Compounds comprising naphthyridine or pyridopyridine core as ptc readthrough

Abstract

Disclosed are compounds of Formula (I): or tautomer forms thereof, or pharmaceutically acceptable salts or N-oxides thereof, wherein R1, R2a, R2b, R3, R4, R5 and X are as defined herein. The compounds of the invention may be useful in the treatment of diseases / conditions associated with PTC mutations. The invention also discloses a pharmaceutical composition containing the compound. And compounds for treating a condition or disorder associated with a PTC mutation in a subject. (I)

Description

Technical Field

[0001] This invention relates to compounds containing pharmacologically active pyridine polycyclic nuclei, methods for their preparation, pharmaceutical compositions containing them, and their use in the treatment of various diseases. Background Technology

[0002] When a ribosome encounters a termination sequence during the translation of messenger RNA (mRNA), there is no pairing transfer RNA (tRNA) to bind. This leads to the cessation of protein production, the binding of release factor (RF) proteins to vacant sites on the ribosome, and conformational changes within the ribosome, all of which result in the breakdown of the ribosome complex. Translation termination, while precise, is not 100% efficient; its efficiency depends on the competition between eRF1 recognizing the stop codon and the decoding of the stop codon by the nearest-pairing tRNA (i.e., the natural repressor tRNA). The latter leads to the suppression of translation termination, also known as "readthrough," in which an amino acid is incorporated into the termination site (Dabrowski, M. et al., RNA Biology 2015, 12, 950-958).

[0003] If a stop codon appears before the full-length protein is formed, then the stop codon is a “premature” stop codon (PTC), and the truncated protein may be nonfunctional. Normal stop codons are usually in a genetic and structural context that enhances their effectiveness and are generally more resistant to readthrough than PTCs produced by truncation mutations (Wangen and Green, 2020 Elife 9:e52611).

[0004] More than 1,800 independent genetic diseases have been identified, with a certain proportion of individuals exhibiting nonsense mutations. In nonsense mutations, premature stop codons (PTCs) within the frame lead to loss of gene function (Kellermayer, R. European Journal of Medical Genetics 2006, 49, 445-450). More than 9,600 PTC mutations have been reported, representing approximately 10% of all reported gene mutations (Krawczak, M. et al., Human Mutation 2000, 15, 45-51; Mort, M. et al., Human Mutation 2008, 29, 1037-1047).

[0005] Nonsense mutations are involved in the pathology of a range of conditions, from polygenic pathologies (such as cancer) to monogenic diseases (such as cystic fibrosis and Duchenne muscular dystrophy), with PTCs accounting for approximately 10% and 5-10% of all cases, respectively (Keeling, KM & Bedwell, DM, Journal of Molecular Medicine 2002, 80, 367-376, Kellermayer, R. European Journal of Medical Genetics 2006, 49, 445-450).

[0006] Although single-gene diseases are caused by genetic or neogenertic mutations that lead to PTC, somatic mutations, such as in cancer, can cause PTC mutations in tumor suppressor genes.

[0007] One of the surveillance systems cells use to clear aberrant mRNA transcripts that prematurely terminate translation is the nonsense-mediated decay (NMD) pathway. It targets mRNAs containing a PTC sequence located approximately 50 base pairs upstream of the penultimate exon-exon junction (Maquat, LE, Nature Reviews, MolecularCell biology 2004, 5, 89-99).

[0008] Premature termination of protein production and binding of NMD to PTC-containing mRNA can lead to almost complete loss of protein production from mutant genes encoding PTC.

[0009] Mechanisms that enable translational readthrough of PTC mutations include, but are not limited to: reducing ribosomal translational fidelity; reducing the efficiency of the translation termination mechanism; inhibiting NMD; interfering with the regulation or stabilization of mRNAs in gene transcription or translation to combat NMD (Kellermayer, R European Journal of Medical Genetics 2006, 49, 445-450, Belgrader, PJC, and Maquat, LE, Proc. Natl. Acad. Sci. USA 1993, 90, 482-486).

[0010] Agents that allow for full translation of PTC mutations have the potential to treat any disease in which the presence of PTC in a gene is a direct cause, risk factor, or aggravating factor.

[0011] Aminoglycoside antibiotics (such as paromomycin, gentamicin, and G418 / genimycin) are a class of antibiotics that reduce translational fidelity. They exert their antibacterial effects by inhibiting prokaryotic protein synthesis; however, at sublethal doses, they reduce translational fidelity in mammalian ribosomes, leading to increased misincorporation of amino acids and increased readability of stop codons (Davies, J. & Gorini, L., Proc. Natl. Acad. Sci. USA 1964, 51, 883-8; Weinstein, Proc. Natl. Acad. Sci. USA 1964, 52, 988-996).

[0012] Aminoglycoside antibiotics have been shown to allow the reading of PTC mutations in the CFTR gene, which causes cystic fibrosis, both in vitro (Bedwell, DM, et al., Nature Medicine 1997, 3, 1280-1284) and in vivo (including in patients) (Ming Du, et al., Journal of Molecular Medicine 2002, 80, 595-604; Clancy, JP et al., Am J Respir CritCare Med 2001, 163, 1683-1692; Wilschanski, M., et al., The New England Journal of Medicine 2003, 139, 1433-1441).

[0013] In an animal model of Duchenne muscular dystrophy (DMD), 7 out of 8 male MDX mice treated with 34 mg / kg gentamicin showed enhanced protection against contractile injury, with wild-type dystrophin levels recovering by 10-20% (Barton-Davis, ER, et al., Journal of Clinical Investigation 1999, 104, 375-381).

[0014] Gentamicin treatment induced functional type VII collagen in patients with subclinical dystrophic epidermolysis bullosa (Woodley, DT et al. Journal of Clinical Investigation 2017, 127, 3028-3038), and in vitro evidence supports the read-through mechanism (Has, C. et al. Journal of Investigative Dermatology 2022, 142, 1227-1230).

[0015] Readthroughs of genes containing PTC mutations associated with cystinosis, Hurler syndrome, hereditary blindness, and cancer genes have been confirmed after treatment with aminoglycoside antibiotics (Helip-Wooley, A., et al., Molecular Genetics and Metabolism 2002, 75, 128-133; Keeling, KM, et al., Human Molecular Genetics 2001, 10, 291-299; Moosajee, MK, et al., Human Molecular Genetics 2008, 17, 3987-4000). However, aminoglycoside antibiotics are unsuitable as PTC readthrough agents because serious toxicity has been observed at high doses or with repeated treatment.

[0016]

[0017] WO2019241633 describes compositions and methods for suppressing nonsense mutations, including the compound triamterene.

[0018] Hurlbert, BS et al. Journal of Medicinal Chemistry (1968), 11(4), 711-17 describes 2,4-diaminopyrido[2,3-d]pyrimidines with antibacterial and antiprotozoal effects, including pyrido[2,3-d]pyrimidine-2,4-diamine.

[0019] Some of the compounds of this invention are suitable for treating diseases / conditions associated with PTC mutations.

[0020] A novel class of compounds has now been discovered that provides PTC readout agents. Summary of the Invention

[0021] According to a first aspect, the present invention provides a compound of formula (I) or its tautomer form or a pharmaceutically acceptable salt or N-oxide thereof:

[0022] (I)

[0023] in

[0024] X is N or CR 6 ;

[0025] R 1 Independently selected from C0-C6-alkylene-R 1a and C2-C6-alkylene-R 1b ;

[0026] R 1a Independently selected from C3-C8 cycloalkyl, C5-C8 cycloalkenyl, 3- to 10-membered heterocyclic alkyl, and 5- to 10-membered heterocyclic alkenyl; wherein R 1a Optionally covered by C0-C6-alkylene-R 9a And / or 1 to 6 R 9 Group substitution; wherein when R 1a When the group is a heterocyclic alkyl or heterocyclic alkenyl group, the heterocyclic alkyl or heterocyclic alkenyl group is optionally fused with a benzene ring, wherein the benzene ring is optionally surrounded by 1 to 4 R groups. 10 Group substitution;

[0027] R 1b Independently selected from NR 7a R 8a and OR 7 ;

[0028] Where R 1 It contains at least one nitrogen atom;

[0029] R 2a Each occurrence is independently selected from H and C1-C4 alkyl groups;

[0030] R 2b Each occurrence is independently selected from H, C1-C4 alkyl, C1-C4-haloalkyl, C0-C4 alkyl-R. 2c C2-C4-alkylene-R 2d C(O)-C1-C4-alkyl, S(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl;

[0031] R 2c Independently selected from C3-C8 cycloalkyl, C5-C8 cycloalkenyl, phenyl, 3-8-membered heterocycloalkyl, 5-8-membered heterocycloalkenyl, and 5- or 6-membered heteroaryl; wherein R 2c When it is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, R 2cChoose from 1 to 4 Rs 9 Group substitution; and when R 2c When it is phenyl or heteroaryl, R 5c Choose from 1 to 5 Rs 10 Group substitution;

[0032] R 2d Independently selected from NR 7 R 8 and OR 7 ;

[0033] Or, R 2a and R 2b Together with the nitrogen atoms to which they are attached, they form 5- to 8-membered heterocyclic alkyl rings; optionally surrounded by 1 to 4 R... 9 Group substitution;

[0034] R 3 Independently selected from H, cyano, C1-C4-alkylene-NR 7 R 8 NR 7 R 8 C1-C4-alkylene-OR 7 OR 7 SR 7 SOR 7 S(O)2R 7 S(O)2NR 7 R 7 CO2R 7 C(O)R 7 C(O)NR 7 R 7 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, NR 7 -C0-C4-alkylene-R 3c O-C0-C4-alkylene-R 3c and C0-C4-alkylene-R 3c ;

[0035] R 3c Independently selected from C3-C8 cycloalkyl, C5-C8 cycloalkenyl, phenyl, 3-10-membered heterocycloalkyl, 5-10-membered heterocycloalkenyl, and 5- or 6-membered heteroaryl; wherein when R 3c When it is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, R 3c Choose from 1 to 4 Rs 9 Group substitution; and when R 3c When it is phenyl or heteroaryl, R 3c Choose from 1 to 5 Rs 10 Group substitution;

[0036] R 4 Independently selected from H, halogen, cyano, NR 7b R 8 OR 7 SR 7 SOR 7 S(O)2R 7 S(O)2NR 7 R 7 、 CO2R 7 C(O)R 7 C(O)NR 7 R 7 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-ynyl, C1-C4-haloalkyl, O-C0-C4-alkylene-R 4c and C0-C4-alkylene-R 4c ;

[0037] R 4c Independently selected from C3-C8 cycloalkyl, C5-C8 cycloalkenyl, 3-10-membered heterocycloalkyl, 5-10-membered heterocycloalkenyl and 5-membered heteroaryl; wherein when R 4c When it is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, R 4c Choose from 1 to 4 Rs 9 Group substitution; and when R 4c When it is a heteroaryl group, R 4c Choose from 1 to 5 Rs 10 Group substitution;

[0038] R 5 Independently selected from H, halogen, cyano, C1-C4-alkylene-NR 7 R 8 NR 7 R 8 C1-C4-alkylene-OR 7 OR 7b SR 7 SOR 7 S(O)2R 7 S(O)2NR 7 R 7 CO2R 7 C(O)R 7 C(O)NR 7 R 7 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, NR 7 -C0-C4-alkylene-R 5c O-C0-C4-alkylene-R5c and C0-C4-alkylene-R 5c ;

[0039] R 5c Independently selected from C3-C8 cycloalkyl, C5-C8 cycloalkenyl, phenyl, 3-10-membered heterocycloalkyl, 5-10-membered heterocycloalkenyl, and 5- or 6-membered heteroaryl; wherein when R 5c When it is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, R 5c Choose from 1 to 4 Rs 9 Group substitution; and when R 5c When it is phenyl or heteroaryl, R 5c Choose from 1 to 5 Rs 10 Group substitution;

[0040] Or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a ring selected from phenyl, C5-C7-cycloalkyl, 5-7-membered heterocycloalkyl, and 5- or 6-membered heteroaryl; wherein when the ring is cycloalkyl or heterocycloalkyl, it is optionally bounded by 1 to 6 R atoms. 9 Group substitution, where the ring is phenyl or heteroaryl, is optionally replaced by 1 to 4 R groups. 10 Group substitution;

[0041] Or R 4 and R 5 Together with the carbon atoms to which they are attached, they form a ring selected from phenyl, C5-C7-cycloalkyl, 5-7-membered heterocycloalkyl, and 5- or 6-membered heteroaryl; wherein when the ring is cycloalkyl or heterocycloalkyl, it is optionally bounded by 1 to 6 R atoms. 9 Group substitution, where the ring is phenyl or heteroaryl, is optionally replaced by 1 to 4 R groups. 10 Group substitution;

[0042] R 6 Independently selected from H, halogens, C1-C6-alkyl groups, and C1-C6-haloalkyl groups;

[0043] R 7 and R 7a Each of the two groups is independently selected from H and C1-C4-alkyl groups in each occurrence;

[0044] R 7b Each occurrence is independently selected from C1-C4 alkyl groups;

[0045] R 8 Each occurrence is independently selected from H, C1-C4-alkyl, C1-C4-haloalkyl, and C(O)-C1-C4-alkyl.

