TW201605853A - Ring-fused bicyclic pyridyl derivatives as FGFR4 inhibitors - Google Patents

Abstract

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof; a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

Description

Fused ring bicyclopyridyl derivatives as FGFR4 inhibitors

The present invention provides bicyclic pyridyl derivative compounds, their use for inhibiting FGFR4, and methods of using the compounds to treat diseases.

Normal growth and tissue repair and remodeling require specific and precise control of activated growth factors and their receptors. Fibroblast growth factor (FGF) constitutes a family of more than twenty structurally related polypeptides that are actively regulated and expressed in a wide variety of tissues. FGF stimulates proliferation, cell migration and differentiation, and plays a major role in bone and limb development, wound healing, tissue repair, hematopoiesis, angiogenesis, and tumor formation (in Ornitz, Novartis Found Symp 232: 63-76; -80,272-82 (2001).

The biological role of FGF is mediated by specific cell surface receptors belonging to the receptor protein tyrosine kinase (RPTK) family of protein kinases. These proteins consist of an extracellular ligand binding domain, a single transmembrane domain, and an intracellular tyrosine kinase domain that is phosphorylated upon binding of FGF. Four FGFRs have been identified to date: FGFR1 (also known as Flg, fms-like gene, flt-2, bFGFR, N-bFGFR or Cek1), FGFR2 (also known as Bek-Bacterial Expressed Kinase-). KGFR, Ksam, Ksaml and Cek3), FGFR3 (also known as Cek2) and FGFR4. All mature FGFRs share an amine-terminated signal peptide, three extracellular immunoglobulin domains (Ig domain I, Ig domain II, Ig domain 1II) And the acidic structure between the Ig domain ("acidic box" domain), the transmembrane domain, and the common structure of the intracellular kinase domain (Ullrich and Schlessinger, Cell 61: 203, 1990; Johnson and Williams (1992) Adv. Cancer Res. 60:1-41). Different FGFR isoforms have different binding affinities for different FGF ligands.

Changes in FGFR have been linked to a variety of human cancers, including myeloma, breast cancer, stomach cancer, colon cancer, bladder cancer, pancreatic cancer, and hepatocellular carcinoma. Recently, FGFR4 has been reported to play an important role especially in liver cancer (PLoS One, 2012, Vol. 7, 36713). Other studies have also involved FGFR4 or its ligand FGF19 in other cancer types (including breast cancer, glioblastoma, prostate cancer, rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer, colon cancer) (Int. J. Cancer 1993;54:378-382;Oncogene 2010;29:1543-1552;Cancer Res 2010;70:802-812;Cancer Res 2011;71:4550-4561;Clin Cancer Res 2004;10:6169-6178;Cancer Res 2013;73:2551-2562;Clin Cancer Res 2012;18:3780-3790;J.Clin.Invest.2009;119:3395-3407;Ann Surg Oncol 2010;17:3354-61;Cancer 2011;117:5304 -13; Clin Cancer Res 2013; 19: 809-820; PNAS 2013; 110: 12426-12431; Oncogene 2008; 27: 85-97).

Therapies involving FGFR4 blocking antibodies have been described, for example, in WO 2009/009173, WO 2007/136893, WO 2012/138975, WO 2010/026291, WO 2008/052798, and WO 2010/004204.

There is a continuing need to develop new FGFR4 inhibitors that are good drug candidates. Such candidates will find applications particularly in the treatment of cancer, especially in the treatment of liver cancer.

The present invention provides a compound, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, and a combination thereof, which are FGFR4 inhibitors. The invention further provides a method of treating, preventing or ameliorating cancer comprising administering to a subject in need thereof an effective amount of an FGFR4 inhibitor.

Various embodiments of the invention are described herein.

In certain aspects, provided herein are compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein X, Y, Z, V, W, R ¹ and R ^{5 are} as defined herein.

In another embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof or a subformula (Ia) as defined herein And (Ia-1), (Ib), (Ic), (Id) and one or more pharmaceutically acceptable carriers.

In another embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof or a subformula thereof as defined herein ( Ia), (Ia-1), (Ib), (Ic), (Id).

In another embodiment, the invention provides a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof or a daughter thereof as defined herein Formula (Ia), (Ia-1), (Ib), (Ic), (Id) and one or more therapeutically active agents.

In another embodiment, the invention relates to a method of inhibiting FGFR4 receptor activity in an individual, wherein the method comprises administering to the individual a therapeutically effective amount of a compound of formula (I) or a subform thereof as defined herein ( Ia), (Ia-1), (Ib), (Ic), (Id) or a pharmaceutically acceptable salt thereof.

In still another embodiment, the invention relates to a treatment selected from the group consisting of cancer (eg, liver cancer, A method of treating a condition or disease of breast cancer, glioblastoma, prostate cancer, rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer, colon cancer, comprising administering to the individual a therapeutically effective amount of formula (I) as defined herein A compound or a subformula (Ia), (Ia-1), (Ib), (Ic), (Id) or a pharmaceutically acceptable salt thereof as defined herein.

Particularly interesting compounds of the invention have good performance in the biological assays described herein. In another aspect, it should have an advantageous safety profile. In another aspect, it should have advantageous pharmacokinetic properties. In addition, the ideal drug candidate will be in a stable, non-hygroscopic, and easily formulated form. The compounds of the invention are more selective for FGFR4 than other receptors, particularly over other FGF receptors such as FGFR1, FGFR2 and FGFR3. Thus, the invention relates to compounds which are selective FGFR4 inhibitors.

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof

Wherein V is selected from the group consisting of CH ₂ , O, CH(OH); W is selected from CH ₂ , CH ₂ CH ₂ ; X is C(R ^X ) or N; Y is C(R ^Y ) or N; Z is CH Or N; wherein when X is N, Y and Z are not N; wherein when Y is N, X and Z are not N; wherein when Z is N, X and Y are not N; R ^X is selected from Hydrogen, halogen, halo C ₁ -C ₃ alkyl, cyano, C ₁ -C ₆ alkyl, hydroxy C ₁ -C ₆ alkyl; R ^Y is selected from 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 , optionally a hydroxy-substituted halo-C ₁ -C ₃ alkoxy group; or R ^X and R ^Y and the ring to which they are attached may further comprise one or two selected from N, O or S, as appropriate a bicyclic aromatic ring system of a hetero atom, which ring is optionally substituted by a C ₁ -C ₃ alkyl group; R ^Y1 is hydrogen and R ^Y2 is a C ₁ -C ₆ alkyl group, a hydroxy C ₁ -C ₆ alkyl group, the optionally substituted hydroxy halo C ₁ -C ₆ alkyl, C ₁ -C ₃ alkoxy C ₁ -C _{6 ^{alkyl, (CH 2) 0-1 -R Y4}} , by hydroxyl Substituted bis (C ₁ -C ₃ alkyl) amino C ₁ -C ₆ alkyl, hydroxy substituted C ₁ -C ₃ alkyl group of bicyclo [2.2.1] heptyl, by S (O) ₂ -CH a (CH ₃ ) ₂ substituted phenyl group; or R ^Y1 and R ^Y2 and the N atom to which they are attached form a saturated or unsaturated non-aromatic 6-membered heterocyclic ring which may contain an O atom, which ring may be substituted once by R ^Y5 or Tw; R ^Y3 is selected from a quinuclidinyl group, a 4-membered, 5- or 6-membered saturated heterocyclic ring containing at least one hetero atom selected from N, O or S, which is optionally C ₁ -C ₃ alkyl Substituted; R ^Y4 is a 4-, 5- or 6-membered saturated heterocyclic ring containing at least one hetero atom selected from N, O or S, which ring is optionally substituted by C ₁ -C ₃ alkyl; R ^{Y5 is} independently selected from C ₁ -C ₃ alkyl, hydroxy, bis(C ₁ -C ₃ alkyl)amino C ₁ -C ₃ alkyl, or two R ^Y5 attached at the same carbon atom and the carbon atom to which they are attached a 5-membered saturated heterocyclic ring containing at least one hetero atom selected from N, O or S, the ring being substituted by a C ₁ -C ₃ alkyl group; R ^Y6 and R ^Y7 and the carbon atom to which they are attached form one selected from N a 6-membered saturated or unsaturated non-aromatic heterocyclic ring of a hetero atom of O or S; R ¹ is selected from the group consisting of 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; R ² is selected from C ₁ -C ₃ alkyl, di(C ₁ -C ₃ alkyl) Amino C ₁ -C ₃ alkyl; R ³ is selected from 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 ; or R ² and R ³ and the N atom to which they are attached form an additional a saturated 5- or 6-membered ring selected from heteroatoms of N, O or S, which ring may be substituted once or more by R ⁴ ; R ^{4 is} independently selected from C ₁ -C ₃ alkyl, di(C ₁ -C ₃ alkyl)amino, C(O)CH ₃ , hydroxy; or two R ⁴ attached to the same carbon atom and the carbon atom to which they are attached form at least one selected from N, O or S a 4-membered, 5-membered or 6-membered non-aromatic heterocyclic ring; or two R ⁴ attached to the same carbon atom to form a pendant oxy group; R ⁵ is selected from hydrogen or a C ₁ -C ₃ alkyl group.

Unless otherwise specified, the terms "compounds of the present invention" or "compounds of the invention" refer to formula (I), (Ia), (Ia-1), Compounds of Ib), (Ic), (Id) and salts thereof as defined herein, and all stereoisomers (including diastereomers and enantiomers), rotamers, tautomers Complex and isotopically labeled compounds (including hydrazine substituents) as well as intrinsic forming moieties.

In particular, compounds of formula (I), (Ia), (Ia-1), (Ib), (Ic), (Id) are capable of readily forming tautomers as described below.

For example, a compound of the invention wherein R ¹ is hydroxymethyl, CH ₂ CO ₂ H (eg, compounds (I-1) and (I-3)) may be in a tautomeric form as described below (compounds) (I-1a) and (I-3a)). Further, the compound of the present invention wherein R ¹ is C(O)H may be in the form of a hydrate thereof to form a tautomer (compounds (I-2) and (I-2a)) as described below.

Thus, the compounds (I-1), (I-2), (I-3) and their tautomers (I-1a), (I) wherein V, W, X, Y and Z are as defined herein, -2a), (1-3a) also form part of the invention.

The presence of tautomers can be identified by a person skilled in the art using tools such as NMR.

As used herein, the term "C ₁ -C ₆ alkyl" refers to a linear chain composed solely of carbon and hydrogen atoms, free of unsaturation, having one to six carbon atoms, and attached to the remainder of the molecule by a single bond. Or branched chain hydrocarbon chain groups. The term "C ₁ -C ₄ alkyl" is understood accordingly. Examples of C ₁ -C ₆ alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl ( isopropyl ), N-butyl , n-pentyl, and 1,1- Dimethylethyl ( t-butyl ).

As used herein, the term "hydroxy C ₁ -C ₆ alkyl" refers to _a radical of the formula -R _a -OH wherein R _a is C _1-6 alkyl as defined above. Examples of hydroxy C ₁ -C ₆ alkyl groups include, but are not limited to, hydroxy-methyl, 2-hydroxy-ethyl, 2-hydroxy-propyl, 3-hydroxy-propyl, and 5-hydroxy-pentyl.

As used herein, the term "C ₃ -C ₆ cycloalkyl" refers to a saturated monocyclic hydrocarbon group of ₃ to 6 carbon atoms. Examples of the C ₃ -C ₆ cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

As used herein, the term "C ₁ -C ₆ alkoxy" refers to _a radical of the formula -OR _a where R _a is C ₁ -C ₆ alkyl as defined generally above. The term "C ₁ -C ₃ alkoxy" is understood accordingly. Examples of C ₁ -C ₆ alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy and hexyloxy.

As used herein, the term "C ₁ -C ₄ alkoxy C ₁ -C ₆ alkyl" refers to _a radical of the formula -R _b -OR _a wherein R _a is C ₁ -C ₄ alkyl, and R _b Is a C ₁ -C ₆ alkyl group as defined above. The oxygen atom can be bonded to any carbon atom in any of the alkyl groups. Examples of C ₁ -C ₄ alkoxy C ₁ -C ₆ alkyl groups include, but are not limited to, methoxy-methyl, methoxy-ethyl, ethoxy-ethyl, 1-ethoxy- Propyl and 2-methoxy-butyl.

"Halogen" or "halo" means bromo, chloro, fluoro or iodo.

As used herein, the term "halo C ₁ -C ₆ alkyl" or "halo C ₁ -C ₆ alkyl" refers to one substituted as defined above or more halo groups as defined above of C ₁ -C ₆ alkyl. Examples of halogen C ₁ -C ₆ alkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl Base-2-fluoroethyl, 3-bromo-2-fluoropropyl and 1-bromomethyl-2-bromoethyl.

As used herein, the term "halo C ₁ -C ₃ alkoxy" means C is composed of one or more halo groups as defined above substituted with the above defined of ₁ -C ₃ alkoxy group. Examples of halo C ₁ -C ₃ alkoxy include, but are not limited to, trifluoromethoxy, difluoromethoxy, trifluoroethoxy.

As used herein, the term "hydroxy C ₁ -C ₃ alkoxy" means the above defined C ₁ -C ₃ alkoxy group, wherein a hydrogen atom C ₁ -C ₃ alkoxy by one of the OH Replacement. Examples of hydroxy C ₁ -C ₃ alkoxy groups include, but are not limited to, hydroxymethoxy, hydroxyethoxy.

As used herein, the term "C ₁ -C ₃ alkoxy C ₁ -C ₃ alkoxy" means C as hereinbefore defined of _1--3 alkoxy, wherein C ₁ - ₃ alkoxy group of a hydrogen atom in the One of them is replaced by -OC ₁ -C ₃ alkyl. Examples of the C _1-3 alkoxy C _1-3 alkoxy group include, but are not limited to, a methoxymethoxy group, an ethoxymethoxy group.

As used herein, the term "C ₁ -C ₃ alkoxy, - halo C ₁ -C ₃ alkoxy" means a halogen group as defined above, the C ₁ -C ₃ alkoxy group, wherein halo _{C. 1} - One of the hydrogen atoms of the C ₃ alkoxy group is substituted by -OC ₁ -C ₃ alkyl. Examples of C ₁ -C ₃ alkoxy-halo C ₁ -C ₃ alkoxy include, but are not limited to, methoxy trifluoropropoxy.

As used herein, the term "di(C ₁ -C ₃ alkyl)amino C ₁ -C ₆ alkyl" refers to a radical of the formula -R _a1 -N(R _a2 )-R _a2 wherein R _a1 is as above A C ₁ -C ₆ alkyl group, as defined herein, and each R _a2 is C ₁ -C ₃ alkyl as defined above, which may be the same or different. The nitrogen atom can be bonded to any carbon atom in any alkyl group. As described herein, "di C ₁ -C ₃ alkylamino C ₁ -C ₆ alkyl" can be substituted with a hydroxy group.

As used herein, the term "di(C ₁ -C ₃ alkyl)amino C ₁ -C ₆ alkoxy" refers to a radical of the formula -R _a1 -N(R _a2 )-R _a2 wherein R _a1 is C ₁ -C ₆ alkoxy as defined above, and each R _a2 is C ₁ -C ₃ alkyl as defined above, which may be the same or different.

As used herein, the term "6-membered saturated heterocyclic ring containing a hetero atom selected from N, O or S" includes piperidinyl, tetrahydropentanyl and tetrahydrothiopyranyl.

As used herein, the term "6-membered unsaturated non-aromatic heterocyclic ring containing a hetero atom selected from N, O or S" includes, but is not limited to, tetrahydropyridyl, dihydropiperidyl, dihydrothiopyranyl.

As used herein, the term "containing at least one hetero atom selected from N, O or S 4 a member, a 5- or 6-membered saturated heterocyclic ring" includes, but is not limited to, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, Tetrahydropyranyl, morpholinyl.

As used herein, the term "5-membered saturated heterocyclic ring" includes, for example, but not limited to, pyrrolidine.

As used herein, the term "saturated 5- or 6-membered ring optionally containing an additional heteroatom selected from N, O or S" includes, but is not limited to, pyrrolidine, oxazolidine, piperazine, morpholine. , thiomorpholine ring, the term relates to embodiments in which R ² and R ³ and the N atom to which they are attached form the ring.

As used herein, the term "a 4 member, 5 member or 6 membered non-aromatic heterocyclic ring comprising at least one hetero atom selected from N, O or S" includes at least one member selected from N, O or S as defined herein. A 4-, 5- or 6-membered saturated heterocyclic ring of a hetero atom. It also includes a 4-, 5- or 6-membered unsaturated heterocyclic ring containing at least one heteroatom selected from N, O or S.

As used herein, for example, the term "further containing one or two bicyclic aromatic ring systems selected from N, O or S heteroatoms" in connection with R ^X and R ^Y includes, but is not limited to, imidazopyridine and Isothiazolidine.

As used herein, the term "optionally substituted" as used in the description of R ^Y , R ^X and R ^Y together with R ^Y2 , R ^Y3 , R ^Y4 includes unsubstituted or substituted once or twice.

As used herein, the term "substituted" as used in the description of, for example, R ^Y2 , two R ^Y5 includes substitution once or twice, preferably once.

As used herein, for example, when referring to the substituent R ⁴ , the term "more than one time" includes 2, 3, 4, 5 or 6 times. Preferably, it comprises 2 or 3 times.

As used herein, the term "FGFR4" refers to fibroblast growth factor receptor 4, also known as CD334, JTK2, TKF, hydroxyaryl protein kinase, tyrosine kinase associated with fibroblast growth factor receptor, cheese Amine-based protein kinase.

In one embodiment of the invention, there is provided a compound of formula (Ia) or a pharmaceutically acceptable salt thereof

Wherein R ¹ , R ^X and R ^Y related to the compound of formula (I) are as defined herein.

In one embodiment of the invention, there is provided a compound of formula (Ia-1) or a pharmaceutically acceptable salt thereof

Wherein R ¹ and R ^Y related to the compound of formula (I) are as defined herein.

In one embodiment of the invention, there is provided a compound of formula (Ia-1) or a pharmaceutically acceptable salt thereof

Wherein R ^Y is selected from _{^{NR Y1 R Y2, C 1 -C}} 3 C ₁ -C ₃ alkoxy _{alkoxy, O- (CH 2) 0-1 -R} Y3, and the formula (I) For a compound of R ¹ , R ^Y1 , R ^Y2 and R ^{Y3 are} as defined herein.

In one embodiment of the invention, there is provided a compound of formula (Ia-1) or a pharmaceutically acceptable salt thereof

Wherein R ^Y is selected from the group consisting of NR ^Y1 R ^Y2 , C ₁ -C ₃ alkoxy C ₁ -C ₃ alkoxy, and R ¹ , R ^Y1 and R ^Y2 related to the compound of formula (I) are as defined herein.

In one embodiment of the invention, there is provided a compound of formula (Ib) or a pharmaceutically acceptable salt thereof

Wherein R ¹ , R ^X and R ^Y related to the compound of formula (I) are as defined herein.

In one embodiment of the invention, there is provided a compound of formula (Ic) or a pharmaceutically acceptable salt thereof

Wherein R ¹ and R ^X related to the compound of formula (I) are as defined herein.

In one embodiment of the invention, a compound of formula (Id) or a pharmaceutically acceptable salt thereof is provided

Wherein R ¹ and R ^Y related to the compound of formula (I) are as defined herein.

Various enumerated embodiments of the invention are described herein. It will be appreciated that features specified in the various embodiments can be combined with other specified features to provide further embodiments of the invention.

Embodiment 1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as described above.

Embodiment 2. A compound of formula (Ia), or a pharmaceutically acceptable salt thereof, as described above, as in Example 1.

Embodiment 3. A compound of formula (Ia-1), or a pharmaceutically acceptable salt thereof, as described above, as in Example 1 or 2.

Embodiment 4. A compound of formula (Ib), or a pharmaceutically acceptable salt thereof, as described above, as in Example 1.

Embodiment 5. A compound of formula (Ic), or a pharmaceutically acceptable salt thereof, as described above, as in Example 1.

Embodiment 6. A compound of formula (Id), or a pharmaceutically acceptable salt thereof, as described above, as in Example 1.

Embodiment 7. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to embodiment 1, wherein V is O.

Embodiment 8. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to embodiment 1, wherein V is CH(OH).

Example 9. acceptable salt of such a compound or a pharmaceutically formula (I) Example of embodiment 1, wherein W is CH _2.

Embodiment 10. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to embodiment 1, wherein W is CH ₂ CH ₂ .

Example 11 Example acceptable compound of formula (I) or a pharmaceutically acceptable salt thereof of embodiment 1, wherein R ⁵ is hydrogen.

Example 12. Example 1 of Embodiment formula (I) compound or a pharmaceutically acceptable salt thereof, wherein R ⁵ is methyl.

The compound of any one of embodiments 1 to 5 and 7 to 12, or a pharmaceutically acceptable salt thereof, wherein R ^X is selected from the group consisting of halogen, halo C ₁ -C ₃ alkyl.

Example 14. The compound according to any one of acceptable, or a pharmaceutically 1,2,4,5 and 7 of Example 12 to salts embodiment, wherein R ^X is cyano.

The compound of any one of the embodiments 1, 2, 4 and 6 to 14 or a pharmaceutically acceptable salt thereof, wherein the R ^Y is selected from the group consisting of hydrogen, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₆ alkoxy, halo C ₁ -C ₃ alkoxy, hydroxy C ₁ -C ₃ alkoxy, NR ^Y1 R ^Y2 , C ₁ -C ₃ alkoxy C ₁ -C ₃ alkoxy a C ₁ -C ₃ alkoxy-halo C ₁ -C ₃ alkoxy group, O-(CH ₂ ) _0-1 -R ^Y3 , wherein R ^Y1 , R ^Y2 and R ^{Y3 are} as defined herein.

The compound of Embodiment 15 or a pharmaceutically acceptable salt thereof, wherein the R ^Y is selected from the group consisting of NR ^Y1 R ^Y2 , C ₁ -C ₃ alkoxy C ₁ -C ₃ alkoxy, O- (CH ₂ ) _0-1 -R ^Y3 , wherein R ^Y1 , R ^Y2 and R ^{Y3 are} as defined herein.

The compound of Embodiment 16 or a pharmaceutically acceptable salt thereof, wherein R ^Y is NR ^Y1 R ^Y2 , R ^Y1 is hydrogen, and R ^Y2 is a C ₁ -C ₆ alkane optionally substituted by a hydroxyl group. A hydroxy group, a C ₁ -C ₆ alkyl group, a C ₁ -C ₃ alkoxy C ₁ -C ₆ alkyl group, or a halogenated C ₁ -C ₆ alkyl group.

The compound of Example 17, or a pharmaceutically acceptable salt thereof, wherein R ^Y is NR ^Y1 R ^Y2 , R ^Y1 is hydrogen, and R ^Y2 is C ₁ -C ₆ alkyl, C ₁ -C ₃ alkoxy C ₁ -C ₆ alkyl.

The compound of Embodiment 16 or a pharmaceutically acceptable salt thereof, wherein R ^Y is NR ^Y1 R ^Y2 , R ^Y1 is hydrogen, and R ^Y2 is (CH ₂ ) _0-1 -R ^Y4 , wherein R ^Y4 is a 5- or 6-membered saturated heterocyclic ring containing at least one hetero atom selected from N, O or S, which is optionally substituted by a C ₁ -C ₃ alkyl group.

The compound of Embodiment 16 or a pharmaceutically acceptable salt thereof, wherein R ^Y is a C ₁ -C ₃ alkoxy C ₁ -C ₃ alkoxy group.

The compound of Embodiment 16 or a pharmaceutically acceptable salt thereof, wherein R ^Y is O-(CH ₂ ) _0-1 -R ^Y3 , and R ^Y3 is at least one selected from the group consisting of N, O or A 4-membered, 5-membered or 6-membered saturated heterocyclic ring of a hetero atom of S, which is optionally substituted by a C ₁ -C ₃ alkyl group.

The compound of any one of the preceding embodiments, wherein R ¹ is hydrogen, halogen, C ₁ -C ₃ alkyl, halo C ₁ -C ₃ alkyl, or a pharmaceutically acceptable salt thereof Hydroxy C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, CH ₂ NR ² R ³ , CH(CH ₃ )NR ² R ³ , wherein R ² and R ^{3 are} as defined herein.

Example 23. The compound or pharmaceutically pharmaceutically salts embodiment of Example 22, wherein R ¹ is hydroxymethyl.

The compound of Embodiment 22, wherein R ¹ is CH ₂ NR ² R ³ or CH(CH ₃ )NR ² R ³ , wherein R ² and R ^{3 are} as defined herein, or a pharmaceutically acceptable salt thereof. definition.

The compound of Embodiment 24, wherein R ² is C ₁ -C ₃ alkyl, and R ³ is selected from C ₁ -C ₃ alkyl, C(O), or a pharmaceutically acceptable salt thereof. -C ₁ -C ₃ alkyl.

The compound of Embodiment 24, or a pharmaceutically acceptable salt thereof, wherein R ² and R ³ and the N atom to which they are attached form an additional hetero atom selected from N, O or S as the case may be. saturated 5 or 6-membered ring which R ⁴ may be substituted one or more times, wherein R ⁴ is as defined herein.

The compound of Example 26, or a pharmaceutically acceptable salt thereof, wherein R ² and R ³ and the N to which they are attached form a pyrrolidine, oxazolidine, piperazine, morpholine or thiomorpholine ring. And the ring may be substituted once or more than once by R ⁴ , wherein R ^{4 is} as defined herein.

The compound of Example 26 or 27, or a pharmaceutically acceptable salt thereof, wherein R ^{4 is} independently selected from C ₁ -C ₃ alkyl, di(C ₁ -C ₃ alkyl)amine or Two R ₄ attached to the same carbon atom form a pendant oxy group.

Example 29. The acceptable compound of Example 26 to 28 or a pharmaceutically acceptable salt thereof, wherein when R ⁴ is present, it is present once, twice or three times.

Embodiment 30. The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of 7-methylindenyl- N- (5-(trifluoromethyl)pyridin-2-yl)-3, 4-dihydro-1,8- Pyridin-1( 2H )-carbamide; N -(4,5-dichloropyridin-2-yl)-7-methylindolyl-3,4-dihydro-1,8- Pyridin-1( 2H )-formamide; N -(5-cyanopyridin-2-yl)-7-methylindol-3,4-dihydro-1,8- Pyridin-1( 2H )-carbamide; N -(5-chloropyridin-2-yl)-7-methylindol-3,4-dihydro-1,8- Pyridin-1( 2H )-carbamamine; 7-mercapto-N-(pyridin-2-yl)-3,4-dihydro-1,8- Pyridin-1( 2H )-carbamide; N -(4,5-dimethylpyridin-2-yl)-7-methylindol-3,4-dihydro-1,8- Pyridin-1( 2H )-carbamide; 7-methylindenyl-N-(5-methylpyridin-2-yl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyanopyrimidin-2-yl)-7-methylindol-3,4-dihydro-1,8- Pyridin-1(2H)-carbenamide; 6-methylindenyl-N-(5-methylpyridin-2-yl)-2H-pyrido[3,2-b][1,4]oxazine- 4(3H)-carbamamine; 6-chloro- N- (5-cyanopyridin-2-yl)-7-methylindol-3,4-dihydro-1,8- Pyridin-1(2H)-carbenamide; 7-mercapto- N- (6-methoxypyrimidin-4-yl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyanopyrazin-2-yl)-7-methylindol-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-methoxypyridin-2-yl)-7-methylindol-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; 6-methylindenyl-N-(5-(trifluoromethyl)pyridin-2-yl)-2H-pyrido[3,2-b][1,4 Oxazine-4(3H)-carbamamine; 6-fluoro-7-methylindolyl-N-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1, 8- Pyridin-1(2H)-carbamide; N- (5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)-7-methylindolyl- 3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (4,5-dicyanopyridin-2-yl)-7-methylindol-3,4-dihydro-1,8- Pyridin-1(2H)-carbamamine; 7-mercapto-6-(hydroxymethyl)-N-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro- 1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-ethoxypyridin-2-yl)-7-methylindol-3,4-dihydro-1,8- Pyridin-1(2H)-carbamamine; 7-mercapto-6-methyl- N- (5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8 - Pyridin-1(2H)-carbamide; N- (5-cyanopyridin-2-yl)-7-methylindol-6-methyl-3,4-dihydro-1,8- Pyridin-1(2H)-carbamamine; 7-mercapto- N- (5-(1-hydroxypentyl)pyridin-2-yl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-methylindolyl-3,4-dihydro -1,8- Pyridin-1(2H)-formamide; N- (4-chloro-5-cyanopyridin-2-yl)-7-methylindol-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-(N-morpholinyl)pyridin-2-yl)-7-methylindolyl-3,4-dihydro-1, 8- Pyridin-1(2H)-formamide; N- (5-cyano-4-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-2-yl)-7-methylindolyl- 3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyanopyridin-2-yl)-7-methylindolyl-6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-(2-methyl-2,8-diazaspiro[4.5]dec-8-yl)pyridin-2-yl)- 7-Mercapto-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyanopyridin-2-yl)-6-cyclopropyl-7-methylindol-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-(3,6-dihydro-2H-piperazin-4-yl)pyridin-2-yl)-7-carboxamido -3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-(tetrahydro-2H-piperazin-4-yl)pyridin-2-yl)-7-methylindolyl-3,4 -dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-chloro-4-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-yl)-7-methylindolyl-3,4-dihydro -1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-isopropoxypyridin-2-yl)-7-methylindol-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-((tetrahydrofuran-2-yl)methoxy)pyridin-2-yl)-7-methylindolyl-3,4- Dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-(oxetan-2-ylmethoxy)pyridin-2-yl)-7-methylindolyl-3,4 -dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-2-yl)-7-formamidine Base-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyanopyridin-2-yl)-6-(difluoromethyl)-7-methylindolyl-3,4-dihydro-1,8 - Acridine-1(2H)-carbamide; N- (5-cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-7-methylindolyl-3,4 -dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-methylindolyl-6-(hydroxymethyl )-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-7-methylindolyl-3,4-di Hydrogen-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-2-yl)-7-methylindolyl- 6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; 7-acetamido-N-(5-cyanopyridin-2-yl)-6-((dimethylamino)methyl)-3,4-dihydro -1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((tetrahydrofuran-2-yl)methoxy)pyridin-2-yl)-7-methylindolyl-6-(hydroxyl Methyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-2-yl)-7-formamidine -6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-(2-methyl-2,8-diazaspiro[4.5]dec-8-yl)pyridin-2-yl)- 7-Mercapto-6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((1-methylpyrrolidin-3-yl)oxy)pyridin-2-yl)-7-methylindolyl- 6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-7-methylindolyl- 6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2-yl)-7-methylindenyl- 6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-7-methylindolyl-6-(hydroxyl Base)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-6-((dimethylamino)methyl )-7-methylmercapto-3,4-dihydro-1,8- Pyridin-1(2H)-carbamidamine; 2-(8-((5-cyanopyridin-2-yl)aminemethanyl)-2-carboxamido-5,6,7,8-tetrahydro -1,8- Aridin-3-yl)acetic acid; N- (5-cyano-4-((tetrahydro-2H-piperidin-4-yl)oxy)pyridin-2-yl)-7-methylindolyl-6- (hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((tetrahydro-2H-pyran-3-yl)methyl)amino)pyridin-2-yl)-7 -Methylmercapto-6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((tetrahydrofuran-3-yl)amino)pyridin-2-yl)-7-methylindolyl-6-(hydroxyl Base)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((2-methoxypropyl)amino)pyridin-2-yl)-7-methylindolyl-6- Hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-chloro-4-((1-methoxypropan-2-yl)oxy)pyrimidin-2-yl)-7-methylindolyl-6 -(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (4-(4-chloro-2-hydroxybutoxy)-5-cyanopyridin-2-yl)-7-methylindolyl-6-(hydroxyl Methyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-methylindol-6-(trifluoromethyl) Base)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-6-cyclopropyl-7-methylindenyl- 3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-6-(difluoromethyl)-7- Mercapto-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-6-((dimethylamino)methyl) -7-methylmercapto-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((3-(hydroxymethyl))bicyclo[2.2.1]hept-2-yl)amino)pyridin-2-yl )- 7-Mercapto-6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)-7-carboxamido -6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-methylindolyl-6-(methoxy Methyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyanopyridin-2-yl)-7-methylindol-6-(( N -methylethylamino)methyl)-3, 4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-chloro-4-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-yl)-7-methylindolyl-6-(hydroxymethyl )-3,4-dihydro-1,8- Pyridin-1(2H)-carbenamide; N- (5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-yl)-7-methylindolyl-6-(hydroxyl) Base)-3,4-dihydro-1,8- Piperidin -1 (2H) - A Amides; 7-acyl-6- (hydroxymethyl) - N - (4 - ( ( tetrahydrofuran-3-yl) oxy) pyridin-2-yl) -3, 4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-chloro-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-7-methylindolyl-6-(hydroxymethyl) )-3,4-dihydro-1,8- Pyridin-1(2H)-carbamimid; N- (5-cyano-4-((1-methylpiperidin-3-yl)methoxy)pyridin-2-yl)-7-carboxamido -6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((1-methylpyrrolidin-2-yl)methoxy)pyridin-2-yl)-7-carboxamido -6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((1-methylpiperidin-2-yl)methoxy)pyridin-2-yl)-7-methylindolyl -6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-fluoropyridin-2-yl)-7-methylindolyl-6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-formamidine- ¹³ C-yl -2H-pyrido[3,2-b][1,4]oxazin-4(3H)-carbenamide; N- (5-cyano-4-((1-methylpiperidin-4-) Methoxy)pyridin-2-yl)-7-methylindol-6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyanopyridin-2-yl)-7-methylindol-4-hydroxy-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-methylindolyl-6- Hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-(2-((dimethylamino)methyl)N-morpholinyl)pyridin-2-yl)-7-- Mercapto-6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-() Pyridin-3-yloxy)pyridin-2-yl)-7-methylindolyl-6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-methylindolyl-6- (4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8- Piperidin -1 (2H) - A Amides; 7-acyl-6- (hydroxymethyl) - N - (4 - ( (2- methoxyethyl) amino) -5- (trifluoromethyl Pyridin-2-yl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-(4-((dimethylamino)methyl)-4-hydroxypiperidin-1-yl)pyridin-2-yl )-7-Methylyl-6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((2-hydroxy-2-methylpropyl)amino)pyridin-2-yl)-7-methylindolyl- 6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((3-(dimethylamino)-2-hydroxy-2-methylpropyl)amino)pyridine-2- Base)-7-methylmercapto-6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-((2-fluoroethyl)amino)pyridin-2-yl)-7-methylindolyl-6-(hydroxyl) Base)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; and N- (5-cyano-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)-7-methylindenyl-6- (hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

