N-(4,5-dichloropyridine-2-yl)-7-formyl-3,4-dihydro-1 ,8-Naphthyridine-1(2H)-Carboxamide; N-(5-cyanopyridine-2-yl)-7-formyl-3,4-dihydro-1,8- Naphthyridine-1(2H)-carboxamide; N-(5-chloropyridine-2-yl)-7-formyl-3,4-dihydro-1,8- Naphthyridine-1(2H)-carboxamide; 7-Formyl-N-(pyridine-2-yl)-3,4-dihydro-1,8-naphthilidi n-1(2H)-carboxamide; N-(4,5-dimethylpyridine-2-yl)-7-formyl-3,4-dihydro-1 ,8-Naphthyridine-1(2H)-Carboxamide; 7-Formyl-N-(5-methylpyridine-2-yl)-3,4-dihydro-1,8- Naphthyridine-1(2H)-carboxamide; N-(5-cyanopyrimidine-2-yl)-7-formyl-3,4-dihydro-1,8 -Naphthyridine-1(2H)-carboxamide; 6-Formyl-N-(5-methylpyridine-2-yl)-2H-pyrido[3,2-b] [1,4]Oxazine-4(3H)-carboxamide; 6-Chloro-N-(5-cyanopyridine-2-yl)-7-formyl-3,4-dihydr Ro-1,8-naphthirizine-1(2H)-carboxamide; 7-Formyl-N-(6-methoxypyrimidine-4-yl)-3,4-dihydro-1, 8-Naphthyridine-1(2H)-Carboxamide; N-(5-cyanopyrazine-2-yl)-7-formyl-3,4-dihydro-1,8- Naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-methoxypyridine-2-yl)-7-formyl-3,4-dihy Dro-1,8-naphthyrizine-1(2H)-carboxamide; 6-Formyl-N-(5-(trifluoromethyl)pyridine-2-yl)-2H-pyryl [3,2-b][1,4]oxazine-4(3H)-carboxamide; 6-Fluoro-7-formyl-N-(5-(trifluoromethyl)pyridine-2-yl) )-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyri Midine-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2 H)-Carboxamide; N-(4,5-dicyanopyridine-2-yl)-7-formyl-3,4-dihydro-1 ,8-Naphthyridine-1(2H)-Carboxamide; 7-Formyl-6-(hydroxymethyl)-N-(5-(trifluoromethyl)pyridin (n-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamyl Do; N-(5-cyano-4-ethoxypyridine-2-yl)-7-formyl-3,4-dihy Dro-1,8-naphthyrizine-1(2H)-carboxamide; 7-Formyl-6-methyl-N-(5-(trifluoromethyl)pyridine-2-yl) -3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyanopyridine-2-yl)-7-formyl-6-methyl-3,4-dihydr Ro-1,8-naphthirizine-1(2H)-carboxamide; 7-Formyl-N-(5-(1-hydroxypentyl)pyridine-2-yl)-3,4 -Dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(2-methoxyethoxy)pyridine-2-yl)-7-form ru-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(4-chloro-5-cyanopyridine-2-yl)-7-formyl-3,4-dihydr Ro-1,8-naphthirizine-1(2H)-carboxamide; N-(5-cyano-4-morpholinopyridine-2-yl)-7-formyl-3,4-di Hydro-1,8-naphthyrizine-1(2H)-carboxamide; N-(5-cyano-4-(4-hydroxy-4-methylpiperidine-1-yl)pyridin (n-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H) -Carboxamide; N-(5-cyanopyridine-2-yl)-7-formyl-6-(hydroxymethyl)- 3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(2-methyl-2,8-diazaspiro[4.5]decane-8- Iyl)pyridine-2-yl)7-formyl-3,4-dihydro-1,8-naphthyridine -1(2H)-carboxamide; N-(5-cyanopyridine-2-yl)-6-cyclopropyl-7-formyl-3,4 -Dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(3,6-dihydro-2H-pyran-4-yl)pyridine-2) -yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-cal Boxamide; N-(5-cyano-4-(tetrahydro-2H-pyran-4-yl)pyridine-2-yl) (L)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carbocyl Samido; N-(5-chloro-4-((tetrahydrofuran-3-yl)oxy)pyrimidine-2 -yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-cal Boxamide; N-(5-cyano-4-isopropoxypyridine-2-yl)-7-formyl-3,4 -Dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((tetrahydrofuran-2-yl)methoxy)pyridine-2 -yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-cal Boxamide; N-(5-cyano-4-(oxetan-2-ylmethoxy)pyridine-2-yl)-7 -Formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((tetrahydro-2H-pyran-2-yl)methoxy)pyri Zin-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H )-Carboxamide; N-(5-cyanopyridine-2-yl)-6-(difluoromethyl)-7-formyl- 3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyridine-2-yl)- 7-Formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide ; N-(5-cyano-4-(2-methoxyethoxy)pyridine-2-yl)-7-form ru-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H) -Carboxamide; N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridine-2- Il)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carb Xamide; N-(5-cyano-4-(4-hydroxy-4-methylpiperidine-1-yl)pyridin (n-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8 -Naphthyridine-1(2H)-carboxamide; 7-Acetyl-N-(5-cyanopyridine-2-yl)-6-((dimethylamino)methylaminoyl) (Tyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((tetrahydrofuran-2-yl)methoxy)pyridine-2 -yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naph Tyrizine-1(2H)-carboxamide; N-(5-cyano-4-((tetrahydro-2H-pyran-2-yl)methoxy)pyri Zin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1, 8-Naphthyridine-1(2H)-Carboxamide; N-(5-cyano-4-(2-methyl-2,8-diazaspiro[4.5]decane-8- Iyl)pyridine-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihy Dro-1,8-naphthyrizine-1(2H)-carboxamide; N-(5-cyano-4-((1-methylpyrrolidine-3-yl)oxy)pyridine-2 -yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naph Tyrizine-1(2H)-carboxamide; N-(5-cyano-4-((1-methylpiperidine-4-yl)oxy)pyridine-2 -yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naph Tyrizine-1(2H)-carboxamide; N-(5-cyano-4-((1-methoxypropan-2-yl)oxy)pyridine-2 -yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naph Tyrizine-1(2H)-carboxamide; N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridine-2- (Iyl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyl Lysine-1(2H)-carboxamide; N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridine-2- Iyl)-6-((dimethylamino)methyl)-7-formyl-3,4-dihydro-1,8 -Naphthyridine-1(2H)-carboxamide; 2-(8-((5-cyanopyridine-2-yl)carbamoyl)-2-formyl-5, 6,7,8-Tetrahydro-1,8-naphthyridine-3-yl)acetic acid; N-(5-cyano-4-((tetrahydro-2H-pyran-4-yl)oxy)pyridyl (n-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8 -Naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((1-methylpyrrolidine-3-yl)oxy)pyridine-2 -yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naph Tyrizine-1(2H)-carboxamide; N-(5-cyano-4-(((tetrahydro-2H-pyran-3-yl)methyl)amide (no)pyridine-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihyde Ro-1,8-naphthirizine-1(2H)-carboxamide; N-(5-cyano-4-((tetrahydrofuran-3-yl)amino)pyridine-2- (Iyl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyl Lysine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxypropyl)amino)pyridine-2-yl)- 7-Formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxamide; N-(5-chloro-4-((1-methoxypropan-2-yl)oxy)pyrimidine- 2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-na Futilisine-1(2H)-carboxamide; N-(4-(4-chloro-2-hydroxybutoxy)-5-cyanopyridine-2-yl) )-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthilidi n-1(2H)-carboxamide; N-(5-cyano-4-(2-methoxyethoxy)pyridine-2-yl)-7-form Lu-6-(trifluoromethyl)-3,4-dihydro-1,8-naphthyridine-1(2H )-Carboxamide; N-(5-cyano-4-(2-methoxyethoxy)pyridine-2-yl)-6-cyclo Propyl-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-cal Boxamide; N-(5-cyano-4-(2-methoxyethoxy)pyridine-2-yl)-6-(diph Luoromethyl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1(2H) -Carboxamide; N-(5-cyano-4-(2-methoxyethoxy)pyridine-2-yl)-6-((di Methylamino)methyl)-7-formyl-3,4-dihydro-1,8-naphthyridine-1 (2H)-carboxamide; N-(5-cyano-4-((3(hydroxymethyl)bicyclo[2.2.1]hepta (-2-yl)amino)pyridine-2-yl)-7-formyl-6-(hydroxymethyl) )-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((tetrahydro-2H-pyran-4-yl)amino)pyrid (n-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8 -Naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(2-methoxyethoxy)pyridine-2-yl)-7-form Lu-6-(methoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)- Carboxamide; N-(5-cyanopyridine-2-yl)-7-formyl-6-((N-methylacetate Mido(methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxami Do; N-(5-chloro-4-((tetrahydrofuran-3-yl)oxy)pyrimidine-2 -yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naph Tyrizine-1(2H)-carboxamide; N-(5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyrimidine-2 -yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naph Tyrizine-1(2H)-carboxamide; 7-Formyl-6-(hydroxymethyl)-N-(4-((tetrahydrofuran-3- Iyl)oxy)pyridine-2-yl)-3,4-dihydro-1,8-naphthyridine-1( 2H)-carboxamide; N-(5-chloro-4-((tetrahydrofuran-3-yl)oxy)pyridine-2- (Iyl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyl Lysine-1(2H)-carboxamide; N-(5-cyano-4-((1-methylpiperidine-3-yl)methoxy)pyridine- 2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-na Futilisine-1(2H)-carboxamide; N-(5-cyano-4-((1-methylpyrrolidine-2-yl)methoxy)pyridine- 2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-na Futilisine-1(2H)-carboxamide; N-(5-cyano-4-((1-methylpiperidine-2-yl)methoxy)pyridine- 2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-na Futilisine-1(2H)-carboxamide; N-(5-fluoropyridine-2-yl)-7-formyl-6-(hydroxymethyl) -3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(2-(dimethylamino)ethoxy)pyridine-2-yl)- 6-Holm- 13 C-yl-2H-pyrido[3,2-b][1,4]oxazine-4(3 H)-Carboxamide; N-(5-cyano-4-((1-methylpiperidine-4-yl)methoxy)pyridine- 2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-na Futilisine-1(2H)-carboxamide; N-(5-cyanopyridine-2-yl)-7-formyl-4-hydroxy-3,4-di Hydro-1,8-naphthyrizine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1 (2H)-carboxamide; N-(5-cyano-4-(2-((dimethylamino)methyl)morpholino)pyridine- 2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-na Futilisine-1(2H)-carboxamide; N-(5-cyano-4-(quinuclidin-3-yloxy)pyridine-2-yl)-7 -Formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1 (2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4 -Dihydro-1,8-naphthyridine-1(2H)-carboxamide; 7-Formyl-6-(hydroxymethyl)-N-(4-((2-methoxyethyl)amide (no)-5-(trifluoromethyl)pyridine-2-yl)-3,4-dihydro-1,8- Naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(4-((dimethylamino)methyl)-4-hydroxypiperine Zin-1-yl)pyridine-2-yl)-7-formyl-6-(hydroxymethyl)-3 ,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-hydroxy-2-methylpropyl)amino)pyridine -2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8- Naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((3-(dimethylamino)-2-hydroxy-2-methyl Ropyr(amino)pyridine-2-yl)-7-formyl-6-(hydroxymethyl)-3 ,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-fluoroethyl)amino)pyridine-2-yl)-7 -Formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1 (2H)-carboxamide; N-(5-cyano-4-(2,2,2-trifluoroethoxy)pyridine-2-yl) -7-Formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine -1(2H)-carboxamide; N-(5-cyano-4-isopropoxypyridine-2-yl)-7-formyl-6-( (4-methyl-2-oxopiperazine-1-yl)methyl)-3,4-dihydro-1,8 -Naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(isopropylamino)pyridine-2-yl)-7-formyl -6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4-dihydro -1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-((3-oxomorpholino)methyl)-3,4-dihydro-1,8-na Futilisine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-((3-hydroxy-2-oxopyrrolidine-1-yl)methyl)-3 ,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(2-methoxyethoxy)pyridine-2-yl)-7-form Ru-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4-dihydr Ro-1,8-naphthirizine-1(2H)-carboxamide; N-(5-cyano-4-ethylpyridine-2-yl)-6,7-diformyl-3,4- Dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-((2-oxopiperazine-1-yl)methyl)-3,4-dihydro- 1,8-Naphthyrizine-1(2H)-Carboxamide hydrochloride; N-(5-cyano-4-((1-methoxypropan-2-yl)oxy)pyridine-2 -yl)-7-formyl-6-((4-methyl-2-oxoxazolidine-3-yl) Methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-((3-methyl-5-oxomorpholino)methyl)-3,4-dihydro -1,8-naphthyridine-1(2H)-carboxamide; 6-((4-acetylpiperazine-1-yl)methyl)-N-(5-cyano-4-iso) Propoxypyridine-2-yl)-7-formyl-3,4-dihydro-1,8-naphthyl Zin-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(1-(N-methylacetamido)ethyl)-3,4-dihydro-1, 8-Naphthyridine-1(2H)-Carboxamide; N-(5-cyano-4-isopropoxypyridine-2-yl)-7-formyl-6-( (2-hydroxy-N-methylacetamide)methyl)-3,4-dihydro-1,8-na Futilisine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-6 -((N-(2-(dimethylamino)ethyl)acetamide)methyl)-7-formyl- 3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-6 -((N-(2-(dimethylamino)ethyl)methylsulfonamide)methyl)-7-H Lumil-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-isopropoxypyridine-2-yl)-6-((2-(dimeth (Luamino)-N-methylacetamido)methyl)-7-formyl-3,4-dihydro-1 ,8-Naphthyridine-1(2H)-Carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-((2-Methoxy-N-methylacetamido)methyl)-3,4-dimethyl Dro-1,8-naphthyrizine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-((3-oxothiomorpholino)methyl)-3,4-dihydro-1,8 -Naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-6 -((1,1-dioxide-3-oxothiomorpholino)methyl)-7-formyl-3, 4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(((4-methylmorpholin-2-yl)methyl)amino) Lysine-2-yl)-6-(difluoromethyl)-7-formyl-3,4-dihydro-1 ,8-Naphthyridine-1(2H)-Carboxamide; N-(5-cyano-4-((1,1,1-trifluoro-3-methoxypropane-2- Iyl)oxy)pyridine-2-yl)-6-(difluoromethyl)-7-formyl-3, 4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-(trifluoromethoxy)ethyl)amino)pyridine -2-yl)-7-formyl-6-((N-methylacetamide)methyl)-3,4-di Hydro-1,8-naphthyrizine-1(2H)-carboxamide; 6-(2-oxa-5-azaspiro[3,4]octan-5-ylmethyl)-N-(5 -Cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7-formyl -3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(4-((2-(tert-butoxy)ethyl)amino)-5-cyanopyridine- 2-yl)-7-formyl-6-((4-methyl-2-oxopiperazine-1-yl) (Tyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-hydroxyethyl)amino)pyridine-2-yl)- 7-Formyl-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3, 4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(2-hydroxyethoxy)pyridine-2-yl)-7-hol Mil-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4-dimethyl Dro-1,8-naphthyrizine-1(2H)-carboxamide; N-(5-cyanopyridine-2-yl)-2-formyl-7,8-dihydro-5H-pyridine Lido[2,3-b]azepine-9(6H)-carboxamide; N-(5-cyano-4-(2-methoxyethoxy)pyridine-2-yl)-2-form Ru-7,8-dihydro-5H-pyrido[2,3-b]azepine-9(6H)-carboxate Mido; N-(5-cyano-4-((1-methoxypropan-2-yl)oxy)pyridine-2 -yl)-7-formyl-6-((4-methyl-2-oxopiperazine-1-yl)meth (Lu)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; 7-Formyl-N-(1-isopropyl-1H-imidazo[4,5-c]pyridine-6) -yl)-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4- Dihydro-1,8-naphthyridine-1(2H)-carboxamide; 7-Formyl-N-(1-isopropyl-1H-imidazo[4,5-c]pyridine-6) -yl)-6-((2-oxopyrrolidine-1-yl)methyl)-3,4-dihydro-1 ,8-Naphthyridine-1(2H)-Carboxamide; 4-((8-((5-cyano-4-((2-methoxyethyl)amino)pyridine-2- (Il)carbamoyl)-2-formyl-5,6,7,8-tetrahydro-1,8-naphthyl Lysine-3-yl(methyl)-1-methyl-3-oxopiperazine 1-oxide; N-(5-cyano-4-((2-oxopiperidine-4-yl)methoxy)pyridine- 2-yl)-7-formyl-6-((2-oxopyrrolidine-1-yl)methyl)-3, 4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(2-methoxyethoxy)pyridine-2-yl)-7-form 2-methyl-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3 ,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-isopropoxypyridine-2-yl)-7-formyl-2-methyl Tyl-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4-dimethyl Dro-1,8-naphthyrizine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-2-methyl-6-((4-methyl-2-oxopiperazine-1-yl)methyl (Lu)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-((3-hydroxy-4-methyl-2-oxopiperazine-1-yl) Methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-isopropoxypyridine-2-yl)-6-formyl-2,3 -dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxamide; 2-((5-cyano-2-(7-formyl-6-((4-methyl-2-oxopiperazi (-1-yl)methyl)-1,2,3,4-tetrahydro-1,8-naphthyridine-1- Carboxamide pyridine-4-yl amino ethyl hydrogen sulfide; N-(4-(Bicyclo[1.1.1]pentan-1-ylamino)-5-cyanopyridyl (-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazine-1-yl) )methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(thiophen-2-ylmethoxy)pyridine-2-yl)-7 -Formyl-6-((N-methylacetamido)methyl)-3,4-dihydro-1,8- Naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-(isopropylthio)pyridine-2-yl)-7-formyl- 6-((N-methylacetamido)methyl)-3,4-dihydro-1,8-naphthyridine -1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-6 -((3,5-dimethylpiperazine-1-yl)methyl)-7-formyl-3,4-dimethyl Dro-1,8-naphthyrizine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-((3,3,4-trimethyl-2-oxopiperazine-1-yl)methyl (Lu)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide; 6-amino-N-(5-cyanopyridine-2-yl)-7-formyl-3,4-dihydro Ro-1,8-naphthirizine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-1, 8-Naphthyridine-1(2H)-Carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-6 -(1,3-dimethyl-1H-pyrazole-4-yl)-7-formyl-3,4-dihydr Ro-1,8-naphthirizine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(1-methyl-1H-pyrazole-4-yl)-3,4-dihydro-1 ,8-Naphthyridine-1(2H)-Carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(2-methylthiazole-5-yl)-3,4-dihydro-1,8-na Futilisine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(thiophen-2-yl)-3,4-dihydro-1,8-naphthyridine -1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(1H-imidazole-1-yl)-3,4-dihydro-1,8-naph Tyrizine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(pyridine-3-yl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(1-methyl-1H-pyrazole-5-yl)-3,4-dihydro-1 ,8-Naphthyridine-1(2H)-Carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(3-methyl-1H-1,2,4-triazole-1-yl)-3,4 -Dihydro-1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(3-methyl-2-oxopyrrolidine-1-yl)-3,4-dihydro -1,8-naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(3-oxomorpholino)-3,4-dihydro-1,8-naphthyridine -1(2H)-carboxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(2-oxoxazolidine-3-yl)-3,4-dihydro-1,8 -Naphthyridine-1(2H)-carboxamide; N-(5-cyano-4-isopropoxypyridine-2-yl)-7-formyl-6-( Tetrahydrofuran-3-yl)-3,4-dihydro-1,8-naphthyridine-1(2H )-Carboxamide; N-(5-cyano-4-isopropoxypyridine-2-yl)-7-formyl-6-( Piperidine-4-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-cal Boxamide; N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-(1-(oxetane-3-yl)piperidine-4-yl)-3,4-di Hydro-1,8-naphthyrizine-1(2H)-carboxamide; and N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-6 -(1-(2,2-difluoroethyl)piperidine-4-yl)-7-formyl-3,4 -Dihydro-1,8-naphthyridine-1(2H)-carboxamide A pharmaceutical combination for use as described in any of embodiments 19 to 22, selected from .