[0046] R 8aEach occurrence is independently selected from H, C1-C4 alkyl, C1-C4-haloalkyl, C(O)-C1-C4-alkyl, and optionally surrounded by 1 to 5 R. 10 Phenyl groups substituted with radicals;

[0047] Or, R 7a and R 8a Together with the nitrogen atoms to which they are attached, they form 5- to 8-membered heterocyclic alkyl rings; optionally surrounded by 1 to 4 R... 9 Group substitution;

[0048] R 9 Each time it appears, it is independently selected from =O, =S, halogen, nitro, cyano, and NR. 7 R 8 OR 7 SR 7 SOR 7 S(O)2R 7 SO2NR 7 R 7 、 CO2R 7 C(O)R 7 CONR 7 R 7 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C1-C3-alkylene-OR 7 and C1-C3-alkylene-NR 7 R 8 ;

[0049] R 9a Each time it appears, it is independently selected from C3-C8 cycloalkyl, C5-C8 cycloalkenyl, phenyl, 3-8-membered heterocycloalkyl, 5-8-membered heterocycloalkenyl, and 5- or 6-membered heteroaryl; wherein when R 9a When it is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, R 9a Choose from 1 to 4 Rs 9 Group substitution; and when R 9a When it is phenyl or heteroaryl, R 9a Choose from 1 to 5 Rs 10 Group substitution;

[0050] R 10 Each time it appears, it is independently selected from halogen, nitro, cyano, and NR. 7 R 8 OR 7 SR 7 SOR 7 S(O)2R 7 SO2NR 7 R 7、 CO2R 7 C(O)R 7 CONR 7 R 7 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, C1-C3-alkylene-NR 7 R 8 and C1-C3-alkylene-OR 7 ;and

[0051] Any of the aforementioned alkyl, alkylene, alkenyl, or cycloalkyl groups may be optionally substituted with 1 to 5 substituents, wherein each substituent is independently selected from the group consisting of: C1-C4-alkyl, oxo, halogen, nitro, cyano, NR. a R b OR a SR a CO2R a C(O)R a CONR a R a S(O)R a and S(O)2R a ;where R a Each time it appears, it is independently selected from H and C1-C4-alkyl; and R b Each time it appears, it is independently selected from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl.

[0052] The following are possible: R 2a Each time it appears, it is independently selected from H and C1-C4 alkyl groups; and R 2b Each occurrence is independently selected from H, C1-C4 alkyl, C1-C4-haloalkyl, C0-C4 alkyl-R 2c C2-C4-alkylene-R 2d C(O)-C1-C4-alkyl, S(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl.

[0053] Depending on the characteristics of the substituents, compounds of formula (I) may be capable of tautomerism, yielding alternative tautomeric forms of the aforementioned compounds. Compounds of formula (I) may be mixtures of these tautomeric forms. These tautomeric forms can interconvert in any given sample. The relative proportions of the tautomeric forms in a given sample will be determined by the equilibrium positions of these tautomeric forms under these conditions. The equilibrium positions, and therefore the extent to which each tautomeric form of the compound is present, can be determined by a variety of factors, including but not limited to the characteristics of the substituents, temperature, pH, and / or solvent (for compounds of formula (I) in solution).

[0054] In one embodiment, the compound of formula (I) is the same as the compound of formula (II):

[0055] (II)

[0056] Where R 1 R 2a R 2b R 3 R 4 and R 5 As defined above for equation (I).

[0057] In one embodiment, the compound of formula (I) is the compound of formula (III):

[0058] (III)

[0059] Where R 1 R 3 R 4 and R 5 As defined above for equation (I).

[0060] In one embodiment, the compound of formula (I) is the compound of formula (IV):

[0061] (IV)

[0062] Cycle A is independently selected from C3-C8 cycloalkyl, C5-C8 cycloalkenyl, 3- to 10-membered heterocyclic alkyl, and 5- to 10-membered heterocyclic alkenyl; wherein cycloA is optionally surrounded by C0-C6-alkylene-R 9a And / or 1 to 6 R 9 Group substitution; wherein when ring A is a heterocyclic alkyl or heterocyclic alkenyl group, the heterocyclic alkyl or heterocyclic alkenyl group is optionally fused with the benzene ring, wherein the benzene ring is optionally substituted with 1 to 4 R groups. 10 Group substitution; and p is selected from 0, 1, 2 or 3; and wherein X, R 1 R 2a R 2b R3 R 4 R 5 R 9 R 9a and R 10 As defined above for equation (I);

[0063] Optionally, where X and R 1 R 2a R 2b R 3 R 4 and R 5 As defined above for formula (I); and wherein ring A is independently selected from C3-C8 cycloalkyl, C5-C8 cycloalkenyl, 3- to 10-membered heterocyclic alkyl and 5- to 10-membered heterocyclic alkenyl; wherein ring A is optionally surrounded by 1 to 4 R 9 Group substitution; wherein when ring A is a heterocyclic alkyl or heterocyclic alkenyl group, the heterocyclic alkyl or heterocyclic alkenyl group is optionally fused with the benzene ring, wherein the benzene ring is optionally substituted with 1 to 4 R groups. 10 Group substitution; and p is selected from 0, 1, 2 or 3.

[0064] In one embodiment, the compound of formula (I) is the compound of formula (V):

[0065] (V)

[0066] Cycle A is independently selected from C3-C8 cycloalkyl, C5-C8 cycloalkenyl, 3- to 10-membered heterocyclic alkyl, and 5- to 10-membered heterocyclic alkenyl; wherein cycloA is optionally surrounded by C0-C6-alkylene-R 9a And / or 1 to 6 R 9 Group substitution; wherein when ring A is a heterocyclic alkyl or heterocyclic alkenyl group, the heterocyclic alkyl or heterocyclic alkenyl group is optionally fused with the benzene ring, wherein the benzene ring is optionally substituted with 1 to 4 R groups. 10 Group substitution; and p is selected from 0, 1, 2 or 3; and wherein X, R 1 R 2a R 2b R 3 R 4 R 5 R 9 R 9a and R 10 As defined above for equation (I);

[0067] Optionally, where X and R 1 R 2a R 2b R 3 R 4 and R 5As defined above for formula (I); and wherein ring A is independently selected from C3-C8 cycloalkyl, C5-C8 cycloalkenyl, 3- to 10-membered heterocyclic alkyl and 5- to 10-membered heterocyclic alkenyl; wherein ring A is optionally surrounded by 1 to 4 R 9 Group substitution; wherein when ring A is a heterocyclic alkyl or heterocyclic alkenyl group, the heterocyclic alkyl or heterocyclic alkenyl group is optionally fused with the benzene ring, wherein the benzene ring is optionally substituted with 1 to 4 R groups. 10 Group substitution; and p is selected from 0, 1, 2 or 3.

[0068] In one embodiment, the compound of formula (I) is the compound of formula (VI):

[0069] (VI)

[0070] Where X and R 1 R 2a R 2b and R 5 As defined above for formula (I); and wherein ring B is independently selected from phenyl, C5-C7-cycloalkyl, 5-7-membered heterocyclic alkyl and 5 or 6-membered heteroaryl; wherein when ring B is cycloalkyl or heterocyclic alkyl, it is optionally surrounded by 1 to 6 R 9 Group substitution, where ring B is phenyl or heteroaryl, is optionally replaced by 1 to 4 R groups. 10 Group substitution;

[0071] Optionally, when ring B is a cycloalkyl or heterocycloalkyl group, it is optionally surrounded by 1 to 4 R groups. 9 The group is substituted, and when ring B is phenyl or heteroaryl, it is optionally substituted with 1 to 4 R groups. 10 Group substitution.

[0072] In one embodiment, the compound of formula (I) is the compound of formula (VII):

[0073] (VII)

[0074] Where X and R 1 R 3 R 2a and R 2b As defined above for formula (I); and wherein the ring C is independently selected from phenyl, C5-C7-cycloalkyl, 5-7-membered heterocyclic alkyl and 5 or 6-membered heteroaryl; wherein when the ring C is cycloalkyl or heterocyclic alkyl, it is optionally surrounded by 1 to 6 R 9 Group substitution, where the ring C is phenyl or heteroaryl, is optionally replaced by 1 to 4 R groups. 10 Group substitution;

[0075] Optionally, when the ring C is a cycloalkyl or heterocycloalkyl group, it is optionally surrounded by 1 to 6 R groups. 9The group is substituted, and when the ring C is phenyl or heteroaryl, it is optionally substituted with 1 to 4 R groups. 10 Group substitution.

[0076] The following embodiments apply to compounds of any one of formulas (I)-(VII). These embodiments are independent and interchangeable. Where chemically permissible, any embodiment may be combined with any other embodiment. In other words, any feature described in the following embodiments may (where chemically permissible) be combined with features described in one or more other embodiments. In particular, where a compound is illustrated or described in this specification, any two or more embodiments of that compound listed below, expressed to any degree of generality, may be combined to provide another embodiment that forms part of this disclosure.

[0077] R 1 It can be C2-C6-alkylene-R 1b R 1b It can be NR 7a R 8a R 7a It can be selected from H and C1-C4-alkyl. R 7a It can be a C1-C4-alkyl group. R 8a It can be selected from H, C1-C4 alkyl groups and optionally surrounded by 1 to 5 R groups. 10 A phenyl group substituted with a radical. R 8a It can be selected from H and C1-C4-alkyl. R 8a It can be a C1-C4-alkyl group. R 7a and R 8a They can form 5- to 8-membered heterocyclic alkyl rings together with the nitrogen atoms to which they are attached; optionally, they are bound by 1 to 4 R... 9 Group substitution.

[0078] R 1 It can be C0-C6-alkylene-R 1a R 1 It can be R 1a R 1 It can be C1-C6-alkylene-R 1a .

[0079] R 1a It can be selected from C3-C8 cycloalkyl, C5-C8 cycloalkenyl, 3-10 heterocyclic alkyl and 5-10 heterocyclic alkenyl.