Embodiment 31. A compound of Embodiment 30, or a pharmaceutically acceptable salt thereof, selected from the group consisting of ( R ) -N- (5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridine -2-yl)-7-methylindolyl-6-(hydroxymethyl)-3,4-dihydro-1,8- Piperidin -1 (2H) - A Amides; (S) - N - ( 5- cyano-4 - ((tetrahydrofuran-3-yl) oxy) pyridin-2-yl) -7-acyl -6 -(hydroxymethyl)-3,4-dihydro-1,8- Piperidin -1 (2H) - A Amides; (R) - N - ( 5- cyano-4 - ((tetrahydrofuran-3-yl) oxy) pyridin-2-yl) -6 - ((dimethylamine Methyl)-7-methylindolyl-3,4-dihydro-1,8- Piperidin -1 (2H) - A Amides; (S) - N - ( 5- cyano-4 - ((tetrahydrofuran-3-yl) oxy) pyridin-2-yl) -6 - ((dimethylamine Methyl)-7-methylindolyl-3,4-dihydro-1,8- Piperidin -1 (2H) - A Amides; (R) - N - ( 5- cyano-4 - ((1-methyl-pyrrolidin-3-yl) oxy) pyridin-2-yl) -7- Methionyl-6-(hydroxymethyl)-3,4-dihydro-1,8- Piperidin -1 (2H) - A Amides; (S) - N - ( 5- cyano-4 - ((1-methyl-pyrrolidin-3-yl) oxy) pyridin-2-yl) -7- Methionyl-6-(hydroxymethyl)-3,4-dihydro-1,8- Piperidin -1 (2H) - A Amides; (S) - N - ( 5- chloro-4 - ((1-methoxy-2-yl) oxy) pyrimidin-2-yl) -7- Mercapto-6-(hydroxymethyl)-3,4-dihydro-1,8- Piperidin -1 (2H) - A Amides; (R) - N - ( 5- chloro-4 - ((1-methoxy-2-yl) oxy) pyrimidin-2-yl) -7- Mercapto-6-(hydroxymethyl)-3,4-dihydro-1,8- Piperidin -1 (2H) - A Amides; (S) - N - ( 5- chloro-4 - ((tetrahydrofuran-3-yl) oxy) pyrimidin-2-yl) -7-acyl-6- (hydroxymethyl)-3,4-dihydro-1,8- Piperidin -1 (2H) - A Amides; (R) - N - ( 5- chloro-4 - ((tetrahydrofuran-3-yl) oxy) pyrimidin-2-yl) -7-acyl-6- (hydroxymethyl)-3,4-dihydro-1,8- Piperidin -1 (2H) - A Amides; (S) - N - ( 5- cyano-4 - ((tetrahydrofuran-3-yl) oxy) pyrimidin-2-yl) -7-acyl -6 -(hydroxymethyl)-3,4-dihydro-1,8- Piperidin -1 (2H) - A Amides; (R) - N - ( 5- cyano-4 - ((tetrahydrofuran-3-yl) oxy) pyrimidin-2-yl) -7-acyl -6 -(hydroxymethyl)-3,4-dihydro-1,8- Piperidin -1 (2H) - A Amides; (S) -7- methyl acyl-6- (hydroxymethyl) -N- (4 - ((tetrahydrofuran-3-yl) oxy) pyridin-2-yl )-3,4-dihydro-1,8- Piperidin -1 (2H) - A Amides; (R) -7- methyl acyl 6- (hydroxymethyl) - N - (4 - ( ( tetrahydrofuran-3-yl) oxy) pyridin-2-yl )-3,4-dihydro-1,8- Pyridin-1(2H)-carbamimid; ( S )-N-(5-chloro-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-7-methylindenyl-6- (hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; ( R )-N-(5-chloro-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-7-methylindenyl-6- (hydroxymethyl)-3,4-dihydro-1,8- Piperidin -1 (2H) - A Amides; (S) - N - ( 5- cyano-4 - ((1-methyl-pyrrolidin-2-yl) methoxy) pyridin-2-yl) -7 -Methylmercapto-6-(hydroxymethyl)-3,4-dihydro-1,8- Piperidin -1 (2H) - A Amides; (R) - N - ( 5- cyano-4 - ((1-methyl-pyrrolidin-2-yl) methoxy) pyridin-2-yl) -7 -Methylmercapto-6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbenamide; N- (5-cyano-4-((1S,2R,3S,4R)-3-(hydroxymethyl)bicyclo[2.2.1]hept-2- Amino)pyridin-2-yl)-7-methylindolyl-6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((1R,2S,3R,4S)-3-(hydroxymethyl)bicyclo[2.2.1]hept-2- Amino)pyridin-2-yl)-7-methylindolyl-6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-((1R,2S,3S,4S)-3-(hydroxymethyl)bicyclo[2.2.1]hept-2- Amino)pyridin-2-yl)-7-methylindolyl-6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; and N- (5-cyano-4-((1S,2R,3R,4R)-3-(hydroxymethyl)bicyclo[2.2.1]hept-2 -yl)amino)pyridin-2-yl)-7-methylindolyl-6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

Embodiment 32. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 31, or a pharmaceutically acceptable salt thereof.

Embodiment 33. A combination comprising a compound of any of embodiments 1 to 31, or a pharmaceutically acceptable salt thereof, in combination with one or more therapeutically active agents, in a therapeutically effective amount.

Embodiment 34. The combination of embodiment 33, wherein the one or more therapeutically active agents are selected from the group consisting of Anticancer agent.

Embodiment 35. A compound according to any one of embodiments 1 to 31, or a pharmaceutically acceptable salt thereof, for use as a medicament.

Embodiment 36. A compound of any one of embodiments 1 to 31, or a pharmaceutically acceptable salt thereof, for use in inhibiting FGFR4 activity in an individual.

The compound of any one of embodiments 1 to 31, or a pharmaceutically acceptable salt thereof, for use in treating a condition or disease, which is treated by inhibiting FGFR4 in an individual.

The compound of any one of embodiments 1 to 31, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition or disease selected from cancer.

The compound or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from the group consisting of liver cancer, breast cancer, glioblastoma, prostate cancer, rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer, colon cancer.

The compound or a pharmaceutically acceptable salt thereof for use in the method of claim 39, wherein the cancer is liver cancer.

Depending on the choice of starting materials and procedures, the compounds may exist as one of the possible isomers or as a mixture thereof, for example in the form of pure optical isomers or as a mixture of isomers, such as racemates. And mixtures of diastereomers (depending on the number of asymmetric carbon atoms). The present invention is intended to include all such possible isomers, including racemic mixtures, diastereomeric mixtures, and optically pure forms. The optically active ( R ) and ( S ) isomers can be prepared using a palm-forming synthetic component or a palmitic reagent, or resolved using conventional techniques. If the compound contains a double bond, the substituent can be in an E or Z configuration. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent can have a cis or trans configuration. It is also intended to include all tautomeric forms.

As used herein, the term "salt" refers to an acid or base addition salt of a compound of the invention. "Salt" includes, inter alia, "pharmaceutically acceptable salts." The term "medicalally Accepted salt refers to a salt that retains the biological utility and properties of the compounds of the invention and is generally biologically or otherwise desirable. In many cases, the compounds of the invention are capable of forming acid and/or base salts by virtue of the presence of amine groups and/or carboxyl groups or the like.

Inorganic acids and organic acids can be used to form pharmaceutically acceptable acid addition salts.

Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, Sulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid and the like.

Pharmaceutically acceptable base addition salts can be formed with inorganic bases and organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from rows I to XII of the periodic table. In certain embodiments, the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

Organic bases from which salts can be derived include, for example, primary amines, secondary amines, and tertiary amines; substituted amines including naturally occurring substituted amines; cyclic amines; alkali ion exchange resins and the like. Certain organic amines include isopropylamine, benzathine, catechin, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

Any formula given herein is also intended to indicate the unlabeled form of the compound as well as the isotopically labeled form. Isotopically labeled compounds have structures depicted by the formulas given herein with the exception that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes which may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ^{18, respectively.} F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl, ¹²³ I, ¹²⁴ I, ¹²⁵ I. The invention includes various isotopically-labeled compounds as defined herein, such as those in which a radioisotope such as ³ H and ¹⁴ C is present, or in which non-radioactive isotopes such as ² H and ¹³ C are present Compound. Such isotopically labeled compounds are suitable for metabolic studies (using ¹⁴ C); reaction kinetic studies (using, for example, ² H or ³ H); detection or imaging techniques such as positron emission tomography (PET) or single photons Radiographic computed tomography (SPECT), including drug or matrix distribution analysis; or radiotherapy for patients. In particular, the ¹⁸ F compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of formula (I) can generally be suitably labeled using isotopes by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying examples and preparations. The reagents were prepared in place of the previously labeled unlabeled reagents.

In addition, substitution with heavier isotopes, particularly guanidine (i.e., ² H or D), may result in certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It should be understood that in this case, hydrazine is regarded as a substituent of the compound of the formula (I). The concentration of such heavier isotopes (especially cesium) can be defined by isotope enrichment factors. The term "isotopic enrichment factor" as used herein means the ratio between the isotope abundance of a given isotope and the natural abundance. If the substituent in the compound of the present invention is labeled as hydrazine, the isotope enrichment factor of each of the specified ruthenium atoms of the compound is at least 3,500 (incorporating 52.5% 各 at each designated ruthenium atom), at least 4000 (60) %氘 incorporation), at least 4500 (67.5% 氘 incorporation), at least 5000 (75% 氘 incorporation), at least 5500 (82.5% 氘 incorporation), at least 6000 (90% 氘 incorporation), at least 6333.3 (95) %氘 incorporation), at least 6466.7 (97% 氘 incorporation), at least 6600 (99% 氘 incorporation) or at least 6633.3 (99.5% 氘 incorporation).

The pharmaceutically acceptable solvates according to the invention include those in which the solvent of the crystals can be isotopically substituted, such as D ₂ O, d ₆ -acetone, d ₆ -DMSO.

The compounds of the invention, i.e., compounds of formula (I) containing a group capable of acting as a donor and/or acceptor for hydrogen bonding, may be capable of forming a eutectic with a suitable eutectic former. Such co-crystals can be prepared from compounds of formula (I) by known eutectic formation procedures. Such procedures include subjecting a compound of formula (I) to a eutectic former under grinding, heating, co-subliming, co-melting or contacting in solution, and isolating the eutectic thereby formed. Suitable eutectic forming agents include those described in Their eutectic formers in WO 2004/078163. The invention therefore further provides a eutectic comprising a compound of formula (I). For example, the invention provides a eutectic comprising a compound of formula (I) and an organic acid such as citric acid.

As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (eg, antibacterial agents) that are known to those skilled in the art. , antifungal agents), isotonic agents, absorption delaying agents, salts, pharmaceutical stabilizers, binders, excipients, disintegrating agents, lubricants, sweeteners, flavoring agents, dyes, and the like, and combinations thereof (see For example, Remington's Pharmaceutical Sciences, 18th ed., Mack Printing Company, 1990, pp. 1289-1329). Unless any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.

The term "therapeutically effective amount" of a compound of the invention refers to an amount of a compound of the invention that will elicit an individual's biological or medical response, such as reducing or inhibiting enzyme or protein activity or ameliorating symptoms, ameliorating the condition, slowing down Or delay disease progression or prevent disease. In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the invention effective to achieve upon administration to an individual: (1) at least partial relief, inhibition, prevention, and/or improvement A condition or disorder or disease, the condition or disease (i) mediated by FGFR4 or (ii) associated with FGFR4 activity or (iii) characterized by activity of FGFR4 (normal or abnormal); or (2) Reducing or inhibiting the activity of FGFR4; or (3) reducing or inhibiting the expression of FGFR4. In another non-limiting embodiment, the term "therapeutically effective amount" refers to a compound of the invention that is effective to at least partially reduce or inhibit the activity of FGFR4 when administered to a cell or tissue or non-cellular biological material or medium. the amount.

As used herein, the term "individual" refers to an animal. Typically, the animal is a mammal. An individual also refers to, for example, a primate (eg, human, male or female), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, and the like. In certain embodiments, the individual is a primate. In other embodiments, the individual is a human.

As used herein, the term "inhibition/inhibition/inhibiting" refers to reducing or arresting a given condition, symptom, or condition or disease, or significantly reducing the baseline activity of a biological activity or process.

As used herein, the term "treat/treating/treatment" in any embodiment refers to amelioration of a disease or condition (ie, slowing or preventing or reducing at least one of a disease or a clinical condition thereof). development of). In another embodiment, "treating" refers to alleviating or ameliorating at least one physical parameter, including physical parameters that the patient may not be able to discern. In yet another embodiment, "treating" refers to modulating a disease or condition both physically (eg, identifiable by the stabilization of symptoms), physiologically (eg, stabilization of body parameters), or both. In yet another embodiment, "treating" refers to preventing or delaying the onset or progression or progression of a disease or condition.

As used herein, an individual "needs" the treatment if the individual will benefit from treatment in biology, medicine, or quality of life.

As used herein, the terms "a", "the" and "the" are used in the context of the present invention (especially in the context of the claims), unless otherwise indicated herein. Similar terms should be interpreted to cover both singular and plural.

All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted. The use of any and all examples or exemplary language(s), such as "such as", is intended to be <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt;

Any asymmetric atom of the compounds of the invention (e.g., carbon or the like) may exist in the form of racemic or enantiomeric enrichment, such as ( R ) configuration, ( S ) configuration or ( R , S ) configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric in the ( R ) configuration or ( S ) configuration. The isomer excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess. Substituents at the atom having an unsaturated double bond, if possible, exist in the cis-(Z)- or trans-(E)- form.

Accordingly, as used herein, the compounds of the invention may be in the form of one of the possible isomers, rotamers, singly isomers, tautomers or mixtures thereof, for example in substantially pure geometry (cis Form or trans) isomer, diastereomer, optical isomer (enantiomer), racemate or a mixture thereof.

Mixtures of any of the resulting isomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates based on physicochemical differences of the components, for example by chromatography and / or step by step.

Any resulting end product or intermediate racemate can be resolved to the optical enantiomer by known methods, for example by separation of its diastereomeric salt (which is obtained from an optically active acid or base) and Release of optically active acidic or basic compounds. In particular, the basic moiety can thus be used to resolve a compound of the invention to its optical enantiomer, for example by virtue of an optically active acid (eg tartaric acid, benzopyrene tartaric acid, dimethicillic tartaric acid, - Salt formed by salt formation of O, O'-p-tolylmethine tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid). The racemic product can also be resolved by palm chromatography, for example by high pressure liquid chromatography (HPLC) using a palmitic adsorbent.

Further, the compounds of the present invention (including salts thereof) may also be obtained in the form of their hydrates or include other solvents for their crystallization. The compounds of the invention may be inherently or designed to form solvates with pharmaceutically acceptable solvents, including water; therefore, the invention is intended to encompass both solvated and unsolvated forms. The term "solvate" refers to a molecular complex of a compound of the invention, including a pharmaceutically acceptable salt thereof, with one or more solvent molecules. Such solvent molecules are commonly used in medical technology and are known to be harmless to the recipient, such as water, ethanol and the like. The term "hydrate" refers to a complex in which the solvent molecule is water.

Examples of solvates of the compounds of the invention are depicted below (Compound (I-4a)).

Thus, the compound of the formula (I-4) and its solvate (I-4a), wherein V, W, X, Y and Z as defined herein are related to the compound of the formula (I), also form part of the invention .

The presence of the solvate can be identified by a person skilled in the art using a tool such as NMR.

The compounds of the invention, including their salts, hydrates and solvates, may be inherently or designed to form polymorphs.

In general, the compounds of formula (I) can be prepared according to the procedures provided below.

Step 1: Activating a compound of formula (IV) using a deuterating agent (Ar-O-CO-X) such as phenyl chloroformate or diphenyl carbonate (wherein with a compound of formula (I) (eg tetrahydrogen) Acridine) relates to R ¹ , R ⁵ , V and W as defined herein to give an aryl carbamate aryl ester compound of formula (III). Examples of suitable aryl groups (Ar) include: phenyl, p-nitrophenyl, 4-fluorophenyl, pentafluorophenyl. Deuteration of a compound of formula (IV) to produce an aryl carbamate compound of formula (III) can be carried out with or without activation. An example of suitable activation is the deprotonation using a base such as lithium hexamethyldidecylamine.

Step 2: NH ₂ -heterocyclic ring (wherein X, Y and Z associated with the compound of formula (I) is as defined herein) is used directly or by activation to replace the aryl carbamate aryl ester compound of formula (III) (wherein with formula (I) a compound according to the OAr moiety of R ¹ , R ⁵ , V and W as defined herein to give a compound of formula (II) wherein R ¹ , R ⁵ , V and W associated with a compound of formula (I) are as herein Definitions. An example of suitable activation is the deprotonation using a base such as lithium hexamethyldidecylamine.

Step 3: An acetal protecting group of a compound of formula (II) wherein R ¹ , R ⁵ , V and W as defined herein are as defined herein is removed by treatment with an aqueous acid solution to give (I) a compound.

Step 1: A compound of formula (IV) wherein R ¹ , R ⁵ , V and W as defined herein are as defined herein and an isocyanate compound (heterocycle-N=C=O) (I) a compound of the formula X, Y and Z as defined herein) or an isocyanate equivalent of an isocyanate which can be released in situ to give a compound of formula (II) wherein R ¹ , R ⁵ are related to the compound of formula (I) , V and W are as defined herein). Examples of suitable isocyanate precursors include phenyl carbamate, mercapto imidazole, mercaptotriazole and amine mercapto chloride.

Step 2: The acetal protecting group of the compound of formula (II) wherein R ¹ , R ⁵ , V and W as defined herein are as defined herein is removed by treatment with an aqueous acid solution to give the formula (I) a compound.

Step 1: A compound of formula (VI) wherein the compound of formula (I) (eg tetrahydrogen) a pyridine or related analog))) wherein R ¹ , R ⁵ , V and W are as defined herein) and an isocyanate compound (heterocycle-N=C=O) wherein X, Y and the compound of formula (I) Z, as defined herein) or an isocyanate equivalent of an isocyanate which can be released in situ to give a compound of formula (V) wherein R ¹ , R ⁵ , V, W, X, Y and Z are related to the compound of formula (I) As defined herein). Examples of suitable isocyanate precursors include phenyl carbamate, mercapto imidazole, mercaptotriazole and amine mercapto chloride.

Step 2: A compound of formula (V) wherein R ¹ , R ⁵ , V, W, X, Y and Z as defined herein are subjected to a halogen-metal exchange reaction to form a 2-pyridyl group Organometallic intermediates. Examples of suitable reagents for carrying out this halogen-metal exchange include n-butyllithium and tert-butyllithium. The intermediate 2-pyridyl organometallic species is then methylated using a suitable formazonization reagent such as DMF to introduce 2-methylindenyl and a compound of formula (I) is obtained.

A method of introducing a substituent at the 3-pyridyl position or the 2-mercapto ortho position is summarized in Scheme 4.

Step 1: Formation of the formula (IV) after treatment with a suitable bromination, iodination or chlorinating agent such as N-bromosuccinimide, N-iodobutylimine or N-chlorobutaneimine -1) (wherein the formula (I) For a compound of R ^5, V, and W are as defined herein) bromide, chloride, iodide, or at the 3-position to give the formula (IV-2) (wherein R ⁵ , V and W associated with the compound of formula (I) are as defined herein).

Step 2: A compound of formula (IV-2) wherein R ⁵ , V and W associated with a compound of formula (I) are as defined herein may be reacted to give a compound of formula (IV-3) wherein the compound of formula (I) The R ⁵ , V and W are as defined herein, which can be used as starting materials in Schemes 1 and 2 as indicated above. The compound of formula (IV-3) can be obtained by halogenation of a halogen-metal exchange reaction followed by 3-metalation of the intermediate product, as outlined in step 2. Suitable reagent combinations include n-butyllithium and DMF.

Steps 3 and 4: The compound of formula (IV-3) wherein R ⁵ , V and W associated with the compound of formula (I) are as defined herein may be further processed at the 3-position, one example being a reduction to a primary alcohol The primary alcohol is protected with a suitable protecting group (PG) as outlined in steps 3 and 4, respectively. Suitable reagents for the reduction step include NaBH ₄ and B ₂ H ₆ , and suitable protecting groups should be trialkyldecylalkyl groups such as tert-butyldimethylmethylalkyl. The protected intermediate (eg, a compound of formula (IV-5) wherein R ⁵ , V and W (as defined herein) in relation to the compound of formula (I)) can be coupled to give a compound of formula (I), such as a scheme Described in 1 and 2.

The 3-brominated and 3-iodinated intermediates (compounds of formula (IV-2) (wherein R ⁵ , V associated with the compound of formula (I) can be as outlined in Scheme 1 W) is converted to the corresponding urea derivative (steps 1 and 2) as defined herein). The 3-position (step 3) can then be further processed according to a variety of methods, including: halogen-metal exchange and reaction with an electrophilic source of fluorine to introduce a 3-fluoro substituent; Palladium-catalyzed cross-coupling of acid derivatives to introduce 3-alkyl and 3-cycloalkyl substituents; trifluoromethylation. Suitable reagent combinations for the fluorination reaction include: n-butyllithium and N-fluoro-N-(phenylsulfonyl)benzenesulfonamide. Suitable reagent combinations for palladium-catalyzed cross-coupling reactions include: trimethylcyclotriboroxane, PdCl ₂ (PPh ₃ ) ₂ catalyst and Na ₂ CO ₃ base aqueous solution; or cyclopropyl An acid, tricyclohexylphosphine catalyst and an aqueous K ₃ PO ₄ base. Suitable trifluoromethylating agents include: (1,10-morpholine)(trifluoromethyl)copper (I). The intermediate product having the processed 3-position can then be deprotected (step 4) to give a compound of formula (I) as described in Schemes 1 and 2.

The 3-methylated intermediate (the compound of formula (IV-3) as outlined in Scheme 4 (wherein R ⁵ , V and W associated with the compound of formula (I) can then be further processed (step 1) according to various methods. As defined)), the methods include: fluorination and deoxygenation to form R ¹ =difluoromethyl; reductive amination to form R ¹ =aminomethyl, wherein the amine group can be primary, secondary or tertiary. In the case where R ¹ is a secondary amine methyl group, another deuteration reaction may be carried out to form a tertiary decylamine or an intrinsic reaction to form an indoleamine derivative. Suitable reagent combinations for the fluorination reaction include: DAST or XtalFluor with triethylamine trihydrofluoric acid. Suitable reagent combinations for reductive amination include: Na(OAc) ₃ BH with the corresponding amine or amino ester. Suitable deuteration reagents include: intramolecular amine hydrolysis of acetic anhydride or ester. Subsequent processing of the 3-position intermediate (the compound of formula (IV) wherein R ⁵ , V and W (as defined herein) in relation to the compound of formula (I)) can be used for urea formation and removal of protecting groups (step 2 And 3) to obtain a compound of formula (I) as described in Schemes 1 and 2.

The acetal groups depicted in the compounds of Schemes 1, 2, 4, 5 and 6 may be The acetal is replaced by a acetal such as a cyclic acetal such as 1,3-dioxolane.

In one embodiment, a compound of formula (IV) or a salt thereof is provided

Wherein R ⁵ , V and W related to the compound of formula (I) are as defined herein

R ¹ is selected from the group consisting of 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.

In other embodiments, a compound or a salt thereof selected from the group consisting of 6-chloro-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8 is provided. - Acridine; 6-bromo-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8- Acridine;6-(((tert-butyldimethylmethylalkyl)oxy)methyl)-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8- (2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8- Pyridin-3-yl)methanol; 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8- Pyridine-3-carbaldehyde; 7-(dimethoxymethyl)-6-iodo-1,2,3,4-tetrahydro-1,8- Acridine; 6-cyclopropyl-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8- Acridine; 1-(2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8- Pyridin-3-yl)-N,N-dimethylmethylamine; 7-(dimethoxymethyl)-6-(methoxymethyl)-1,2,3,4-tetrahydro-1 ,8- 6-(dimethoxymethyl- ¹³ C-yl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine; 6-(dimethoxy) Methyl-C-yl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine.

In another embodiment, a compound or a salt thereof selected from the group consisting of 6-bromo-7-(dimethoxymethyl)-3,4-dihydro-1,8- is provided. Phenyl-1(2H)-phenyl formate; 6-(((tert-butyldimethylmethylalkyl)oxy)methyl)-7-(dimethoxymethyl)-3,4-dihydro -1,8- Pyridin-1(2H)-formate; 7-(dimethoxymethyl)-6-iodo-3,4-dihydro-1,8- Phenyl-1(2H)-phenyl formate; 6-(difluoromethyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- Phenyl-1(2H)-phenylcarboxylate; 4-((t-butyldiphenylsulfonyl)oxy)-7-(dimethoxymethyl)-1,2,3,4-tetrahydrogen -1,8- Acridine; 5-((t-butyldiphenylphosphonyl)oxy)-5,6,7,8-tetrahydro-1,8- Pyridine-2-carbaldehyde; 7-bromo-4-((t-butyldiphenylsulfanyl)oxy)-1,2,3,4-tetrahydro-1,8- Acridine.

In another aspect, the invention relates to a process for the preparation of a compound of formula (I) in free form or in a pharmaceutically acceptable salt form, which comprises the steps of: a) using a suitable reagent as defined herein Converting a compound of formula (IV) to a compound of formula (III) as defined herein; b) coupling a compound of formula (III) as defined herein in step a) with a suitable amine compound to give a definition as defined herein a compound of formula (II); c) deprotecting a compound of formula (II) as defined herein in step b) to give a compound of formula (I); d) in free form or pharmaceutically acceptable The compound of formula (I) thus obtained is recovered in the form of a salt.

In another aspect, the invention relates to a process for the preparation of a compound of formula (1) in free form or in a pharmaceutically acceptable salt form, which comprises the steps of: a) coupling a compound of formula (IV) as defined herein with a suitable isocyanate compound to give a compound of formula (II) as defined herein; b) formula (II) as defined herein, obtained in step a) The compound is deprotected to give a compound of formula (I); c) the compound of formula (I) thus obtained is recovered in free form or as a pharmaceutically acceptable salt.

Compounds of formula (II), (III), (IV), (V) and (VI) as defined herein are suitable for use in the preparation of compounds of the invention, for example compounds of formula (I).

The invention further encompasses any variant of the process of the invention, wherein the intermediate product obtainable at any stage thereof is used as a starting material and the remaining steps are carried out, or wherein the starting material is formed in situ under the reaction conditions, or wherein the reaction component It is used in the form of its salt or optically pure material.

The compounds and intermediates of the present invention can also be converted to each other according to methods generally known to those skilled in the art.

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In another embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. For the purposes of the present invention, solvates and hydrates are generally considered to be compositions unless otherwise specified. Preferably, the pharmaceutically acceptable carrier is sterile. The pharmaceutical composition can be formulated for specific administration routes such as oral administration, parenteral administration, and rectal administration. In addition, the pharmaceutical compositions of the present invention may be in solid form (including but not limited to capsules, troches, pills, granules, powders or suppositories) or in liquid form (including but not limited to solutions, suspensions or emulsions) Production. The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and/or such pharmaceutical compositions may contain conventional inert diluents, lubricants or buffers, and adjuvants such as preservatives, stabilizers, wetting agents, Emulsifiers and buffers, etc.).