[0139] Embodiment 24. The FGFR4 inhibitor is in free form or in the form of a pharmaceutically acceptable salt. N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)- 7-Formyl-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3, Embodiment 2 is 4-dihydro-1,8-naphthyridine-1(2H)-carboxamide. Pharmaceutical combinations for use as described in 2 or 23.

[0140] Embodiment 25. The FGFR4 inhibitor is in the citrate form N-(5-cyano-4- ((2-methoxyethyl)amino)pyridine-2-yl)-7-formyl-6-((4- Methyl-2-oxopiperazine-1-yl)methyl)3,4-dihydro-1,8-naph The tyridine-1(2H)-carboxamide is described in any of Embodiments 22 to 24. A pharmaceutical combination for use.

[0141] Embodiment 26. The side effect is an increase in liver enzymes, as described in any of Embodiments 19 to 25. A pharmaceutical combination for use in the field.

[0142] Embodiment 27. The side effect is an increase in ALT, as described in any of Embodiments 19 to 26. A pharmaceutical combination for use in the field.

[0143] Embodiment 28. The side effect is an increase in AST, as described in any of Embodiments 19 to 26. A pharmaceutical combination for use in the field.

[0144] Embodiment 29. The side effect is an increase in miRNA122, as in Embodiments 19 to 25. A pharmaceutical combination for use as described below.

[0145] Embodiment 30. Embodiment 19, in which FGFR4 inhibitor therapy is a treatment for cancer. Pharmaceutical combinations for use as described in any of the 29s.

[0146] Embodiment 31. FGFR4 inhibitor therapy is effective in treating liver cancer, breast cancer, glioblastoma, prostate cancer, A treatment for rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer, and colon cancer, and an embodiment of the treatment. Pharmaceutical combinations for use as described in any of paragraphs 19 to 30.