[0080] R 1a It can be a 3- to 10-membered heterocyclic alkyl group. R 1a It can be a 3- to 10-membered heterocyclic alkyl group having nitrogen in the ring system, such as pyrrolidine. R 1aIt can be a 3- to 10-membered heterocyclic alkyl group having an amine nitrogen in the ring system. When R 1a When it is a 3- to 10-membered heterocyclic alkyl group with an amine nitrogen in the ring system, it can be attached to the rest of the molecule through a carbon atom in the ring system. When R 1a When a 3- to 10-membered heterocyclic alkyl group has an amine nitrogen atom in the ring system, it can be attached to the rest of the molecule through the nitrogen atom in the ring system. 1a It can be a monocyclic 3- to 7-membered heterocyclic alkyl group. R 1a It can be piperidine, for example, piperidine-4-yl. R 1a It could be morpholine. R 1a It can be azaheptane. R 1a It can be pyrrolidine. R 1a It can be a bicyclic 7- to 10-membered heterocyclic alkyl group. In these embodiments, R 1a It can be 1 to 6 R 9 Group substitution.

[0081] The following are possible: R 1 yes

[0082] ,in:

[0083] R 9b Independently selected from H and SOR 7 S(O)2R 7 SO2NR 7 R 7 CO2R 7 C(O)R 7 CONR 7 R 7 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C2-C3-alkylene-OR 7 and C2-C3-alkylene-NR 7 R 8 ;

[0084] R 9c Each time it appears, it is independently selected from =O, =S, halogen, nitro, cyano, and NR. 7 R 8 OR 7 SR 7 SOR 7 S(O)2R 7 SO2NR 7 R 7 、 CO2R 7 C(O)R 7 CONR 7 R7 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C1-C3-alkylene-OR 7 and C1-C3-alkylene-NR 7 R 8 ;and

[0085] m is an integer from 0 to 5.

[0086] The following are possible: R 1 yes

[0087] ,in:

[0088] R 9b Independently selected from H and SOR 7 S(O)2R 7 SO2NR 7 R 7 、 CO2R 7 C(O)R 7 CONR 7 R 7 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C2-C3-alkylene-OR 7 and C2-C3-alkylene-NR 7 R 8 ;

[0089] R 9c Independently selected from =O, =S, halogen, nitro, cyano, NR 7 R 8 OR 7 SR 7 SOR 7 S(O)2R 7 SO2NR 7 R 7 、 CO2R 7 C(O)R 7 CONR 7 R 7 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C1-C3-alkylene-OR 7 and C1-C3-alkylene-NR 7 R 8 .

[0090] The following are possible: R 1 yes

[0091] ,in:

[0092] q is an integer from 0 to 6; and

[0093] R 9 and R 9a As defined in this article.

[0094] The following are possible: R 1 yes

[0095] ,in:

[0096] q is an integer from 0 to 6;

[0097] R 9 As defined in this article; and

[0098] R 9a Independently selected from phenyl and 5- or 6-membered heteroaryl, wherein R 9a Choose from 1 to 5 Rs 10 Group substitution.

[0099] The following are possible: R 1 yes

[0100] ,in:

[0101] q is an integer from 0 to 6;

[0102] r is an integer from 0 to 5; and

[0103] R 9 and R 10 As defined in this article.

[0104] R 9b It can be independently selected from H, C1-C4-alkyl, and C1-C4-haloalkyl. R 9b It can be independently selected from H and C1-C4-alkyl. R 9b It can be H.R independently. 9b It can be methyl independently.

[0105] m can be 0. m can be 1. m can be 2.

[0106] R 9c It can be independently selected from halogen, nitro, cyano, and NR. 7 R 8 OR 7 SR 7 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C1-C3-alkylene-OR 7and C1-C3-alkylene-NR 7 R 8 .

[0107] R 9c Can be selected independently from NR 7 R 8 OR 7 C1-C4-alkyl, C1-C4-haloalkyl, C1-C3-alkylene-OR 7 and C1-C3-alkylene-NR 7 R 8 R 9c Can be selected independently from OR 7 and C1-C4-alkyl groups. R 9c It can be methyl. R 9c It can be OH.

[0108] R 1a It can be a 3- to 10-membered heterocyclic alkyl group, wherein the heterocyclic alkyl group is fused to the benzene ring. R 1a It can be a 3- to 6-membered heterocyclic alkyl group, wherein the heterocyclic alkyl group is fused to the benzene ring. R 1a It can be a 5-membered heterocyclic alkyl group, wherein the heterocyclic alkyl group is fused with a benzene ring. When the heterocyclic alkyl group is fused with a benzene ring, R 1a It may be bicyclic. The benzene ring can be composed of 1 to 4 R groups. 10 Group substitution.

[0109] R 1a It can be a 5- to 10-membered heterocyclic alkenyl group, wherein the heterocyclic alkenyl group is fused to the benzene ring. R 1a It can be a 5- or 6-membered heterocyclic alkenyl group, wherein the heterocyclic alkenyl group is fused with the benzene ring. When the heterocyclic alkenyl group is fused with the benzene ring, R 1a It may be bicyclic. The benzene ring can be composed of 1 to 4 R groups. 10 Group substitution.

[0110] R 1a It can be selected from nitrogen-free C3-C6-cycloalkyl or 3- to 10-membered heterocyclic alkyl groups in the ring system, and R 1a by at least one NR 7 R 8 Group substitution.

[0111] R 1 It can contain 1, 2, or 3 nitrogen atoms. R 1 It can contain a single nitrogen atom. R 1 It can contain two nitrogen atoms. When R 1 When it contains 2 or 3 nitrogen atoms, at least one nitrogen atom is an amine nitrogen. R 1 It may contain 1, 2 or 3 amine nitrogen atoms, with the option of a single amine nitrogen atom.

[0112] Ring A can be a 3- to 10-membered heterocyclic alkyl group. Ring A can be a 3- to 10-membered heterocyclic alkyl group having a nitrogen atom in the ring system, such as pyrrolidine. Ring A can be a 3- to 10-membered heterocyclic alkyl group having an amine nitrogen atom in the ring system. When ring A is a 3- to 10-membered heterocyclic alkyl group having an amine nitrogen atom in the ring system, it can be linked to the rest of the molecule through a carbon atom in the ring system. When ring A is a 3- to 10-membered heterocyclic alkyl group having an amine nitrogen atom in the ring system, it can be linked to the rest of the molecule through a nitrogen atom in the ring system. Ring A can be a monocyclic 3- to 7-membered heterocyclic alkyl group. Ring A can be piperidine, such as piperidin-4-yl. Ring A can be morpholine. Ring A can be an azirrocycloheptane. Ring A can be pyrrolidine. Ring A can be a bicyclic 7- to 10-membered heterocyclic alkyl group. p can be 0. p can be 1. p can be 2. p can be 3.

[0113] Ring A can be selected from nitrogen-free C3-C6-cycloalkyl or 3- to 10-membered heterocyclic alkyl groups in the ring system, and ring A is surrounded by at least one NR. 7 R 8 Group substitution.

[0114] Ring A can be a 3- to 10-membered heterocyclic alkyl group, wherein the heterocyclic alkyl group is fused to the benzene ring. Ring A can be a 3- to 6-membered heterocyclic alkyl group, wherein the heterocyclic alkyl group is fused to the benzene ring. Ring A fused to the benzene ring can be a bicyclic system. The benzene ring can be composed of 1 to 4 R groups. 10 Group substitution.

[0115] Ring A can be a 5- to 10-membered heterocyclic alkenyl group, wherein the heterocyclic alkenyl group is fused to the benzene ring. Ring A fused to the benzene ring can be a bicyclic system. The benzene ring can have 1 to 4 R groups. 10 Group substitution.

[0116] R 1 It may contain at least one amine nitrogen. The amine nitrogen is the nitrogen in the amine group. For the avoidance of doubt, the term "amine" as used herein includes primary amines, such as methylamine; secondary amines, such as dimethylamine; tertiary amines, such as trimethylamine; and cyclic amines, such as piperidine. For the avoidance of doubt, the term "amine" as used herein does not include amides (including lactams) and sulfonamides (including cyclic sulfonamides).

[0117] R 2a It can be independently selected from H and C1-C2-alkyl. R 2a It can be H.

[0118] R 2b It can be independently selected from H, C1-C4-alkyl, C1-C4-haloalkyl, and C0-C4-alkyl-R. 2c and C2-C4-alkylene-R2d R 2b It can be independently selected from H, C1-C4-alkyl and C0-C4-alkyl-R. 2c R 2b It can be independently selected from H and C1-C4-alkyl. R 2b It can be independently selected from H and C1-C2-alkyl. R 2b It can be H.

[0119] R 2b It can be C2-C4-alkylene-R 2d R 2d It can be NR 7 R 8 R 2d It can be OR 7 .

[0120] Possible: R 2a and R 2b At least one of them is H. Possible possibilities are: R 2a It is H and R 2b Selected from H and methyl. Possible: R 2a It is H and R 2b It is a methyl group. Possible possibilities: R 2a and R 2b Both are H.

[0121] X can be N. X can be CR. 6 For example, CH.

[0122] R 3 It can be H. R 3 It can be a C1-C4 alkyl group, such as methyl.

[0123] R 4 It can be independently selected from H, halogen, cyano, OR 7 SR 7 SOR 7 S(O)2R 7 S(O)2NR 7 R 7 、 CO2R 7 C(O)R 7 C(O)NR 7 R 7 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-ynyl, C1-C4-haloalkyl, O-C0-C4-alkylene-R 4c and C0-C4-alkylene-R 4c .

[0124] R 4 It can be H. R4 It can be a C1-C4 alkyl group, such as methyl.

[0125] R 4 It can be C0-alkylene-R 4c R 4 It is R 4c .

[0126] R 4c It can be independently selected from C3-C8 cycloalkyl, C5-C8 cycloalkenyl, 3-10 membered heterocyclic alkyl, and 5-10 membered heterocyclic alkenyl; wherein R 4c Choose from 1 to 4 Rs 9 Group substitution.

[0127] R 3 and R 4 Together with the carbon atoms to which they are attached, they can form rings selected from C5-C7-cycloalkyl and 5-7-membered heterocyclic alkyl; optionally, wherein the ring is separated by 1 to 6 R atoms. 9 Group substitution. R 3 and R 4 Together with the carbon atoms to which they are attached, they can form rings selected from C5-C7-cycloalkyl and 5-7-membered heterocyclic alkyl; optionally, wherein the ring is separated by 1 to 4 R atoms. 9 Group substitution.

[0128] R 3 and R 4 Together with the carbon atoms to which they are attached, they can form C5-C7 cycloalkyl rings; optionally, the ring is divided by 1 to 6 R atoms. 9 Group substitution. R 3 and R 4 Together with the carbon atoms to which they are attached, they can form C5-C7 cycloalkyl rings; optionally, the ring is divided by 1 to 4 R atoms. 9 Group substitution.

[0129] R 3 and R 4 Together with the carbon atoms to which they are attached, they can form a C5-cycloalkyl ring; optionally, the ring is divided by 1 to 6 R atoms. 9 Group substitution. R 3 and R 4 Together with the carbon atoms to which they are attached, they can form a C5-cycloalkyl ring; optionally, the ring is divided by 1 to 4 R atoms. 9 Group substitution.

[0130] R 5 It can be independently selected from H, halogen, cyano, C1-C4-alkylene-NR 7 R 8 C1-C4-alkylene-OR 7SR 7 SOR 7 S(O)2R 7 S(O)2NR 7 R 7 、 CO2R 7 C(O)R 7 C(O)NR 7 R 7 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-ynyl, -haloalkyl, O-C0-C4-alkylene-R 5c and C0-C4-alkylene-R 5c .

[0131] R 5 It can be H. R 5 It can be a C1-C4 alkyl group, such as methyl.

[0132] R 5 It can be R 5c R 5c It can be any of 1 to 5 R's. 10 A phenyl group substituted with a radical. R 5c It can be any of 1 to 5 R's. 10 Five- or six-membered heteroaryl groups substituted with radicals. R 5c It can be any of 1 to 5 R's. 10 A 6-membered heteroaryl group substituted with a functional group.