Typically, the pharmaceutical composition is a lozenge or gelatin capsule containing the active ingredient and one or more of the following: a) a diluent such as lactose, dextrose, sucrose, mannitol, sorbitol, fiber And/or glycine; b) a lubricant such as cerium oxide, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycol; and for the tablet also contains c) a binder For example, magnesium aluminum citrate, starch paste, gelatin, scutellaria, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if necessary, d) disintegrants such as starch, agar, alginic acid Or a sodium salt or foaming mixture thereof; and e) an adsorbent, a coloring agent, a flavoring agent, and a sweetener.

In one embodiment, the pharmaceutical composition is a capsule that contains only the active ingredient.

The tablets may be coated with a film or an enteric coating according to methods known in the art.

Suitable compositions for oral administration include an effective amount of a tablet, an ingot, an aqueous or oily suspension, a dispersible powder or granule, an emulsion, a hard or soft capsule, or a syrup or elixir. A compound of the invention in the form of a solution or solid dispersion. Compositions for oral use are prepared according to any of the methods known in the art for making pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of: sweet Flavoring agents, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically elegant and palatable preparation. Tablets may contain the active ingredient in admixture with pharmaceutically acceptable non-toxic excipients suitable for the manufacture of tablets. Such excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin or arabic Glue; and a lubricant such as magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. For example, a time delay material such as glyceryl monostearate or distearyl can be employed. Acid glyceride. The formulation for oral use can be presented in the form of a hard gelatin capsule in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin; or in the form of a soft gelatin capsule, the active ingredient and water Mix with an oily medium such as peanut oil, liquid paraffin or olive oil.

Certain injectable compositions are isotonic aqueous solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. The compositions may be sterilized and/or contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, dissolution promoters, salts for regulating osmotic pressure and/or buffers. In addition, it may also contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulating or coating methods and contain from about 0.1% to about 75% of the active ingredient or from about 1% to about 50% of the active ingredient.

Suitable compositions for transdermal administration comprise an effective amount of a compound of the invention and a suitable carrier. Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to aid passage through the skin of the host. By way of example, the transdermal device is in the form of a bandage comprising a substrate member, a reservoir containing a compound (as appropriate with the carrier), optionally over a prolonged period of time to deliver the host at a controlled and predetermined rate The rate of the skin compound controls the barrier and the means for securing the device to the skin.

Suitable compositions for topical application to, for example, the skin and the eye include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations (for example for delivery by a spray or the like). Such topical delivery systems will be particularly suitable for transdermal administration, for example for the treatment of skin cancer, for example in the form of sunscreens, lotions, sprays and the like for prophylactic use. Therefore, it is particularly suitable for topical (including cosmetic) formulations well known in the art. Such formulations may contain solubilizers, stabilizers, tonicity enhancing agents, buffers, and preservatives.

Topical administration, as used herein, may also involve inhalation or intranasal administration. It may suitably be delivered as a dry powder (either alone as a mixture (for example with an anhydrous blend of lactose) or as a mixed component granule (for example with a phospholipid), from a dry powder inhaler, or as a spray spray. Delivery from a pressurized container, pump, ejector, nebulizer or nebulizer with or without the use of a suitable propellant.

The compound of formula (I) in free form or in the form of a pharmaceutically acceptable salt exhibits valuable pharmacological properties, such as FGFR4 regulatory properties (for example as indicated in the in vitro test provided in the subsequent section), and It is therefore intended for use in therapy or as a research chemical (for example as a tool compound).

Considered its activity as an inhibitor of FGFR4, a compound of formula (I) in the form of a free or pharmaceutically acceptable salt is suitable for the treatment of conditions mediated by the activity of the FGFR4 protein (such as cancer) and/or for FGFR4 It inhibits a condition that is reactive (meaning particularly in a therapeutically beneficial manner), most particularly a disease or condition as referred to herein below.

The compounds of the invention are useful in the treatment of cancer. In particular, the compounds of the invention are useful in the treatment of indications selected from the group consisting of liver cancer, breast cancer, glioblastoma, prostate cancer, rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer, and colon cancer.

Thus, as a further embodiment, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in therapy. In another embodiment, the therapy is for a disease selected from the group consisting of inhibition by FGFR4. In another embodiment, the disease is selected from the list mentioned above, suitable for liver cancer.

Thus, as another embodiment, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy. In another embodiment, the therapy is for a disease that can be treated by inhibition of FGFR4. In another embodiment, the disease is selected from the list mentioned above, suitable for liver cancer.

In another embodiment, the invention provides a method of treating a condition treated by inhibition of FGFR4, comprising administering a therapeutically acceptable amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In another embodiment, the disease is selected from the list mentioned above, suitable for liver cancer.

Thus, as another embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable thereof Acceptable salts are used for the manufacture of pharmaceutical agents. In another embodiment, the agent is for treating a condition treatable by inhibition of FGFR4. In another embodiment, the disease is selected from the list mentioned above, suitable for liver cancer.

In one embodiment of the invention, N- (5-cyanopyridin-2-yl)-7-methylindolyl-3,4-dihydro-1,8- is provided. Pyridin-1(2H)-formamide or a pharmaceutically acceptable salt thereof is used for the treatment of liver cancer.

In another embodiment of the present invention, N- (5-cyanopyridin-2-yl)-7-methylindolyl-6-(hydroxymethyl)-3,4-dihydro-1,8- is provided. Pyridin-1(2H)-formamide or a pharmaceutically acceptable salt thereof is used for the treatment of liver cancer.

In one embodiment of the invention, N- (5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-methylindolyl-6-(hydroxymethyl) is provided. -3,4-dihydro-1,8- Pyridin-1(2H)-formamide or a pharmaceutically acceptable salt thereof is used for the treatment of liver cancer.

In one embodiment of the present invention, there is provided (R) - N - (5- cyano-4 - ((tetrahydrofuran-3-yl) oxy) pyridin-2-yl) -7-acyl-6- (hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide or a pharmaceutically acceptable salt thereof is used for the treatment of liver cancer.

In one embodiment of the present invention, there is provided (S) - N - (5- cyano-4 - ((tetrahydrofuran-3-yl) oxy) pyridin-2-yl) -7-acyl-6- (hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide or a pharmaceutically acceptable salt thereof is used for the treatment of liver cancer.

In one embodiment of the invention, N- (5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-6-(difluoromethyl)-7-formamidine is provided. Base-3,4-dihydro-1,8- Pyridin-1(2H)-formamide or a pharmaceutically acceptable salt thereof is used for the treatment of liver cancer.

In one embodiment of the invention, N- (5-cyanopyridin-2-yl)-7-methylindolyl-6-(( N -methylethylammonio)methyl)-3,4 is provided -dihydro-1,8- Pyridin-1(2H)-formamide or a pharmaceutically acceptable salt thereof is used for the treatment of liver cancer.

In one embodiment of the invention, N- (5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-methylindolyl-6-(hydroxyl) is provided Methyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide or a pharmaceutically acceptable salt thereof is used for the treatment of liver cancer.

In one embodiment of the invention, N- (5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-methylindolyl-6-(( 4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide or a pharmaceutically acceptable salt thereof is used for the treatment of liver cancer.

For an individual of from about 50 to 70 kg, the pharmaceutical composition or combination of the invention may have from about 1 to 1000 mg, or from about 1 to 500 mg, or from about 1 to 250 mg, or from about 1 to 150 mg, or from about 0.5 to 100 mg, or about A unit dose of 1-50 mg of the active ingredient. The therapeutically effective amount of the compound, pharmaceutical composition or combination thereof will depend on the species, weight, age and individual condition of the individual, the condition or disease being treated, or the severity thereof. A generally skilled physician, clinician or veterinarian can readily determine the effective amount of each active ingredient required to prevent, treat or inhibit the progression of a condition or disease.

The above-cited dosage characteristics can be advantageously demonstrated using in vitro and in vivo tests in mammals (e.g., mice, rats, dogs, monkeys) or isolated organs, tissues, and specimens thereof. The compounds of the invention may be administered in vitro in the form of a solution (e.g., an aqueous solution), and administered in vivo, enterally, parenterally, advantageously intravenously (e.g., in suspension or in aqueous solution). The extracorporeal dose can range between about 10 ^-3 moles and ^10-9 moles. Depending on the route of administration, the therapeutically effective amount in vivo may range from about 0.1 to 500 mg/kg or between about 1 to 100 mg/kg.

The activity of the compounds according to the invention can be assessed by the in vitro method described in the examples.

The compounds of the invention may be administered simultaneously with, or before, or after, one or more other therapeutic agents. The compounds of the invention may be administered separately by the same or different routes of administration or together with other agents in the same pharmaceutical composition. A therapeutic agent is, for example, a compound, peptide, antibody, antibody fragment or nucleic acid that is therapeutically active or enhances therapeutic activity when administered to a patient in combination with a compound of the invention.

In one embodiment, the invention provides a compound comprising formula (I) and at least one other The therapeutic agent product is a combined preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is treatment of a disease or condition mediated by FGFR4. The product provided in the form of a combined preparation comprises a composition comprising a compound of formula (I) and other therapeutic agents co-present in the same pharmaceutical composition, or comprising a compound of formula (I) and in a separate form (eg, in a kit) Form) other therapeutic agents.

In certain instances, the compounds of the invention may be combined with other therapeutic agents, such as other anticancer agents, antiallergic agents, anti-nausea agents (or antiemetic agents), pain relievers, cytoprotective agents, and combinations thereof.

Anticancer agents of particular interest for use in combination with the compounds of the invention include: tyrosine kinase inhibitors; vascular endothelial growth factor (VEGF) receptor inhibitors; platelet-derived growth factor (PDGF) receptor inhibitors; Parental growth factor receptor (FGFR) inhibitor; aurora kinase inhibitor; cyclin-dependent kinase (CDK) inhibitor; checkpoint kinase (CHK) inhibitor; 3-phosphoinositide-dependent kinase-1 (PDK1) Or PDPK1) inhibitor; pyruvate dehydrogenase kinase (PDK) inhibitor; protein kinase B (PKB) or AKT inhibitor; protein kinase C (PKC) activator; B-RAF inhibitor; C-RAF inhibitor; Human granule ball colony-stimulating factor (G-CSF) modulator; RET inhibitor; FMS-class tyrosine kinase 3 (FLT3) inhibitor or CD135; c-KIT inhibitor; Bcr/Ab1 kinase inhibitor; IGF- 1R inhibitor; PIM kinase inhibitor; MET inhibitor; human epidermal growth factor receptor 2 (HER2 receptor) (also known as Neu, ErbB-2, CD340 or p185) inhibitor; epidermal growth factor receptor (EGFR) Inhibitor; Porcupine antagonist; mTOR inhibitor; phosphoinositide 3-kinase (PI3K) inhibitor; Bcl-2 protein family Inhibitor; mitogen inducer activated protein kinase (MEK) inhibitor; P38 MAPK inhibitor; JAK inhibitor; alkylating agent; aromatase inhibitor; topoisomerase I inhibitor; topoisomerase II inhibitor; DNA synthesis inhibitor; folate antagonist or antifolate; immunomodulator; pro-apoptotic receptor agonist (PARA), including DR4 (TRAILR1) and DR5 (TRAILR2); phospholipase A2 (PLA ₂ ) inhibitor; SRC inhibitor; osteoclast resorbing inhibitor; G-protein-coupled somatostain receptor inhibitor; interleukin-11 and synthetic interleukin-11 (IL-11); erythropoietin and Synthetic erythropoietin; nuclear factor kappa B receptor activator (RANK) inhibitor; thrombopoietin mimetic peptide; cell growth stimulating agent; histone deacetylase (HDAC) inhibitor; biological response modifier, Including therapeutic agents such as interferons, interleukins, colony-stimulating factors, monoclonal antibodies, vaccines (therapeutic and prophylactic), gene therapy and non-specific immunomodulators; anti-tumor antibiotics; anti-microtubules or anti-microbial agents Mitosis; plant base; taxane antibiotic; Proteinase K inhibitor; epothilone B analogue; heat shock protein (HSP) inhibitor; farnesyl transferase inhibitor (FTI); thrombopoietin (TpoR) agonist; proteasome inhibitor; Spindle protein (KSP) inhibitor (also known as Eg5 inhibitor); Polo-like kinase (Plk) inhibitor; adrenal steroid inhibitor; antiandrogen; anabolic steroid; proteasome inhibitor; gonadotropin releasing hormone ( GnRH) receptor agonist; HPV vaccine; iron chelator; antimetabolite; bisphosphonate; demethylation agent; retinoid; cytokine; estrogen receptor down-regulation; anti-estrogen; Estrogen receptor modulator (SERM); luteinizing hormone releasing hormone (LHRH) agonist; progesterone; 17α-hydroxylase/C17,20 dissociation enzyme (CYP17A1) inhibitor; promiscuous cytotoxic agent; CC chemotaxis Cytokine receptor 4 (CCR4) antibody; CD20 antibody; CD20 antibody drug conjugate; CD22 antibody drug conjugate; CD30 mAb cytotoxin conjugate; CD33 antibody drug conjugate; CD40 antibody; CD52 antibody; anti-CS1 antibody; -4 antibody; p53-MDM2 inhibitor; p53 activator.

Some patients may experience an allergic reaction to a compound of the invention and/or other anti-cancer agents during or after administration; therefore, anti-allergic agents are typically administered to minimize the risk of allergic reactions. Suitable antiallergic agents include corticosteroids, antihistamines, and bronchodilators.

Some patients may experience nausea during and after administration of a compound of the invention and/or other anti-cancer agents; therefore, antiemetics are used to prevent nausea (upper stomach) and vomiting.

The medication is typically prescribed to alleviate the pain experienced during the treatment period to make the patient more comfortable.

Cytoprotective agents (such as neuroprotective agents, free radical scavengers, cardioprotective agents, anthracycline spill neutralizers, nutrients, and the like) can be used to protect normal cells from therapeutic toxicity and limit organ toxicity. Used as an adjuvant therapy.

In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (I) and other therapeutic agents. As described above, the pharmaceutical composition may optionally comprise a pharmaceutically acceptable carrier.

In one embodiment, the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which comprises a compound of formula (I). In one embodiment, the kit includes components for separately retaining the compositions, such as a container, a separate vial, or a separate foil wrap. An example of such a kit is a blister package, such as is typically used in packages for tablets, capsules, and the like.

The kit of the invention can be used to administer different dosage forms (e.g., oral and parenteral) for administration of individual compositions at different dosing intervals, or for titrating individual compositions relative to one another. To aid compliance, the kits of the present invention typically include guidance for administration.

In the combination therapies of the invention, the compounds of the invention and other therapeutic agents can be made and/or formulated by the same or different manufacturers. Furthermore, the compounds of the invention and other therapeutic agents may be combined therapy in the following situations: (i) prior to the release of the combination product to the physician (eg, where the kit comprises a compound of the invention and other therapeutic agents); Ii) shortly before administration by the physician (or under the direction of a physician); (iii) during the patient's own, for example, during sequential administration of the compounds of the invention and other therapeutic agents.

Accordingly, the invention provides the use of a compound of formula (I) for the treatment of a disease or condition mediated by FGFR4, wherein the agent is prepared for administration with another therapeutic agent. The invention also provides the use of another therapeutic agent for the treatment of a disease or condition mediated by FGFR4, wherein the agent is administered with a compound of formula (I).

The invention also provides a compound of formula (I) for use in a method of treating a disease or condition mediated by FGFR4, wherein a compound of formula (I) is prepared for administration with another therapeutic agent. The invention also provides a further therapeutic agent for the treatment of a disease or condition mediated by FGFR4, wherein another therapeutic agent is prepared for administration with a compound of formula (I). The invention also provides a compound of formula (I) for use in a method of treating a disease or condition mediated by FGFR4, wherein the compound of formula (I) is administered with another therapeutic agent. The invention also provides a further therapeutic agent for the treatment of a disease or condition mediated by FGFR4, wherein another therapeutic agent is administered with a compound of formula (I).

The invention also provides the use of a compound of formula (I) for the treatment of a disease or condition mediated by FGFR4, wherein the patient has been previously treated with another therapeutic agent (e.g., within 24 hours). The invention also provides the use of another therapeutic agent for the treatment of a disease or condition mediated by FGFR4, wherein a patient has been previously treated (e.g., within 24 hours) with a compound of formula (I).

In one embodiment, the additional therapeutic agent is selected from the group consisting of an anticancer agent.

The following examples are intended to illustrate the invention and are not to be construed as limiting. The temperature is given in degrees Celsius. If not mentioned otherwise, all evaporation is carried out under reduced pressure, usually between about 15 mm Hg and 100 mm Hg (= 20-133 mbar). The structure of the final product, intermediate product, and starting material is determined by standard analytical methods (eg, microanalysis) and spectral characterization (eg, MS, IR, NMR). Abbreviations used are those of ordinary skill in the art.

All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts useful in the synthesis of the compounds of the present invention are either commercially available or can be synthesized by those skilled in the art. Method to produce. Additionally, the compounds of the present invention can be produced by organic synthesis methods as generally known to those skilled in the art, as shown in the Examples below.

abbreviation

Analysis details

NMR: on ^{Bruker Ultrashield TM 400 (400MHz),} Bruker Ultrashield TM 600 (600MHz), with or without the use of trimethyl Silane be measured as the internal standard on (500MHz) spectrometer 400MHz DRX Bruker CryoProbe (400MHz) or 500MHz DRX Bruker CryoProbe . The chemical shift (d value) is reported as a low magnetic field from ppm of tetramethyl decane, with singlet (s), double ( d ), triple ( t ), quadruple ( q ), multiplet, unresolved The or more overlapping signal ( m ) and wide peak signal ( br ) forms indicate the spectral separation mode. The solvent is given in parentheses.

UPLC-MS 1:

System: Waters Acquity UPLC with Waters SQ detector.

Column: Acquity HSS T3 1.8 μm 2.1 × 50 mm.

Flow rate: 1.2 mL/min. Column temperature: 50 ° C.

Gradient: 2% B to 98% B in 1.4 min, A = water + 0.05% formic acid + 3.75 mM ammonium acetate, B = acetonitrile + 0.04% formic acid.

UPLC-MS 2:

System: Waters Acquity UPLC with Waters SQ detector.

Column: Acquity HSS T3 1.8 μm 2.1 × 50 mm.

Flow rate: 1.2 mL/min. Column temperature: 50 ° C.

Gradient: 2% B to 98% B in 9.4 min, A = water + 0.05% formic acid + 3.75 mM ammonium acetate, B = acetonitrile + 0.04% formic acid.

UPLC-MS 3:

System: Waters Acquity UPLC with Waters SQ detector.

Column: Acquity HSS T3 1.8 μm 2.1 × 50 mm.

Flow rate: 1.0 mL/min. Column temperature: 60 ° C.

Gradient: 5% B to 98% B in 1.4 min, A = water + 0.05% formic acid + 3.75 mM ammonium acetate, B = acetonitrile + 0.04% formic acid.

UPLC-MS 4:

System: Waters Acquity UPLC with Waters SQ detector.

Column: Acquity HSS T3 1.8 μm 2.1 × 50 mm.

Flow rate: 1.0 mL/min. Column temperature: 60 ° C.

Gradient: 5% B to 98% B in 9.4 min, A = water + 0.05% formic acid + 3.75 mM B Ammonium acid, B = acetonitrile + 0.04% formic acid.

UPLC-MS 5:

System: Waters Acquity UPLC with Waters SQ detector.

Column: Sunfire C18 3.5μm 2.1×20mm.

Flow rate: 0.62 mL/min. Column temperature: 40 ° C.

Gradient: 5% B to 100% B in 4 min, A = water + 0.1% trifluoroacetic acid, B = acetonitrile + 0.1% trifluoroacetic acid.

UPLC-MS 6:

System: Waters Acquity Ultra Performance with Waters SQ detector.

Column: Acquity HSS T3 1.8 μm 2.1 × 50 mm.

Flow rate: 1.0 mL/min. Column temperature: 60 ° C.

Gradient: 5% B to 98% B in 1.4 min, A = water + 0.05% formic acid + 3.75 mM ammonium acetate, B = acetonitrile + 0.04% formic acid.

UPLC-MS 7:

System: Waters Acquity Ultra Performance with Waters SQ detector.

Column: Acquity HSS T3 1.8 μm 2.1 × 50 mm.

Flow rate: 1.0 mL/min. Column temperature: 60 ° C.

Gradient: from 1.4 min to % B, A = water + 0.05% formic acid + 3.75 mM ammonium acetate, B = acetonitrile + 0.04% formic acid.

UPLC-MS 8:

System: Waters Acquity Ultra Performance with Waters SQ detector.

Column: Acquity HSS T3 1.8 μm 2.1 × 50 mm.

Flow rate: 1.4 mL/min. Column temperature: 60 ° C.

Gradient: 1% B to 98% B in 1.4 min, A = water + 0.05% formic acid + 3.75 mM ammonium acetate, B = acetonitrile + 0.04% formic acid.

Preparation method: Rapid chromatography system:

System: Teledyne ISCO, CombiFlash Rf.

Column: Pre-filled with RediSep Rf cartridge.

The sample is absorbed on Isolute or on silicone or coated as a solution.

Supercritical Fluid Chromatography (SFC 1):

System: Waters SFC 100 preparative system with Waters 2998 Photodiode Array (PDA) detector and Waters 3100 mass detector.

Column size: 250 × 30mm.

Column:

Flow rate: 100mL/min 120 bar return pressure

Gradient: Optimize gradient elution using supercritical CO ₂ /MeOH.

Reverse phase HPLC (RP 1):

System: Waters HPLC preparative system with UV detector Waters 2487 dual wavelength absorbance detector, MS detector Waters micromass ZQ.

Column: SunFire Prep, C-18 OBD, 100 x 30 mm, 5 μm or 100 x 19 mm, 5 μm.

Gradient: Optimum gradient elution using acetonitrile/water each containing 0.1% TFA.

Reverse phase HPLC (RP 2):

System: Büchi C-620 control unit, Büchi C-660 dissolving collector, Büchi C-605 pump module

Detector, Büchi UV Photometer C-635

Column: Büchi Sepacore C18 80g

Gradient: Optimum gradient elution using acetonitrile/water containing 0.1% formic acid.

Reverse phase HPLC (RP 3):

System: Gilson preparative HPLC system with UV triggered collection system (254 nm).

Column: Sunfire Prep C18 OBD 5μm 30×100cm, temperature 25°C

Gradient: A gradient of 20 minutes from 5%-100% acetonitrile containing 0.05% TFA in water at a flow rate of 30 mL/min.

mid product

Intermediate 1: 7- (dimethoxymethyl) - N - (5- (trifluoromethyl) pyridin-2-yl) -3,4-dihydro-1,8 Pyridin-1(2H)-formamide

To a solution of phosgene (20% solution in toluene, 0.265 mL, 0.504 mmol) in THF (2 mL) was added triethylamine (0.20 mL, 1.44 mmol). Next, 7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8- was added dropwise. A solution of pyridine (intermediate 4, 100 mg, 0.480 mmol) in THF (2 mL). The resulting yellow suspension was stirred for 15 min then added 5-(trifluoromethyl)pyridin-2-amine (93 mg, 0.576 mmol). It was diluted with saturated aqueous NaHCO ₃ and the reaction mixture was extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptane / EtOAc 100:0 to 0:100). The title compound was obtained as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.83 (s, 1H), 8.78 (s, 1H), 8.26 (d, 1H), 8.20-8.12 (m, 1H), 7.73 (d, 1H), 7.18 (d, 1H), 5.37 (s, 1H), 4.01-3.93 (m, 2H), 3.39 (s, 6H), 2.86 (t, 2H), 1.98-1.87 (m, 2H). (UPLC-MS 1) t _R 1.29 min; ESI-MS 397.0 [M+H] ⁺ .

The following intermediates have been synthesized in the same manner as intermediate 1:

Intermediate 1B: 6-Bromo- N- (5-methylpyridin-2-yl)-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-carboxamide

(UPLC-MS 1) t _R 1.12 min; ESI-MS 349.0, 351.0 [M+H] ⁺ .

Intermediate 2: N- (5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

7-(Dimethoxymethyl)-3,4-dihydro-1,8- under argon at -15 °C A solution of pyridine-1(2H)-phenylcarboxylate (intermediate product 3,262 mg, 0.798 mmol) and 2-amino-5-cyanopyridine (190 mg, 1.60 mmol) in THF (7.5 mL). The THF solution, 1.60 mL, 1.60 mmol) was treated dropwise. The reaction mixture was stirred for 25min at -15 ℃, and then by the addition of aqueous saturated NH ₄ Cl and extracted quenched with EtOAc (2 ×). Washed with brine the organic layers were combined, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by EtOAc EtOAc (EtOAc:EtOAc: (UPLC-MS 1) t _R 1.09 min; ESI-MS 354.1 [M+H] ⁺ .

The following example has been synthesized in a similar manner as intermediate 2:

Intermediate 3 : 7-(dimethoxymethyl)-3,4-dihydro-1,8- Phenyl-1(2H)-formic acid phenyl ester.

7-(Dimethoxymethyl)-1,2,3,4-tetrahydro-1,8- at -15 °C A solution of pyridine (intermediate 4, 2 g, 9.60 mmol) and diphenyl carbonate (4.11 g, 19.21 mmol) in THF (40 mL) The reaction mixture was quenched with saturated aqueous NH ₄ Cl, (2 ×) and extracted with EtOAc. Washed with brine the organic layers were combined, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude product was purified by EtOAc (EtOAc): ^{1 H-NMR (400MHz, DMSO-} d 6) δ 7.65 (d, 1 H), 7.46-7.38 (m, 2 H), 7.27-7.18 (m, 4H), 5.17 (s, 1 H), 3.87- 3.80 (m, 2 H), 3.26 (s, 6 H), 2.83 (t, 2 H), 2.00-1.92 (m, 2 H).

Intermediate 4 : 7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8- Acridine.

Use the procedure described in J. Org. Chem. , 2004 , 69 (6), pp. 1959-1966. 2-(Dimethoxymethyl)-1,8- Pyridine (intermediate 5,200 g, 979 mmol), ethanol (3 L), and PtO ₂ (12 g) were placed in a 5 L pressure tank reactor (5 atm). The reactor was evacuated and purged three times with nitrogen, using a hydrogen purge. The mixture was stirred overnight at 23 ° C under a hydrogen atmosphere. This reaction was repeated four times. The solid was filtered and the title compound was crystallisjjjjjjj

^{1 H-NMR (400MHz, DMSO-} d 6) δ 7.14 (d, 1H), 6.51 (d, 1H), 6.47-6.41 (m, 1H), 4.98 (s, 1H), 3.28-3.19 (m, 2H ), 3.23 (s, 6H), 2.64 (t, 2H), 1.73-1.79 (m, 2H).

Intermediate 5 : 2-(dimethoxymethyl)-1,8- Acridine.

The procedure described in J. Org. Chem. , 2004 , 69(6), pp. 1959-1966 is used. 2-Aminopyridine-3-carbaldehyde (1000 g, 8.19 mol), 1,1-dimethoxypropan-2-one (1257 g, 10.64 mol), ethanol (10 L) and water (2 L) were placed in 20 L of four In a round bottom flask. Thereafter, a solution of sodium hydroxide (409.8 g, 10.24 mol) in water (1000 mL) was added dropwise with stirring at 0-15 °C. The solution was stirred at 0-20 °C for 3 h and then concentrated in vacuo. The resulting solution was extracted with 3 x 1200 mL of ethyl acetate and organic layers were combined. The mixture was dried over sodium sulfate and concentrated in vacuo. The residue was washed with 3 x 300 mL hexanes and collected by filtration. This gave the title compound as a yellow solid. ^{1 H-NMR (400MHz, DMSO-} d 6) δ 9.11 (dd, 1H), 8.53 (d, 1H), 8.50 (dd, 1H), 7.73 (d, 1H), 7.67 (dd, 1H), 5.44 ( s, 1H), 3.41 (s, 6H).

Intermediate 6: N - (5- cyano-2-yl) -7- (dimethoxymethyl) -3,4-dihydro-1,8 Pyridin-1(2H)-formamide.

7-(Dimethoxymethyl)-3,4-dihydro-1,8- A solution of pyridine-1(2H)-carboxylate (intermediate 3, 50 mg, 0.152 mmol) in THF (1.sub.5mL) eluted with 2-amino-5-cyanopyrimidine (45.7 mg, 0.381 mmol) It was cooled to 0.degree. C. and treated with EtOAc (1M EtOAc, EtOAc. The reaction mixture was stirred at 0&lt;0&gt;C for 1 h, warmed to rt and stirred for 45 min. Add additional 2-amino-5-cyano-pyrimidine (22.9mg, 0.190mmol) and LHMDS (1M THF solution, 0.152 mL, 0.152 mmol), the reaction mixture was stirred for 35min, by the addition of aqueous saturated NH ₄ Cl and quenched Extract with EtOAc (2×). Washed with brine the organic layers were combined, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptane / EtOAc 100:0 to 0:100). The fractions containing the product were concentrated and re-purified by reverse phase chromatography (13 g C18 cartridge, water containing 0.1% TFA / acetonitrile 95:5 to 5:95). The solution containing the product fractions were treated with saturated aqueous NaHCO _3, it was concentrated until the organic solvent was removed and extracted with DCM (3 ×). The combined organic layers were dried over Na ₂ SO _4, filtered and concentrated under reduced pressure to give a white solid of the title compound. (UPLC-MS 1) t _R 0.87 min; ESI-MS 355.2 [M+H] ⁺ .

The following intermediates have been synthesized in a similar manner as intermediate 6:

Intermediate 6a : 7-(dimethoxymethyl) -N- (6-methoxypyrimidin-4-yl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

(UPLC-MS 1) t _R 1.06 min; ESI-MS 360.2 [M+H] ⁺ .

Intermediate 7 : 6-chloro- N- (5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

6-chloro-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8- A solution of the pyridine (3,50 mg, 0.206 mmol). The resulting mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with water and extracted with EtOAc EtOAc. The combined organic layers were dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified twice by normal phase chromatography (4 g silica gel cartridge, heptane / EtOAc) and then by reverse phase chromatography (4.3 g C18 cartridge, water containing 0.1% TFA / acetonitrile 95: 5 to 5:95) to afford the product was dissolved from the parts treated with saturated aqueous NaHCO ₃ and it was concentrated until the organic solvent was removed, and extracted with DCM (3 ×). The dried the combined organic layers were dried over Na ₂ SO _4, filtered and concentrated under reduced pressure to give a white solid of the title compound. (UPLC-MS 1) t _R 1.15 min; ESI-MS 387.8 [M+H] ⁺ .

Intermediate 8 : 6-chloro-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8- Acridine.

7-(Dimethoxymethyl)-1,2,3,4-tetrahydro-1,8- Piperidine (Intermediate 4,200mg, 0.960mmol) in MeCN solution (5mL) in only N - (, 1.086mmol 145mg) treated chloroprene, (PEI), stirred for 20h. The reaction mixture was concentrated; the residue with Et ₂ O and EtOAc, and washed with water (2 ×) and brine, dried over Na ₂ SO _4, filtered and concentrated. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptane / EtOAc 100:0 to 0:100) to concentrate. The residue was dissolved in EtOAc, washed with water (2 ×) and was washed twice with brine, dried over Na ₂ SO _4, filtered and concentrated to give a pale yellow oil of the title compound. (UPLC-MS 1) t _R 0.68 min; ESI-MS 243.1 [M+H] ⁺ .