[0147] Embodiment 32. Embodiment in which FGFR4 inhibitor therapy is a treatment for liver cancer. Pharmaceutical combinations for use as described in 30.

[0148] Embodiment 33. Simultaneous or sequential administration of an FGFR4 inhibitor and a bile acid scavenger. For use in therapeutic regimens including the FGFR4 inhibitor and bile acid scavenging, A pharmaceutical combination containing drugs.

[0149] Embodiment 34. The FGFR4 inhibitor is in the citrate form N-(5-cyano-4- ((2-methoxyethyl)amino)pyridine-2-yl)-7-formyl-6-((4- Methyl-2-oxopiperazine-1-yl)methyl)3,4-dihydro-1,8-naph Tyrizine-1(2H)-carboxamide is a bile acid scavenger, and cholestyramine is another bile acid scavenger. , the pharmaceutical combination for use described in Embodiment 33.

[0150] Embodiment 35. The treatment regimen is a treatment regimen for the treatment of liver cancer, Pharmaceutical combinations for use as described in form 33 or 34.

[0151] The following examples are intended to illustrate the present invention and should be construed as limitations on the present invention. It shouldn't be done. [Examples]

[0152] [Example 1] N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4 -Dihydro-1,8-naphthyridine-1(2H)-carboxamide was introduced in International Publication No. 201 It was synthesized as described in Example 83 of pamphlet No. 5059668.

[0153] N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7 -Formyl-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4 -Dihydro-1,8-naphthyridine-1(2H)-carboxamide (compound A(Cpd A)) and cholestyramine (CHO) (Questran Powder [oral suspension Also known as Cholestyramine [USP]; NDC number: 49884-09366- 66; Lot number: 26079601) Each vehicle [100 in the case of compound A] [ mM citrate buffer, pH 2.5; in the case of cholestyramine, administered as a compound in water] .

[0154] A male Beagle dog, Marshall BioResources (North Ro Obtained from SE, NY. All animals used in the study were naive to the treatment. Yes, it was. All animals used in the test were healthy and suitable for use. CPD A and The dosage (volume) of the vehicle was 5 mL / kg. In the case of CHO, the medication was administered as an aliquot. This was dispersed in a total of 75 mL of animal drinking water.

[0155] In the trial, the medication paradigm was the vehicle or CH on the last day before the trial (-1 day). The initial loading dose of O was followed, and the administration of vehicle or CHO was followed from day 1 to day 7.

[0156] [Table 1]

[0157] For the vehicle or CHO, N-(5-cyano-4-((2-methoxyethyl) Mino)pyridine-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazi (1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-cal Voxamide administration was started on day 8, and a second dose event was performed daily. After the medication event, the animals were fed. No medication was given to the animals on day 15. Medication was given on day 24. The medication was restarted, and the treatment groups were cross-treated between days 38 and 44, with day 44 being the final day of medication.

[0158] Clinical observation, twice-weekly weight monitoring, and determination of daily food intake were performed.

[0159] For bile acid (BA) analysis, once before the test, and also on days 7, 10, 14, 17, and 24. Fecal samples were collected on days 28, 35, 42, and 49.

[0160] Simultaneously with sample collection for clinical pathology and / or toxicology, bile acid progenitor during testing Plasma was collected from all animals as follows for the file: 1, 3, 7, 8, 11, 1 4, 15, 18, 21, 23, 25, 28, 31, 35, 38, 42, 45, 49, oyo Approximately 3 hours after the medication on day 52 (after vehicle, CHO, or Cpd A as appropriate). 8. Only on days 14, 25, and 39, approximately 0.5, 1, 3, 7, and 7 minutes before and after medication administration. Samples were collected 24 hours after administration of Cpd A. Furthermore, on day 44, 3 Bile acid biomarker samples were collected 7, and 24 hours later (last toxicological blood samples). (Simultaneously with liquid collection).

[0161] Regarding serum ALT activity, generally speaking, a slight to moderate increase in serum ALT activity is due to the compound This was related to the administration of A, but it improved with the simultaneous administration of cholestyramine. These changes are shown in Figure 1.

[0162] Therefore, simultaneous administration of cholestyramine, which leads to bile acid scavenging in the intestines, is effective in controlling bile acid in the liver. This reduces accumulation and, consequently, mitigates the increase in ALT activity associated with compound A.

[0163] Compared to pre-test results, administration of compound A alone (Group 1) showed only a slight increase in serum ALT activity. This resulted in a moderate increase (≤3.5 times). In contrast, animals in group 2 (Colestria) The administration of compound A (administered simultaneously with lamin) over the same period affected serum ALT activity. It did not show any related changes.

[0164] After the first crossover, the administration of compound A and cholestyramine (Group 1) during this drug administration period However, in group 2 (compound A only), During this period, the increase in serum ALT activity was slight to moderate (≤6 times). In contrast, the animals in group 2 (administered compound A simultaneously with cholestyramine) No changes in serum ALT activity were observed during the same period.

[0165] After the second crossover, administration of compound A alone (Group 1) resulted in slight to moderate serum ALT activity. This resulted in an increase (≤3.5 times). In contrast, animals in group 2 (same as cholestyramine) The administration of compound A at that time resulted in a return to pre-test ALT activity.

[0166] These findings suggest that the combination of FGFR4 inhibitors and bile acid scavengers is effective in reducing FGFR4 Related to inhibitory therapy, for example, related to the administration of compound A or a pharmaceutically acceptable salt thereof. This indicates that it may be useful in reducing or mitigating side effects.