[0133] R 4 and R 5 Together with the carbon atoms to which they are attached, they can form rings selected from C5-C7-cycloalkyl and 5-7-membered heterocyclic alkyl; optionally, wherein the ring is separated by 1 to 6 R atoms. 9 Group substitution. R 4 and R 5 Together with the carbon atoms to which they are attached, they can form rings selected from C5-C7-cycloalkyl and 5-7-membered heterocyclic alkyl; optionally, wherein the ring is separated by 1 to 4 R atoms. 9 Group substitution.

[0134] R 4 and R 5 Together with the carbon atoms to which they are attached, they can form C5-C7 cycloalkyl rings; optionally, the ring is divided by 1 to 6 R atoms. 9 Group substitution. R 4 and R 5 Together with the carbon atoms to which they are attached, they can form C5-C7 cycloalkyl rings; optionally, the ring is divided by 1 to 4 R atoms. 9 Group substitution.

[0135] R4 and R 5 Together with the carbon atoms to which they are attached, they can form a C5-cycloalkyl ring; optionally, the ring is divided by 1 to 6 R atoms. 9 Group substitution. R 4 and R 5 Together with the carbon atoms to which they are attached, they can form a C5-cycloalkyl ring; optionally, the ring is divided by 1 to 4 R atoms. 9 Group substitution.

[0136] Cycle B can be independently selected from C5-C7 cycloalkyl and 5- to 7-membered heterocycloalkyl; optionally, wherein cycloB is surrounded by 1 to 6 R... 9 Group substitution. Cycle B can be independently selected from C5-C7 cycloalkyl and 5- to 7-membered heterocyclic alkyl; optionally, wherein cycle B is replaced by 1 to 4 R groups. 9 Group substitution.

[0137] Ring B can be a C5-C7 cycloalkyl group; optionally surrounded by 1 to 6 R groups. 9 Group substitution. Cycle B can be a C5-cycloalkyl group; optionally replaced by 1 to 6 R groups. 9 Group substitution. Cycle B can be a C5-C7 cycloalkyl group; optionally replaced by 1 to 6 R groups. 9 Group substitution. Cycle B can be a C5-cycloalkyl group; optionally, it is replaced by 1 to 4 R groups. 9 Group substitution.

[0138] The ring C can be independently selected from C5-C7 cycloalkyl and 5- to 7-membered heterocycloalkyl; optionally, the ring C is surrounded by 1 to 6 R... 9 Group substitution. The ring C can be independently selected from C5-C7 cycloalkyl and 5- to 7-membered heterocyclic alkyl; optionally, the ring C is replaced by 1 to 4 R groups. 9 Group substitution.

[0139] The ring C can be a C5-C7 cycloalkyl group; optionally surrounded by 1 to 6 R groups. 9 Group substitution. The ring C can be a C5-cycloalkyl group; optionally, it is replaced by 1 to 6 R groups. 9 Group substitution. The ring C can be a C5-C7 cycloalkyl group; optionally, it is replaced by 1 to 4 R groups. 9 Group substitution. The ring C can be a C5-cycloalkyl group; optionally, it is replaced by 1 to 4 R groups. 9 Group substitution.

[0140] R 9 Each time it appears, it can be independently selected from =O, =S, halogen, nitro, cyano, and NR. 7 R 8 OR 7 SR 7 SOR 7 S(O)2R 7 SO2NR7 R 7 、 CO2R 7 C(O)R 7 CONR 7 R 7 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and C1-C3-alkylene-NR 7 R 8 .

[0141] R 9 Each time it appears, it can be independently selected from halogen, NR. 7 R 8 OR 7 CO2R 7 CONR 7 R 7 C1-C4-alkyl, C1-C3-alkylene-OR 7 and C1-C3-alkylene-NR 7 R 8 .

[0142] R 9 Each time it appears, it can be independently selected from F, Cl, Br, NR. 7 R 8 OR 7 CO2R 7 CONR 7 R 7 C1-C4-alkyl, C1-C3-alkylene-OR 7 and C1-C3-alkylene-NR 7 R 8 .

[0143] R 9 Each time it appears, it can be independently selected from F and NR. 7 R 8 OR 7 CO2R 7 CONR 7 R 7 C1-C4-alkyl, C1-C3-alkylene-OR 7 and C1-C3-alkylene-NR 7 R 8 .

[0144] R 9 Each time it appears, it can be independently selected from F and NR. 7 R 8 OR 7 CO2R 7 CONR7 R 7 And C1-C4-alkyl.

[0145] R 9 Each occurrence can be independently selected from OH and C1-C4-alkyl.

[0146] R 9a Each time it appears, it can be independently selected from C3-C8 cycloalkyl, phenyl, 3-8 membered heterocycloalkyl, and 5- or 6-membered heteroaryl; wherein when R 9a When it is a cycloalkyl or heterocycloalkyl group, R 9a Choose from 1 to 4 Rs 9 Group substitution; and when R 9a When it is phenyl or heteroaryl, R 9a Choose from 1 to 5 Rs 10 Group substitution.

[0147] R 9a Each time it appears, it can be phenyl independently, optionally surrounded by 1 to 5 R. 10 Group substitution.

[0148] R 10 Each time it appears, it can be independently selected from halogen, cyano, OR. 7 C1-C4-alkyl, C1-C4-haloalkyl, C1-C3-alkylene-NR 7 R 8 and C1-C3-alkylene-OR 7 .

[0149] R 10 Each time it appears, it can be independently selected from halogen, cyano, OR. 7 C1-C4-alkyl and C1-C4-haloalkyl.

[0150] R 10 Each time it appears, it can be independently selected from F, Cl, Br, cyano, and OR. 7 C1-C4-alkyl and C1-C4-haloalkyl.

[0151] R 10 Each time it appears, it can be independently selected from F, cyano, or OR. 7 C1-C4-alkyl and C1-C4-haloalkyl.

[0152] In one embodiment, where chemically possible, any alkyl, alkylene, alkenyl, or cycloalkyl group may optionally be substituted with 1 to 5 substituents, each substituent being independently selected from the group consisting of: oxo, fluorinated, NR. a R b OR aand S(O)2R a ;where R a Each time it appears, it is independently selected from H and C1-C4-alkyl; and R b Each time it appears, it is independently selected from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl.

[0153] Possible: R 1 It is a 3- to 10-membered heterocyclic alkyl group having nitrogen in the ring system, such as pyrrolidine, optionally surrounded by C0-C6-alkylene-R 9a And / or 1 to 6 R 9 Group substitution; and R 4 and R 5 Together with the carbon atoms to which they are attached, they form a C5-C7 cycloalkyl ring; optionally, wherein the ring is divided by 1 to 6 R atoms. 9 Group substitution.

[0154] Possible: R 1 It is a 3- to 10-membered heterocyclic alkyl group having nitrogen in the ring system, such as pyrrolidine, optionally surrounded by C0-C6-alkylene-R 9a And / or 1 to 6 R 9 Group substitution; and R 4 and R 5 Together with the carbon atoms to which they are attached, they form a C5-cycloalkyl ring; optionally, wherein the ring is composed of 1 to 6 R atoms. 9 Group substitution.

[0155] Possible: R 1 It is a 3- to 10-membered heterocyclic alkyl group having nitrogen in the ring system, such as pyrrolidine, optionally surrounded by C0-C6-alkylene-R 9a And / or 1 to 6 R 9 Group substitution; and the ring C is a C5-C7 cycloalkyl ring; optionally substituted with 1 to 6 R groups. 9 Group substitution.

[0156] Possible: R 1 It is a 3- to 10-membered heterocyclic alkyl group having nitrogen in the ring system, such as pyrrolidine, optionally surrounded by C0-C6-alkylene-R 9a And / or 1 to 6 R 9 Group substitution; and the ring C is a C5-cycloalkyl; optionally substituted with 1 to 6 R groups. 9 Group substitution.

[0157] In one embodiment, the compound of formula (I) is selected from:

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[0159] According to a second aspect, the present invention provides a pharmaceutical composition comprising a compound as defined in the first aspect and one or more pharmaceutically acceptable excipients.

[0160] According to a third aspect, the present invention provides compounds as defined in the first aspect or pharmaceutical compositions as defined in the second aspect, which are used as pharmaceuticals.

[0161] According to the fourth aspect, the present invention provides the use of compounds as defined in the first aspect or pharmaceutical compositions as defined in the second aspect in the preparation of pharmaceuticals.

[0162] According to a fifth aspect, the present invention provides compounds as defined in the first aspect or pharmaceutical compositions as defined in the second aspect for the treatment or prevention of diseases or conditions of the musculoskeletal system, skin diseases, metabolic diseases, nervous system diseases, cardiovascular diseases, endocrine disorders, eye diseases, diseases affecting the genitourinary system, blood or lymphatic diseases, respiratory diseases, inflammatory or autoimmune diseases, gastrointestinal diseases, tumors, cancers, or diseases or conditions selected from amelioration, dentition, tooth dysplasia, gill-oto-kidney syndrome, Sothos syndrome, and Waardenburg syndrome.

[0163] According to a sixth aspect, the present invention provides a method for treating or preventing diseases of the musculoskeletal system, skin diseases, metabolic diseases, nervous system diseases, cardiovascular diseases, endocrine disorders, eye diseases, diseases affecting the genitourinary system, blood or lymphatic diseases, respiratory diseases, inflammatory or autoimmune diseases, gastrointestinal diseases, tumors, cancers, or diseases or conditions selected from amelioration, dentition, tooth dysplasia, gill-oto-kidney syndrome, Sothos syndrome, and Waardenburg syndrome, said method comprising administering to a subject an effective amount of a compound as defined in the first aspect or a pharmaceutical composition as defined in the second aspect.

[0164] According to a seventh aspect, the present invention provides a compound as defined in the first aspect or a pharmaceutical composition as defined in the second aspect, for use in treating or preventing diseases selected from the following: latent dystrophic epidermolysis bullosa, junctional epidermolysis bullosa, xeroderma pigmentosum, Natherton syndrome, Duchenne muscular dystrophy, Becker muscular dystrophy, cystic fibrosis, Allport syndrome, Dlavit syndrome, aniridia, methylmalonic acidemia, colorectal cancer, endometrial cancer, breast cancer, ovarian cancer, squamous cell carcinoma of the lung, squamous cell carcinoma of the head and neck, familial adenomatous polyposis, hemophilia A, hemophilia B, choroidal agenesis, pulmonary hypertension, ataxia-telangiectasia, Shwachman-Diamond syndrome, mucopolysaccharidosis type I, mucopolysaccharidosis type VI, mucopolysaccharidosis type III, Niemann-Pick disease, primary ciliary dyskinesia, Usher syndrome, and retinitis pigmentosa.

[0165] According to the eighth aspect, the present invention provides a method for treating or preventing diseases selected from: latent dystrophic epidermolysis bullosa, junctional epidermolysis bullosa, xeroderma pigmentosum, Natherton syndrome, Duchenne muscular dystrophy, Becker muscular dystrophy, cystic fibrosis, Allport syndrome, Dlavit syndrome, aniridia, methylmalonic acidemia, colorectal cancer, endometrial cancer, breast cancer, ovarian cancer, squamous cell carcinoma of the lung, squamous cell carcinoma of the head and neck, familial adenomatous polyposis, hemophilia A, hemophilia B, choroidal agenesis, pulmonary hypertension, ataxia-telangiectasia, Shwachman-Diamond syndrome, mucopolysaccharidosis type I, mucopolysaccharidosis type VI, mucopolysaccharidosis type III, Niemann-Pick disease, primary ciliary dyskinesia, Usher syndrome, and retinitis pigmentosa.

[0166] According to the ninth aspect, the present invention provides the use of compounds as defined in the first aspect or pharmaceutical compositions as defined in the second aspect in the preparation of medicaments for the treatment or prevention of the following diseases: musculoskeletal disorders, skin diseases, metabolic diseases, nervous system diseases, cardiovascular diseases, endocrine disorders, eye diseases, diseases affecting the genitourinary system, blood or lymphatic diseases, respiratory diseases, inflammatory or autoimmune diseases, gastrointestinal diseases, tumors, cancer, or selected from amelioration, dentition, tooth dysplasia, gill-oto-kidney syndrome, Sothos syndrome, and Waardenburg syndrome.