Intermediate 9 :

To the dioxane (160 mL) was added hexane chloride (14.7 mL, 168 mmol). The resulting mixture was heated to 90.degree. C., EtOAc (EtOAc m. The reaction mixture was cooled to room temperature and concentrated to give Intermediate 9 as a brown solid.

Intermediate 10 : 7-(dimethoxymethyl)-6-fluoro- N- (5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

At -78 deg.] C under argon for 6-bromo-7- (dimethoxymethyl) - N - (5- (trifluoromethyl) pyridin-2-yl) -3,4-dihydro - 1,8- A solution of the pyridine-1(2H)-carbamide (intermediate 2D, 50 mg, 0.105 mmol) in EtOAc (1 mL) . The resulting brown solution was stirred for 2 min then a solution of N -fluoro- N- (phenylsulfonyl)benzenesulfonamide (80 mg, 0.254 mmol) in THF (0.5 mL). The resulting yellow solution was stirred at -78 °C for 10 min. The reaction mixture by the addition of saturated aqueous NH ₄ Cl quenched warmed to room temperature and extracted with EtOAc (2 ×). Washed with brine the organic layers were combined, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by EtOAc EtOAc (EtOAc:EtOAc: (UPLC-MS 1) t _R 1.25 min; ESI-MS 415.1 [M+H] ⁺ .

Intermediate 11 : 6-bromo-7-(dimethoxymethyl)-3,4-dihydro-1,8- Phenyl-1(2H)-formic acid phenyl ester.

A 6-bromo-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8- at -17 °C A solution of pyridine (intermediate 12, 2.28 g, 7.94 mmol) and diphenyl carbonate (2.13 g, 9.93 mmol) in THF (40 mL) The yellow reaction mixture was stirred for 30 minutes, quenched with saturated aqueous NH ₄ Cl and extracted with EtOAc (2 ×). Washed with brine the organic layers were combined, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude product was purified by EtOAc EtOAc EtOAc:EtOAc ^{1 H NMR (400MHz, DMSO- d} 6) δ 7.94 (s, 1H) 7.37-7.45 (m, 2H) 7.19-7.28 (m, 3H) 5.46 (s, 1H) 3.80-3.87 (m, 2H) 3.29 ( s, 6H) 2.84 (t, 2H) 1.90-2.00 (m, 2H).

Intermediate 12 : 6-bromo-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8- Acridine.

Will contain 7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8- Acetonitrile (2 L) of pyridine (intermediate 4, 114.6 g, 550.3 mmol) was placed in a 3 L four-necked round bottom flask. Thereafter, NBS (103 g, 578 mol) was added portionwise with stirring at 25 °C. The resulting solution was stirred at 25 ° C for 30 min. The resulting mixture was concentrated in vacuo and the residue was purified eluting elut The mixture was washed with 3 x 100 mL ice/water. The aqueous phase was extracted with 2 x 100 mL diethyl ether and organic layers were combined. The mixture was washed with EtOAc (EtOAc m. LC-MS: (ES, m / z): 286.03 [M + H] +. ¹ H-NMR: (300MHz, CDCl ₃ ) δ 1.86-1.94 (2H, m), 2.70-2.74 (2H, m), 3.9-3.43 (2H, m), 3.47 (6H, s), 5.23 (1H, s), 5.58 (1H, s), 7.29 (1H, s).

Intermediate 13 : 5-chloro-N ⁴ -(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine.

Stir 2,5-dichloro- N- (2-(isopropylsulfonyl)phenyl)pyrimidine-4-amine (100 mg, 0.289 mmol) and ammonia (in 2-propanol) in a sealed tube at 80 °C Mixture of 2M, 1.44 mL, 2.89 mmol) in 2-propanol (1.5 mL) for 2 days, then EtOAc (2M, EtOAc, EtOAc, 7 days. The reaction mixture was cooled to room temperature and evaporated; the crude mixture was then diluted with EtOAc and washed with water; the organic phase is then dried over Na ₂ SO _4, filtered and evaporated to afford the title compound as yellow resin. (UPLC-MS 1) t _R 0.83 min; ESI-MS 327.0 [M+H] ⁺ .

Intermediate 14: 7- (dimethoxymethyl) -6- (hydroxymethyl) - N - (5- (trifluoromethyl) pyridin-2-yl) -3,4-dihydro-1, 8- Pyridin-1(2H)-formamide.

At -78 deg.] C under argon for 6-bromo-7- (dimethoxymethyl) - N - (5- (trifluoromethyl) pyridin-2-yl) -3,4-dihydro - 1,8- A solution of the pyridine-1(2H)-carboxamide (intermediate 2D, 100 mg, 0.210 mmol) in THF (2 mL) eluted with n-butyl lithium (1.5M in hexanes . The resulting brown solution was stirred for 2 min and then DMF (0.1 mL, 1.. The resulting yellow solution was stirred at -78 °C for 15 min. The reaction mixture by the addition of saturated NH ₄ Cl aqueous quenched warmed to room temperature and extracted with EtOAc (2 ×). Washed with brine the organic layers were combined, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue was purified by normal phase chromatography (12 g silica gel cartridge, heptane / EtOAc 100:0 to 0:100) to give 7-(dimethoxymethyl)-6-carbazyl- N -(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8- The dissolved fraction of pyridine-1(2H)-carbamide was concentrated to give a white solid. This material was dissolved in (1 mL) in MeOH (2mL), and DCM, the use of NaBH ₄ (6.36mg, 0.168mmol) and stirred at rt for 0.5h. The reaction mixture was quenched with saturated aqueous NH ₄ Cl, and (3 ×) and extracted with DCM. The dried with Na ₂ SO ₄ the combined organic layers were, filtered, and concentrated under reduced pressure. The crude material was purified by EtOAc (EtOAc:EtOAc:EtOAc: (UPLC-MS 1) t _R 1.10 min; ESI-MS 421.0 [M+H] ⁺ .

Intermediate 15 : 6-Amino-4-ethoxy nicotinic nitrile.

6-Amino-4-chloronicotinonitrile (intermediate 16, 40 mg, 0.260 mmol) and EtOH (0.076 mL, 1.302 mmol) were placed in a sealed vial. NMP (1.5 mL), NaH (60% dispersion in mineral oil, 62.5 mg, 1.56 mmol) was added sequentially to the mixture at room temperature. The mixture was then heated at 70 ° C for 2.5 days. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The dried organic layer was ₂ SO ₄ Na, filtered, and concentrated in vacuo. The crude material was purified by EtOAc EtOAc (EtOAc) (UPLC-MS 1) t _R 0.50 min; ESI-MS 164.0 [M+H] ⁺ .

Intermediate 16 : 6-Amino-4-chloronicotinonitrile.

5-Bromo-4-chloropyridin-2-amine (500 mg, 2.41 mmol), zinc cyanide (297 mg, 2.53 mmol), zinc (31.5 mg, 0.482 mmol), Pd ₂ (dba) ₃ (under argon) 221 mg, 0.241 mmol), dppf (267 mg, 0.482 mmol) and DMA (20 mL) were placed in a flask. The reaction mixture was stirred at 70 ° C for 16 h. The reaction mixture was diluted in EtOAc and washed with saturated NaHCO ₃ (2 ×) and brine. The combined organic layers were dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by EtOAc EtOAc (EtOAc:EtOAc: (UPLC-MS 1) t _R 0.57 min; ESI-MS 154.0 [M+H] ⁺ .

Intermediate 17 : 7-(dimethoxymethyl)-6-methyl- N- (5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

Under argon for 6-bromo-7- (dimethoxymethyl) - N - (5- (trifluoromethyl) pyridin-2-yl) -3,4-dihydro-1,8 Pyridin-1(2H)-formamide (intermediate product 2D, 50 mg, 0.105 mmol), trimethylcyclotriboroxane (50% in THF, 39.6 mg, 0.158 mmol), Na ₂ CO ₃ (in water) 2M, 0.053 mL, 0.105 mmol), PdCl ₂ (PPh ₃ ) ₂ (7.38 mg, 10.52 μmol) and DME (1 mL) were placed in a sealed vial. The mixture was stirred at 100 ° C for 1 h. The reaction mixture was diluted with EtOAc and washed 1× with brine. The combined organic layers were dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptane / EtOAc 100:0 to 58:42). The title compound was obtained as a white solid. (UPLC-MS 1) t _R 1.37 min; ESI-MS 411.1 [M+H] ⁺ .

The following intermediates have been synthesized in a similar manner as intermediate 17:

Intermediate 18 : N- (5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-6-methyl-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

(UPLC-MS 3) t _R 1.18 min; ESI-MS 368.1 [M+H] ⁺ .

Intermediate racemic :( 19) 7- (dimethoxymethyl) - N - (5- (1- hydroxypentyl) pyridin-2-yl) -3,4-dihydro-1,8 Pyridin-1(2H)-formamide.

6-Bromo- N- (5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- at -78 °C A solution of the pyridine-1(2H)-carbamide (intermediate 2H, 50 mg, 0.116 mmol) elut elut elut elut elut . The reaction mixture was treated with N,N -dimethylformamide- ¹³ C-decylamine (45.6 [mu]L, 0.578 <RTIgt; The reaction by the addition of saturated NH ₄ Cl aqueous quenched warmed to room temperature and extracted with EtOAc (2 ×). The combined organic layers were dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue was dissolved in MeOH (2mL) and DCM (1mL) and treated with NaBH ₄ (8.75mg, 0.231mmol) and stirred for 10min. The reaction by the addition of aqueous saturated NH ₄ Cl and extracted quenched with EtOAc (2 ×). The combined organic layers were dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by EtOAc (EtOAc:EtOAc:EtOAc: _{(UPLC-MS 3) t R} 1.09min; ESI-MS 415.2 [M + H] +.

Intermediate 20 : 6-Amino-4-(2-methoxyethoxy)nicotinonitrile.

A solution of KHMDS in THF (1M, 48.1 mL, 48.1 mmol) was obtained from EtOAc (EtOAc) After 6 minutes, 6-amino-4-fluoronicotinonitrile (intermediate 21, 3.00 g, 21.9 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between NH ₄ Cl saturated solution and EtOAc, and extracted with EtOAc (2 ×), so that the combined EtOAc layers were washed with brine, dried over MgSO ₄ and evaporated. The residue was triturated with EtOAc (EtOAc) ^{1 H NMR (400MHz, DMSO- d} 6) δ 8.14 (s, 1H), 6.91 (s, br, 2H), 6.03 (s, 1H), 4.19-4.13 (m, 2H), 3.34-3.28 (m, 2H), 2.51 (s, 3H).

Intermediate 21 : 6-Amino-4-fluoronicotinonitrile.

4-Fluoro-5-iodopyridin-2-amine (intermediate product 22, 240 g, 1 mol), zinc cyanide (125 g, 1.05 mol), zinc (13 g, 0.2 mol), Pd ₂ (dba) under nitrogen ₃ (25 g, 25 mmol) was degassed with dppf (55 g, 0.1 mol) DMA (800 mL) and placed in a round bottom flask. The mixture was stirred at 100 ° C for 3 h. The reaction mixture was diluted with 5% NaHCO ₃ (2L), and extracted with EtOAc (4 × 600mL). Washed with 5% NaOH (1L) will use the organic layers were combined, dried over Na ₂ SO _4, and concentrated to 700mL. The resulting organic phase was taken up via EtOAc (EtOAc) (EtOAc). The combined organic filtrates were washed with 2M EtOAc (3×EtOAc). The pH of the aqueous phase with saturated NaHCO ₃ was adjusted to 10. The aqueous phase was extracted with DCM (3×500 mL). The dried the combined DCM over Na ₂ SO ₄ and concentrated. The residue was purified with EtOAc EtOAc m. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.40 (d, 1H), 7.40 (s, 2H), 6.34 (d, 1H).

Intermediate 22 : 4-fluoro-5-iodopyridin-2-amine.

A suspension of 4-fluoropyridin-2-amine (336 g, 2.5 mol) and NIS (745 g, 2.75 mol) in MeCN (9 L) was treated with TFA (114 g, 1 mol). The reaction mixture was then stirred at room temperature for 8 h. The reaction mixture was diluted with EtOAc (10L),, brine (4 × 5L) was washed with aqueous (2 × 5L) saturated Na ₂ S ₂ O _3. The combined organic layers were dried over Na ₂ SO _4, filtered and concentrated to give a crude product. The crude product was purified by EtOAc EtOAc (EtOAc) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.14 (d, 1H), 6.45 (s, 2H), 6.33 (d, 1H).

Intermediate 23 : N- (5-Cyano-4-(N-morpholinyl)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

N- (4-chloro-5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- under argon Pyridin-1(2H)-carbamide (intermediate 2J, 60 mg, 0.155 mmol) and morpholine (500 μL, 5.74 mmol) were dissolved in DMA (1 mL). The mixture was stirred at 100 ° C for 1 h. The reaction mixture was cooled to rt, diluted in EtOAc and washed with aqueous saturated NH ₄ Cl 2 was washed with brine × 1 ×. The combined organic layers were dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was sequentially subjected to normal phase chromatography (4 g silica gel cartridge, heptane / EtOAc 100:0 to 0:100), reverse phase chromatography (4.3 g C18 cartridge, water containing 0.1% TFA / Purification of acetonitrile from 90:10 to 0:100) gave the title compound as a white solid.

(UPLC-MS 3) t _R 1.13 min; ESI-MS 439.2 [M+H] ⁺ .

Intermediate 24 : N- (5-Cyano-4-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-2-yl)-7-(dimethoxymethyl)-3, 4-dihydro-1,8- Pyridin-1(2H)-formamide.

N- (4-chloro-5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- under argon Pyridine-1(2H)-carbamide (intermediate 2J, 50 mg, 0.129 mmol) and 4-methylpiperidin-4-ol (21.5 mg, 0.142 mmol) were dissolved in DMF (1 mL). The mixture was stirred at 100 ° C for 16 h.

Excess 4-methylpiperidin-4-ol was added and the mixture was stirred at 100 ° C for 45 min. The reaction mixture was diluted in EtOAc and washed with saturated aqueous NaHCO ₃ (2 ×) and brine. The dried organic layer was ₂ SO ₄ Na, filtered, and concentrated in vacuo. The crude material was purified by EtOAc EtOAc (EtOAc) (UPLC-MS 3) t _R 1.08 min; ESI-MS 467.2 [M+H] ⁺ .

Intermediate 25 : N- (5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

To 6-bromo- N- (5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- at -78 °C Piperidin -1 (2H) - A Amides (Intermediate 2H, 171mg, 0.396mmol) in THF (5mL) was added a solution of MeLi in the (in Et ₂ O to 1.6M, 0.247mL, 0.396mmol), the solution was stirred for 5min. Subsequently, n-butyllithium (1.6 M in hexanes, 0.272 mL, 0.435 mmol) was added and the solution was stirred for 20 min. Subsequently, DMF (0.184 mL, 2.37 mmol) was added. The mixture was stirred at -78 °C for 1.5 h and then allowed to warm to room temperature. The reaction mixture was poured into saturated aqueous NH ₄ Cl and extracted with DCM twice the line. The organic phase is then dried over Na ₂ SO _4, filtered and evaporated. The residue was purified by normal phase chromatography (12 g EtOAc, EtOAc/EtOAc:EtOAc:EtOAc Containing N- (5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-6-methylindolyl-3,4-dihydro-1,8- The dissolved fraction of pyridine-1(2H)-carbamide is concentrated. The residue was dissolved in MeOH (1.5mL) and in DCM (1.5mL) and treated with NaBH ₄ (5.32mg, 0.141mmol). The reaction mixture was stirred at rt for 30min, then it was poured into saturated aqueous NH ₄ Cl and extracted with DCM (3 ×). Then the combined organic phase was dried over Na ₂ SO _4, filtered and evaporated. The crude material was sequentially subjected to normal phase chromatography (4 g silica gel cartridge, heptane / EtOAc 100:0 to 0:100) reverse phase chromatography (13 g C18 cartridge, water containing 0.1% TFA / acetonitrile 80) : 20 to 0: 100) Purification. The solution containing the product fractions were treated with saturated aqueous Na ₂ CO _3, it was concentrated until the organic solvent was removed and extracted with DCM (3 ×). The combined organic layers were dried Na ₂ SO _4, filtered and evaporated to give a colorless resin of the title compound. _{(UPLC-MS 3) t R} 0.92min; ESI-MS 384.1 [M + H] +.

Intermediate 26 : N- (5-cyanopyridin-2-yl)-6-cyclopropyl-7-(dimethoxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

The tube was charged with 6-bromo- N- (5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide (intermediate 2H, 30mg, 0.069mmol), cyclopropyl Acid (7.75 mg, 0.090 mmol), tricyclohexylphosphine (0.195 mg, 0.694 μmol), K ₃ PO ₄ (51.6 mg, 0.243 mmol), toluene (0.5 mL) and H ₂ O (0.05 mL) with argon Purge. Subsequently, Pd(OAc) ₂ (0.779 mg, 3.47 μmol) was added, the tube was sealed and the reaction mixture was stirred at 100 ° C for 1 h. The reaction mixture was cooled to room temperature, diluted with DCM and washed with water. The organic phase is then dried over Na ₂ SO _4, filtered and evaporated. The crude material was purified by supercritical fluid chromatography (SFC 1, DEAP column) to give the title compound as a colourless solid. (UPLC-MS 3) t _R 1.25 min; ESI-MS 394.2 [M+H] ⁺ .

Intermediate 27 : N- (5-Cyano-4-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)-7-(dimethoxymethyl)-3 ,4-dihydro-1,8- Pyridin-1(2H)-formamide.

N- (4-chloro-5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- under argon Pyridin-1(2H)-formamide (intermediate 2J, 60 mg, 0.155 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetra Methyl-1,3,2-dioxaboron (65.0 mg, 0.309 mmol), PdCl ₂ (PPh ₃ ) ₂ (10.9 mg, 0.015 mmol), Na ₂ CO ₃ (2M in water, 0.232 mL, 0.464 mmol) and DME (2 mL) were placed in a sealed vial. The mixture was stirred at 100 IH deg.] C, cooled to rt, diluted in EtOAc and washed with saturated aqueous NaHCO ₃ (2 ×) and brine. The dried organic layer was ₂ SO ₄ Na, filtered, and concentrated in vacuo. The crude material was purified by EtOAc EtOAc (EtOAc) (UPLC-MS 3) t _R 1.19 min; ESI-MS 436.2 [M+H] ⁺ .

Intermediate 28 : N- (5-Cyano-4-(tetrahydro-2H-piperidin-4-yl)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-di Hydrogen-1,8- Pyridin-1(2H)-formamide.

N- (5-Cyano-4-(3,6-dihydro-2H-piperidin-4-yl)pyridin-2-yl)-7-(dimethoxymethyl)-3,4- Dihydro-1,8- Pyridine-1(2H)-carbamide (intermediate 27, 35 mg, 0.080 mmol) was dissolved in MeOH (1 mL) and THF (3 mL). The solution was treated with palladium (on charcoal 10%, 8.55mg, 8.04μmol) and stirred at room temperature under H ₂ atmosphere for 16h. The reaction mixture was filtered through a plug of diatomaceous earth. The plug was rinsed with EtOAc and the filtrate was concentrated in vacuo. The residue was purified by EtOAc EtOAc EtOAc:EtOAc _{(UPLC-MS 3) t R} 1.18min; ESI-MS 438.2 [M + H] +.

Intermediate 29 : (racemic) N- (5-chloro-4-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-yl)-7-(dimethoxymethyl)-3,4 -dihydro-1,8- Pyridin-1(2H)-formamide.

7-(Dimethoxymethyl)-3,4-dihydro-1,8- under argon at room temperature Phenyl-1(2H)-phenylformate (intermediate 3, 11.4 mg, 0.035 mmol) and 5-chloro-4-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-amine (intermediate 30, 7.5 A solution of mg, 0.035 mmol) in EtOAc (EtOAc m. The reaction mixture was stirred for 20min, by the addition of saturated NH ₄ Cl solution was quenched and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by EtOAc EtOAc (EtOAc) (UPLC-MS 3) t _R 1.10 min; ESI-MS 450.1 [M+H] ⁺ .

Intermediate 30 : (racemic) 5-chloro-4-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-amine.

2,5-dichloro-4 - ((tetrahydrofuran-3-yl) oxy) pyrimidine (intermediate 31,100mg, 0.425mmol) in NH ₃ (in MeOH 7M, 608μL, 4.25mmol) was heated in the Stir to 70 ° C for 16 h. The reaction mixture was cooled to room temperature and concentrated. The crude material was purified by EtOAc EtOAc (EtOAc) ^{1 H NMR (400MHz, DMSO- d} 6) δ 8.04 (s, 1H), 6.78 (br.s, 2H), 5.47-5.54 (m, 1H), 3.72-3.94 (m, 4H), 2.18-2.29 ( m, 1H), 1.95-2.04 (m, 1H).

Intermediate 31 : (racemic) 2,5-dichloro-4-((tetrahydrofuran-3-yl)oxy)pyrimidine.

A solution of 3-hydroxy-tetrahydrofuran (115 mg, 1.31 mmol) in D.sub.4 (4 mL). It was stirred for 15 min and then added to a solution of 2,4,5-trichloropyrimidine (200 mg, 1.09 mmol) in DMF (4 mL). The reaction mixture was stirred at 0 ° C for 0.5 h. The reaction mixture by the addition of saturated NH ₄ Cl solution was quenched and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na ₂ SO _4, filtered and concentrated. The crude material was purified by EtOAc (EtOAc:EtOAc:EtOAc: ^{1 H NMR (400MHz, DMSO- d} 6) δ 8.67 (s, 1H), 5.67-5.62 (m, 1H), 3.91-3.84 (m, 3H), 3.81-3.74 (m, 1H), 2.36-2.25 ( m, 1H), 2.14 - 2.06 (m, 1H).

Intermediate 32 : N- (5-Cyano-4-isopropoxypyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

2-Propanol (16.2 mg, 0.269 mmol) was diluted in EtOAc (1 mL) and EtOAc (EtOAc) The reaction mixture was stirred at room temperature for 30 min. To N- (5-cyano-4-fluoropyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- This mixture was added to a solution of pyridine-1(2H)-carbamide (intermediate product 33, 25 mg, 0.054 mmol) in DMA (1 mL). The reaction mixture was then stirred at room temperature for 1 h and at 110 ° C for 4 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with saturated aqueous NaHCO _3, water and brine. The dried organic layer was ₂ SO ₄ Na, filtered, and concentrated in vacuo. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptane / EtOAc 100:0 to 0:100). The title compound was obtained as a white solid. _{(UPLC-MS 3) t R} 1.27min; ESI-MS 412.2 [M + H] +.

Intermediate 33 : N- (5-Cyano-4-fluoropyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

N- (4-chloro-5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- Pyridine-1(2H)-carbamide (intermediate 2J, 106 mg, 0.273 mmol) and KF (159 mg, 2.73 mmol) were dissolved in DMSO (3 mL). The mixture was stirred at 110 ° C for 16 h. The mixture was cooled to rt, diluted in EtOAc and washed with saturated aqueous NaHCO ₃ (2 ×) and brine. The dried organic layer was ₂ SO ₄ Na, filtered, and concentrated in vacuo. The crude material was purified by EtOAc EtOAc (EtOAc) (UPLC-MS 3) t _R 1.20 min; ESI-MS 372.1 [M+H] ⁺ .

Intermediate 34 : (rac) 6-amino-4-((tetrahydrofuran-2-yl)methoxy)nicotinonitrile.

6-Amino-4-chloronicotinonitrile (intermediate 16, 70 mg, 0.456 mmol) and (tetrahydrofuran-2-yl)methanol (233 mg, 2.28 mmol) were placed in a vial. DMA (1 mL), NaH (60% dispersion in mineral oil, 109 mg, 2.73 mmol) was added sequentially to the mixture at room temperature. The mixture was then heated at 70 ° C for 16 h. The reaction mixture was cooled to room temperature, diluted with EtOAc EtOAc. The dried organic layer was ₂ SO ₄ Na, filtered, and concentrated in vacuo. The crude material was purified by EtOAc EtOAc (EtOAc:EtOAc: _{(UPLC-MS 3) t R} 0.56min; ESI-MS 220.1 [M + H] +.

The following example has been synthesized into an intermediate product 34 in a similar manner:

Intermediate 35 : N- (5-cyanopyridin-2-yl)-6-(difluoromethyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

To N- (5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-6-methylindolyl-3,4-dihydro-1,8- Add DAST (0.012 mL, 0.089 mmol) to a solution of pyridine-1(2H)-carbamide (intermediate 36, 20 mg, 0.052 mmol) in DCM (0.5 mL). (0.012 mL, 0.089 mmol) and the reaction mixture was stirred for 6d then EtOAc (EtOAc &lt The reaction mixture was poured into a saturated aqueous solution of NaHCO ₃ and extracted twice with DCM. Then the combined organic phase was dried over Na ₂ SO _4, filtered and evaporated. The crude material was purified by supercritical fluid chromatography (SFC1, NH2 column) to give the title compound as a colorless powder. (UPLC-MS 3) t _R 1.22; ESI-MS 404.1 [M+H] ⁺ .

Intermediate 36 : N- (5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-6-methylindolyl-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

To 6-bromo- N- (5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- at -78 °C Piperidin -1 (2H) - A Amides (Intermediate 2H, 300mg, 0.694mmol) in THF (10mL) was added a solution of MeLi in the (in Et ₂ O to 1.6M, 0.434mL, 0.694mmol), the solution was stirred for 5min, Then n-butyllithium (1.6 M in hexanes, 0.477 mL, 0.763 mmol) was added and the solution was stirred for 20 min. DMF (0.322 mL, 4.16 mmol) was then added, and the mixture was stirred at -78 °C for 1 h and then warmed to room temperature. The reaction mixture was poured into saturated aqueous NH ₄ Cl and extracted with DCM twice the line. Then the combined organic phase was dried over Na ₂ SO _4, filtered and evaporated. The crude material was purified by EtOAc (EtOAc:EtOAc:EtOAc: (UPLC-MS 3) t _R 1.10; ESI-MS 382.2 [M+H] ⁺ .

Intermediate 37: 6 - (((tert-butyl dimethyl silicone alkyl) oxy) methyl) - N - (5- cyano-4- (2-methoxyethoxy) pyridine-2 Base)-7-(dimethoxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

To 6-(((tert-butyldimethylmethylalkyl)oxy)methyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- at -78 °C Phenyl-1(2H)-phenyl formate (intermediate product 38, 206 mg, 0.436 mmol) and 6-amino-4-(2-methoxyethoxy)nicotinonitrile (intermediate product 20,93 mg, 0.479 mmol) LHMDS (1M in THF, 0.959 mL, 0.959 mmol) was slowly added to a solution in THF (3 mL). The reaction mixture was stirred at -78 °C for 30 min then allowed to warm to room temperature. The reaction mixture was poured into saturated aqueous NH ₄ Cl and extracted with DCM twice the line. The organic phase is then dried over Na ₂ SO _4, filtered and evaporated. The crude material was sequentially subjected to normal phase chromatography (12 g silica gel cartridge, heptane / EtOAc 100:0 to 50:50), reverse phase chromatography (43 g C18 cartridge, water containing 0.1% TFA / acetonitrile) Purification from 90:10 to 0:100) gave the title compound. (UPLC-MS 3) t _R 1.59; ESI-MS 572.3 [M+H] ⁺ .

The following intermediates have been synthesized in a similar manner as intermediate 37:

Intermediate 38 : 6-(((t-butyldimethylsilyl)oxy)methyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- Phenyl-1(2H)-formic acid phenyl ester.

To 6-(((t-butyldimethylmethylalkyl)oxy)methyl)-7-(dimethoxymethyl)-1,2,3,4-tetrahydro- at -78 °C 1,8- A solution of the pyridine (1M THF solution, 25.3 mL, 25.3 mmol) was slowly added to a solution of pyridine (methanol, EtOAc, EtOAc (EtOAc) The reaction mixture was stirred at -78 °C for 30 min then allowed to warm to room temperature. The reaction mixture was poured into saturated aqueous NH ₄ Cl tied the extracted twice with DCM. Then the combined organic phase was dried over Na ₂ SO _4, filtered and concentrated. The crude material was purified by EtOAc EtOAc (EtOAc) ^{1 H NMR (400MHz, DMSO- d} 6) δ 7.68 (s, 1H), 7.37-7.45 (m, 2H), 7.19-7.27 (m, 3H), 5.17 (s, 1H), 4.84 (s, 2H) , 3.80-3.86 (m, 2H), 3.27 (s, 6H), 2.84 (t, 2H), 1.91-2.02 (m, 2H), 0.91 (s, 9 H), 0.08 (s, 6H).

Intermediate 39 : 6-(((t-butyldimethylmethylalkyl)oxy)methyl)-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1, 8- Acridine.

To (2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8- at 0 °C Add a solution of pyridine-3-yl)methanol (intermediate 40, 6.5 g, 27.3 mmol) in DCM (100 mL) EtOAc. (4.93 g, 32.7 mmol) and DMAP (0.067 g, 0.546 mmol). The reaction mixture was then stirred for 1h at room temperature before it was poured into a saturated aqueous solution of NaHCO ₃ and extracted twice with DCM. The combined so that the organic phase was dried over Na ₂ SO _4, filtered and evaporated. The crude material was purified by normal phase chromatography (EtOAc: EtOAc (EtOAc:EtOAc) . (UPLC-MS 3) t _R 1.10; ESI-MS 353.3 [M+H] ⁺ .

Intermediate 40 : (2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8- Pyridin-3-yl)methanol.

To 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8- Pyridine-3-carbaldehyde (intermediate 41,10g, 38.2mmol) in MeOH (120mL) and DCM (60mL) was added in the NaBH ₄ (1.16g, 30.6mmol). The reaction mixture was stirred at rt for 30min, then slowly quenched with saturated aqueous NH ₄ Cl, and concentrated until the organic solvent has been largely removed. The resulting mixture was extracted with DCM (4×). The combined so that the organic phase was dried over Na ₂ SO _4, filtered and evaporated. The crude material was purified by EtOAc (EtOAc: EtOAc:EtOAc: (UPLC-MS 3) t _R 0.38; ESI-MS 239.2 [M+H] ⁺ .

Intermediate 41 : 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8- Pyridine-3-carbaldehyde.