[0167] [Example 2] Liver-enriched microRNAs (Starkey Lewis) used as biomarkers for liver injury Plasma miR-122 levels (s PJ et al., Clin Pharmacol Ther, 2012, 291-293) This was determined. miR-122 is considered a liver-specific marker.

[0168] material and method Extraction of low molecular weight RNA from plasma Using the miRNeasy / MinElute kit, from the manufacturer (Qiagen) Following the instructions, low molecular weight RNA was extracted from 50 μl of plasma. The elution of low molecular weight RNA was 1 This was achieved in 4 μl of nucleic acid-free H2O.

[0169] Reverse transcription and pre-amplification Megaplex RT Primer Human Pools A and B and Taqman Mi corRNA Reverse Transcription Kit (Applied Biosystems / Life Technologies, Reference No. 4366596 Using the method described by the manufacturer, reverse the extraction of 3.2 μl of eluted small RNA into cDNA. I transcribed it.

[0170] Megaplex Preamp Primer Human Pools A and B (Applied Biosystems / Life Technologies, Reference No. 4399201 and 4399233) and Taqman PreAmp MasterMix(A Applied Biosystems / Life Technologies, reference number Using 4391128), pre-amplify 2.5 μl of cDNA according to the manufacturer's instructions. It widened.

[0171] Amplification of miR-122 Taqman MasterMix II (Applied Biosystems / L A commercially available, effective Taqman assay (diluted in iFe Technologies) Using reference number 002245), pre-amplified cDNA according to the manufacturer's instructions. microRNA miR-122 was amplified from this.

[0172] Standard curve method is used to generate expression values ​​as the number of molecules in plasma microRNA The relative levels were quantified.

[0173] statistical analysis Using a two-sample heteroscedastic two-tailed distribution (heteroscedastic Student's t-test, Excel) The statistical significance of mRNA measurements was evaluated. A coefficient of variation with a P value < 0.05 was statistically significant. I assumed that was the intention.

[0174] Days 1-7 of the trial: Group 1: Vehicle; Group 2: Cholestyramine Treatment with vehicles and CHO did not affect miR-122 levels.

[0175] Days 8-14 of the trial: Group 1: Vehicle + Cpd A; Group 2: CHO + Cpd A Compared to the results from days 1-7 of the trial, the group receiving only Cpd A and vehicle (Group 1) Furthermore, the administration of CHO and Cpd A (Group 2) was associated with the accidental miR-122 level This resulted in an increase in irrelevance (maximum mean, Group 1 ≤ 2.5 times on day 14; Group 2 on day 14) group ≦11.6 times).

[0176] Days 15-23 of the trial: Group 1 and Group 2: Recovery Compared to the results from days 1-7 of the test, the recovery period was similar to the miR-122 level of accidental occurrences. This resulted in an increase that was not biologically significant (maximum mean, Group 1 ≤ 5.4 times on day 21); On day 21, Group 2 was ≤11.7 times.

[0177] Days 25-38 of the trial: Group 1: Cpd A + Cholestyramine; Group 2: Cpd A + Bifidobacterium Kuru Compared to the results from days 1-7 of the trial, the administration of CHO and Cpd A (Group 1) showed that m This resulted in an accidental and non-biologically significant increase in iR-122 levels (maximum mean) (On day 35, Group 1 was ≤5.8 times). In Group 2, administration of CPD A and vehicle alone was: In animals, 2003, this resulted in a significant time-dependent increase in miR-122 levels (most Large: ≤151 times on day 38). This treatment also resulted in miR-122 in animals in 2006. This induced a significant increase in Bell (maximum mean on day 31: ≤63 times).

[0178] Days 39-42 of the examination: Group 1: CPD A+ vehicle; Group 2: CPD A+ cholesterol Min After the second crossover, administration of Cpd A and vehicle alone (Group 1) resulted in miR-122 This resulted in a small, accidental increase in Bell (mean ≤ 7.8 times). In contrast, within the second group... Animals (administered Cpd A concurrently with cholestyramine) showed miR-122 He showed signs of returning to his level.

[0179] Days 45-52 of the trial: Group 1 and Group 2: Recovery Compared to the results from days 1-7 of the experiment, the recovery period was m in the two animals from group 1. This resulted in a significant transient increase in iR-122 levels (peak at day 49: 100% of animals). 3: ≤ 47.9 times; Animal 1006: ≤ 40.1 times). Similarly, the other two animals from the first group In the material, a slight transient increase in miR-122 levels was observed (on day 49). K: Animal 1001: ≤22.2 times; Animal 1005: ≤16.4 times). In the second group, Animal 2 The miR-122 level in 003 showed a moderate but time-dependent increase. Day 45: ≤12 times; Day 49: ≤39 times; Day 52: ≤89 times). Similarly, from the second group... A slight transient increase in miR-122 levels was observed in the two animals (52 days). Eye: Animal 2001: ≦42 times; Animal 2006: ≦43 times).

[0180] Several animals treated with compound A showed a slight decrease in miR122 compared to each control. A moderate increase was observed, but this was followed by a decrease in miR-122 levels after simultaneous treatment with CHO. It followed the trend.