[0167] According to a tenth aspect, the present invention provides a method for enabling PTC mutation translation readthrough in a subject, the method comprising administering to the subject an effective amount of a compound as defined in the first aspect or a pharmaceutical composition as defined in the second aspect.

[0168] According to the eleventh aspect, the present invention provides a method for treating a condition or symptom associated with PTC mutation in a subject using a compound as defined in the first aspect or a pharmaceutical composition as defined in the second aspect, the method comprising administering to the subject an effective amount of the compound as defined in the first aspect or the pharmaceutical composition as defined in the second aspect.

[0169] According to a twelfth aspect, the present invention provides a method for treating a condition or ailment associated with a PTC mutation in a subject, the method comprising administering to the subject an effective amount of a compound as defined in the first aspect or a pharmaceutical composition as defined in the second aspect.

[0170] Suitablely, a PTC mutation can be any mutation that produces an in-frame premature stop codon (PTC) in a gene. Suitablely, a PTC mutation can be any mutation that produces an in-frame premature stop codon (PTC) in a gene. Suitablely, a PTC mutation occurs in the nucleotide sequence of a gene. Suitablely, a PTC mutation can occur in the coding or non-coding region of a gene. Suitablely, a PTC mutation can occur in the coding region of a gene.

[0171] Suitable mutations can be point mutations, such as substitution, deletion, or insertion mutations. Suitable mutations can be substitution mutations. Suitablely, a substitution mutation can suitably replace one nucleotide with another different nucleotide within the nucleotide sequence of a gene. Suitablely, the mutation can therefore be considered a nonsense mutation. Suitablely, the mutation can be a nonsense mutation resulting in a PTC within a frame in the gene. Suitablely, the PTC can be any known stop codon, such as TAG, TAA, or TGA. Suitablely, the PTC can be TGA. Suitablely, therefore, in some embodiments, a PTC mutation can be a substitution mutation that produces a PTC in the gene containing TAG, TAA, or TGA. Suitablely, therefore, in some embodiments, a PTC mutation can be a CGA to TGA or CAG to TAG substitution mutation in the gene.

[0172] Conditions or symptoms associated with PTC mutations in subjects can be conditions or symptoms directly or indirectly caused by a PTC mutation. Suitablely, conditions or symptoms associated with PTC mutations in subjects can be conditions or symptoms directly caused by a PTC mutation. Suitablely, conditions or symptoms associated with PTC mutations in subjects can be conditions or symptoms caused by PTC mutations in one or more genes in the subject. Suitablely, conditions or symptoms associated with PTC mutations in subjects can be conditions or symptoms directly caused by PTC mutations in one or more genes in the subject. Suitablely, conditions or symptoms associated with PTC mutations in subjects can be conditions or symptoms caused by PTC mutations in one or more genes in the subject resulting in loss of function of that gene or each gene. The appropriate reference to "one" PTC mutation in this document may be understood to mean one or more PTC mutations, or multiple PTC mutations, which may suitably be present in one or more genes of the subject.

[0173] Suitablely, one or more genes containing PTC mutations are genes associated with one or more diseases described herein. Suitablely, one or more genes may be directly or indirectly associated with one or more diseases described herein. Suitablely, the one or more genes may contribute to or cause the phenotype of one or more diseases described herein. Such genes may be, for example, LAMB3, COL7A, COL4, CFTR, and DMD, each of which is associated with one or more diseases identified herein. In some embodiments, such as in the case of cancer, one or more genes containing PTC mutations may be cell cycle genes, tumor suppressor genes, etc. Such tumor suppressor genes may include, for example, TP53, PTEN, APC, ARID1A, or CTCF. Suitablely, such mutations may be considered driver mutations, suitablely driving disease phenotypes, such as tumor growth. Therefore, in some embodiments, PTC mutations may be considered driver mutations. In other embodiments, one or more genes containing PTC mutations may not contribute to or cause disease phenotypes. Suitablely, such mutations may be considered bystander mutations. Therefore, in some embodiments, PTC mutations may be considered bystander mutations.

[0174] Conditions or symptoms associated with PTC mutations are well known in the art, and suitable such conditions can be treated or prevented by the present invention are described below. However, suitably, such conditions associated with PTC mutations can also be identified or determined using standard molecular biology techniques. Diseases or conditions associated with PTC mutations can be suitably identified using molecular biology techniques such as sequencing, single-strand conformation polymorphism, denaturing gradient gel electrophoresis, heteroduplex analysis, or restriction fragment length polymorphism. Suitably, such techniques can be used to identify PTC mutations present in one or more genes of a subject that can lead to a disease or condition. Suitably, whole-genome sequencing or whole-exome sequencing can be used to identify PTC mutations in one or more genes of a subject, suitably those mutations that can lead to a disease or condition. Suitable methods may be described, for example, in Karagiannakos et al. Cancers (Basel) 2022, 14, 664, Stark et al. 'A prospective evaluation of whole-exome sequencing as a first-tiermolecular test in infants with suspected monogenic disorders' Genetics inMedicine, Volume 18, Issue 11, 2016, North et al. Neuromuscular Disorders, Volume 24, Issue 2, 2014.

[0175] Suitably, these techniques can be applied to samples obtained from subjects who have or are suspected of having a disease or condition, which may suitably be caused by a PTC mutation. Suitably, this technique may include comparing results from said sample with results obtained from a reference sample. Suitably, the reference sample may be a sample of the same type from a healthy subject, suitably from equivalent healthy subjects of the same age, nationality, ethnicity, height, weight, etc. Suitable samples may include: blood samples, serum samples, CNS fluid samples, tissue samples, cell samples, etc. Suitably, in the context of the above techniques, the comparison results may include comparing the sequences of one or more genes from a subject with the sequences of the same one or more genes from a healthy subject. Suitably, identifying PTC mutations within one or more genes in a subject with a disease or condition. Suitably, this sequence comparison may be performed using available software, such as alignment software.

[0176] PTC read-through agents, such as the compounds disclosed herein, may be valuable in one or more embodiments and for use in treating or improving examples of the following non-limiting conditions and diseases. Suitably, any of the following conditions and diseases can be considered as a disease or symptom associated with a PTC mutation in a subject. Suitably, therefore, the present invention suitably provides a method for treating a condition or symptom associated with a PTC mutation in a subject, wherein said condition or symptom is selected from any of the following paragraphs.

[0177] The disease can be a musculoskeletal disorder. Such musculoskeletal disorders can be selected from the following: Shwachman-Diamond syndrome, rickets, Laron syndrome, muscular dystrophy (e.g., Duchenne muscular dystrophy (DMD)), microcephaly, congenital limb deformities, muscle spasms, dwarfism, gigantism, osteophytic dysplasia, clavicle-craniophysema, premature suture closure, mitochondrial myopathy and encephalopathy, premature craniosynostosis, mandibular-facial dysplasia, scoliosis, osteoporosis, osteopenia, osteoproliferative disorders, osteosclerosis, osteogenesis imperfecta, holoprosencephaly, acromegaly, joint contractures, and flexion dysplasia.

[0178] The disease may be a skin condition. The skin condition may be selected from the following: ectodermal dysplasia, epidermolysis bullosa, focal cutaneous dysplasia, ichthyosis vulgaris, autosomal recessive congenital ichthyosis (ARCI), recessive X-linked ichthyosis, lamellar ichthyosis, congenital ichthyosiform erythroderma, harlequin ichthyosis, epidermolysis bullosa, superficial epidermolysis bullosa, CHILD syndrome, Natherton syndrome, Mednik syndrome, neutral lipid storage disease with ichthyosis, atopic dermatitis, alopecia, papular dermatitis, hypotrichosis, pigment incontinence, simple epidermolysis bullosa, lipodystrophy. Hidradenitis suppurativa, hyperpigmentation, borderline bullous epidermolysis, oculocutaneous albinism, chronic mucocutaneous candidiasis, chronic mucocutaneous ichthyosis, X-linked hypopigmentation, skin laxity, Menkes knot syndrome, palmoplantar keratoderma, Ehlers-Danlos syndrome, congenital tinea corporis, onychomycosis, benign familial pemphigus, albinism; Kindler syndrome, Cowden syndrome, xeroderma pigmentosum, epidermophys verrucous dysplasia, lipoprotein deposition syndrome, hereditary symmetrical pigmentary abnormalities, keratosis pilaris, autosomal recessive congenital unnamed malformation, focal dermal dysplasia, and fragility / trichosis syndrome.

[0179] The disease can be a metabolic disorder. Such metabolic disorders may include congenital adrenal hyperplasia, congenital amino acid metabolism defects, hypertriglyceridemia, type 1 and type 2 diabetes, glycogen storage disease, optic nerve atrophy, calcification, polysulfatase deficiency, Fabry disease, hyperinsulinemia, familial hypophosphatemia, pseudohypoaldosteronism, Tangier disease, amyotrophic lateral sclerosis, lactic acidosis, familial amyloidosis, mucopolysaccharidosis, anemia, Sandhof's disease, cytochrome C oxidase deficiency, pyruvate dehydrogenase complex deficiency, hypoglycemia, neuronal ceroid-lipofuscinosis, and severe combined immune disorders. Immunological deficiencies, chronic idiopathic jaundice, premature aging, hyponatremia, wasting syndrome, cystinuria, glycogen storage disease, Gaucher disease, hypolipoproteinemia, oculoencephalopathy-renal syndrome, Smith-Limeley-Oppitz syndrome, adrenoleukodystrophy, ataxia-telangiectasia, Canavan disease, carbamoyl phosphate synthase I deficiency, β-mannoside storage disease, and lysosomal storage disease, wherein the lysosomal storage disease may be selected from Niemann-Pick disease mucopolysaccharidosis type 1 (Hurler syndrome), mucopolysaccharidosis type 6, mucopolysaccharidosis type 7, CLN1 disease, and CL3 disease.

[0180] The disease can be a neurological disorder. This neurological disorder may include Rett syndrome, ataxia, sensorineural hearing loss, epilepsy, Charcot-Marie-Tooth disease, spinal muscular atrophy, spastic paraplegia, hydrocephalus, migraine with aura, chorea, tremor, Usher syndrome, De Lange syndrome, Duane withdrawal syndrome, dementia, myoclonus, hereditary sensory and autonomic neuropathy, intellectual disability, X-linked intellectual disability, Fragile X syndrome, hypopituitarism, leukoencephalopathy, dystonia, congenital pain insensitivity, Tourette syndrome, Alzheimer's disease, Parkinson's disease, Angerman syndrome, apraxia, cerebral palsy, and frontotemporal dementia.

[0181] The disease can be a cardiovascular disease. The cardiovascular disease can be selected from coronary heart disease, ventricular fibrillation, telangiectasia, Katagan syndrome, Allajeller syndrome, Anderson syndrome, atrioventricular block, and cardiomyopathy.

[0182] The condition mentioned can be an endocrine disorder. Endocrine disorders may include hypogonadism, goiter, macrosomia, thyroid hormone resistance syndrome, gonadal dysgenesis, hypoparathyroidism, neurogenic diabetes insipidus, and androgen insensitivity syndrome.

[0183] The disease may be an eye condition. This eye condition may include Leber syndrome, hereditary optic atrophy, lens displacement, defects, aphakia, and choroidal loss.

[0184] The disease can be one that affects the urogenital system. Diseases affecting the urogenital system may include hypospadias, hydrops fetus, interstitial nephritis, polycystic kidney disease, azoospermia, Alport syndrome, and azoospermia.