To 6-bromo-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8- under argon at -78 °C Piperidine (Intermediate 12,15.0g, 52.2mmol) in THF (400mL) was added a solution of MeLi of Zhong (Zhong in Et _{1.6M, 32.6mL, 52.2mmol 2 O)} , the solution was stirred for 5min, followed by slow addition of n-butyllithium ( 1.6 M, 35.9 mL, 57.5 mmol in hexanes and the solution was stirred for 20 min. To the reaction was added THF (100 mL) at -78. Next, n-butyllithium (1.6 M in hexanes, 49.0 mL, 78 mmol) was added and the reaction mixture was stirred for 20 min then n-butyllithium (1.6M in hexanes, 6. The mixture was stirred at 78 ° C for 10 min. Was added DMF (2.10mL, 27.2mmol) and stirred the reaction mixture at -78 deg.] C for 45 min, then allowed to warm to room temperature, poured into saturated aqueous NH ₄ Cl and extracted twice with DCM. The combined organic phase was the dried Na ₂ SO _4, filtered and evaporated to give an orange oil of the title compound. (UPLC-MS 3) t _R 0.63; ESI-MS 237.2 [M+H] ⁺ .

Intermediate 42 : 6-Amino-4-(4-hydroxy-4-methylpiperidin-1-yl)nicotinonitrile.

Suspension of 6-amino-4-chloronicotinonitrile (intermediate 16, 31.6 mg, 0.206 mmol) and 4-hydroxy-4-methylpiperidine (47.4 mg, 0.412 mmol) in DMA (0.75 mL) The liquid was heated to 100 ° C and stirred for 1 h. The resulting brown solution was heated to 120 ° C and stirred for 18 h.

The reaction mixture was cooled to rt EtOAc (EtOAc) Washed with brine the organic layers were combined, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (4g silica gel cartridge, DCM / (DCM / (MeOH 1M NH ₃ containing it) 9/1) 100: 0 to 0: 100) to give a brown solid of the title Compound. ^{1 H NMR (400MHz, DMSO- d} 6) δ 8.04 (s, 1H), 6.62 (s, 2H), 5.91 (s, 1H), 4.38 (s, 1H), 3.29-3.37 (m, 2H), 3.06 -3.20 (m, 2H), 1.50-1.62 (m, 4H), 1.16 (s, 3H).

The following intermediates have been synthesized into intermediates 42 in a similar manner:

Intermediate 42A : 8-(2-Amino-5-cyanopyridin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester.

^{1 H NMR (400MHz, DMSO- d} 6) δ 8.06 (s, 1H), 6.66 (s, 2H), 5.90 (s, 1H), 3.10-3.32 (s, 8H), 1.69-1.79 (m, 2H) , 1.52-1.66 (m, 4H), 1.40 (s, 9H).

Intermediate 43 : N- (5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-6-((dimethylamino)methyl)-3,4-dihydro- 1,8- Pyridin-1(2H)-formamide.

To N- (5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-6-methylindolyl-3,4-dihydro-1,8- Add a solution of pyridine-1(2H)-carbamide (intermediate product 36, 25 mg, 0.066 mmol) and dimethylamine (7.9 M in water, 0.017 mL, 0.131 mmol) in DCM (0.5 mL) Sodium borohydride (27.8 mg, 0.131 mmol). The reaction mixture was stirred for 1h at room temperature, it was poured into saturated aqueous NaHCO ₃ and extracted with DCM (3 ×). The combined the organic phases were dried over Na ₂ SO _4, filtered and concentrated. The crude material was purified by supercritical fluid chromatography (SFC1, NH2 column) to give the title compound as a colorless solid. (UPLC-MS 3) t _R 0.73; ESI-MS 411.2 [M+H] ⁺ .

Intermediate 44 : N- (5-Cyano-4-(2,8-diazaspiro[4.5]dec-8-yl)pyridin-2-yl)-7-methylindolyl-6-(hydroxymethyl) )-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

To 8-(2-(6-(((tert-butyldimethylmethyl)alkyl)oxy)methyl)-7-(dimethoxymethyl)-1,2,3,4-tetrahydro -1,8- Pyridin-1-carboxamido)-5-cyanopyridin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (intermediate product 37D, 70 mg, 0.095 mmol) ) in THF was added in the (0.5mL) and H ₂ O (0.5mL) solution of concentrated HCl (0.1mL, 1.2mmol). The reaction mixture was stirred at room temperature for 4 h then EtOAc (EtOAc &lt The reaction mixture was poured into a saturated aqueous solution and ₃ (4 ×) and extracted with DCM (4 ×) and EtOAc NaHCO. Then the combined organic phase was dried over Na ₂ SO _4, filtered and evaporated. The crude material was triturated with EtOAc (EtOAc) (UPLC-MS 3) t _R 0.64; ESI-MS 476.2 [M+H] ⁺ .

Intermediate 45 : (rac) 6-amino-4-((1-methylpyrrolidin-3-yl)oxy)nicotinonitrile.

1-Methylpyrrolidin-3-ol (89 mg, 0.875 mmol) was treated with KHMDS (1M EtOAc EtOAc. The reaction mixture was stirred for 10 min then added a solution of 6-amino-4-fluoronicotinonitrile (intermediate 21, 60 mg, 0.438 mmol) in DMA (1 mL). The mixture was then heated at 100 &lt;0&gt;C for 40 min, cooled to rt and diluted with EtOAc & water. The layers were separated and aqueous layer was extracted with EtOAc (EtOAc). The combined organic layers were dried over Na ₂ SO _4, filtered and concentrated. The crude material was purified by normal phase chromatography twice (4g silica gel cartridge, DCM / (DCM / (MeOH 1M NH ₃ containing it) 9/1) 100:: 0 to 0100) to give a light brown wax The title compound. (UPLC-MS 3) t _R 0.27; ESI-MS 219.1 [M+H] ⁺ .

The following intermediates have been synthesized in a similar manner as intermediate 45:

Intermediate 46 : (rac) 6-amino-4-((1-methoxypropan-2-yl)oxy)nicotinonitrile.

1-Methoxypropan-2-ol (329 mg, 3.65 mmol) was treated with KHMDS (1M EtOAc EtOAc. The reaction mixture was stirred for 10 min. Subsequently, a mixture of 6-amino-4-fluoronicotinonitrile (intermediate 21, 50 mg, 0.365 mmol) in NMP (0.5 mL) was added. The solution was then heated at 50 ° C for 1 h. The reaction mixture was quenched with water and diluted EtOAc. The layers were separated and the aqueous extracted with EtOAc EtOAc. The combined organic layers were dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptane / EtOAc 100:0 to 0:100). The product-containing fractions are concentrated; the obtained oil is dissolved in water and lyophilized to give the title compound as a white solid. (UPLC-MS 3) t _R 0.57; ESI-MS 208.1 [M+H] ⁺ .

Intermediate 47 : ( R )-6-Amino-4-((tetrahydrofuran-3-yl)oxy)nicotinonitrile.

( R )-Tetrahydrofuran-3-ol (161 mg, 1.82 mmol) was treated with KHMDS (1M THF, 1.09 mL, 1.09 mmol). The reaction mixture was stirred for 2 min. Subsequently, a mixture of 6-amino-4-fluoronicotinonitrile (intermediate 21, 50 mg, 0.365 mmol) in NMP (0.5 mL) was added. The resulting dark brown solution was stirred at room temperature for 1 hour and 50 minutes. The reaction mixture was quenched with saturated aqueous NH ₄ Cl and extracted 2 × with EtOAc. The combined organic layers were dried over Na ₂ SO _4, filtered and concentrated. The crude material was purified by normal phase chromatography (4g silica gel cartridge, DCM / (DCM / (MeOH 1M NH ₃ containing it) 9/1) 100: 0 to 0: 100) to give a brown solid of the title Compound. (UPLC-MS 3) t _R 0.48; ESI-MS 206.1 [M+H] ⁺ .

The following intermediates have been synthesized into intermediates 47 in a similar manner:

Intermediate 48 : 2-(8-((5-Cyanopyridin-2-yl)aminemethanyl)-2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1 ,8- Third butyl pyridine-3-yl)acetate.

6-Bromo-N-(5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide (intermediate 2H, 41.7 mg, 0.096 mmol), Pd(dba) ₂ (2.8 mg, 4.8 μmol) and 1,2,3,4,5-fused pentaphenyl- 1'-(di-t-butylphosphino)ferrocene (3.4 mg, 4.8 μmol) was charged into a tube and purged with argon, followed by sequential addition of THF (1 mL), 2-tert-butoxyl chloride 2-oxoethyl zinc (0.5 M in Et ₂ O, 0.386 mL, 0.193 mmol), and the reaction mixture was stirred at 70 ° C under argon for 1 h. The reaction mixture was poured into water and extracted with DCM (2×). The organic phase is then dried over Na ₂ SO _4, filtered and evaporated. The crude material was sequentially subjected to normal phase chromatography (12 g silica gel cartridge, heptane / EtOAc 95:5 to 50:50), reverse phase chromatography (13 g C18 cartridge, water containing 0.1% TFA / acetonitrile) Purification from 95:5 to 5:95) gave the title compound as a red resin. (UPLC-MS 3) t _R 1.33; ESI-MS 468.2 [M+H] ⁺ .

Intermediate 49 : 6-Amino-4-((tetrahydro-2H-piperidin-4-yl)methyl)amino)nicotinonitrile.

6-Amino-4-fluoronicotinonitrile (intermediate 21, 50 mg, 0.365 mmol) and (tetrahydro-2H-piperidin-4-yl)methylamine (84 mg, 0.729 mmol) were dissolved in NMP (1 mL) It was treated with DIPEA (0.219 mL, 1.09 mmol) at room temperature. The reaction mixture was then stirred at 50 ° C for 4 h and at 90 ° C for 4 h. The reaction mixture was cooled to rt EtOAc (EtOAc) The layers were separated and the organic layer was washed with water and brine. The dried organic layer was ₂ SO ₄ Na, filtered and concentrated. The crude material was purified by EtOAc EtOAc (EtOAc) (UPLC-MS 3) t _R 0.40; ESI-MS 233.1 [M+H] ⁺ .

The following intermediates have been synthesized in a similar manner as intermediate 49:

Intermediate 50 : N- (5-Cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-(dimethoxymethyl)-6-(trifluoromethyl) -3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

N- (5-Cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-(dimethoxymethyl)-6-iodo-3,4-dihydro- 1,8- Pyridin-1(2H)-formamide (intermediate 51, 83 mg, 0.150 mmol) and (1,10-morpholine)(trifluoromethyl)copper (I) (70.4 mg, 0.225 mmol) in a vial And purged with argon. DMF (0.6 mL) was added and the vial was capped. The resulting brown solution was stirred at room temperature for 23 h. The reaction was treated with saturated aqueous NaHCO ₃ and (2 ×) and extracted with EtOAc. The combined organic layers were dried over Na ₂ SO _4, filtered and concentrated. The crude material was purified by preparative supercritical fluid chromatography (SFC1, EtOAc). (UPLC-MS 4) t _R 5.18; ESI-MS 496.2 [M+H] ⁺ .

Intermediate 51 : 7-(dimethoxymethyl)-6-iodo-3,4-dihydro-1,8- Phenyl-1(2H)-formic acid phenyl ester.

7-(Dimethoxymethyl)-6-iodo-1,2,3,4-tetrahydro-1,8- at -78 °C A solution of the pyridine (m.p., EtOAc, EtOAc (EtOAc) (EtOAc) The reaction was then allowed to warm to room temperature over 20min, by the addition of aqueous saturated NH ₄ Cl and extracted quenched with DCM (2 ×). The dried organic layer was ₂ SO ₄ Na, filtered and concentrated. The crude material was purified by EtOAc EtOAc (EtOAc:EtOAc: (UPLC-MS 3) t _R 1.19; ESI-MS 455.1 [M+H] ⁺ .

The following intermediates have been synthesized in the same manner as intermediates 51:

Intermediate 52 : 7-(dimethoxymethyl)-6-iodo-1,2,3,4-tetrahydro-1,8- Acridine.

7-(Dimethoxymethyl)-1,2,3,4-tetrahydro-1,8- A solution of pyridine (intermediate 4, 1 g, 4.8 mmol) in EtOAc (EtOAc) (EtOAc) Subsequently, the reaction mixture was concentrated. The dried residue was washed with DCM and Et ₂ O treated with water (2 ×) and brine over Na ₂ SO _4, filtered and concentrated. The crude material was purified by EtOAc EtOAc (EtOAc:EtOAc: (UPLC-MS 3) t _R 0.73; ESI-MS 335.3 [M+H] ⁺ .

Intermediate 53 : 6-cyclopropyl-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8- Acridine.

6-bromo-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8- Pyridine (intermediate product 12,670 mg, 2.333 mmol), cyclopropyl Acid (401mg, 4.67mmol), tricyclohexylphosphine _{(6.54mg, 0.023mmol), K 3} PO 4 (1733mg, 8.17mmol) and dioxane (10 mL) was charged in a tube and purged with argon. Subsequently, Pd(OAc) ₂ (26.2 mg, 0.117 mmol) was added, the tube was sealed, and the reaction mixture was stirred at 100 ° C for 1 day. The reaction mixture was cooled to room rt, diluted with EtOAc EtOAc. The organic phase is then dried over Na ₂ SO _4, filtered and evaporated. The crude material was purified by normal phase chromatography (40g silica gel cartridge, DCM / (DCM / (MeOH 7M NH ₃ containing it) 9/1) 100: 0 to 50:50) to give an orange solid of the title Compound. (UPLC-MS 3) t _R 0.64; ESI-MS 249.2 [M+H] ⁺ .

Intermediate 54 : 6-(Difluoromethyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- Phenyl-1(2H)-formic acid phenyl ester.

To 7-(dimethoxymethyl)-6-methylindolyl-3,4-dihydro-1,8- Add DAST (0.185 mL, 1.40 mmol) to a solution of pyridine-1(2H)-carboxylate (m.p. (0.037 mL, 0.281 mmol) and the reaction mixture was stirred 1 h. The reaction mixture was poured into a saturated aqueous solution of NaHCO ₃ and extracted twice with DCM. The organic phase is then dried over Na ₂ SO _4, filtered and evaporated. The crude material was purified by EtOAc (EtOAc:EtOAc:EtOAc:

(UPLC-MS 3) t _R 1.19; ESI-MS 379.5 [M+H] ⁺ .

Intermediate 55 : 1-(2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8- Pyridin-3-yl)-N,N-dimethylmethylamine.

To 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8- Add a solution of pyridine-3-carbaldehyde (intermediate product 41,300 mg, 1.15 mmol) and dimethylamine (7.9 M in water, 1.45 mL, 11.5 mmol) in DCM (7 mL) , 2.29mmol). The reaction mixture was stirred at room temperature overnight. Subsequently, dimethylamine (7.9 M in water, 1.45 mL, 11.5 mmol) and sodium triethoxysulfonylborohydride (486 mg, 2.29 mmol) were added, and the reaction mixture was stirred at room temperature for 8 h, then sequentially added two Methylamine (7.9 M in water, 1.45 mL, 11.5 mmol), sodium <RTI ID=0.0></RTI></RTI><RTIgt; And the reaction mixture was poured (3 ×) and extracted with DCM into a saturated aqueous solution of NaHCO _3. The organic phase was then dried over Na ₂ SO _4, filtered and evaporated. The crude material was purified by normal phase chromatography (24g silica gel cartridge, DCM / (DCM / (MeOH 7M NH ₃ containing it) 9/1) 100: 0 to 0: 100) to give the title as a yellow solid of Compound. (UPLC-MS 3) t _R 0.37; ESI-MS 266.2 [M+H] ⁺ .

Intermediate 56 : (racemic) 6-amino-4-(((1 S *, 2 R *, 3 S *, 4 R *)-3-(((triethyldecyl)oxy)) Methyl)bicyclo[2.2.1]hept-2-yl)amino)nicotinonitrile.

Racemic 6-Amino-4-(((1 S *, 2 R *, 3 S *, 4 R *)-3-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl) The amine nicotinic nitrile (intermediate 57, 420 mg, 1.63 mmol) was dissolved in EtOAc (EtOAc) (EtOAc) The reaction mixture was then stirred at 70 ° C for 2 h. The reaction mixture was quenched with water and diluted EtOAc. The organic layer was separated, washed with water and brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo. The crude material was purified by EtOAc EtOAc (EtOAc:EtOAc: ^{1 H NMR (400MHz, DMSO- d} 6) δ 7.92 (s, 1H), 6.41 (s, 2H), 6.08 (d, 1H), 5.64 (s, 1H), 3.72 (d, 2H), 3.43 (t , 1H), 2.10-2.20 (m, 2H), 1.85-1.92 (m, 1H), 1.73 (d, 1H), 1.43-1.58 (m, 2H), 1.21 (t, 2H), 1.06 (d, 1H) ), 0.91 (t, 9H), 0.55-0.64 (m, 6H).

Intermediate 57 : (rac) 6-amino-4-(((1 S *, 2 R *, 3 S *, 4 R *)-3-(hydroxymethyl)bicyclo[2.2.1]g -2-yl)amino) nicotine nitrile.

6-Amino-4-fluoronicotinonitrile (intermediate 21, 280 mg, 2.04 mmol) and racemic ((1 R *, 2 S *, 3 R *, 4 S *)-3-aminobicyclic [2.2.1] Hept-2-yl)methanol hydrochloride (435 mg, 2.45 mmol) in EtOAc (EtOAc m. Stir at °C (MW) for 30 min. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The dried organic layer was ₂ SO ₄ Na, filtered and concentrated. The crude material was purified by EtOAc EtOAc (EtOAc) (UPLC-MS 3) t _R 0.53; ESI-MS 259.2 [M+H] ⁺ .

Intermediate 58 : 7-(dimethoxymethyl)-6-(methoxymethyl)-1,2,3,4-tetrahydro-1,8- Acridine.

To (2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8- To a solution of pyridine-3-yl)methanol (intermediate 40, 94 mg, 0.394 mmol) in THF (2 mL), NaH (60% dispersion in mineral oil, 16.6 mg, 0.414 mmol). The resulting suspension was stirred at room temperature for 15 min then EtOAc (EtOAc &lt The reaction mixture was poured into water and extracted with DCM (2×). The organic phase is then dried over Na ₂ SO _4, filtered and evaporated. The crude material was purified by EtOAc EtOAc (EtOAc:EtOAc: (UPLC-MS 3) t _R 0.51; ESI-MS 253.2 [M+H] ⁺ .

Intermediate 59 : N- (5-Cyanopyridin-2-yl)-7-(dimethoxymethyl)-6-(( N -methylethylammonio)methyl)-3,4- Dihydro-1,8- Pyridin-1(2H)-formamide.

To N- (5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-6-((methylamino)methyl)-3,4-dihydro-1,8- Piperidin -1 (2H) - A Amides (intermediate 60,14.5mg, 0.037mmol) in DCM solution (0.5mL) was added in the Et ₃ N (10.2μL, 0.073mmol) and acetic anhydride (6.9μL, 0.073mmol ). The reaction mixture was stirred for 30min at room temperature, it was poured into saturated aqueous NaHCO ₃ and extracted with DCM (2 ×). The organic phase is then dried over Na ₂ SO _4, filtered and concentrated. The crude material was purified by EtOAc EtOAc (EtOAc:EtOAc: (UPLC-MS 3) t _R 0.98; ESI-MS 439.3 [M+H] ⁺ .

Intermediate 60 : N- (5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-6-((methylamino)methyl)-3,4-dihydro-1, 8- Pyridin-1(2H)-formamide.

Sequentially methylamine hydrochloride (7.79mg, 0.115mmol), methylamine (in MeOH 2M, 0.058mL, 0.115mmol) and NaCNBH ₃ (14.5mg, 0.231mmol) was charged tube. Subsequently, N- (5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-6-methylindolyl-3,4-dihydro-1,8- was added. A suspension of the pyridine-1(2H)-carbamide (intermediate 36, 22 mg, 0.058 mmol) in MeOH (1 mL). The reaction mixture was quenched with water and concentrated until most of the organic solvent had been removed. Water was added and the mixture was extracted with DCM (3×). The organic phase is then dried over Na ₂ SO _4, filtered and evaporated. The crude material was purified by normal phase chromatography (4g silica gel cartridge, DCM / (DCM / (MeOH 7M NH ₃ containing it) 9/1) 100: 0 to 50:50) to give the title as a yellow resinous of Compound. (UPLC-MS 3) t _R 0.72; ESI-MS 397.3 [M+H] ⁺ .

Intermediate 61 : ( S )-5-chloro-4-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-amine.

A solution of ( S )-4-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-amine (intermediate 62, 100 mg, 0.552 mmol) in EtOAc (4 mL) And stirred at 25 ° C for 24 h. Subsequently, the mixture was heated at 80 ° C for 3 h. The resulting solution was cooled to room temperature, diluted with DCM and washed with EtOAc (1M in water) and brine. The dried organic layer was ₂ SO ₄ Na, filtered and concentrated. The crude product was purified by EtOAc EtOAc EtOAc:EtOAc (UPLC-MS 3) t _R 0.64; ESI-MS 216.1 [M+H] ⁺ .

The following intermediates have been synthesized in the same manner as intermediates 61:

Intermediate 61A : ( S )-5-chloro-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-amine.

^{1 H NMR (400MHz, DMSO- d} 6) δ 7.76 (s, 1H), 6.08 (s, 1H), 6.03 (s, 2H), 5.02-4.96 (m, 1H), 3.93-3.72 (m, 4H) , 2.30-2.19 (m, 1H), 2.03-1.93 (m, 1H).

Intermediate 62 : ( S )-4-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-amine.

( S )-Tetrahydrofuran-3-ol (612 mg, 6.95 mmol) was treated with KHMDS (1M in THF, 5.09 mL, 5.09 mmol). The reaction mixture was stirred for 5 min. Subsequently, a mixture of 4-chloropyrimidin-2-amine (300 mg, 2.32 mmol) in THF (10 mL) was added. The resulting brown solution was stirred at room temperature for 5 h. The reaction mixture was quenched with saturated aqueous NH ₄ Cl and extracted 2 × with EtOAc. The combined organic layers were dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by EtOAc EtOAc (EtOAc:EtOAc: (UPLC-MS 3) t _R 0.31; ESI-MS 182.1 [M+H] ⁺ .

Intermediate 63 : ( S )-2-amino-4-((tetrahydrofuran-3-yl)oxy)pyrimidine-5-carbonitrile.

( S )-5-Bromo-4-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-amine (intermediate 64, 38 mg, 0.146 mmol), zinc cyanide (18.0 mg, 0.153) under argon Methyl) (1.9 mg, 0.029 mmol), Pd ₂ (dba) ₃ (13.4 mg, 0.015 mmol) and dppf (16.2 mg, 0.029 mmol) were treated with DMA (2 mL) and stirred at 100 ° C for 16 h. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NaHCO ₃ and diluted with EtOAc. The organic layer was separated, (2 ×) and washed with water (2 ×) and brine, dried over Na ₂ SO _4, filtered and concentrated. The crude material was purified by EtOAc EtOAc EtOAc (EtOAc) (UPLC-MS 3) t _R 0.54; ESI-MS 207.2 [M+H] ⁺ .

Intermediate 64 : ( S )-5-bromo-4-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-amine.

( S )-4-((Tetrahydrofuran-3-yl)oxy)pyrimidin-2-amine (Intermediate 62, 33 mg, 0.182 mmol) was dissolved in EtOAc (EtOAc) And stirred at 25 ° C for 1 h. The reaction solution was diluted in DCM and washed with NaOH (1M in water) and brine. The dried organic layer was ₂ SO ₄ Na, filtered, and concentrated to obtain a white solid of the title compound in vacuo. _{(UPLC-MS 3) t R} 0.67; ESI-MS 260.1,262.0 [M + H] +.

Intermediate 65 : ( S )-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-amine

( S )-Tetrahydrofuran-3-ol (707 mg, 8.03 mmol). Subsequently, the mixture was added to a solution of 4-fluoropyridin-2-amine (300 mg, 2.68 mmol) in THF (15 mL). The resulting brown solution was stirred for 16 h. KHMDS (1M in THF, 2.68 mL, 2.68 mmol) was. The reaction mixture was quenched with saturated aqueous NH ₄ Cl, and (3 ×) and extracted with EtOAc. The combined organic layers were dried over Na ₂ SO _4, filtered and concentrated. The crude material was purified by EtOAc EtOAc (EtOAc:EtOAc: (UPLC-MS 3) t _R 0.30; ESI-MS 181.1 [M+H] ⁺ .

Intermediate 66 : 6-(dimethoxymethyl- ¹³ C-yl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine.

A solution of 6-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (193 mg, 0.897 mmol) in THF (4 mL) at -78. methyl lithium (in Et ₂ O to 1.6M, 0.56mL, 0.90mmol) processing, and stirred for 10min. Subsequently, n-butyllithium (1.6 M in hexanes, 0.67 mL, 1.1 mmol) was added dropwise, and the reaction mixture was stirred for 1 h. The reaction mixture was warmed to -50 ° C and allowed to warm to -20 ° C over 30 min. The reaction mixture was cooled to -78.degree. C. and then more n-butyl lithium (1.6M in hexanes, 0.28 <RTIgt; The reaction mixture was warmed to -50 ° C and allowed to warm to -20 ° C over 30 min. The reaction mixture was cooled to -78 deg.] C, and, N by N - dimethylformamide XI - ¹³ C- Amides (399mg, 5.38mmol), stirred at -78 ℃ 45min. The reaction mixture by the addition of saturated NH ₄ Cl aqueous quenched warmed to room temperature, (3 ×) and extracted with DCM. The combined organic layers were dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptane / EtOAc 100:0 to 0:100) to yield 87 mg of 3,4-dihydro-2H-pyridine as a yellow resin. , 2-b][1,4]oxazin-6- ¹³ C-formaldehyde. A solution of this material in MeOH (2 mL) EtOAc (EtOAc,EtOAc. The heating was turned off and the reaction was stirred at room temperature for 16 h. The reaction mixture was concentrated and treated with saturated aqueous NaHCO _3. The residue was treated with water and extracted with DCM (3x). The combined organic layers were dried over Na ₂ SO _4, filtered and concentrated. The crude material was purified by normal phase chromatography (4 g of silica gel cartridge, heptane / EtOAc 100:0 to 0:100) to afford 3,4-dihydro-2H-pyrido[3,2-b [1,4] The title compound of the oxazin as a pale yellow oil in a mixture of 2:1. (UPLC-MS 3) t _R 0.50; ESI-MS 212.1 [M+H] ⁺ .

Intermediate 67 : 6-Amino-4-(2-(dimethylamino)ethoxy)nicotinonitrile.

2-(Dimethylamino)ethanol (0.293 mL, 2.92 mmol) was treated with KHMDS (1M EtOAc EtOAc. The reaction mixture was stirred for 2 min and then was added EtOAc EtOAc (EtOAc) Was stirred at room temperature resulting dark brown solution was 60min, with a saturated aqueous solution of NH ₄ Cl quenched directly absorbed on Isolute and dried in vacuo. The crude material was purified by reverse phase chromatography (13 g C18 cartridge, water containing 0.1% TFA / acetonitrile 100:0 to 0:100). The fractions containing the product are concentrated. The residue was treated with small amount of saturated NaHCO ₃ solution and NaCl (s) treatment, and (5 ×) and extracted with CH ₂ Cl _2. The combined organic layers over Na ₂ SO ₄ dried and concentrated to give the title compound as a white solid. (UPLC-MS 3) t _R 0.45; ESI-MS 207.2 [M+H] ⁺ .

Intermediate 68 : 6-Amino-4-((1-methylpiperidin-4-yl)methoxy)nicotinonitrile.

(1-Methylpiperidin-4-yl)methanol (283 mg, 2.19 mmol) was purified eluting eluting eluting The reaction mixture was stirred for 2 min and then was added EtOAc EtOAc (EtOAc) The resulting dark brown solution was stirred at room temperature for 1h, quenched with saturated aqueous NH ₄ Cl and extracted with EtOAc (2 ×). The combined organic layers were dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (4g silica gel cartridge, DCM / (DCM / (MeOH 1M NH ₃ containing it) 9/1) 100: 0 to 0: 100) was purified twice to give a light brown resin The title compound. (UPLC-MS 3) t _R 0.31, 0.33; ESI-MS 247.2, 247.2 [M+H] ⁺ .

Intermediate 69 : (racemic) N- (5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-4-hydroxy-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

(Rac) 4 - ((tert-butyl-diphenyl silicon alkyl) oxy) - N - (5- cyano-pyridin-2-yl) -7- (dimethoxymethyl) -3 ,4-dihydro-1,8- A solution of the pyridine-1(2H)-carbamide (intermediate 37Y, 30 mg, 0.049 mmol) in EtOAc (EtOAc (EtOAc) 2h. The reaction mixture was partitioned between DCM and saturated aqueous NaHCO _3. The aqueous layer was extracted with DCM (2×). The combined organic layers were dried over Na ₂ SO _4, filtered and concentrated in vacuo. The crude material was purified by EtOAc EtOAc (EtOAc:EtOAc: ^{1 H NMR (400MHz, DMSO- d} 6) δ 13.93 (s, 1H), 8.76-8.81 (m, 1H), 8.19-8.27 (m, 2H), 7.95 (d, 1H), 7.26 (d, 1H) , 5.71 (d, 1H), 5.39 (s, 1H), 4.67-4.75 (m, 1H), 3.96-4.01 (m, 2H), 3.38 (d, 6H), 2.01-2.10 (m, 1H), 1.79 -1.90 (m, 1H).

Intermediate 70 : (rac) 4-((t-butyldiphenylphosphonyl)oxy)-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1 ,8- Acridine.

5-((Tertiarybutyldiphenylsulfanyl)oxy)-5,6,7,8-tetrahydro-1,8- A solution of the pyridine-2-carbaldehyde intermediate 71, 300 mg, EtOAc (EtOAc) (EtOAc) The reaction mixture was cooled to room temperature, treated with saturated aqueous NaHCO _3, and (3 ×) and extracted with DCM. Washed with brine the organic layers were combined, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by EtOAc EtOAc (EtOAc) (UPLC-MS 3) t _R 1.42; ESI-MS 463.5 [M+H] ⁺ .

Intermediate 71 : (racemic) 5-((t-butyldiphenylsulfanyl)oxy)-5,6,7,8-tetrahydro-1,8- Pyridine-2-carbaldehyde.

7-Bromo-4-((t-butyldiphenylsulfanyl)oxy)-1,2,3,4-tetrahydro-1,8- at -78 °C A solution of the pyridine (m.p., EtOAc, EtOAc (EtOAc) The reaction mixture was stirred at -78 °C for 15 min, and then the solution was warmed to -20 ° C and stirred at this temperature for 30 min. The mixture was then cooled to -78.degree. C., treated with DMF (0.66 <RTI ID=0.0></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI> The reaction was quenched with water and EtOAc (EtOAc) The dried organic layer was ₂ SO ₄ Na, filtered, and concentrated in vacuo. The crude material was purified by EtOAc (EtOAc) ^{1 H NMR (400MHz, DMSO- d} 6) δ 9.66-9.71 (m, 1H), 7.63-7.69 (m, 2H), 7.43-7.56 (m, 6H), 7.35-7.42 (m, 2H), 7.21 ( Br.s.,1H),7.01(d,1H),6.88(d,1H), 4.80-4.85(m,1H),3.43-3.52(m,1H),3.23-3.31(m,1H),1.77 -1.87 (m, 1H), 1.56-1.67 (m, 1H), 1.00 (s, 9H).