[0181] These data suggest that cholestyramine can be used concurrently with or sequentially with FGFR4 inhibitors, thereby reducing side effects associated with FGFR4 inhibitory therapy. The following embodiments may be included. [1] A pharmaceutical combination comprising a selective FGFR4 inhibitor and a bile acid scavenger. [2] Formula (I) of the free form or the pharmaceutically acceptable salt form [ka] [In the formula, V is CH 2 Selected from , O, CH(OH); W is CH 2 CH 2 CH 2 , selected from the combination; X is C(RX ) or N; Y is C(R Y ) or N; Z is either CH or N; If X is N, then Y and Z are not N; If Y is N, then X and Z are not N; If Z is N, then X and Y are not N; R X This is hydrogen, halogen, halo C 1 ~C 3 Alkyl, cyano, C 1 ~C 6 Alkyl, hydroxy C 1 ~C 6 Selected from alkyl groups; R Y is hydrogen, halogen, C 1 ~C 3 Alkyl, C 1 ~C 6 Alkoxy, Hydroxy C 1 ~C 3 Alkoxy, NR Y1 R Y2 , cyano, C 1 ~C 3 Alkoxy C 1 ~C 3 Alkoxy, C 1 ~C 3 Alkoxy-halo C 1 ~C 3 Alkoxy, di(C) 1 ~C 3 Alkyl)amino C 1 ~C 6 Alkoxy, O-(CH 2 ) 0~1 -R Y3 , CR Y6 R Y7 SC 1 ~C 3 Alkyl, optionally substituted with hydroxyl, halo C 1 ~C 6 Selected from alkoxy; or R X and R Y Together with the ring to which they are bonded, they form a bicyclic aromatic ring system which optionally further contains one or two heteroatoms selected from N, O, or S, and this ring system optionally contains C 1 ~C 3 It is substituted with alkyl; R Y1 It is hydrogen, R Y2 C 1 ~C 6 Alkyl; Hydroxy C 1 ~C 6 Alkyl; optionally substituted with hydroxyl. 1 ~C 6 Alkyl; C 1 ~C 4 Alkoxy C 1 ~C 6 alkyl; Hello C 1 ~C 3 Alkoxy C 1 ~C 6 Alkyl; (CH 2 ) 0~1 -R Y4 ; Di(C) substituted with hydroxyl 1 ~C 3 Alkyl)amino C 1 ~C 6 Alkyl; optional hydroxy C 1 ~C 3 Alkyl-substituted bicycloC 5 ~C 8 Alkyl; S(O) 2 -CH(CH 3 ) 2 Phenyl substituted with C 2 ~C 3 Selected from alkyl sulfonic acids; or R Y1 and R Y2 These, together with the N atoms to which they are bonded, form a saturated or unsaturated non-aromatic 6-membered heterocyclic ring which may also contain an O atom, and this ring is R Y5 It may be substituted once or twice by this; R Y3 This is selected from a 4, 5, or 6-membered saturated heterocyclic ring or a 5 or 6-membered aromatic heterocyclic ring containing at least one heteroatom selected from quinuclidinyl, N, O, or S, wherein this saturated or aromatic heterocyclic ring is optionally C 1 ~C 3 Substituted with alkyl and / or oxo; R Y4 is a 4, 5, or 6-membered saturated heterocyclic ring containing at least one heteroatom selected from N, O, or S, wherein the ring is optionally C 1 ~C 3 It is substituted with alkyl; R Y5 C 1 ~C 3 Alkyl, hydroxy, di(C) 1 ~C 3 Alkyl)amino C 1 ~C 3 Selected independently of alkyl, or Two R atoms bonded to the same carbon atom Y5 Together with the carbon atoms to which they are bonded, they form a five-membered saturated heterocyclic ring containing at least one heteroatom selected from N, O, or S, and this ring is C 1 ~C 3 Substituted with one or more alkyl groups; R Y6 and R Y7 These, together with the carbon atoms to which they are bonded, form a six-membered saturated or unsaturated non-aromatic heterocyclic ring containing one heteroatom selected from N, O, or S; R 1 is hydrogen; halogen; C 1 ~C 3 alkyl; halo C 1 ~C 3 Alkyl; Hydroxy C 1 ~C 3 Alkyl; C 3 ~C 6 Cycloalkyl; CH 2 NR 2 R 3 ;CH(CH 3 )NR 2 R 3 ;C 1 ~C 3 Alkoxy C 1 ~C 3 Alkyl; CH 2 CO 2 H;C(O)H;C 1 ~C 3 Alkoxy; selected from a 5 or 6-membered saturated heterocyclic or aromatic heterocyclic ring containing at least one heteroatom selected from N, O, or S, wherein the ring is optionally C 1 ~C 3 Alkyl, Halo C 1 ~C 3 Substituted with one or more groups independently selected from alkyl, oxetanyl, or oxo; R 2 C 1 ~C 3 Alkyl, di(C) 1 ~C 3 Alkyl)amino C 1 ~C 3 Selected from alkyl groups; R 3 C 1 ~C 3 Alkyl, C(O)C 1 ~C 3 Alkyl, C(O)-CH 2 -OH,C(O)-CH 2 -O-CH 3 , C(O)-CH 2 -N(CH 3 ) 2 , S(O) 2 CH 3 Selected from; or R 2 and R 3 Together with the N atom to which they are bonded, they form a saturated 5 or 6-membered ring which optionally contains one additional heteroatom selected from N, N-oxide, O, or S, and this ring is R 4 It is also acceptable if one or more substitutions are made; R 4 C 1 ~C 3 Alkyl, di(C) 1 ~C 3 Alkyl)amino, C(O)CH 3 , independently selected from hydroxyl; or Two R atoms bonded to the same carbon atom 4 Together with the carbon atoms to which they are bonded, they form a 4, 5, or 6-membered non-aromatic heterocyclic ring containing at least one heteroatom selected from N, O, or S; or Two R atoms bonded to the same ring atom 4 It forms an oxo group; R 5 is hydrogen or C 1 ~C 3 Selected from alkyl groups] A pharmaceutical combination containing the FGFR4 inhibitor, which is a compound of [unclear]. [3] The pharmaceutically acceptable combination according to [1] or [2], wherein the FGFR4 inhibitor is N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide in free form or in the form of a pharmaceutically acceptable salt. [4] The pharmaceutical combination according to any one of [1] to [3], wherein the FGFR4 inhibitor is N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide in citrate form. [5] The pharmaceutical combination according to any one of [1] to [4], wherein the bile acid scavenger is selected from cholestyramine, coleseveram, coleseveram hydrochloride, colestipol, or sevelamer, and preferably the bile acid scavenger is cholestyramine. [6] A pharmaceutical combination described in any one of the items [1] to [5] for use as a medicine. [7] Pharmaceutical combinations of the above [6] for use in the treatment of cancer, particularly liver cancer. [8] A pharmaceutical combination according to any one of [1] to [5] for use in reducing or preventing adverse effects associated with FGFR4 inhibitor therapy, wherein the adverse effect is not diarrhea. [9] Any of the pharmaceutical combinations described in any one of [1] to [5] for use in reducing or preventing an increase in hepatic enzymes in serum, plasma, or blood in subjects receiving FGFR4 inhibitor therapy.