[0185] The disease or condition may be a hematologic or lymphatic condition. The hematologic or lymphatic condition may be selected from α- and β-thalassemia, afibrinogenemia, hemophagocytic lymphohistiocytosis, factor XI deficiency, hemophilia A, von Willebrand disease, factor V deficiency, sideroblastic anemia, hereditary elliptic cell disease, neutropenia, chronic granulomatous disease, hereditary spherocytosis, polycythemia vera, hemophilia B, factor VII deficiency, Bernard-Soulier syndrome, erythropoietic anemia, hemolytic anemia, idiopathic thrombocytopenic purpura, thrombocytosis, factor XIII deficiency, hepatoerythropoietic porphyria, and acute intermittent porphyria.

[0186] The disease may be a respiratory disease. Such respiratory diseases may include cystic fibrosis, pulmonary hypertension, Urbach and Wiethe's lipoprotein deposition syndrome, neonatal respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), asthma, and posterior nasal atresia.

[0187] The disease or condition may be an inflammatory or autoimmune disease. The inflammatory or autoimmune disease may be selected from immunodeficiency syndromes and leukocyte adhesion deficiency syndromes.

[0188] The disease can be a gastrointestinal disorder. This gastrointestinal disorder can be selected from chronic hepatitis B, colitis, intestinal polyposis, inflammatory bowel disease, congenital megacolon, pancreatic exocrine insufficiency, Crohn's disease, and cholestasis.

[0189] The disease or condition mentioned may be a tumor. The tumor may be selected from acute myeloid leukemia, paraganglioma, rhabdoid tumor, rhabdomyosarcoma, adenoid cystic carcinoma, large cell carcinoma, lobular carcinoma, skin appendage carcinoma, squamous cell carcinoma, alveolar rhabdomyosarcoma, neuroectodermal tumor, multiple hamartoma syndrome, pheochromocytoma, nevus, osteosarcoma, teratoma, and adenoma.

[0190] The disease or condition mentioned can be cancer. The cancer may be selected from acoustic neuroma, anal cancer, bladder cancer, Bowen's disease, brain cancer, breast cancer, various carcinomas (including basal cell carcinoma, bile duct carcinoma, bronchial carcinoma, choriocarcinoma, embryonal carcinoma, cystadenocarcinoma, epithelial carcinoma, medullary carcinoma, midline NUT carcinoma (NMC), papillary carcinoma, papillary gland carcinoma, renal cell carcinoma, sebaceous gland carcinoma, small cell lung cancer, squamous cell carcinoma, and sweat gland carcinoma), cervical cancer, chordoma, colon cancer, colorectal cancer, craniopharyngioma, proliferative dysplasia (developmental abnormalities and metaplasia), endometrial cancer, ependymoma, esophageal cancer, essential thrombocytosis, estrogen receptor-positive breast cancer, Ewing's tumor, and genital cancer. Cervical cancer, vulvar cancer, vulvar intraepithelial neoplasia (VIN), vaginal cancer, germ cell testicular cancer, gastrointestinal cancer, gastric cancer, glioblastoma, glioma, heavy chain disease, angioblastoma, hepatocellular carcinoma, liver cancer, hormone-insensitive prostate cancer, keratinocyte carcinoma, kidney cancer, leukemia (including acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic... Myeloid leukemia, erythroleukemia, lymphoblastic leukemia, and myeloid leukemia; liver cancer; lung cancer; T-cell or B-cell lymphomas; lymphomas (Hodgkin's and non-Hodgkin's (including cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma), cutaneous (skin) lymphoma); malignant tumors and hyperproliferative disorders (including bladder, breast, colon, lung, ovary, pancreas, prostate, skin, and uterus); advanced malignant tumors; medulloblastoma; melanoma; meningioma; Merkel cell carcinoma; mesothelioma; metastatic cancer; multiple myeloma; myeloma; pancreatic cancer; myelofibrosis; myeloproliferative neoplasms. Neuroblastoma, non-small cell lung cancer, head and neck cancer, oligodendroglioma, oral cancer, ovarian cancer, pancreatic cancer, pineal tumor, polycythemia vera, prostate cancer, rectal cancer, retinoblastoma, sarcoma (including chondrosarcoma, endothelial sarcoma, fibrosarcoma, glial sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, lymphangiosarcoma, myxosarcoma, Castreman's disease and Kaposi's sarcoma, osteoblastic sarcoma and rhabdomyosarcoma, seminoma, skin cancer, skin appendage tumors and sarcomas), small cell lung cancer, solid tumors, gastric cancer, synovial tumors, testicular tumors, thyroid cancer, uterine cancer, Waldenström macroglobulinemia, and Wilms' tumor.

[0191] The diseases or conditions mentioned can be selected from amelioration, dentition, tooth dysplasia, gill-ear-kidney syndrome, Sothos syndrome, and Waldenberg syndrome.

[0192] The diseases or conditions mentioned may be selected from: subclinical epidermolysis bullosa, junctional epidermolysis bullosa, xeroderma pigmentosum, Netherton syndrome, Duchenne muscular dystrophy, Becker muscular dystrophy, cystic fibrosis, Dellaway syndrome, aniridia, methylmalonic acidemia, colorectal cancer, endometrial cancer, breast cancer, ovarian cancer, squamous cell carcinoma of the lung, squamous cell carcinoma of the head and neck, familial adenomatous polyposis, hemophilia A, hemophilia B, choroidal agenesis, pulmonary hypertension, ataxia-telangiectasia, Shwachman-Diamond syndrome, mucopolysaccharidosis type I, mucopolysaccharidosis type VI, mucopolysaccharidosis type III, Niemann-Pick disease, primary ciliary dyskinesia and ciliopathy (such as Usher syndrome or retinitis pigmentosa).

[0193] The disease or condition may be selected from: recessive dystrophic epidermolysis bullosa, borderline epidermolysis bullosa, Duchenne muscular dystrophy, cystic fibrosis, colorectal cancer, endometrial cancer, breast cancer, ovarian cancer, squamous cell carcinoma of the lung, squamous cell carcinoma of the head and neck, and familial adenomatous polyposis. Suitably, this condition may be associated with a PTC mutation in the subject. Suitably, for example, the disease may be borderline epidermolysis bullosa associated with a PTC mutation in the LAMB3 gene. Suitably, for example, the disease may be recessive dystrophic epidermolysis bullosa associated with a PTC mutation in the COL7A1 gene. Suitably, for example, the disease may be Duchenne muscular dystrophy associated with a PTC mutation in the DMD gene. Suitably, for example, the disease may be cystic fibrosis associated with a PTC mutation in the CTFR gene. Suitably, for example, the disease may be familial adenomatous polyposis associated with a PTC mutation in the APC gene. Suitable, for example, the disease could be one of the cancers listed above that is associated with a PTC mutation in a gene selected from TP53, PTEN, ARID1A, or CTCF.

[0194] Accordingly, the present invention provides a method for treating a condition or symptom associated with a PTC mutation in a subject, wherein the condition or symptom associated with a PTC mutation in the subject is selected from subclinical epidermolysis bullosa, junctional epidermolysis bullosa, xeroderma pigmentosum, Natherton syndrome, Duchenne muscular dystrophy, Becker muscular dystrophy, cystic fibrosis, Dravet syndrome, aniridia, methylmalonic acidemia, familial adenomatous polyposis, hemophilia A, hemophilia B, choroidal agenesis, pulmonary hypertension, ataxia-telangiectasia, Shwachman-Diamond syndrome, mucopolysaccharidosis type I, mucopolysaccharidosis type VI, mucopolysaccharidosis type III, Niemann-Pick disease, primary ciliary dyskinesia, ciliary disorders (such as Usher syndrome or retinitis pigmentosa), and Alport syndrome. In some embodiments, the present invention provides a method for treating a condition or symptom associated with PTC mutation in a subject, wherein the condition or symptom associated with PTC mutation in the subject is selected from subclinical epidermolysis bullosa, junctional epidermolysis bullosa, Duchenne muscular dystrophy, cystic fibrosis, and familial adenomatous polyposis.

[0195] In one or more embodiments, a PTC read-through agent, such as the compounds disclosed herein, may also be valuable and used to alleviate, diagnose, or prevent any human disease, condition, or symptom among one or more of the aforementioned non-limiting conditions and illnesses. Suitably, any of the aforementioned conditions and illnesses may be considered a disease or symptom associated with a PTC mutation in a subject. Accordingly, the present invention further provides a method for alleviating, diagnosing, or preventing a condition or symptom associated with a PTC mutation in a subject, wherein said condition or symptom is selected from any of those listed in the preceding paragraphs.

[0196] In some embodiments, treatment or improvement with a PTC transducer, such as a composition comprising a compound disclosed herein or a salt thereof (or a combination thereof), may be effective if administered orally. In some other embodiments, topical application may be effective; and in some further embodiments, both topical and oral application may be effective.

[0197] In some embodiments, compositions comprising the novel compounds disclosed herein or their salts (or combinations thereof) may be administered to young children. In some embodiments, compositions comprising the compounds of the present invention or their salts (or combinations thereof) may be administered to adolescents. In some embodiments, compositions comprising the compounds of the present invention or their salts (or combinations thereof) may be administered to adults.

[0198] This disclosure may also be defined according to any of the following numbered clauses:

[0199] 1. A compound of formula (I) or its tautomer form or its pharmaceutically acceptable salt or N-oxide:

[0200] (I)

[0201] in

[0202] X is N or CR 6 ;

[0203] R 1 Independently selected from C0-C6-alkylene-R 1a and C2-C6-alkylene-R 1b ;

[0204] R 1a Independently selected from C3-C8 cycloalkyl, C5-C8 cycloalkenyl, 3- to 10-membered heterocyclic alkyl, and 5- to 10-membered heterocyclic alkenyl; wherein R 1a Optionally by 1 to 4 R 9 Group substitution; wherein when R 1a When the group is a heterocyclic alkyl or heterocyclic alkenyl group, the heterocyclic alkyl or heterocyclic alkenyl group is optionally fused with a benzene ring, wherein the benzene ring is optionally surrounded by 1 to 4 R groups. 10 Group substitution;

[0205] R 1b Independently selected from NR 7a R 8a and OR 7 ;

[0206] Where R 1 It contains at least one nitrogen atom;

[0207] R 2a Each occurrence is independently selected from H and C1-C4 alkyl groups;

[0208] R 2b Each occurrence is independently selected from H, C1-C4-alkyl, C0-C4-alkyl-R. 2c C(O)-C1-C4-alkyl, S(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl;

[0209] R 2c Independently selected from C3-C8 cycloalkyl, C5-C8 cycloalkenyl, phenyl, 3-8-membered heterocycloalkyl, 5-8-membered heterocycloalkenyl, and 5- or 6-membered heteroaryl; wherein R 2c When it is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, R 2c Choose from 1 to 4 Rs 9 Group substitution; and when R 2c When it is phenyl or heteroaryl, R 5c Choose from 1 to 5 Rs10 Group substitution;

[0210] Or, R 2a and R 2b Together with the nitrogen atoms to which they are attached, they form 5- to 8-membered heterocyclic alkyl rings; optionally surrounded by 1 to 4 R... 9 Group substitution;

[0211] R3 is independently selected from H, cyano, C1-C4-alkylene-NR7R8, NR7R8, C1-C4-alkylene-OR 7 OR 7 SR 7 SOR 7 S(O)2R 7 S(O)2NR 7 R 7 、 CO2R 7 C(O)R 7 C(O)NR 7 R 7 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, NR7-C0-C4-alkylene-R 3c O-C0-C4-alkylene-R 3c and C0-C4-alkylene-R 3c ;

[0212] R 3c Independently selected from C3-C8 cycloalkyl, C5-C8 cycloalkenyl, phenyl, 3-10-membered heterocycloalkyl, 5-10-membered heterocycloalkenyl, and 5- or 6-membered heteroaryl; wherein when R 3c When it is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, R 3c Choose from 1 to 4 Rs 9 Group substitution; and when R 3c When it is phenyl or heteroaryl, R 3c Choose from 1 to 5 Rs 10 Group substitution;