Intermediate 72 : (racemic) 7-bromo-4-((t-butyldiphenyldecyl)oxy)-1,2,3,4-tetrahydro-1,8- Acridine.

7-bromo-1,2,3,4-tetrahydro-1,8- A solution of the pyridine-4-ol (intermediate product 73, 420 mg, 1.83 mmol) in EtOAc (EtOAc) Stir at 25 ° C for 16 h. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. The combined organic layers were dried over Na ₂ SO _4, filtered and concentrated. The crude material was subjected to normal phase chromatography (12 g silica gel cartridge, heptane / EtOAc 100:0 to 30:70) and reverse phase chromatography (43 g C18 cartridge, water containing 0.1% TFA / acetonitrile 90: Purification to give the title compound as a white solid. (UPLC-MS 3) t _R 1.61; ESI-MS 467.2, 469.2 [M+H] ⁺ .

Intermediate 73 : (racemic) 7-bromo-1,2,3,4-tetrahydro-1,8- Pyridin-4-ol.

7-bromo-2,3-dihydro-1,8- Piperidine -4 (1H) - one (500mg, 2.20mmol) in THF (15mL) in the (, 4.40mmol 167mg) was treated with NaBH ₄ and stirred at 25 ℃ 2h. The reaction mixture was quenched with saturated aqueous NH ₄ Cl and extracted 2 × with DCM. The dried organic layer was ₂ SO ₄ Na, filtered, and concentrated in vacuo. The crude material was purified by EtOAc EtOAc (EtOAc) _{(UPLC-MS 3) t R} 0.59; ESI-MS 229.0,231.0 [M + H] +.

Intermediate 74: 6 - (((tert-butyl dimethyl silicone alkyl) oxy) methyl) - N - (5- cyano-4 - ((2-methoxyethyl) amino) pyridine -2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

6-(((t-butyldimethyl)alkyl)oxy)methyl)-7-(dimethoxy) under argon at -70 ° C (dry ice / 2 -PrOH bath, internal temperature) Methyl)-3,4-dihydro-1,8- Phenyl-1(2H)-phenylformate (intermediate product 38, 2.98 g, 6.29 mmol) and 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile (intermediate product 75, A solution of 1.10 g, 5.72 mmol) in EtOAc (EtOAc m. The resulting solution was stirred with cooling for 35 min. The cold bath was then removed and the reaction mixture was allowed to warm to -25 °C before being cooled again to -70 °C. The resulting solution was treated with saturated NH ₄ Cl aqueous quenched allowed to warm to room temperature and extracted with EtOAc / heptane 1: 1 and extracted twice. Washed with brine the organic layers were combined, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (80 g of silica gel cartridge, heptane / EtOAc 100:0 to 0:100). The product-containing fractions are concentrated and dried in vacuo to give the title compound. (UPLC-MS 3) t _R 1.60; ESI-MS 571.4 [M+H] ⁺ .

Intermediate 75 : 6-Amino-4-((2-methoxyethyl)amino nicotine nitrile.

A solution of 6-amino-4-fluoronicotinonitrile (intermediate 21, 1.10 g, 8.02 mmol) in EtOAc (20 mL) eluted with 2-methoxyethylamine (2.07 mL, 24.1 mmol) and DIPEA (4.20) Treatment with mL, 24.1 mmol), heated to 50 ° C and stirred for 15 h. The reaction mixture was cooled to room temperature and concentrated. The crude material was purified by normal phase chromatography (24 g silica gel cartridge, heptane / EtOAc 100:0 to 0:100). The product-containing fractions are concentrated and dried in vacuo to give the title compound. ^{1 H NMR (400MHz, DMSO- d} 6) δ 7.92 (s, 1H), 6.39 (s, 2H), 6.15 (t, 1H), 5.61 (s, 1H), 3.46 (t, 2H), 3.27 (s , 3H), 3.24 (q, 2H). (UPLC-MS 3) t _R 0.62; ESI-MS 193.1 [M+H] ⁺ .

Intermediate 76 : (racemic) 6-(((t-butyldimethylmethylalkyl)oxy)methyl) -N- (5-cyano-4-(2-((dimethylamino)) )methyl)N-morpholinyl)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

To 6-(((t-butyldimethylmethylalkyl)oxy)methyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- Phenyl-1(2H)-phenyl formate (intermediate product 38, 120 mg, 0.254 mmol) and racemic 6-amino-4-(2-((dimethylamino)methyl) N-morpholinyl) A mixture of nicotinic nitrile (intermediate 77, 66 mg, 0.254 mmol) was added anhydrous THF (5 mL). The resulting solution was evaporated, the flask was flushed with argon, THF (l. A solution of LHMDS in methylcyclohexane (0.9 M, 0.62 mL, 0.559 mmol) was added dropwise over 5 min and the reaction mixture was stirred at -78 ° C for another 15 min then warmed to 0 ° C and added Aqueous NH ₄ Cl (1 M). The mixture (3 ×) and extracted with DCM, and dried over MgSO ₄ and evaporated. The residue was applied as a DCM solution to a 4 g EtOAc EtOAc EtOAc EtOAc. The product-containing fractions are combined and evaporated to give the title compound as crystals. (UPLC-MS 6) t _R 1.21; ESI-MS 640.5 [M+H] ⁺ .

Intermediate 77 : (rac) 6-amino-4-(2-((dimethylamino)methyl) N-morpholinylnicotinonitrile.

Racemic 2-dimethylaminomethylmorpholine (670 mg, 4.65 mmol), 6-amino-4-fluoronicotinonitrile (intermediate 21, 637 mg, 4.65 mmol) and triethylamine (2.59 mL) A mixture of 18.6 mmol) was heated in a septum sealed reaction vessel at 60 ° C for 10 h under argon. The reaction mixture was evaporated, partitioned between aqueous hydrochloric acid (2M) and DCM (2 ×) between, and the aqueous layer was basified with aqueous NaHCO _3, containing the DCM 10% MeOH, and the combined basic extracts from the in DCM layer was extracted further 10 ×, dried over Na ₂ SO ₄ and evaporated. The residue was applied as a DCM solution to a pad of EtOAc (EtOAc) eluting The product-containing fractions were combined and evaporated to give the title compound. (UPLC-MS 6) t _R 0.28; ESI-MS 262.2 [M+H] ⁺ .

Rac :( Intermediate 78) 6 - (((tert-butyl dimethyl silicone alkyl) oxy) methyl) - N - (5- cyano-4- (quinuclidin-3-yloxy Pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

6-(((Tertiary butyldimethylalkyl)oxy)methyl)-7-(dimethoxymethyl)-3,4-dihydrogen cooled to -78 ° C over 5 minutes -1,8- Phenyl-1(2H)-phenylcarboxylate (intermediate product 38, 135 mg, 0.287 mmol) and racemic 6-amino-4-(quinuclidin-3-yloxy)nicotinonitrile (intermediate product 79, A solution of LHMDS in methylcyclohexane (0.9 M, 0.70 mL, 0.630 mmol) was added dropwise EtOAc. Stirring the reaction mixture at -78 deg.] C for another 10 minutes and then allowed to warm to 0 deg.] C, and was added an aqueous solution of NH ₄ Cl (1M). The mixture (3 ×) and extracted with DCM, and dried over Na ₂ SO ₄ and evaporated. The residue was applied as a DCM solution to a 4 g EtOAc EtOAc EtOAc EtOAc. The title compound was obtained as a white solid. (UPLC-MS 6) t _R 1.27; ESI-MS 623.3 [M+H] ⁺ .

The following intermediates have been synthesized in a similar manner as intermediates 78:

Intermediate 79 : (racemic) 6-amino-4-(quinuclidin-3-yloxy)nicotinonitrile.

A solution of KHMDS in THF (1 M, 6.6 mL, 6.60 mmol) was added dropwise to EtOAc (EtOAc) After 55 min, a solution of 6-amino-4-fluoronicotinonitrile (intermediate 21,500 mg, 3.65 mmol) in THF (2 mL) was added and the mixture was stirred at room temperature for 3 days. The reaction mixture was partitioned between NH ₄ Cl saturated solution and DCM, extracted with DCM (8 ×), the ₂ SO ₄ dried and evaporated of the combined DCM layers were dried over Na. The residue was pre-absorbed onto silica gel and purified by normal phase chromatography using a 12 g RediSep silica gel column eluting with gradient from DCM to 20% MeOH in DCM. The title compound was obtained as a beige solid. (UPLC-MS 6) t _R 0.32; ESI-MS 245.2 [M+H] ⁺ .

Intermediate 80 : N-(5-Cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-(4 -methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

6-Amino group was added dropwise to a mixture of bis(1H-1,2,4-triazol-1-yl)methanone (410 mg, 2.50 mmol) and DMF (1.5 mL) cooled at 0 ° C over 10 min. A solution of -4-((2-methoxyethyl)amino) nicotine nitrile (intermediate 75, 481 mg, 2.50 mmol) in anhydrous DMF ( 1.5 mL). After stirring at 0 ° C for 45 minutes, the reaction mixture was allowed to warm to room temperature, and stirred at room temperature for another 90 minutes, then added 1-((2-(dimethoxymethyl)-5,6,7,8- Tetrahydro-1,8- A solution of pyridine-3-yl)methyl)-4-methylpiperazin-2-one (intermediate 81, 418 mg, 1.00 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature for 17.5 h, quenched with EtOAc and evaporated. The residue was applied as a DCM solution to a pad of EtOAc (EtOAc) EtOAc. The product-containing fractions were combined and evaporated to give the title compound as an orange foam.

^{1 H NMR (400MHz, DMSO- d} 6) δ 13.50 (s, 1H), 8.27 (s, 1H), 7.52 (s, 1H), 7.39 (s, 1H), 6.93 (t, 1H), 5.45 (s , 1H), 4.65 (s, 2H), 3.94-3.89 (m, 2H), 3.54-3.50 (m, 2H), 3.40-3.35 (m, 2H), 3.38 (s, 6H), 3.29 (s, 3H) ), 3.20-3.16 (m, 2H), 3.05 (s, 2H), 2.86-2.80 (m, 2H), 2.61-2.55 (m, 2H), 2.22 (s, 3H), 1.94-1.88 (m, 2H) ). (UPLC-MS 6) t _R 0.72; ESI-MS 553.3 [M+H] ⁺ .

Intermediate 81 : 1-((2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8- Pyridin-3-yl)methyl)-4-methylpiperazin-2-one.

To 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8- at room temperature Pyridin-3-carbaldehyde (intermediate product 41, 2.30 g, 9.74 mmol), 2-((2-aminoethyl)(methyl)amino)acetate dihydrochloride (intermediate product 82, 2.6 g, 14.61) To a mixture of triethylamine (6.75 mL, 48.7 mmol) in EtOAc (EtOAc) The reaction mixture was stirred at room temperature for 21 h, and additional sodium tris-sodium hydride hydride (2.6 g, 9.74 mmol). After stirring at room temperature for a further 4 h additional sodium triethoxysulfonate (1.3 g, 4.87 mmol) was added and the mixture was maintained at 4 °C for 2.5 days. The reaction mixture was warmed to room temperature, saturated aqueous NaHCO ₃ was added, the mixture (3 ×) and extracted with DCM, the combined organic layers were dried over Na ₂ SO ₄ dried and evaporated. The residue was applied as a DCM solution to a 120 g EtOAc EtOAc EtOAc EtOAc. The product-containing fractions were combined and evaporated to give the title compound as an orange foam. _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.08 (s, 1H), 5.30 (s, br, 1H), 5.20 (s, 1H), 4.69 (s, 2H), 3.44-3.34 (m, 2H), 3.40 (s, 6H), 3.22-3.15 (m, 2H), 3.24 (s, 2H), 2.71-2.64 (m, 2H), 2.58-2.50 (m, 2H), 2.31 (s, 3H), 1.98-1.82 (m, 2H). (UPLC-MS 6) t _R 0.33; ESI-MS 335.3 [M+H] ⁺ .

Intermediate 82 : 2-((2-Aminoethyl)(methyl)amino)acetate dihydrochloride.

Ethyl 2-((2-((t-butoxycarbonyl))amino)ethyl)(methyl)amino)acetate (intermediate 83, 3.05 g, 11.13 mmol) in THF Concentrated hydrochloric acid (10 mL) was added to a solution of 20 mL) and EtOH (100 mL). After stirring at room temperature for 1 h, the reaction mixture was evaporated, EtOAc (EtOAc) The cooled reaction mixture was evaporated to give the title compound as a pale yellow glass. ^{1 H NMR (400MHz, DMSO- d} 6) δ 8.58 (s, br, 3H), 4.19 (q, 2H), 4.26-4.15 (m, 2H), 3.44 (s, br, 2H), 3.21 (s, Br, 2H), 2.88 (s, 3H), 1.21 (t, 3H).

Intermediate 83 : ethyl 2-((2-((t-butoxycarbonyl))amino)ethyl)(methyl)amino)acetate.

Add ethyl bromoacetate to a mixture of (2-(methylamino)ethyl)carbamic acid tert-butyl ester (2.0 g, 11.48 mmol), triethylamine (4.81 mL) and THF (24 mL). (1.27 mL, 11.48 mmol). After the reaction was stirred at room temperature for 24h the mixture was partitioned between saturated aqueous NaHCO ₃ and DCM, extracted 2 × with DCM, the organic layer was dried over Na ₂ SO ₄ and evaporated to give a clear pale yellow oil of the title compound. _{^{1 H NMR (400MHz, CDCl 3}} ) δ 5.20 (s, br, 1H), 4.18 (q, 2H), 3.24 (s, 2H), 3.22-3.16 (m, 2H), 2.65-2.61 (m, 2H) , 2.38 (s, 3H), 1.42 (s, 9H), 1.24 (t, 3H).

Intermediate 84 : N ⁴ -(2-methoxyethyl)-5-(trifluoromethyl)pyridine-2,4-diamine.

To N ² -(4-methoxybenzyl)-N4-(2-methoxyethyl)-5-(trifluoromethyl)pyridine-2,4-diamine (intermediate product) at room temperature 85,280 mg, 0.788 mmol) Concentrated hydrochloric acid (1.5 mL) was added. After stirring for 4.5h the reaction mixture was neutralized with saturated aqueous NaHCO _3, extracted with DCM (4 ×), dried over Na ₂ SO ₄ and evaporated. The residue was applied as a DCM solution to a 12 g EtOAc EtOAc EtOAc EtOAc. The title compound was obtained as a white solid. _{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.02 (s, 1H), 5.68 (s, 1H), 4.95 (s, br, 1H), 4.50 (s, br, 2H), 3.62-3.57 (m, 2H) , 3.38 (s, 3H), 3.30-3.25 (m, 2H). (UPLC-MS 6) t _R 0.44; ESI-MS 236.1 [M+H] ⁺ .

Intermediate 85 : N ² -(4-methoxybenzyl)-N ⁴ -(2-methoxyethyl)-5-(trifluoromethyl)pyridine-2,4-diamine.

Add 4-methoxybenzylamine to 2-chloro-N-(2-methoxyethyl)-5-(trifluoromethyl)pyridin-4-amine (intermediate 86, 300 mg, 1.18 mmol) (485 mg, 3.53 mmol) and heated in a septum sealed vial at MW for 3 h at 60 °C. Subsequent heating was continued at 80 ° C for 18 h, the reaction mixture was cooled, additional 4-methoxybenzylamine (162 mg, 1.18 mmol) was added and heating was continued at 100 ° C for 22 h. The reaction mixture was heated at 120 ℃ 9h, cooled, partitioned between DCM and saturated aqueous NaHCO _3, and extracted 3 × with DCM, the organic layer was dried over Na ₂ SO ₄ and evaporated. The residue was applied as a DCM solution to a EtOAc (EtOAc) EtOAc. The title compound was obtained as a white solid. (UPLC-MS 6) t _R 0.77; ESI-MS 356.3 [M+H] ⁺ .

Intermediate 86 : 2-chloro-N-(2-methoxyethyl)-5-(trifluoromethyl)pyridin-4-amine.

2-methoxyethylamine (1.0 mL, 11.57 mmol) was added dropwise to 2,4-dichloro-5-(trifluoromethyl)pyridine (500 mg, 2.32 mmol) at EtOAc. The mixture was stirred for 2.5 h. The reaction mixture was partitioned between saturated aqueous NaHCO ₃ and DCM, and the organic layer was dried over Na ₂ SO ₄ and evaporated. The residue was applied as a DCM solution to a EtOAc (EtOAc) EtOAc. The title compound was obtained predominantly as a regioisomer and was isolated before 4-chloro-N-(2-methoxyethyl)-5-(trifluoromethyl)pyridin-2-amine (ratio 2:1) . The title compound was obtained as a yellow-white solid. (UPLC-MS 6) t _R 0.96; ESI-MS 255.1 [M+H] ⁺ .

Intermediate 87 : 6-Amino-4-(4-((dimethylamino)methyl)-4-hydroxypiperidin-1-yl)nicotinonitrile.

Heating of racemic 4-[(dimethylamino)methyl]-4-piperidinol (1.0 g, 4.33 mmol), 6-amino group in a septum sealed reaction vessel under argon at 80 °C A mixture of 4-fluoronicotinonitrile (intermediate 21, 593 mg, 4.33 mmol) and triethylamine (3.62 mL, 26.00 mmol). The reaction mixture was cooled, EtOAc (5 mL) was evaporated and evaporated. The reaction mixture was then evaporated, partitioned between DCM and aqueous NaHCO _3, with the DCM 10% MeOH containing extracted with 5 ×, the combined DCM layers dried over MgSO ₄ and evaporated. The residue was washed with Et ₂ O (20mL) and DCM (1mL) triturated to afford a beige solid of the title compound. _{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.15 (s, 1H), 5.82 (s, 1H), 4.70 (s, br, 2H), 3.65-3.58 (m, 2H), 3.27-3.20 (m, 2H) , 2.38 (s, 6H), 2.26 (s, 2H), 1.68-1.62 (m, 4H). (UPLC-MS 6) t _R 0.25; ESI-MS 276.3 [M+H] ⁺ .

Intermediate 88 : 6-Amino-4-((2-hydroxy-2-methylpropyl)aminonicotinonitrile.

Heating 1-amino-2-methylethanol (1.0 g, 11.22 mmol), 6-amino-4-fluoronicotinonitrile (intermediate product 21) in a septum sealed reaction vessel under argon at 60 °C. A mixture of 1.54 g, 11.22 mmol) and triethylamine (6.26 mL, 44.9 mmol). The reaction mixture was cooled, evaporated, partitioned between aqueous NaHCO ₃ and n-butanol, n-butanol and extracted with 3 ×, of the combined organic layers were dried over Na ₂ SO ₄ and evaporated. The residue was washed with Et ₂ O (100mL) and DCM (5mL) triturated to afford a beige solid of the title compound. (UPLC-MS 6) t _R 0.35; ESI-MS 207.2 [M+H] ⁺ .

The following intermediates have been synthesized in a similar manner as intermediates 88:

Intermediate 89 : 6-Amino-4-(2,2,2-trifluoroethoxy)nicotinonitrile.

To a solution of 2,2,2-trifluoroethanol (0.53 mL, 7.29 mmol) in THF (40 mL) EtOAc (EtOAc) After 2 min a solution of 6-amino-4-fluoronicotinonitrile (intermediate 21, 1.0 g, 7.29 mmol) in THF (10 mL). The reaction mixture was partitioned between NH ₄ Cl saturated solution and EtOAc, and extracted with EtOAc (2 ×), the organic layers were combined and dried over Na ₂ SO ₄ and evaporated. The residue was washed with Et ₂ O and triturated in heptane to afford the title compound. (UPLC-MS 7) t _R 0.70; ESI-MS 218.1 [M+H] ⁺ .

Intermediate 90 : ( S )-5-Chloro-4-((1-methoxypropan-2-yl)oxy)pyrimidin-2-amine.

Heating ( S )-2,5-dichloro-4-((1-methoxypropan-2-yl)oxy)pyrimidine (intermediate product 91, 1.26 g, 4.15 mmol) and 4-A at 50 °C A mixture of oxybenzylamine (0.65 mL, 4.97 mmol) in EtOAc m. The reaction mixture was partitioned between 1M HCl solution and DCM, (2 ×) and extracted with DCM, the combined DCM layers were washed with water, dried over Na ₂ SO ₄ and evaporated. Trifluoroacetic acid (3.93 mL, 51.0 mmol) was added to the residue, and the reaction mixture was allowed to stand at room temperature for 18 h, heated at 70 ° C for 5 h, allowed to stand at room temperature for 3 days, and heated at 80 ° C for 2 days. . The reaction mixture was evaporated and purified by EtOAcqqqqqq (UPLC-MS 7) t _R 0.74; ESI-MS 218.1 and 220.1 [M+H] ⁺ .

Intermediate 91 : ( S )-2,5-Dichloro-4-((1-methoxypropan-2-yl)oxy)pyrimidine

To a mixture of 2,4,5-trichloropyrimidine (0.63 mL, 5.34 mmol) and NaH (60% dispersion in mineral oil, 0.24 g, 5.88 mmol) in THF (10 mL) S )-1-methoxypropan-2-ol (0.58 mL, 5.88 mmol). After 30 minutes the reaction mixture was partitioned between water and DCM, the organic layer was washed with water, dried over Na ₂ SO ₄ and evaporated to give a yellow-brown oil of the title compound. (UPLC-MS 7) t _R 1.01; ESI-MS 237.0 and 238.9 [M+H] ⁺ .

The following intermediates have been synthesized in the same manner as intermediate 90:

Intermediate 92 : ( R )-5-chloro-4-((1-methoxypropan-2-yl)oxy)pyrimidin-2-amine.

^{1 H NMR (400MHz, DMSO- d} 6) δ 8.00 (s, 1H), 6.71 (s, br, 2H), 5.44-5.32 (m, 1H), 3.53-3.42 (m, 2H), 3.27 (s, 3H), 1.23 (d, 3H). (UPLC-MS 7) t _R 0.74; ESI-MS 218.1 and 220.1 [M+H] ⁺ .

The following intermediates have been synthesized in a similar manner as intermediates 91:

Intermediate 93 : ( R )-2,5-Dichloro-4-((1-methoxypropan-2-yl)oxy)pyrimidine

(UPLC-MS 7) t _R 1.02; ESI-MS 237.1 and 239.0 [M+H] ⁺ .

Instance

Example 1 : 7-Methylmercapto-N-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

At room temperature, 7- (dimethoxymethyl) - N - (5- (trifluoromethyl) pyridin-2-yl) -3,4-dihydro-1,8 A solution of the pyridine-1(2H)-carbamide (intermediate 1, 64.5 mg, 0.163 mmol) in EtOAc (EtOAc) After the addition, additional THF (0.2 mL) was added and the mixture was stirred at room temperature for 2.5 h. Next, NMP (0.1 mL) and TFA (0.10 mL, 1.3 mmol) were sequentially added, and the resulting solution was stirred for 2 h. The reaction was then added by saturated NaHCO ₃ solution (gas evolution) quenched, and (2 ×) and extracted with EtOAc. Washed with brine the combined organic layers were dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by EtOAc EtOAc (EtOAc:EtOAc: ^{1 H NMR (400MHz, DMSO- d} 6) δ 13.78 (s, 1H), 9.97 (s, 1H), 8.76-8.70 (m, 1H), 8.28 (d, 1H), 8.20 (dd, 1H), 7.94 (d, 1H), 7.68 (d, 1H), 4.05-3.97 (m, 2H), 2.96 (t, 2H), 2.02-1.91 (m, 2H). (UPLC-MS 1) t _R 1.19 min; ESI-MS 351.0 [M+H] ⁺

Example 2 : N -(4,5-Dichloropyridin-2-yl)-7-methylindolyl-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

To a solution of phosgene (20% solution in toluene, 0.186 mL, 0.353 mmol) in THF (2 mL) To the resulting white suspension, 7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8- was added dropwise. A solution of pyridine (intermediate 4, 70 mg, 0.336 mmol) in THF (2 mL). The resulting yellow suspension was stirred at room temperature for 1 h. 4,5-Dichloropyridin-2-amine (65.7 mg, 0.403 mmol) in THF (1 mL). The reaction mixture was filtered with EtOAc EtOAc (EtOAc)EtOAc. The residue was taken up in EtOAc (1 mL)EtOAcEtOAc The mixture was stirred at rt for 2h, diluted with DCM and washed with saturated aqueous NaHCO ₃ was quenched. The organic layer was collected and the aqueous layer was extracted with DCM. The dried Na ₂ SO ₄ the combined organic layers were dried over anhydrous and concentrated under reduced pressure. The crude product was dissolved in acetonitrile / NMP / TFA, filtered on a syringe filter (0.2 m), and purified by preparative reverse phase LC-MS (RP1). The cleansing solution was combined and lyophilized to give the title compound as a white solid. ^{1 H NMR (400MHz, DMSO- d} 6) δ 13.73 (s, 1H), 9.94 (s, 1H), 8.56 (s, 1H), 8.34 (s, 1H), 7.94 (d, 1H), 7.68 (d , 1H), 4.03-3.95 (m, 2H), 2.95 (t, 2H), 2.01-1.90 (m, 2H). (UPLC-MS 1) Preparation of samples in _{MeOH; t R 1.15,1.28min; ESI-MS} 383.1 [M + MeOH + H] +, 351.0 [M + H] +.

Example 3 : N- (5-Cyanopyridin-2-yl)-7-methylindolyl-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

N- (5-Cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- A solution of the pyridine-1(2H)-carbamide (intermediate 2, 150 mg, 0.424 mmol) in THF (3 mL)EtOAc. The reaction mixture was stirred at room temperature for 15 min. The reaction by the addition of saturated NaHCO ₃ solution (gas evolution) and quenched (3 ×) and extracted with DCM. Washed with brine the organic layers were combined, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by EtOAc EtOAc (EtOAc:EtOAc: ^{1 H NMR (400MHz, DMSO- d} 6) δ 13.86 (s, 1H), 9.96 (d, 1H), 8.80 (dd, 1H), 8.27 (dd, 1H), 8.22 (dd, 1H), 7.94 (d , 1H), 7.68 (d, 1H), 4.30-3.96 (m, 2H), 2.95 (t, 2H), 2.03-1.90 (m, 2H). (UPLC-MS 1) t _R 0.98 min; ESI-MS 308.1 [M+H] ⁺ .

The following example has been synthesized into instance 2 in a similar manner:

The following example has been synthesized into instance 3 in a similar manner:

Example 8 : N -(5-Cyanopyrimidin-2-yl)-7-methylindolyl-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

It was repurified by reverse phase chromatography (4.3 g C18 cartridge, water containing 0.1% TFA / acetonitrile 95:5 to 5:95). ^{1 H NMR (400MHz, DMSO- d} 6) δ 14.00 (s, 1H), 9.92 (s, 1H), 9.13 (s, 2H), 7.95 (d, 1H), 7.68 (d, 1H), 4.00-3.91 (m, 2H), 2.95 (t, 2H), 2.00-1.88 (m, 2H). (UPLC-MS 1) t _R 0.76; ESI-MS 309.1 [M+H] ⁺ .

Example 9 : 6-Methylmercapto- N- (5-methylpyridin-2-yl)-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-carboxamide .

6-Bromo- N- (5-methylpyridin-2-yl)-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-carbenamide (intermediate 1B) , 110 mg, 0.284 mmol) was dissolved in THF (3 mL). The solution was purged with argon and cooled to -78 °C. Next, n-butyllithium (1.4 M in hexanes, 0.506 mL, 0.709 mmol) was added dropwise, and the mixture was stirred at -78 ° C for 1 h before the addition of DMF (200 μL, 2.58 mmol). The reaction mixture was stirred at -78 °C for 1 h and then slowly warmed to room temperature. The reaction mixture was quenched with saturated aqueous NH ₄ Cl and diluted with EtOAc. The organic layer was separated, washed with water, dried over Na ₂ CH ₄ The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptane / EtOAc 80:20 to 0:100) and preparative supercritical fluid chromatography (SFC 1, Hilic column). The title compound is obtained as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.83 (s, 1H) 9.89 (s, 1H) 8.18 (d, 1H) 7.97 (d, 1H) 7.73 (d, 1H) 7.64 (dd, 1H) 7.60 ( d, 1H) 4.40-4.44 (m, 2H) 4.12-4.16 (m, 2H) 2.26 (s, 3H). (UPLC-MS 2) t _R 3.01; ESI-MS 299.1 [M+H] ⁺ .

The following example has been synthesized into instance 3 in a similar manner:

Example 12 : N -(5-Cyanopyrazin-2-yl)-7-methylindolyl-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

N- (5-Cyanopyrazin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- The pyridine-1(2H)-carbamide (intermediate 2A, 32 mg, EtOAc) eluted elute The reaction mixture was concentrated under vacuum to dryness. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, DCM/(DCM/MeOH 9:1) 100:0 to 0:100). The title compound was obtained as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 14.12 (s, 1H) 9.95 (s, 1H) 9.46 (d, 1H) 8.9 (d, 1H) 7.78 (d, 1H) 7.73 (d, 1H) 3.99- 4.05 (m, 2H) 2.96 (t, 2H) 1.92-2.01 (m, 2H). (UPLC-MS 1) t _R 0.97; ESI-MS 309.0 [M+H] ⁺ .

Example 13 : N- (5-Cyano-4-methoxypyridin-2-yl)-7-methylindolyl-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

N- (5-Cyano-4-methoxypyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- The pyridine-1(2H)-carbamide (intermediate 2B, 36 mg, 0.094 mmol) was taken from EtOAc (EtOAc m. The solution was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum. The residue was triturated with EtOAc (EtOAc) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.84 (s, 1H), 9.94 (s, 1H) 8.60 (s, 1H) 7.91 - 7.98 (m, 2H) 7.68 (d, 1H) 3.97-4.03 (m, 5H) 2.95 (t, 2H) 1.91-2.00 (m, 2H). (UPLC-MS 1) t _R 1.01; ESI-MS 338.4 [M+H] ⁺ .

The following example has been synthesized into Example 9 in a similar manner.

Example 14 : 6-Mercapto- N- (5-(trifluoromethyl)pyridin-2-yl)-2H-pyrido[3,2-b][1,4]oxazine-4 (3H) - formamide.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.32 (s, 1H) 9.91 (s, 1H) 8.74-8.77 (m, 1H) 8.20-8.30 (m, 2H) 7.76 (d, 1H) 7.63 (d, 1H) 4.42-4.47 (m, 1H) 4.13-4.19 (m, 2H).

(UPLC-MS 1) t _R 1.11; ESI-MS 352.7 [M+H] ⁺ .

The following example has been synthesized into instance 3 in a similar manner:

Example 15 : 6-Fluoro-7-methylindenyl- N- (5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.31 (s, 1H) 10.09 (s, 1H) 8.72 - 8.75 (m, 1H) 8.16 - 8.29 (m, 2H) 7.96 (d, 1H) 3.96-4.01 ( m, 2H) 2.97 (t, 2H) 1.90-1.99 (m, 2H). (UPLC-MS 1) t _R 1.14; ESI-MS 369.5 [M+H] ⁺ .