[10] FGFR4 inhibitory therapy is the administration of an FGFR4 inhibitor as described in [2], or a pharmaceutically acceptable combination for use as described in [8] or [9], wherein the FGFR4 inhibitory therapy is the administration of N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide or a pharmaceutically acceptable salt thereof.

[11] A bile acid scavenger for use in reducing or preventing side effects associated with FGFR4 inhibitor therapy, wherein the side effect is not diarrhea.

[12] Bile acid scavengers for use in reducing or preventing adverse effects associated with FGFR4 inhibitor therapy, wherein the adverse effects include an increase in liver enzymes in the serum, plasma or blood of a subject receiving FGFR4 inhibitor therapy, and optionally, the FGFR4 inhibitor therapy is a treatment for liver cancer.

[13] A bile acid scavenger for use according to

[11] or

[12] , wherein the hepatic enzyme is alanine aminotransferase (ALT).

[14] Bile acid scavengers for use as described in

[11] , wherein the aforementioned side effects include an increase in miRNA122 in subjects receiving FGFR4 inhibitor therapy.

[15] Cholestyramine, a bile acid scavenger for use as described in any one of items

[11] to

[14] .

[16] Bile acid scavengers for use in reducing or preventing an increase in hepatic enzymes in the serum, plasma, or blood of a subject, wherein the subject is administered the FGFR4 inhibitor described in [2] or N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4-dihydro-1,8-naphthirizine-1(2H)-carboxamide or a pharmaceutically acceptable salt thereof.

[17] A method for reducing the occurrence or severity of adverse events other than diarrhea associated with FGFR4 inhibitor therapy, comprising the step of administering a combination of a bile acid scavenger and a selective FGFR4 inhibitor, either concurrently or sequentially, to a subject requiring FGFR4 inhibitor therapy.

[18] The method according to

[17] , wherein the bile acid scavenger is cholestyramine.

[19] The FGFR4 inhibitor is in the form of a free form or a pharmaceutically acceptable salt of formula (I)

change

[17] or

[18] , which is a compound of

[17] .

[20] The method according to

[19] , wherein the FGFR4 inhibitor is N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide in free form or in the form of a pharmaceutically acceptable salt.

[21] The method according to any one of

[17] to

[20] , wherein the side effect is an increase in liver enzymes, particularly an increase in ALT.

[22] The method according to any one of

[17] to

[20] , wherein the side effect is an increase in miRNA122.

[23] The method according to any one of

[17] to

[22] , wherein the FGFR4 inhibitory therapy is a treatment for cancer.

[24] The method according to

[23] , wherein the FGFR4 inhibitory therapy is a treatment for liver cancer.

[25] Treatment regimens including simultaneous or sequential administration of FGFR4 inhibitors and bile acid scavengers.

[26] A therapeutic regimen comprising the concurrent or sequential administration of cholestyramine and N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4-dihydro-1,-naphthyridine-1(2H)-carboxamide in its free form or in the form of a pharmaceutically acceptable salt.

[27] Therapeutic regimens described in

[25] or

[26] for the treatment of liver cancer including HCC.

Claims

1. A pharmaceutical composition comprising a bile acid scavenger for reducing or preventing side effects associated with FGFR4 inhibitor therapy, The aforementioned side effect is an increase in liver enzymes in the serum, plasma, or blood of the patient receiving FFFR4 inhibitor therapy. The aforementioned FGFR4 inhibitor therapy is for the treatment of liver cancer. A pharmaceutical composition wherein the FGFR4 inhibitory therapy comprises the administration of an FGFR4 inhibitor, which is N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide in free form or in the form of a pharmaceutically acceptable salt.

2. The pharmaceutical composition according to claim 1, wherein the FFFR4 inhibitor is N-(5-cyano-4-((2-methoxyethyl)amino)pyridine-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazine-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide in citrate form.

3. The pharmaceutical composition according to claim 1 or 2, wherein the bile acid scavenger is selected from cholestyramine, cholesevelam, cholesevelam hydrochloride, colestipol, and sevelamer.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the bile acid scavenging agent is cholestyramine.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the liver enzyme is alanine aminotransferase (ALT).

6. The pharmaceutical composition according to claim 5, wherein the increased ALT in serum, plasma, or blood is more than twice the upper limit of the normal level.

7. The pharmaceutical composition according to claim 5, wherein the increased ALT in serum, plasma, or blood is 110 to 165 units / liter.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the side effect is not diarrhea.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the daily dose of the FGFR4 inhibitor is 25 to 200 mg.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the daily dose of the bile acid scavenging agent is 4 to 24 g.

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