[0213] R 4 Independently selected from H, halogen, cyano, NR 7b R 8 OR 7 SR 7 SOR 7 S(O)2R 7 S(O)2NR 7 R 7 、 CO2R 7 C(O)R 7 C(O)NR7 R 7 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-ynyl, C1-C4-haloalkyl, O-C0-C4-alkylene-R 4c and C0-C4-alkylene-R 4c ;

[0214] R 4c Independently selected from C3-C8 cycloalkyl, C5-C8 cycloalkenyl, 3-10-membered heterocycloalkyl, 5-10-membered heterocycloalkenyl and 5-membered heteroaryl; wherein when R 4c When it is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, R 4c Choose from 1 to 4 Rs 9 Group substitution; and when R 4c When it is a heteroaryl group, R 4c Choose from 1 to 5 Rs 10 Group substitution;

[0215] R 5 Independently selected from H, halogen, cyano, C1-C4-alkylene-NR 7 R 8 NR 7 R 8 C1-C4-alkylene-OR 7 OR 7b SR 7 SOR 7 S(O)2R 7 S(O)2NR 7 R 7 CO2R 7 C(O)R 7 C(O)NR 7 R 7 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, NR 7 -C0-C4-alkylene-R 5c O-C0-C4-alkylene-R 5c and C0-C4-alkylene-R 5c ;

[0216] R 5c Independently selected from C3-C8 cycloalkyl, C5-C8 cycloalkenyl, phenyl, 3-10-membered heterocycloalkyl, 5-10-membered heterocycloalkenyl, and 5- or 6-membered heteroaryl; wherein when R 5c When it is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, R 5c Choose from 1 to 4 Rs 9 Group substitution; and when R 5c When it is phenyl or heteroaryl, R5c Choose from 1 to 5 Rs 10 Group substitution;

[0217] Or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a ring selected from phenyl, C5-C7-cycloalkyl, 5-7-membered heterocycloalkyl, and 5- or 6-membered heteroaryl; wherein when the ring is cycloalkyl or heterocycloalkyl, it is optionally bounded by 1 to 4 R atoms. 9 Group substitution, where the ring is phenyl or heteroaryl, is optionally replaced by 1 to 4 R groups. 10 Group substitution;

[0218] Or R 4 and R 5 Together with the carbon atoms to which they are attached, they form a ring selected from phenyl, C5-C7-cycloalkyl, 5-7-membered heterocycloalkyl, and 5- or 6-membered heteroaryl; wherein when the ring is cycloalkyl or heterocycloalkyl, it is optionally bounded by 1 to 4 R atoms. 9 Group substitution, where the ring is phenyl or heteroaryl, is optionally replaced by 1 to 4 R groups. 10 Group substitution;

[0219] R 6 Independently selected from H, halogens, C1-C6-alkyl groups, and C1-C6-haloalkyl groups;

[0220] R 7 and R 7a Each of the two groups is independently selected from H and C1-C4-alkyl groups in each occurrence;

[0221] R 7b Each occurrence is independently selected from C1-C4 alkyl groups;

[0222] R 8 Each occurrence is independently selected from H, C1-C4-alkyl, C1-C4-haloalkyl, and C(O)-C1-C4-alkyl.

[0223] R 8a Each occurrence is independently selected from H, C1-C4 alkyl, C1-C4-haloalkyl, C(O)-C1-C4-alkyl, and optionally surrounded by 1 to 5 R. 10 Phenyl groups substituted with radicals;

[0224] Or, R 7a and R 8a Together with the nitrogen atoms to which they are attached, they form 5- to 8-membered heterocyclic alkyl rings; optionally surrounded by 1 to 4 R... 9 Group substitution;

[0225] R 9 Each time it appears, it is independently selected from =O, =S, halogen, nitro, cyano, and NR.7 R 8 OR 7 SR 7 SOR 7 S(O)2R 7 SO2NR 7 R 7 、 CO2R 7 C(O)R 7 CONR 7 R 7 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, C1-C3-alkylene-NR 7 R 8 and C0-C3-alkylene-phenyl;

[0226] R 10 Each time it appears, it is independently selected from halogen, nitro, cyano, and NR. 7 R 8 OR 7 SR 7 SOR 7 S(O)2R 7 SO2NR 7 R 7 、 CO2R 7 C(O)R 7 CONR 7 R 7 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, C1-C3-alkylene-NR 7 R 8 and C1-C3-alkylene-OR 7 ;and

[0227] Any of the aforementioned alkyl, alkylene, alkenyl, or cycloalkyl groups may be optionally substituted with 1 to 5 substituents, wherein each substituent is independently selected from the group consisting of: C1-C4-alkyl, oxo, halogen, nitro, cyano, NR. a R b OR a SR a CO2R a C(O)R a CONR a R a S(O)R a and S(O)2R a ;where R aEach time it appears, it is independently selected from H and C1-C4-alkyl; and R b Each time it appears, it is independently selected from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl.

[0228] 2. The compound according to Clause 1, wherein X is N.

[0229] 3. The compound according to Clause 1 or Clause 2, wherein R 2a and R 2b Each is represented by H.

[0230] 4. The compound according to any one of clauses 1 to 3, wherein R 1 It contains at least one amine nitrogen.

[0231] 5. The compound according to any one of clauses 1 to 4, wherein R 1 It is C0-C6-alkylene-R 1a .

[0232] 6. The compound according to Clause 5, wherein R 1 It is R 1a .

[0233] 7. Compounds pursuant to Clause 5 or Clause 6, wherein R 1a It is a 3- to 10-membered heterocyclic alkyl group that has nitrogen in the ring system.

[0234] 8. The compound according to any one of clauses 1 to 7, wherein R 3 It's H.

[0235] 9. The compound according to any one of clauses 1 to 7, wherein R 3 It is a C1-C4-alkyl group.

[0236] 10. The compound according to any one of clauses 1 to 9, wherein R 4 It's H.

[0237] 11. The compound according to any one of clauses 1 to 9, wherein R 4 It is a C1-C4-alkyl group.

[0238] 12. The compound according to any one of clauses 1 to 11, wherein R 5 It is R 5c .

[0239] 13. The compound according to any one of clauses 1 to 12, wherein R 5c It can be selected from 1 to 5 Rs. 10 A phenyl group substituted with a radical.

[0240] 14. The compound according to any one of clauses 1 to 12, wherein R 5c It can be selected from 1 to 5 Rs. 10 A 6-membered heteroaryl group substituted with a functional group.

[0241] 15. The compound according to any one of clauses 1 to 11, wherein R 5 It's H.

[0242] 16. The compound according to any one of clauses 1 to 11, wherein R 5 It is a C1-C4-alkyl group.

[0243] 17. A pharmaceutical composition comprising any one of the compounds described in clauses 1 to 16 and one or more pharmaceutically acceptable excipients.

[0244] 18. A compound according to any one of Clauses 1 to 16 or a pharmaceutical composition according to Clause 17, which is used as a medicine.

[0245] 19. The compound according to any one of Clauses 1 to 16 or the pharmaceutical composition according to Clause 17, for the treatment of: musculoskeletal disorders, skin diseases, metabolic diseases, nervous system diseases, cardiovascular diseases, endocrine disorders, eye diseases, diseases affecting the genitourinary system, blood or lymphatic diseases, respiratory diseases, inflammatory or autoimmune diseases, gastrointestinal diseases, tumors, cancers, or selected from amelioration, dentition, tooth dysplasia, gill-oto-kidney syndrome, Sothos syndrome, and Waardenburg syndrome.

[0246] 20. The compound according to any one of Clauses 1 to 16 or the pharmaceutical composition according to Clause 17, for the treatment of diseases selected from: subclinical epidermolysis bullosa, junctional epidermolysis bullosa, xeroderma pigmentosum, Nitherton syndrome, Duchenne muscular dystrophy, Becker muscular dystrophy, cystic fibrosis, Dellaway syndrome, aniridia, methylmalonic acidemia, colorectal cancer, endometrial cancer, breast cancer, ovarian cancer, squamous cell carcinoma of the lung, squamous cell carcinoma of the head and neck, familial adenomatous polyposis, hemophilia A, hemophilia B, choroidal agenesis, pulmonary hypertension, ataxia-telangiectasia, Shwachman-Diamond syndrome, mucopolysaccharidosis type I, mucopolysaccharidosis type VI, mucopolysaccharidosis type III, Niemann-Pick disease, and primary ciliary dyskinesia.

[0247] 21. A method of using a compound according to any one of Clauses 1 to 16 or a pharmaceutical composition according to Clause 17 for treating a condition or symptom associated with a PTC mutation in a subject. Attached Figure Description

[0248] The embodiments of the present invention will be further described below with reference to the accompanying drawings, wherein:

[0249] Figure 1 The effects of treating HDQ-P1 cells with Example 5 (0.03–80 µM) on truncated and full-length (FL) p53 expression compared to DMSO (0.3%) and G418 (200 µM), and the effects of treating HDQ-P1 cells with Example 5 (33 µM) on p21 expression were shown.

[0250] Figure 2 The effects of treating transiently transfected Col7a1R578X HEK293 cells with Example 5 (10–50 μM) compared to DMSO (1%) and G418 (200 μM) were shown. These data were normalized to the effects of G418 (200 μM).

[0251] Figure 3 The effects of treating Col7a1R137X stably transfected HEK293 cells with Example 5 (10–30 μM) compared to DMSO (1%) and G418 (200 μM) were shown. These data were normalized to the effects of G418 (200 μM). Detailed Implementation

[0252] Term C m -C n This refers to a group having m to n carbon atoms. For clarity, the term "C0" refers to a group having 0 carbon atoms.

[0253] The term "branched alkyl" refers to a monovalent straight-chain or branched saturated hydrocarbon chain. For example, C1-C6 alkyl can refer to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. Alkyl groups can be unsubstituted or substituted with one or more substituents.

[0254] The term "alkylene" refers to a divalent, straight-chain saturated hydrocarbon chain. For example, C1-C3-alkylene might refer to methylene, ethylene, or propylene. Alkylenes can be unsubstituted or substituted with one or more substituents. For clarity, the term "CO-alkylene" refers to a group in which no alkylene chain is present. For example, "CO-alkylene-R..." a " refers to R a .

[0255] The term "haloalkyl carbonyl" refers to a hydrocarbon chain substituted with at least one halogen atom, chosen independently each time it appears: fluorine, chlorine, bromine, and iodine. The halogen atom can be present at any position in the hydrocarbon chain. For example, C1-C6-haloalkyl can refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl (e.g., 1-chloromethyl and 2-chloroethyl), trichloroethyl (e.g., 1,2,2-trichloroethyl, 2,2,2-trichloroethyl), fluoroethyl (e.g., 1-fluoromethyl and 2-fluoroethyl), trifluoroethyl (e.g., 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl), chloropropyl, trichloropropyl, fluoropropyl, and trifluoropropyl. A haloalkyl group can be a fluoroalkyl group, i.e., a hydrocarbon chain substituted with at least one fluorine atom. Therefore, a haloalkyl group can have any number of halogen substituents. The group may contain a single halogen substituent, may have two or three halogen substituents, or may be saturated with halogen substituents.

[0256] The term "alkenyl" refers to a branched or straight-chain hydrocarbon chain containing at least one double bond. The double bond can exist as an E or Z isomer. The double bond can be at any possible position on the hydrocarbon chain. For example, "C2-C6-alkenyl" can refer to vinyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, and hexadienyl. The alkenyl group can be unsubstituted or substituted with one or more substituents.

[0257] The term "alkynyl" refers to a branched or straight hydrocarbon chain containing at least one triple bond. The triple bond can be in any possible position on the hydrocarbon chain. For example, "C2-C6-alkynyl" can refer to ethynyl, propynyl, butynyl, pentyynyl, and hexynyl. The alkynyl group can be unsubstituted or substituted with one or more substituents.