Example 16 : N- (5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)-7-carboxyl-3,4-dihydro-1 ,8- Pyridin-1(2H)-formamide.

N- (5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)-7-(dimethoxymethyl)-3,4-di Hydrogen-1,8- The pyridine-1(2H)-carboxamide (intermediate 2E, 25 mg, 0.045 mmol) was taken eluted with EtOAc (EtOAc EtOAc EtOAc The reaction by the addition of saturated aqueous NaHCO ₃ was quenched, and the (3 ×) and extracted with DCM. The dried Na ₂ SO ₄ the combined organic layers were dried over anhydrous, filtered and concentrated under reduced pressure. The crude material was wet milled in a hot EtOAc/heptane 10:1 mixture, then the suspension was centrifuged, the liquid phase was removed, some heptane was added and it was again centrifuged. The liquid phase was removed and the solid was dried under high vacuum to give the title compound as a colourless powder. ^{1 H NMR (400MHz, DMSO- d} 6) δ 13.63 (s, 1H) 9.90 (s, 1H) 9.85 (s, 1H) 9.25 (d, 1H) 8.50 (s, 1H) 7.92 (d, 1H) 7.85 ( Dd,1H)7.76-7.83(m,1H)7.65(d,1H)7.34-7.42(m,1H)3.96-4.02(m,2H)3.51(s,1H)2.94(t,2H)1.89-1.98( m, 2H) 1.18 (d, 6H). (UPLC-MS 1) t _R 1.16; ESI-MS 515.0 [M+H] ⁺ .

Example 17 : N -(4,5-dicyanopyridin-2-yl)-7-methylindolyl-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

N- (4,5-dicyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- The pyridine-1(2H)-carbamide (intermediate 2F, 15 mg, EtOAc) was dissolved in EtOAc (EtOAc) The reaction mixture was stirred at rt for 1.5h, diluted in EtOAc and washed with saturated aqueous NaHCO ₃ (2 ×) and brine. The combined organic layers were dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue was triturated with EtOAc (EtOAc)EtOAc. ^{1 H NMR (400MHz, DMSO- d} 6) δ 14.20 (s, 1H), 9.95 (s, 1H), 9.08 (d, 1H), 8.56 (d, 1H), 7.97 (d, 1H), 7.72 (d , 1H), 4.05-3.97 (m, 2H), 2.96 (t, 2H), 2.02-1.91 (m, 2H). (UPLC-MS 1) t _R 1.04; ESI-MS 333.1 [M+H] ⁺ .

Example 18: 7-acyl-6- (hydroxymethyl) - N - (5- (trifluoromethyl) pyridin-2-yl) -3,4-dihydro-1,8 Pyridin-1(2H)-formamide.

7- (dimethoxy-methyl) -6- (hydroxymethyl) - N - (5- (trifluoromethyl) pyridin-2-yl) -3,4-dihydro-1,8 A solution of the pyridine-1(2H)-carbamide (Intermediate 14, 18 mg, 0.042 mmol) in EtOAc EtOAc (EtOAc) The reaction mixture by the addition of saturated NaHCO ₃ solution (gas evolution) quenched, (3 ×) and extracted with DCM. The dried Na ₂ SO ₄ the combined organic layers were dried over anhydrous, filtered and concentrated under reduced pressure. The crude material was triturated with EtOAc / EtOAc (EtOAc) ¹ H NMR (400 MHz, DMSO- d ₆ ) indicates the title compound (small amount) at a ratio of about 1:2.1 with the corresponding 5-membered lactol (mainly) as determined by integrating the signals at 13.87 ppm and 13.38 ppm. Partially overlapping the mixture. δ Main: 13.38 (s, 1H), 8.69-8.66 (m, 1H), 8.28 (d, 1H), 8.19 (td, 1H), 7.73 (s, 1H), 7.02 (d, 1H), 6.19 (dd , 1H), 5.09-5.01 (m, 1H), 4.94-4.87 (m, 1H), 4.06-3.89 (m, 2H), 2.89 (t, 2H), 2.00-1.88 (m, 2H); small amount: 13.87 (s, 1H), 10.11 (s, 1H), 8.75-8.72 (m, 1H), 8.28 (d, 1H), 8.19 (td, 1H), 8.03 (s, 1H), 5.50 (t, 1H), 4.94-4.87 (m, 2H), 4.06-3.89 (m, 2H), 2.98 (t, 2H), 2.00-1.88 (m, 2H). (UPLC-MS 1) t _R 0.97, 1.05; ESI-MS 381.1, 381.1 [M+H] ⁺ .

The following example has been synthesized into instance 18 in a similar manner:

Example 19 : N- (5-Cyano-4-ethoxypyridin-2-yl)-7-methylindolyl-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 13.81 (s, 1H) 9.94 (s, 1H) 8.58 (s, 1H) 7.89-7.98 (m, 2H) 7.67 (d, 1H) 4.29 (q, 2H) 3.95-4.03 (m, 2H) 2.95 (t, 2H) 1.91-2.00 (m, 2H) 1.42 (t, 3H).

(UPLC-MS 1) t _R 1.08; ESI-MS 352.0 [M+H] ⁺ .

The following example has been synthesized into instance 3 in a similar manner:

The following example has been synthesized into instance 18 in a similar manner:

Example 27 : N- (5-Cyanopyridin-2-yl)-7-methylindolyl-6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

¹ H NMR (400 MHz, DMSO-d ₆ ) indicates the title compound (small amount) at a ratio of about 1:3.1 with the corresponding 5-membered lactol (mainly) as determined by integrating the signals at 13.93 ppm and 13.48 ppm. Partially overlapping the mixture. Mainly: δ 13.48 (s, 1H), 8.77-8.74 (m, 1H), 8.31-8.20 (m, 2H), 7.73 (s, 1H), 7.05 (d, 1H), 6.19 (d, 1H), 5.09 -5.01 (m, 1H), 4.95-4.87 (m, 1H), 4.06-3.88 (m, 2H), 2.88 (t, 2H), 2.02-1.86 (m, 2H); small amount: 13.93 (s, 1H) , 10.09 (s, 1H), 8.82-8.78 (m, 1H), 8.31-8.20 (m, 2H), 8.06-8.01 (m, 1H), 5.51 (t, 1H), 4.95-4.87 (m, 2H) , 4.06-3.88 (m, 2H), 2.98 (t, 2H), 2.02-1.86 (m, 2H). (UPLC-MS 3) t _R 0.81, 0.86; ESI-MS 338.1, 338.1 [M+H] ⁺ .

Example 28 : N- (5-Cyano-4-(2-methyl-2,8-diazaspiro[4.5]dec-8-yl)pyridin-2-yl)-7-methylindolyl-3, 4-dihydro-1,8- Pyridin-1(2H)-formamide.

N- (4-chloro-5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- under argon Pyridin-1(2H)-formamide (intermediate 2J, 40 mg, 0.103 mmol) and 2-methyl-2,8-diazaspiro[4.5]decane (31.8 mg, 0.206 mmol) were dissolved in DMF (1 mL) )in. The mixture was stirred at 100 ° C for 2 h. KF (12.0 mg, 0.206 mmol) and K ₂ CO ₃ (42.8 mg, 0.309 mmol) were added and the mixture was stirred at 100 ° C for 3 h. The reaction mixture was then cooled to room temperature, treated with cone. EtOAc (EtOAc) and stirred 30 min. The reaction mixture was diluted in EtOAc and washed with saturated aqueous NaHCO ₃ (2 ×) and brine. The dried organic layer was ₂ SO ₄ Na, filtered, and concentrated in vacuo. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptane / EtOAc 100:0 to 0:100) and supercritical fluid chromatography (SFC 1, DEAP column). The title compound is obtained as a solid. ¹ H NMR (400 MHz, chloroformamide - d ) δ 13.65 (s, 1H) 10.13 (s, 1H) 8.30 (s, 1H) 7.79 (s, 1H) 7.61 - 7.71 (m, 2H) 4.07 - 4.14 (m) , 2H) 3.42-3.58 (m, 4H) 2.97 (t, 2H) 2.60 (t, 2H) 2.35 (s, 3H) 2.03-2.11 (m, 2H) 1.67-1.84 (m, 8H). (UPLC-MS 3) t _R 0.76; ESI-MS 460.2 [M+H] ⁺ .

The following example has been synthesized into instance 3 in a similar manner:

Example 37 : N- (5-Cyanopyridin-2-yl)-6-(difluoromethyl)-7-methylindolyl-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

To N- (5-cyanopyridin-2-yl)-6-(difluoromethyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- Piperidin -1 (2H) - A Amides (Intermediate 35,11mg, 0.027mmol) in THF of (0.5mL) and H ₂ O (0.1mL) was added concentrated HCl (0.017mL), stirred at room temperature The reaction mixture was stirred for 8 h then concentrated EtOAc (EtOAc &lt And the reaction mixture was poured (3 ×) and extracted with DCM into a saturated aqueous solution of NaHCO _3. The organic phase is then dried over Na ₂ SO _4, filtered and evaporated to give the compound of the title as a colorless solid. ^{1 H NMR (400MHz, DMSO- d} 6) δ 13.68 (s, 1H), 10.03 (s, 1H), 8.82 (dd, 1H), 8.29 (dd, 1H), 8.23 (dd, 1H), 8.17 (s , 1H), 7.57 (t, 1H), 4.05-3.99 (m, 2H), 3.01 (t, 2H), 2.02-1.93 (m, 2H). (UPLC-MS 3) t _R 1.12; ESI-MS 358.1 [M+H] ⁺ .

The following example has been synthesized into instance 3 in a similar manner:

Example 38 : N- (5-Cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-7-carboxamido-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

^{1 H NMR (400MHz, DMSO- d} 6) δ13.82 (s, 1H), 9.95 (s, 1H), 8.59 (s, 1H), 7.92-7.97 (m, 2H), 7.68 (d, 1H), 4.30 (t, 2H), 3.97-4.03 (m, 2H), 2.95 (t, 2H), 2.72 (t, 2H), 2.25 (s, 6H), 1.90-2.00 (m, 2H). (UPLC-MS 3) t _R 0.67; ESI-MS 395.2 [M+H] ⁺ .

Example 39 : N- (5-Cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-methylindolyl-6-(hydroxymethyl)-3,4-dihydro -1,8- Pyridin-1(2H)-formamide.

Solution of 6 - (((tert-butyl dimethyl silicone alkyl) oxy) methyl) - N - (5- cyano-4- (2-methoxyethoxy) pyridin-2-yl) - 7-(dimethoxymethyl)-3,4-dihydro-1,8- Piperidin -1 (2H) - A Amides (Intermediate 37,98mg, 0.171mmol) in THF (1mL) and H ₂ O (1mL) was added in the concentrated HCl 0.5mL), the reaction mixture was stirred at room temperature for 6h . The reaction mixture was poured into saturated aqueous NaHCO _3, and the (2 ×) and extracted with DCM. The organic phase is then dried over Na ₂ SO _4, filtered and evaporated. The title compound was obtained as a colorless powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) indicates the title compound (small amount) at a ratio of about 1:2.8 with the corresponding 5-membered lactol (mainly) as determined by integrating the signals at 13.90 ppm and 13.42 ppm. Partially overlapping the mixture. δ main: 13.42 (s, 1H), 8.55 (s, 1H), 7.97 (s, 1H), 7.73 (s, 1H), 7.02-7.10 (m, 1 H), 6.14-6.23 (m, 1H), 5.05(dd,1H),4.86-4.94(m,1H)4.29-4.38(m,2H),3.88-4.03(m,2H),3.71-3.77(m,2H),2.88(t,2H),1.86 -2.00 (m, 2H). A small amount: 13.90 (s, 1H), 10.07 (s, 1H), 8.60 (s, 1H), 8.04 (s, 1H), 7.95 (s, 1H), 5.51 (t, 1H), 4.86-4.94 (m, 2H), 4.29-4.38 (m, 2H), 3.88-4.03 (m, 2H), 3.71-3.77 (m, 2H), 2.98 (t, 2H), 1.86-2.00 (m, 2H). (UPLC-MS 3) t _R 0.87, 0.91; ESI-MS 412.2, 412.2 [M+H] ⁺ .

The following example has been synthesized into instance 3 in a similar manner:

Example 40 : (racemic) N- (5-Cyano-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-7-methylindol-3,4-dihydro-1 ,8- Pyridin-1(2H)-formamide.

^{1 H NMR (400MHz, DMSO- d} 6) δ 13.83 (s, 1H), 9.95 (s, 1H), 8.61 (s, 1H), 7.90-7.97 (m, 2H), 7.68 (d, 1H), 5.24 -5.31 (m, 1H), 3.97-4.03 (m, 2H), 3.85-3.95 (m, 3H), 3.75-3.83 (m, 1H), 2.95 (t, 2H), 2.29-2.40 (m, 1H) , 2.02-2.12 (m, 1H), 1.90-2.00 (m, 2H).

(UPLC-MS 3) t _R 1.02; ESI-MS 394.1 [M+H] ⁺ .

The following example has been synthesized into instance 39 in a similar manner:

Example 41 : N- (5-Cyano-4-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-2-yl)-7-methylindolyl-6-(hydroxymethyl)- 3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

(UPLC-MS 3) t _R 0.83, 0.87; ESI-MS 451.2, 451.2 [M+H] ⁺ .

The following example has been synthesized into instance 3 in a similar manner:

Example 45 : N- (5-Cyano-4-(2-methyl-2,8-diazaspiro[4.5]dec-8-yl)pyridin-2-yl)-7-carboxamido-6- (hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

To N- (5-Cyano-4-(2,8-diazaspiro[4.5]dec-8-yl)pyridin-2-yl)-7-methylindol-6-(hydroxymethyl)-3 ,4-dihydro-1,8- Addition of formaldehyde (37% in H ₂ O, 0.035 mL, 0.463 mmol) and AcOH (yield of hexane-1 (2H)-carbamide ( Intermediate 44, 22 mg, 0.046 mmol) in DCM (0.5 mL) 2.65 μL, 0.046 mmol). The reaction mixture was stirred at rt for 15 min then EtOAc EtOAc EtOAc &lt The reaction mixture was poured and the (2 ×) and extracted with DCM into a saturated aqueous solution of NaHCO _3. The organic phase is then dried over Na ₂ SO _4, filtered and evaporated. The crude material was purified by normal phase chromatography (4 g of silica gel cartridge, DCM / MeOH 9/1 + 1% Et ₃ N) 100:0 to 0:100 to give the title compound as colorless powder. . (UPLC-MS 3) t _R 0.65; ESI-MS 490.2 [M+H] ⁺ .

The following example has been synthesized into instance 39 in a similar manner:

Example 52: 2- (8 - ((5-cyano-pyridin-2-yl) carbamoyl acyl) -2-acyl-5,6,7,8-tetrahydro-1,8 Pyridin-3-yl)acetic acid.

To 2-(8-((5-cyanopyridin-2-yl)aminemethanyl)-2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8- Mixture of 3-yl) acetic acid tert-butyl ester (Intermediate 48,33mg, 0.071mmol) in THF (1mL) and H ₂ O (1mL) was added concentrated HCl (0.5mL). The suspension was stirred at room temperature for 2 days, then concentrated HCl (0.5 mL) was added and the mixture was stirred at room temperature for 2 days. Concentrated HCl (0.5 mL) was then added and the reaction mixture was stirred 1 h. The reaction mixture was poured and the (5 ×) and extracted with DCM into a saturated aqueous solution of NaHCO _3. The aqueous phase was acidified with cone. HCl and extracted with DCM (3x). All aqueous and organic phases were combined and evaporated. The residue was subjected to reverse phase chromatography (13 g C18 cartridge, water containing 0.1% TFA / acetonitrile 90:10 to 0:100). The product-containing fractions were lyophilized to give the title compound as a colorless powder. ^{1 H NMR (400MHz, DMSO- d} 6) δ 13.92 (s, 1H), 12.52 (s, 1H), 10.04 (s, 1H), 8.82-8.78 (m, 1H), 8.29-8.20 (m, 2H) , 7.80 (s, 1H), 4.04-3.95 (m, 4H), 2.93 (t, 2H), 2.01-1.92 (m, 2H). (UPLC-MS 3) t _R 0.86; ESI-MS 366.2 [M+H] ⁺ .

Example 53 : N- (5-Cyano-4-((tetrahydro-2H-piperidin-4-yl)oxy)pyridin-2-yl)-7-methylindolyl-6-(hydroxymethyl) -3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

6-(((Tertiary butyl dimethyl decyl) oxy)methyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- under argon Pyridin-1(2H)-formate (intermediate 38, 40 mg, 0.085 mmol) and 6-amino-4-((tetrahydro-2H-piperidin-4-yl)oxy)nicotinonitrile (middle Product 45B, 22.3 mg, 0.102 mmol) was dissolved in THF (1 mL). The resulting solution was cooled to -78.degree. C. and worked slowly with &lt;RTI ID=0.0&gt;&gt; The reaction mixture was stirred at -78 °C for 45 min and then slowly warmed to room temperature. The reaction mixture was poured into saturated aqueous NH ₄ Cl and extracted twice with DCM and the. The organic phase is then dried over Na ₂ SO _4, filtered and evaporated. The crude material was purified by preparative supercritical fluid chromatography (SFC 1, NH2 column). Will contain 6-(((tert-butyldimethylmethylalkyl)oxy)methyl) -N- (5-cyano-4-((tetrahydro-2H-pyran-4-yl)oxy) Pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- The aliquot of the pyridine-1(2H)-carboxamide was concentrated and then dissolved in THF (1 mL) and water (1 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated aqueous NaHCO _3, and (3 ×) and extracted with DCM. The dried organic layer was ₂ SO ₄ Na, filtered, and concentrated in vacuo. The crude material was treated with a small amount of DCM and then the product was precipitated by the addition of heptane. The title compound was obtained as a white solid. (UPLC-MS 3) t _R 0.89, 0.93; ESI-MS 438.2, 438.2 [M+H] ⁺ .

The following example has been synthesized in a similar manner as Example 53:

Example 60 : (racemic) N- (4-(4-chloro-2-hydroxybutoxy)-5-cyanopyridin-2-yl)-7-methylindolyl-6-(hydroxymethyl) -3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

6-(((Tertiary butyl dimethyl decyl) oxy)methyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- under argon Pyridin-1(2H)-formate (intermediate 38, 105 mg, 0.222 mmol) and 6-amino-4-(oxetan-2-ylmethoxy)nicotinonitrile (intermediate product 34A, 54.7 Mg, 0.267 mmol) was dissolved in THF (2 mL). The resulting solution was cooled to -78.degree. C. and worked slowly with &lt;RTI ID=0.0&gt;&gt; The reaction mixture was stirred at -78 °C for 45 min and then slowly warmed to room temperature. The reaction mixture was poured into saturated aqueous NH ₄ Cl, and the extracted twice with DCM. The organic phase is then dried over Na ₂ SO _4, filtered and evaporated. The crude material was purified by preparative supercritical fluid chromatography (SFC 1, NH2 column). Containing 6 - (((tert-butyl dimethyl silicone alkyl) oxy) methyl) - N - (5- cyano-4- (oxetan-2-ylmethoxy) pyridin-2 -yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- The aliquot of the pyridine-1(2H)-carbamide was concentrated, and then dissolved in THF (2 mL) and water (2 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated aqueous NaHCO _3, and extracted 3 × with DCM. The dried organic layer was ₂ SO ₄ Na, filtered, and concentrated in vacuo. The crude material was treated with a small amount of DCM and then the product was precipitated by the addition of heptane. The title compound was obtained as a white solid. (UPLC-MS 3) t _R 0.89, 0.93; ESI-MS 460.2, 460.2 [M+H] ⁺ .

The following example has been synthesized into instance 39 in a similar manner:

Example 61 : N- (5-Cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-methylindol-6-(trifluoromethyl)-3,4-di Hydrogen-1,8- Pyridin-1(2H)-formamide.

(UPLC-MS 3) t _R 0.98, 1.17; ESI-MS 468.2 [M+H ₂ O+H] ⁺ , 450.2 [M+H] ⁺ .

Example 62: N - (5- cyano-4- (2-methoxyethoxy) pyridin-2-yl) -6-cyclopropyl-3,4-dihydro-7-acyl -1 ,8- Pyridin-1(2H)-formamide.

To 6-cyclopropyl-7-(dimethoxymethyl)-3,4-dihydro-1,8- at -78 °C Phenyl-1(2H)-phenyl formate (intermediate 51A, 52 mg, 0.141 mmol) and 6-amino-4-(2-methoxyethoxy)nicotinonitrile (intermediate product 20, 30.0 mg, 0.155) LHMDS (1 M in THF, 0.311 mL, 0.311 mmol) was slowly added to a solution in THF (1 mL). The reaction mixture was stirred at -78 °C for 30 min and then allowed to warm to room temperature. The reaction mixture was poured into saturated aqueous NH ₄ Cl and extracted with DCM twice the line. The organic phase is then dried over Na ₂ SO _4, filtered and concentrated. The residue was subjected to reverse phase chromatography (13g C18 cartridge containing water / acetonitrile 90:10 to 0 0.1% TFA of: 100) to give an off-white powder of the title compound N - (5- cyano-4 -(2-methoxyethoxy)pyridin-2-yl)-6-cyclopropyl-7-(dimethoxymethyl)-3,4-dihydro-1,8- Mixture of pyridine-1(2H)-formamide. This material was dissolved in THF (2mL) and the H ₂ O (2mL), treated with concentrated HCl (1.0mL), the reaction mixture was stirred at room temperature for 1h. The reaction mixture was poured and the (2 ×) and extracted with DCM into a saturated aqueous solution of NaHCO _3. The organic phase was dried over Na ₂ SO _4, filtered and concentrated to give a pale brown powder of the title compound. ^{1 H NMR (400MHz, DMSO- d} 6) δ 13.93 (s, 1H), 10.20 (s, 1H), 8.60 (s, 1H), 7.94 (s, 1H), 7.46 (s, 1H), 4.31-4.37 (m, 2H), 3.93-3.99 (m, 2H), 3.71-3.78 (m, 2H), 3.35 (s, 3H), 2.91-2.99 (m, 1H), 2.89 (t, 2H), 1.87-1.98 (m, 2H), 1.04-1.10 (m, 2H), 0.80-0.86 (m, 2H).

(UPLC-MS 3) t _R 1.21; ESI-MS 422.2 [M+H] ⁺ .

The following example has been synthesized into instance 3 in a similar manner:

Example 65 : (racemic) N- (5-cyano-4-(((1S*,2R*,3S*,4R*)-3-(hydroxymethyl)bicyclo[2.2.1]hept-2 -yl)amino)pyridin-2-yl)-7-methylindolyl-6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

Racemic 6-(((t-butyldimethylmethylalkyl)oxy)methyl) -N- (5-cyano-4-(((1 S *,2 R *,3 S *) , 4 R *)-3-(((Triethyldecyl)oxy)methyl)bicyclo[2.2.1]hept-2-yl)amino)pyridin-2-yl)-7-(dimethyl Oxymethyl)-3,4-dihydro-1,8- The pyridine-1(2H)-carbamide (intermediate 37N, 64 mg, 0.085 mmol) was dissolved in THF (2 mL) and water (1 mL). The reaction mixture was stirred at room temperature for 30 h. The reaction mixture was quenched with saturated aqueous NaHCO ₃ and extracted 3 × with DCM. The dried organic layer was ₂ SO ₄ Na, filtered, and concentrated in vacuo. The residue was wet-milled in a small amount of DCM and then the product was precipitated by the addition of heptane. The title compound was obtained as a white solid. _{(UPLC-MS 3) t R} 0.97,1.01; ESI-MS 477.3,477.3 [M + H] +.

The following example has been synthesized in a similar manner as Example 53:

Example 66 : N- (5-Cyano-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)-7-methylindolyl-6-(hydroxymethyl) -3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

(UPLC-MS 3) t _R 0.83, 0.86; ESI-MS 437.3, 437.3 [M+H] ⁺ .

The following example has been synthesized into instance 39 in a similar manner:

Example 67 : N- (5-Cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-methylindolyl-6-(methoxymethyl)-3,4- Dihydro-1,8- Pyridin-1(2H)-formamide.

^{1 H NMR (400MHz, DMSO- d} 6) δ 13.85 (s, 1H), 10.06 (s, 1H), 8.59 (s, 1H), 7.95-7.92 (m, 2H), 4.79 (s, 2H), 4.37 -4.33 (m, 2H), 4.02-3.97 (m, 2H), 3.77-3.73 (m, 2H), 3.41 (s, 3H), 3.35 (s, 3H), 2.97 (t, 2H), 2.00-1.91 (m, 2H).

(UPLC-MS 3) t _R 1.13; ESI-MS 426.2 [M+H] ⁺ .

The following example has been synthesized into instance 3 in a similar manner:

Example 68 : N- (5-Cyanopyridin-2-yl)-7-methylindol-6-(( N -methylethylamino)methyl)-3,4-dihydro-1,8 - Pyridin-1(2H)-formamide.

^{1 H NMR (400MHz, DMSO- d} 6) δ 13.91 (s, 0.75H), 13.89 (s, 0.25H), 10.12 (s, 0.75H), 10.09 (s, 0.25H), 8.85-8.78 (m, 1H), 8.31-8.19 (m, 2H), 7.58 (s, 0.75H), 7.55 (s, 0.25H), 4.95 (s, 0.5H), 4.87 (s, 1.5H), 4.04-3.94 (m, 2H), 3.02 - 2.91 (m, 4.25H), 2.83 (s, 0.75H), 2.12 (s, 2.25H), 2.00-1.89 (m, 2.75H). A 3:1 mixture of rotamers.

(UPLC-MS 3) t _R 0.91; ESI-MS 393.2 [M+H] ⁺ .

The following example has been synthesized into instance 39 in a similar manner:

Example 69 :( S) - N - ( 5- chloro-4 - ((tetrahydrofuran-3-yl) oxy) pyrimidin-2-yl) -7-acyl-6- (hydroxymethyl) -3, 4-dihydro-1,8- Pyridin-1(2H)-formamide.

(UPLC-MS 3) t _R 0.82, 0.87; ESI-MS 434.2, 434.2 [M+H] ⁺ .

Example 70 :( S) - N - ( 5- cyano-4 - ((tetrahydrofuran-3-yl) oxy) pyrimidin-2-yl) -7-acyl-6- (hydroxymethyl) -3 ,4-dihydro-1,8- Pyridin-1(2H)-formamide.

( S )-6-(((Tert-butyldimethylmethylalkyl)oxy)methyl) -N- (5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyrimidine- 2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- The pyridine-1(2H)-carboxamide (intermediate 37Q, 76 mg, 0.13 mmol) was dissolved in EtOAc (2 mL) The reaction mixture was quenched with saturated aqueous NaHCO _3, and (3 ×) and extracted with DCM. The dried organic layer was ₂ SO ₄ Na, filtered, and concentrated in vacuo. The crude material was purified by preparative supercritical fluid chromatography (SFC, EtOAc). (UPLC-MS 3) t _R 0.77, 0.79; ESI-MS 425.3, 425.3 [M+H] ⁺ .

The following example has been synthesized into instance 39 in a similar manner:

Example 77: N- (5- cyano-4- (2- (dimethylamino) ethoxy) pyridin-2-yl) -6-acyl - ¹³ C- group -2H- pyrido [3, 2-b][1,4]oxazin-4(3H)-carbenamide.

6-(Dimethoxymethyl- ^13C -yl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (intermediate 66) at -78 °C A solution of 20 mg) of diphenyl carbonate (30.4 mg, 0.142 mmol) in EtOAc (1 mL) The reaction was allowed to warm to room temperature for 35 min. The reaction mixture by the addition of aqueous saturated NH ₄ Cl and extracted quenched with DCM (3 ×). The dried Na ₂ SO ₄ the combined organic layers were dried over anhydrous, filtered and concentrated under reduced pressure. The crude material was sequentially subjected to normal phase chromatography (4 g silica gel cartridge, heptane / EtOAc 100:0 to 0:100), reverse phase chromatography (4.3 g C18 cartridge, water containing 0.1% TFA / Purification of acetonitrile from 90:10 to 0:100) to give 6.2 mg of 6-(dimethoxymethyl- ¹³ C-yl)-2H-pyrido[3,2-b][1,4]oxazin-4 Benzyl (3H)-benzoate and 6-formamidine- ¹³ C-yl-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-carboxylic acid phenyl ester of about 1:0.7 mixture. This material was combined with 6-amino-4-(2-(dimethylamino)ethoxy)nicotinonitrile (intermediate 67, 7.8 mg, 0.038 mmol) in THF (0.5 mL). The solution was treated with LHMDS (1M EtOAc, EtOAc. The reaction mixture was quenched with saturated aqueous NaHCO _3, and warmed to room temperature (3 ×) and extracted with DCM. The dried Na ₂ SO ₄ the combined organic layers were dried over anhydrous, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (4g silica gel cartridge, DCM / (DCM / (MeOH 1M NH ₃ containing it) 9/1) 100: 0 to 0: 100) to give N - (5- cyano 4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-(dimethoxymethyl- ¹³ C-yl)-2H-pyrido[3,2-b] [1,4]oxazin-4(3H)-carbenamide. This material was dissolved in THF (1mL) and H ₂ O (0.4mL), treated with concentrated HCl (0.13mL), and stirred for 15min. The reaction mixture was quenched with saturated aqueous NaHCO _3, and (3 ×) and extracted with DCM. The dried Na ₂ SO ₄ the combined organic layers were dried over anhydrous, filtered and concentrated under reduced pressure to give the title compound as a white solid. ¹ H NMR (400 MHz, chloroformamide- d ) δ 13.37 (s, 1H), 10.05 (d, 1H), 8.39 (s, 1H), 7.92 (s, 1H), 7.73 (dd, 1H), 7.43 ( d, 1H), 4.43-4.39 (m, 2H), 4.30 (t, 2H), 4.27-4.22 (m, 2H), 2.85 (t, 2H), 2.38 (s, 6H). (UPLC-MS 3) t _R 0.63, ESI-MS 398.2, [M+H] ⁺ .

The following example has been synthesized into instance 39 in a similar manner:

Example 80 : N- (5-Cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-methylindol-6-(hydroxymethyl)-3,4 -dihydro-1,8- Pyridin-1(2H)-formamide.

6 - (((tert-butyl dimethyl silicone alkyl) oxy) methyl) - N - (5- cyano-4 - ((2-methoxyethyl) amino) pyridin-2 Base)-7-(dimethoxymethyl)-3,4-dihydro-1,8- Piperidin -1 (2H) - A Amides (intermediate 74,3.10g, 5.43mmol) in THF (40 mL) in the (30mL) was treated with H ₂ O, then added dropwise concentrated HCl (10mL), and stirred 40min. The reaction mixture by the addition of saturated NaHCO ₃ solution (gas evolution) quenched, and then (3 ×) and extracted with DCM. Washed with brine the combined organic layers were dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue was taken up in EtOAc (25 mL)EtOAc Subsequently, heptane (25 mL) was added, and the resulting suspension was filtered. The solid was washed with EtOAc (EtOAc) elute ¹ H NMR (400 MHz, DMSO-d ₆ ) indicates the title compound (small amount) at a ratio of about 1:2.5 with the corresponding 5-membered lactol (mainly) as determined by integrating the signals at 13.52 ppm and 13.01 ppm. Partially overlapping the mixture. δ Main: 13.01 (s, 1H), 8.22 (s, 1H), 7.70 (s, 1H), 7.54 (s, 1H), 7.01 (d, 1H), 6.91 (t, 1H), 6.16 (dd, 1H) ), 5.04 (dd, 1H), 4.92-4.85 (m, 1H), 4.01-3.87 (m, 2H), 3.56-3.50 (m, 2H), 3.43-3.35 (m, 2H), 3.30-3.28 (m , 3H), 2.87 (t, 2H), 2.00-1.83 (m, 2H); small amount: 13.52 (s, 1H), 10.05 (s, 1H), 8.26 (s, 1H), 8.02 (s, 1H), 7.52 (s, 1H), 6.96 (t, 1H), 5.47 (t, 1H), 4.92-4.85 (m, 2H), 4.01-3.87 (m, 2H), 3.56-3.50 (m, 2H), 3.43 3.35 (m, 2H), 3.30-3.28 (m, 3H), 2.96 (t, 2H), 2.00-1.83 (m, 2H). (UPLC-MS 3) t _R 0.82, ESI-MS 411.2, [M+H] ⁺ .

Example 81 : (racemic) N-(5-cyano-4-(2-((dimethylamino)methyl)N-morpholinyl)pyridin-2-yl)-7-methylindolyl- 6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

To 6-(((tert-butyldimethylmethylalkyl)oxy)methyl) -N- (5-cyano-4-(2-((dimethylamino)methyl)) at room temperature N-morpholinyl)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- A solution of the pyridine-1(2H)-carbamide (intermediate 76, 168 mg, 0.262 mmol) in THF ( 1.6 mL After stirring IH, saturated aqueous NaHCO ₃ was added, the mixture was extracted with DCM (3 ×), the organic layer was dried over Na ₂ SO ₄ and evaporated. The residue was taken with EtOAc (EtOAc)EtOAc. (UPLC-MS 6) t _R 0.60 and 0.61, ESI-MS 480.3, [M+H] ⁺ .

Example 82 : (racemic) N-(5-cyano-4-(quinuclidin-3-yloxy)pyridin-2-yl)-7-methylindolyl-6-(hydroxymethyl)- 3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

At room temperature rac-6 - (((tert-butyl dimethyl silicone alkyl) oxy) methyl) - N - (5- cyano-4- (quinuclidin-3-yloxy Pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- A solution of the pyridine-1(2H)-carbamide (intermediate 78, 120 mg, 0.193 mmol) in EtOAc (l. 100min After stirring, saturated aqueous NaHCO ₃ was added, the mixture was extracted with DCM (3 ×), the organic layer was dried over Na ₂ SO ₄ and evaporated. The residue was taken with EtOAc (EtOAc)EtOAc. (UPLC-MS 6) t _R 0.58 and 0.62, ESI-MS 463.3, [M+H] ⁺ .

Example 83 : N- (5-Cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-methylindolyl-6-((4-methyl-2-) Oxyloxypiperazin-1-yl)methyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

To N- (5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-(( 4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8- To a solution of pyridine-1(2H)-carbamide (intermediate 80, 470 mg, 0.808 mmol) in THF (3 mL) Was added After stirring 3h at room temperature with saturated aqueous NaHCO _3, the mixture was extracted with DCM (3 ×), the organic layer was dried over Na ₂ SO ₄ and evaporated. The residue was sonicated with EtOAc (6 mL) and pentane (6 mL) and then filtered. The white solid obtained was then taken up in EtOAc (3 mL). Filtration and drying gave the title compound as a white solid. ^{1 H NMR (400MHz, DMSO- d} 6) δ 13.43 (s, 1H), 10.06 (s, 1H), 8.24 (s, 1H), 7.49 (s, 1H), 7.47 (s, 1H), 6.96 (t , br, 1H), 4.86 (s, 2H), 3.96-3.90 (m, 2H), 3.52-3.46 (m, 2H), 3.39-3.33 (m, 2H), 3.30-3.21 (m, 2H), 3.37 (s, 3H), 3.02 (s, 2H), 2.93-2.86 (m, 2H), 2.61-2.56 (m, 2H), 2.21 (s, 3H), 1.95-1.85 (m, 2H). (UPLC-MS 6) t _R 0.70, ESI-MS 507.2, [M+H] ⁺ .

From the above N- (5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-methylindolyl-6-(() by using appropriate relative ionic precipitation 4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8- The following salt was prepared as the free base form of the pyridine-1(2H)-carbamide.

1:1 stoichiometric maleate (mw 640.66), mp (DSC) 181.1 ° C (starting).

1:0.5 stoichiometric tartrate (mw 581.72), mp (DSC) 176.7 ° C (starting).

1:1 stoichiometric tartrate (mw 656.66), mp (DSC) 169.9 ° C (starting).

1:0.5 stoichiometric citrate (mw 602.73), mp (DSC) 168.4 ° C (starting).

1:1 stoichiometric citrate (mw 698.70), mp (DSC) 168.8 ° C (starting).

The following example has been synthesized into instance 82 in a similar manner:

Example 86 : N- (5-Cyano-4-((2-hydroxy-2-methylpropyl)amino)pyridin-2-yl)-7-methylindolyl-6-(hydroxymethyl)- 3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

At room temperature to 6 - (((tert-butyl dimethyl silicone alkyl) oxy) methyl) - N - (5- cyano-4 - ((2-hydroxy-2-methylpropyl) Amino)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- To a solution of pyridine-1(2H)-carbamide (intermediate 78C, 30 mg, 0.051 mmol) EtOAc (1 mL) After stirring at room temperature for 1 h additional additional hydrochloric acid (0.17 mL) was added and stirring was continued for 4.5 h. Followed by the addition of saturated aqueous NaHCO _3, dried DCM (2 ×) the mixture was extracted, the organic layer was dried over Na ₂ SO ₄ and evaporated. The residue was purified by EtOAc (EtOAc) (UPLC-MS 6) t _R 0.78, ESI-MS 425.3, [M+H] ⁺ .

Example 87 : (racemic) N- (5-Cyano-4-((3-(dimethylamino)-2-hydroxy-2-methylpropyl)amino)pyridin-2-yl)- 7-Mercapto-6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide.

At room temperature to 6 - (((tert-butyl dimethyl silicone alkyl) oxy) methyl) - N - (5- cyano-4 - ((3- (dimethylamino) -2- Hydroxy-2-methylpropyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8- To a solution of pyridine-1(2H)-carbamide (intermediate 78D, 33 mg, 0.053 mmol) EtOAc (1 mL) After stirring for 18h and then was added at room temperature, saturated aqueous NaHCO _3, the mixture was extracted with DCM (2 ×), the organic layer was dried over Na ₂ SO ₄ and evaporated. The residue was triturated with Et ₂ O to give the title compound. (UPLC-MS 6) t _R 0.78, ESI-MS 425.3, [M+H] ⁺ .

The following example has been synthesized into instance 87 in a similar manner:

In vitro biochemical kinase analysis of FGFR4

All analyses were performed in 384 well microtiter plates. Each assay plate contained an 8-point serial dilution of 40 test compounds and an 8-point serial dilution of four staurosporins as a reference compound plus 16 high controls and 16 low controls.

The liquid handling and incubation steps were performed on an Innovadyne Nanodrop Express equipped with a robotic handle (Thermo CatX, Caliper Twister II) and an incubator (Liconic STX40, Thermo Cytomat 2C450). Analytical plates were prepared by the addition of 50 nL per well of 90% DMSO containing the compound. Kinase reaction by stepwise addition of 4.5 μL/well peptide/ATP solution (50 mM HEPES, pH 7.5, 1 mM DTT, 0.02% Tween 20, 0.02% BSA, 0.6% DMSO, 10 mM beta glycerol phosphate and 10 μM sodium orthovanadate, 16 mM MgCl ₂ , 1122 μM ATP, 4 μM peptide (5-Fluo-Ahx-KKKKEEIYFFFG-NH2, Biosyntan GmbH) and 4.5 μL/well enzyme solution (50 mM HEPES, pH 7.5, 1 mM DTT, 0.02% Tween 20, 0.02% BSA, 0.6%) DMSO, 10 mM beta glycerol phosphate and 10 μM sodium orthovanadate, 16 mM MgCl ₂ , 6 nM FGFR4 (GST-FGFR4 (388-802), generated by expression in insect cells and affinity chromatography)). The kinase reaction was incubated at 30 ° C for 60 minutes and then stopped by adding 16 μL of stop solution (100 mM HEPES, pH 7.5, 5% DMSO, 0.1% Caliper coating reagent, 10 mM EDTA and 0.015% Brij35) per well. The plate with the terminated kinase reaction was transferred to a Caliper LC3000 workstation to read the data. Phosphorylated and unphosphorylated peptides were separated using the Caliper microfluid migration bias technique. Briefly, a sample from a terminated kinase reaction is applied to the wafer. The analyte is transferred by passing a constant buffer through the wafer and the migration of the peptide is monitored by its labeled fluorescent signal. The phosphorylated peptide (product) and the unphosphorylated peptide (substrate) are separated by their charge/mass ratio in the electric field. The kinase activity was calculated from the amount of phosphate-based peptide formed. IC50 values were determined by non-linear regression analysis of percent inhibition at different compound concentrations.

In vitro cell kinase analysis of FGFR4

An assay for measuring the phosphorylation level of tyrosine on FGFR4 was developed to read cellular FGFR4 kinase activity. Based on this, a BaF3-Tel-FGFR4 cell line was generated: a retrovirus stably transfected with a fusion protein consisting of an amino terminal portion of TEL (aa1-337) fused to the cytoplasmic domain of FGFR4 (including the juxtamembrane domain) Guide BaF3 cells. The TEL domain present will mediate constitutive activation of the fused FGFR4 kinase by oligo-polymerization and thus autophosphorylate at the tyrosine site.

A capture ELISA based on MSD (Meso Scale Discovery) was developed and used as follows:

- Cell treatment: in a 96-well tissue culture dish (Corning Cat #3359) in 40 μL of growth medium (supplemented with 10% fetal bovine serum, 10 mM HEPES, 1 mM sodium pyruvate, 2 mM stable glutamic acid and 1× penicillin) In RPMI-1640 (Amimed Cat #1 - 41F01-I) of streptomycin, 250,000 BaF3-Tel-FGFR4 cells were seeded per well. Serial 3-fold dilutions of the compound were prepared in DMSO using a liquid handling device (Velocity 11 Bravo, Agilent), pre-diluted prior to growth medium, and then 10 μL/well was transferred to the cell culture dish. After incubation for 1 hour at 37 ° C / 5% CO ₂ , 50 μL of lysis buffer (150 mM NaCl, 20 mM Tris (pH 7.5), 1 mM EDTA, 1 mM EGTA, 1% Triton X-100, 10 mM NaF) was added, supplemented with protease inhibition. (Complete Mini, Roche Cat #11836153001) and phosphatase inhibitor (According to the supplier's instructions Phosphatase Inhib I, SIGMA Cat #P2850; Phosphatase Inhib II, SIGMA Cat #P5726)), and incubated on ice at 300 rpm 30 minutes. The sample plates were then frozen and stored at -70 °C. After melting on ice, the sample plates were centrifuged at 1200 rpm for 15 minutes at 6 °C.

- ELISA analysis: Multi-well 96-well plates were coated with 25 μL of mouse anti-H-TEL antibody (Santa Cruz, Cat# sc-166835) diluted 1:400 in PBS/O at room temperature. (MSD, Cat#L15XB-3) 1 hour. After 150 μL of TBS-T (50 mM Tris, 150 mM NaCl, 0.02% Tweeen-20) containing 3% MSD Blocker A (Cat# R93BA-1) was added, the plate was incubated for 1 hour at room temperature with shaking. The plate was then washed 3 times with 200 μL/well TBS-T. Subsequently, 50 μL of cell lysate was transferred to the coated plate and incubated at 4 ° C for 15 hours, followed by washing 3 times with 200 μl of TBS-T/well and adding 25 μl/well to TBS-T+1% MSD blocker A 1:250 dilution of MSD SULFOTAGGED PY20 antibody (MSD Cat# R32AP-5). After incubation for 1 h at room temperature with shaking, the wells were washed 3 times with 200 μL of TBS-T/well. Immediately after 150 μL of the MSD reading buffer (MSD, Cat# R92TC-2) stock solution aliquot diluted 1:4 with nano water, the generated electrochemiluminescence signal was quantified on a SectorImager 6000 (MSD).

- IC ₅₀ calculation: For data analysis, the analytical background was determined in wells containing medium and lysis buffer but no cells, and the corresponding values were subtracted from all data points. The effect of specific test compound concentration on FGFR4 phosphorylation is expressed as the percentage of background corrected ECG readings obtained for cells treated with vehicle (DMSO, 0.2% fc), which was set to 100. With a standard four parameter curve fit (XLfit 5.4, IDBS) to determine the concentration of compound (IC ₅₀₎ of the half-maximal inhibition signal.

Preparation of compound diluent

Test compounds were dissolved in DMSO (10 mM) and transferred to a 1.4 mL flat bottom or V-shaped matrix tube with a unique 2D matrix. If not used immediately, store the stock solution at +2 °C. When used in a test procedure, the vials are thawed and identified by a scanner, thereby creating a work form that guides subsequent work steps.

Compound dilutions were prepared in 96-well plates. This format maximizes the analysis of 40 individual test compounds (including 4 reference compounds) at 8 concentrations (single point). The dilution program includes the production of "pre-dilution plates", "mother plates" and "analytical plates".

Pre-dilution plate: A polypropylene 96-well plate was used as a pre-dilution plate. A total of 4 pre-diluted plates were prepared, each containing 10 test compounds at plate positions A1-A10, a standard compound at A11, and a DMSO control at A12. All dilution steps were performed on a Hamilton STAR robot.

Mother Plate: Transfer 30 μL of individual compound dilutions (including standard compounds and 4 “pre-dilution plates”) to 384 “parent plates” including the following concentrations 1'810, 362, 72.5, 54.6 14.5, 2.9, 0.58 and 0.12 μM in 90% DMSO, respectively.

Analysis of the plates: The same "analytical plates" were subsequently prepared by pipetting 50 nL of each of the "mother plates" of the compound dilution into a 384-well "analytical plate" by means of a HummingBird 384 channel dispenser. These plates were used directly for analysis and the analysis was performed in a total volume of 9.05 μL. This resulted in a final compound concentration of 10, 2.0, 0.4, 0.08, 0.016, 0.0032, 0.00064, and 0.000128 μM and a final DMSO concentration of 0.5% in the analysis.

Compound (S) -7- methyl acyl 6- (hydroxymethyl) - N - (4 - ( ( tetrahydrofuran-3-yl) oxy) pyrimidin-2-yl) -3,4-dihydro-1 ,8- Pyridin-1(2H)-carbenamide and N- (5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-methylindolyl-6-((2- Syloxypyrrolidin-1-yl)methyl)-3,4-dihydro-1,8- The pyridine-1(2H)-formamide exhibited efficacy in the biochemical analysis described above with an IC ₅₀ > 1 μM. Preferably, (S) -7- methyl acyl 6- (hydroxymethyl) - N - (4 - ( ( tetrahydrofuran-3-yl) oxy) pyrimidin-2-yl) -3,4- Hydrogen-1,8- Pyridin-1(2H)-carbenamide and N- (5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-methylindolyl-6-((2- Syloxypyrrolidin-1-yl)methyl)-3,4-dihydro-1,8- The pyridine-1(2H)-formamide is not part of the invention.

The following data measured and are considered outliers, and not included in the above table: for example, cell analysis of BaF ₃ FGFR4 66; ₅₀ value greater than 3000nM of the IC.

In vitro biochemical kinase analysis of FGFR1, FGFR2 and FGFR3

The compounds of the invention were tested using the following kinase domain sequences in an assay format similar to that described above: FGFR1 (407-822), FGFR2 (406-821) and FGFR3 (411-806). The data demonstrate that the compounds of the invention are selective FGFR4 inhibitors.

Claims (14)

a compound of formula (I) or a pharmaceutically acceptable salt thereof Wherein V is selected from the group consisting of CH ₂ , O, CH(OH); W is selected from CH ₂ , CH ₂ CH ₂ ; X is C(R ^X ) or N; Y is C(R ^Y ) or N; Z is CH Or N; wherein when X is N, Y and Z are not N; wherein when Y is N, X and Z are not N; wherein when Z is N, X and Y are not N; R ^X is selected from Hydrogen, halogen, halo C ₁ -C ₃ alkyl, cyano, C ₁ -C ₆ alkyl, hydroxy C ₁ -C ₆ alkyl; R ^Y is selected from 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 , optionally a hydroxy-substituted halo-C ₁ -C ₃ alkoxy group; or R ^X and R ^Y and the ring to which they are attached may further comprise one or two selected from N, O or S, as appropriate a bicyclic aromatic ring system of a hetero atom, which ring is optionally substituted by a C ₁ -C ₃ alkyl group; R ^Y1 is hydrogen and R ^Y2 is a C ₁ -C ₆ alkyl group, a hydroxy C ₁ -C ₆ alkyl group, a halogen-substituted C ₁ -C ₆ alkyl group, a C ₁ -C ₃ alkoxy C ₁ -C ₆ alkyl group, (CH ₂ ) _0-1 -R ^Y4 , a hydroxyl group, optionally substituted by a hydroxy group Substituted bis(C ₁ -C ₃ alkyl)amino C ₁ -C ₆ alkyl, bicyclo[2.2.1]heptyl substituted by hydroxy C ₁ -C ₃ alkyl, via S(O) ₂ -CH a (CH ₃ ) ₂ substituted phenyl group; or R ^Y1 and R ^Y2 and the N atom to which they are attached form a saturated or unsaturated non-aromatic 6-membered heterocyclic ring which may contain an O atom, which ring may be substituted once by R ^Y5 or Tw; R ^Y3 is selected from a quinuclidinyl group, a 4-membered, 5- or 6-membered saturated heterocyclic ring containing at least one hetero atom selected from N, O or S, which is optionally C ₁ -C ₃ alkyl Substituted; R ^Y4 is a 4-, 5- or 6-membered saturated heterocyclic ring containing at least one hetero atom selected from N, O or S, which ring is optionally substituted by a C ₁ -C ₃ alkyl group; R ^{Y5 is} independently selected from C ₁ -C ₃ alkyl, hydroxy, bis(C ₁ -C ₃ alkyl)amino C ₁ -C ₃ alkyl, or two R ^Y5 attached at the same carbon atom and the carbon atom to which they are attached a 5-membered saturated heterocyclic ring containing at least one hetero atom selected from N, O or S, the ring being substituted by a C ₁ -C ₃ alkyl group; R ^Y6 and R ^Y7 and the carbon atom to which they are attached form one selected from N a 6-membered saturated or unsaturated non-aromatic heterocyclic ring of a hetero atom of O or S; R ¹ is selected from the group consisting of 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; R ² is selected from C ₁ -C ₃ alkyl, di(C ₁ -C ₃ alkyl)amine a C ₁ -C ₃ alkyl group; R ³ is selected from the group consisting of 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 ; or R ² and R ³ and the N atom to which they are attached form an additional selected from N, a saturated 5 heteroatoms of O or S or a 6-membered ring which R ⁴ may be substituted one or more times; R ⁴ is independently selected from C ₁ -C ₃ alkyl, di (C ₁ - C ₃ alkyl)amino, C(O)CH ₃ , hydroxy; or two R ⁴ attached to the same carbon atom and the carbon atom to which they are attached form a hetero atom comprising at least one selected from N, O or S 4, 5 or 6 member non-aromatic heterocyclic rings; or two R ⁴ attached to the same carbon atom to form a pendant oxy group; R ⁵ is selected from hydrogen or C ₁ -C ₃ alkyl. A compound of the formula (Ia) of claim 1 or a pharmaceutically acceptable salt thereof The request acceptable compound of item 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R ^X is selected from halogen, halo C ₁ -C ₃ alkyl group, a cyano group; R ^Y is selected from hydrogen, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₆ alkoxy, halo C ₁ -C ₃ alkoxy, hydroxy C ₁ -C ₃ alkoxy, NR ^Y1 R ^Y2 , 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 ; R ¹ is selected from the group consisting of 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 . A compound of the formula (Ia-1), or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, The compound of the formula (Ia-1), or a pharmaceutically acceptable salt thereof, wherein R ^Y is selected from the group consisting of NR ^Y1 R ^Y2 , C ₁ -C ₃ alkoxy C ₁ -C ₃ alkoxy, O-(CH ₂ ) _0-1 -R ^Y3 . A compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1, which is selected from the group consisting of 7-methylindenyl- N- (5-(trifluoromethyl)pyridine- 2-yl)-3,4-dihydro-1,8- Pyridin-1( 2H )-carbamide; N -(4,5-dichloropyridin-2-yl)-7-methylindolyl-3,4-dihydro-1,8- Pyridin-1( 2H )-formamide; N -(5-cyanopyridin-2-yl)-7-methylindol-3,4-dihydro-1,8- Pyridin-1( 2H )-carbamide; N -(5-chloropyridin-2-yl)-7-methylindol-3,4-dihydro-1,8- Pyridin-1( 2H )-carbamide; 7-carbamimidyl- N- (pyridin-2-yl)-3,4-dihydro-1,8- Pyridin-1( 2H )-carbamide; N -(4,5-dimethylpyridin-2-yl)-7-methylindol-3,4-dihydro-1,8- Pyridin-1( 2H )-formamide; 7-methylindenyl- N- (5-methylpyridin-2-yl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyanopyrimidin-2-yl)-7-methylindol-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; 6-methylindenyl- N- (5-methylpyridin-2-yl)-2H-pyrido[3,2-b][1,4]oxazine- 4(3H)-carbamamine; 6-chloro- N- (5-cyanopyridin-2-yl)-7-methylindol-3,4-dihydro-1,8- Pyridin-1(2H)-carbenamide; 7-mercapto- N- (6-methoxypyrimidin-4-yl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyanopyrazin-2-yl)-7-methylindol-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-methoxypyridin-2-yl)-7-methylindol-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; 6-methylindenyl- N- (5-(trifluoromethyl)pyridin-2-yl)-2H-pyrido[3,2-b][1,4 Oxazine-4(3H)-carbamamine; 6-fluoro-7-methylindolyl- N- (5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1, 8- Pyridin-1(2H)-carbamide; N- (5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)-7-methylindolyl- 3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (4,5-dicyanopyridin-2-yl)-7-methylindol-3,4-dihydro-1,8- Piperidin -1 (2H) - A Amides; 7-acyl-6- (hydroxymethyl) - N - (5- (trifluoromethyl) pyridin-2-yl) -3,4-dihydro - 1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-ethoxypyridin-2-yl)-7-methylindol-3,4-dihydro-1,8- Pyridin-1(2H)-carbamamine; 7-mercapto-6-methyl- N- (5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8 - Pyridin-1(2H)-carbamide; N- (5-cyanopyridin-2-yl)-7-methylindol-6-methyl-3,4-dihydro-1,8- Pyridin-1(2H)-carbamamine; 7-mercapto- N- (5-(1-hydroxypentyl)pyridin-2-yl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-methylindolyl-3,4-dihydro -1,8- Pyridin-1(2H)-formamide; N- (4-chloro-5-cyanopyridin-2-yl)-7-methylindol-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-( N -morpholinyl)pyridin-2-yl)-7-methylindolyl-3,4-dihydro-1, 8- Pyridin-1(2H)-formamide; N- (5-cyano-4-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-2-yl)-7-methylindolyl- 3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyanopyridin-2-yl)-7-methylindolyl-6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-(2-methyl-2,8-diazaspiro[4.5]dec-8-yl)pyridin-2-yl)- 7-Mercapto-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyanopyridin-2-yl)-6-cyclopropyl-7-methylindol-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-(3,6-dihydro-2H-piperazin-4-yl)pyridin-2-yl)-7-carboxamido -3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-(tetrahydro-2H-piperazin-4-yl)pyridin-2-yl)-7-methylindolyl-3,4 -dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-chloro-4-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-yl)-7-methylindolyl-3,4-dihydro -1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-isopropoxypyridin-2-yl)-7-methylindol-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-((tetrahydrofuran-2-yl)methoxy)pyridin-2-yl)-7-methylindolyl-3,4- Dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-(oxetan-2-ylmethoxy)pyridin-2-yl)-7-methylindolyl-3,4 -dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-2-yl)-7-formamidine Base-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyanopyridin-2-yl)-6-(difluoromethyl)-7-methylindolyl-3,4-dihydro-1,8 - Pyridin-1(2H)-carbamide; N- (5-cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-7-methylindolyl-3,4 -dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-methylindolyl-6-(hydroxymethyl )-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-7-methylindolyl-3,4-di Hydrogen-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-2-yl)-7-methylindolyl- 6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; 7-acetamido- N- (5-cyanopyridin-2-yl)-6-((dimethylamino)methyl)-3,4-dihydro -1,8- Piperidin -1 (2H) - A Amides; N - (5- cyano-4 - ((tetrahydrofuran-2-yl) methoxy) pyridin-2-yl) -7-acyl-6- (hydroxy Methyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-2-yl)-7-formamidine -6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-(2-methyl-2,8-diazaspiro[4.5]dec-8-yl)pyridin-2-yl)- 7-Mercapto-6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((1-methylpyrrolidin-3-yl)oxy)pyridin-2-yl)-7-methylindolyl- 6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-7-methylindolyl- 6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2-yl)-7-methylindenyl- 6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-7-methylindolyl-6-(hydroxyl Base)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-6-((dimethylamino)methyl )-7-methylmercapto-3,4-dihydro-1,8- Pyridin-1(2H)-carbamidamine; 2-(8-((5-cyanopyridin-2-yl)aminemethanyl)-2-carboxamido-5,6,7,8-tetrahydro -1,8- Aridin-3-yl)acetic acid; N- (5-cyano-4-((tetrahydro-2H-piperidin-4-yl)oxy)pyridin-2-yl)-7-methylindolyl-6- (hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((1-methylpyrrolidin-3-yl)oxy)pyridin-2-yl)-7-methylindolyl- 6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((tetrahydro-2H-pyran-3-yl)methyl)amino)pyridin-2-yl)-7 -Methylmercapto-6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((tetrahydrofuran-3-yl)amino)pyridin-2-yl)-7-methylindolyl-6-(hydroxyl Base)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((2-methoxypropyl)amino)pyridin-2-yl)-7-methylindolyl-6- Hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-chloro-4-((1-methoxypropan-2-yl)oxy)pyrimidin-2-yl)-7-methylindolyl-6 -(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (4-(4-chloro-2-hydroxybutoxy)-5-cyanopyridin-2-yl)-7-methylindolyl-6-(hydroxyl Methyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-methylindol-6-(trifluoromethyl) Base)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-6-cyclopropyl-7-methylindenyl- 3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-6-(difluoromethyl)-7- Mercapto-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-6-((dimethylamino)methyl) -7-methylmercapto-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((3-(hydroxymethyl))bicyclo[2.2.1]hept-2-yl)amino)pyridin-2-yl )-7-Methylyl-6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)-7-carboxamido -6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-(2-methoxyethoxy)pyridin-2-yl)-7-methylindolyl-6-(methoxy Methyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyanopyridin-2-yl)-7-methylindol-6-(( N -methylethylamino)methyl)-3, 4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-chloro-4-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-yl)-7-methylindolyl-6-(hydroxymethyl )-3,4-dihydro-1,8- Pyridin-1(2H)-carbenamide; N- (5-cyano-4-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-yl)-7-methylindolyl-6-(hydroxyl) Base)-3,4-dihydro-1,8- Piperidin -1 (2H) - A Amides; 7-acyl-6- (hydroxymethyl) - N - (4 - ( ( tetrahydrofuran-3-yl) oxy) pyridin-2-yl) - 3 4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-chloro-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)-7-methylindolyl-6-(hydroxymethyl) )-3,4-dihydro-1,8- Pyridin-1(2H)-carbamimid; N- (5-cyano-4-((1-methylpiperidin-3-yl)methoxy)pyridin-2-yl)-7-carboxamido -6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((1-methylpyrrolidin-2-yl)methoxy)pyridin-2-yl)-7-carboxamido -6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((1-methylpiperidin-2-yl)methoxy)pyridin-2-yl)-7-methylindolyl -6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-fluoropyridin-2-yl)-7-methylindolyl-6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6-formamidine- ¹³ C-yl -2H-pyrido[3,2-b][1,4]oxazin-4(3H)-carbenamide; N- (5-cyano-4-((1-methylpiperidin-4-) Methoxy)pyridin-2-yl)-7-methylindolyl-6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyanopyridin-2-yl)-7-methylindol-4-hydroxy-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-methylindolyl-6- Hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-(2-((dimethylamino)methyl) N -morpholinyl)pyridin-2-yl)-7-A Mercapto-6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-(quinuclidin-3-yloxy)pyridin-2-yl)-7-methylindolyl-6-(hydroxyl) Base)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-methylindolyl-6- (4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8- Piperidin -1 (2H) - A Amides; 7-acyl-6- (hydroxymethyl) - N - (4 - ( (2- methoxyethyl) amino) -5- (trifluoromethyl Pyridin-2-yl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-(4-((dimethylamino)methyl)-4-hydroxypiperidin-1-yl)pyridin-2-yl )-7-Methylyl-6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((2-hydroxy-2-methylpropyl)amino)pyridin-2-yl)-7-methylindolyl- 6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-carbamide; N- (5-cyano-4-((3-(dimethylamino)-2-hydroxy-2-methylpropyl)amino)pyridine-2- Base)-7-methylmercapto-6-(hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; N- (5-cyano-4-((2-fluoroethyl)amino)pyridin-2-yl)-7-methylindolyl-6-(hydroxyl) Base)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide; and N- (5-cyano-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)-7-methylindenyl-6- (hydroxymethyl)-3,4-dihydro-1,8- Pyridin-1(2H)-formamide. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers. A combination comprising a therapeutically effective amount of a compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof and one or more therapeutically active agents. A use of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting FGFR4 activity in an individual. A compound according to any one of claims 1, 2, 5 or 6, or a pharmaceutically acceptable salt thereof, for use as a medicament. A compound according to any one of claims 1, 2, 5 or 6 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer. A compound or a pharmaceutically acceptable salt thereof for use according to claim 11, wherein the cancer is selected from the group consisting of liver cancer, breast cancer, glioblastoma, prostate cancer, rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer, colon cancer. A use of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer. a compound of formula (IV) or a pharmaceutically acceptable salt thereof Wherein V is selected from the group consisting of CH ₂ , O, CH(OH); W is selected from the group consisting of CH ₂ and CH ₂ CH ₂ ; and R ¹ is selected from the group consisting of halogen, C ₁ -C ₃ alkyl, halo C ₁ -C ₃ alkane Base, 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; R ⁵ is selected from hydrogen or C ₁ -C ₃ alkyl.