[0258] The term "cycloalkyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, or 6 carbon atoms. For example, "C3-C6-cycloalkyl" can refer to cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The cycloalkyl group can be unsubstituted or substituted with one or more substituents.

[0259] The term "y- to z-membered heterocyclic alkyl" refers to a y- to z-membered heterocyclic alkyl group. Therefore, it can refer to a ring system having y and z atoms and containing one or two heteroatoms independently selected from O, S, and N (in other words, one or two atoms forming the ring system are selected from O, S, and N). Examples of heterocyclic alkyl groups include: piperidine, piperazine, morpholine, thiomorpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, dihydrofuran, tetrahydropyran, dihydropyran, dioxane, and azepine. Heterocyclic alkyl groups can be unsubstituted or substituted with one or more substituents. Heterocyclic alkyl groups can be monocyclic. Heterocyclic alkyl groups can be bicyclic. Bicyclic heterocyclic alkyl groups can be fused, spirofused, or bridged groups. The term "heterocyclic alkyl fused with a benzene ring" can refer to a bicyclic system where one ring is a phenyl ring and the other is a saturated heterocyclic alkyl ring. For example, the term "heterocyclic alkyl group fused with a benzene ring" can refer to a group: For example, 5-membered heterocyclic alkyl groups fused with a benzene ring.

[0260] The aryl group can be any aromatic carbocyclic system (i.e., a ring system containing 2(2n+1) π electrons). The aryl group can have 6 to 10 carbon atoms in the ring system. The aryl group is typically phenyl. The aryl group can also be naphthyl or biphenyl.

[0261] The term "heterocyclic group" refers to a ring containing one to four heteroatoms independently selected from O, S, and N. These rings can be heterocyclic alkyl rings (including saturated and partially saturated rings) or heteroaryl rings. The term "heterocyclic group" also includes tautomers of hydroxyheteroaryl groups, such as pyridinones, and tautomers of nitrogen-substituted hydroxyheteroaryl groups, such as N-alkylpyridinones.

[0262] The term "heterocyclic alkenyl" refers to a partially saturated ring containing one or two heteroatoms independently selected from O, S, and N. The term "heterocyclic alkenyl fused to a benzene ring" can refer to a bicyclic system in which one ring is a phenyl ring and the other ring is a partially saturated heterocyclic alkenyl ring.

[0263] The term "heteroaryl" refers to any aromatic (i.e., a ring system containing 2(2n+1)π electrons) ring system containing 1 to 4 heteroatoms independently selected from O, S, and N (in other words, the 1 to 4 atoms forming the ring system are selected from O, S, and N). Therefore, any heteroaryl group can be independently selected from: 5-membered heteroaryls, where the heteroaryl ring is substituted by 1-4 heteroatoms independently selected from O, S, and N; and 6-membered heteroaryls, where the heteroaryl ring is substituted by 1-3 (e.g., 1-2) nitrogen atoms. Specifically, the heteroaryl group can be independently selected from: pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, triazole, oxadiazole, thiadiazole, tetraazole; pyridine, pyridazine, pyrimidine, pyrazine, triazine, quinoline, isoquinoline, indole, benzofuran, benzopyrazole, and benzimidazole.

[0264] The compounds of the present invention containing one or more asymmetric carbon atoms can exist in two or more stereoisomers. Geometric cis / trans (or Z / E) isomers are possible when the compounds of the present invention contain double bonds (e.g., C=C or C=N groups). Tautomerism (“tautomerism”) occurs when the structural isomers interconvert through a low-energy barrier. This can take the form of proton tautomerism in compounds of the present invention containing, for example, imino, ketone, or oxime groups, or the so-called valence tautomerism in compounds containing aromatic moieties. Thus, a single compound can exhibit more than one type of isomerism.

[0265] Included within the scope of this invention are all stereoisomers, geometric isomers, and tautomers of the compounds of this invention, including compounds exhibiting more than one type of isomer, and mixtures of one or more isomers. Also included are acid addition salts or base salts wherein the counterion is optically active, such as d-lactate or l-lysine, or racemic salts, such as dl-tartrate or dl-arginine.

[0266] The cis / trans isomers can be separated using conventional techniques known to those skilled in the art, such as chromatography and fractional crystallization.

[0267] Conventional techniques for preparing / separating individual enantiomers, if necessary, include chiral synthesis from suitable optically pure precursors, or resolution of racemic compounds (or racemic compounds of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). Therefore, the chiral compounds (and their chiral precursors) of the present invention can be obtained enantiomerically enriched on an asymmetric resin using chromatographic methods (typically HPLC) with a mobile phase consisting of hydrocarbons (typically heptane or hexane) containing 0-50 vol% (typically 2-20 vol%) of isopropanol, and, in a specific example, 0-5 vol% of an alkylamine (e.g., 0.1% diethylamine). The eluent is concentrated to obtain an enriched mixture.

[0268] Alternatively, the racemic compound (or racemic precursor) can be reacted with a suitable optically active compound (e.g., an alcohol), or, in the case where the compound of the present invention contains an acidic or basic moiety, with a base or acid (e.g., 1-phenylethylamine or tartaric acid). The resulting mixture of diastereomers can be separated by chromatography and / or fractional crystallization, and one or both of the diastereomers can be converted into the corresponding pure enantiomers by methods well known to those skilled in the art.

[0269] Throughout the instruction manual, use the down or up wedge key (i.e. or The absolute configuration is described by a wedge-shaped bond (R or S) at a specific position. When a downward or upward wedge-shaped bond is used at a particular position, the compound essentially has a single configuration (R or S) at that position. A downward or upward rectangular bond (i.e., a wedge-shaped bond)... or The sigma symbol is used to describe the relative stereochemistry between two positions. In the case of a downward or upward rectangular bond at the chiral center, the compound is in a mixture of R and S configurations at the specified position (usually a 1:1 mixture).

[0270] When any racemic crystal crystallizes, two different types of crystals are possible. The first type is the racemic compound mentioned above (a true racemate), in which a homogeneous form of crystal is produced, containing equimolar amounts of the two enantiomers. The second type is a racemic mixture or aggregate, in which two forms of crystal are produced in equimolar amounts, each containing a single enantiomer.

[0271] Although the two crystal forms present in a racemic mixture have the same physical properties, they can have different physical properties compared to the true racemate. Racemic mixtures can be separated by conventional techniques known to those skilled in the art, for example, see "Stereochemistry of Organic Compounds" by E.L. Eliel and S.H. Wilen (Wiley, 1994).

[0272] Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, boric acid, aminosulfonic acid, and hydrobromic acid, or salts of pharmaceutically acceptable organic acids, such as acetic acid, propionic acid, butyric acid, tartaric acid, maleic acid, hydroxymaleic acid, fumaric acid, malic acid, citric acid, lactic acid, mucoic acid, gluconic acid, benzoic acid, succinic acid, oxalic acid, phenylacetic acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, salicylic acid, sulfanilic acid, aspartic acid, glutamic acid, ethylenediaminetetraacetic acid, stearic acid, palmitic acid, oleic acid, lauric acid, pantothenic acid, tannic acid, ascorbic acid, and valeric acid. Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum, arginine, benzylamine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts. It can also form half-salts of acids and bases, such as half-sulfates and half-calcium salts.

[0273] The compounds and salts described in this specification may be isotopically labeled (or “radiolabeled”). Therefore, one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of radioactive nuclides that may be incorporated include… 2 H (deuterium is also written as "D") 3 H (tritium is also written as "T")11 C 13 C 14 C 15 O、 17 O、 18 O、 13 N、 15 N、 18 F, 36 Cl、 123 I, 25 I, 32 P, 35 S, etc. The radionuclide used will depend on the specific application of the radiolabeled derivative. For example, for in vitro competitive analysis, 3 H or 14 C is generally useful. For radiographic imaging applications, 11 C or 18 F is often useful. In some implementations, the radionuclide is... 3 H. In some implementations, the radionuclide is 14 C. In some implementations, the radionuclide is 11 C. In some implementations, the radionuclide is 18 F.

[0274] Isotope-labeled compounds can typically be prepared using conventional techniques known to those skilled in the art or by methods similar to those described using appropriate isotope-labeled reagents instead of previously used unlabeled reagents.

[0275] Selective substitution of hydrogen with deuterium in compounds can modulate the metabolism, PK / PD properties, and / or toxicity of the compounds. For example, deuteration can increase the half-life of a compound in vivo or reduce its clearance. Deuteration can also inhibit the formation of toxic metabolites, thereby improving safety and tolerability. It should be understood that the present invention includes deuterated derivatives of compounds of formula (I). As used herein, the term deuterated derivative refers to compounds of the present invention wherein at least one hydrogen atom is substituted with deuterium at a specific position. Thus, in the compounds of the present invention, one or more hydrogen atoms are optionally substituted with deuterium. For example, C 1-4 One or more hydrogen atoms in an alkyl group can be substituted with deuterium to form a deuterated C. 1-4 -alkyl. For example, if R 2a R 2b R 3 R 4 R 5 R 6 R 7 R 7a R 7b R 8 R8a R 9 or R 10 If any of them is a methyl group, then the present invention also includes -CD3, -CHD2, and -CH2D. Similarly, R 2a R 2b R 3 R 4 R 5 R 6 R 7 R 7a R 8 or R 8a It could be D.

[0276] The activity of the compounds of this invention can be evaluated through various computer simulations in in vitro and in vivo experiments. Computer analysis of a variety of compounds has been shown to predict the final in vitro and even in vivo activities.

[0277] It should be understood that references to “treatment” or “management” include prevention and relief of established symptoms of a condition. Therefore, “treatment” or “management” of a state, condition or illness includes: (1) preventing or delaying the development of clinical symptoms of the state, condition or illness in a person who may have or is susceptible to the state, condition or illness but has not yet experienced or exhibited clinical or subclinical symptoms of the state, condition or illness; (2) suppressing the state, condition or illness, i.e., preventing, reducing or delaying the development of the disease or its recurrence (in the case of maintenance treatment) or at least one of its clinical or subclinical symptoms; or (3) alleviating or reducing the disease, i.e. causing the disappearance of the state, condition or illness or at least one of its clinical or subclinical symptoms.

[0278] "Therapeutic effective amount" refers to the amount of a compound that, when administered to a mammal to treat a disease, is sufficient to affect the treatment of that disease. The "therapeutic effective amount" will vary depending on the compound, the disease and its severity, and the age and weight of the mammal being treated.

[0279] The compounds of the present invention or pharmaceutically acceptable salts thereof may be used alone, but are generally administered in the form of pharmaceutical compositions, wherein the compounds of the present invention or pharmaceutically acceptable salts thereof are used in combination with pharmaceutically acceptable adjuvants, diluents or carriers.

[0280] The selection of suitable pharmaceutical formulations and routine procedures for their preparation are described, for example, in "Pharmaceuticals - The Science of Dosage Form Designs", ME Aulton, Churchill Livingstone, 1988.

[0281] According to the method of administration of the compound of the present invention, the pharmaceutical composition for administering the compound of the present invention will preferably contain 0.05 to 99% w / w of the compound of the present invention, more preferably 0.05 to 80% w / w of the compound of the present invention, even more preferably 0.10 to 70% w / w of the compound of the present invention, and even more preferably 0.10 to 50% w / w of the compound of the present invention (all weight percentages are based on the total composition).

[0282] The pharmaceutical composition may be applied topically (e.g., to the skin) in the form of, for example, creams, ointments, gels, lotions, solutions, or suspensions; or systemically, for example, orally, in the form of tablets, lozenges, hard capsules or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs; or by parenteral administration (including intravenous, intracoronary, subcutaneous, intramyocardial, intraperitoneal, intramuscular, or intravascular injection or infusion) in the form of sterile aqueous or oily solutions, suspensions, or emulsions for injection; by rectal administration in the form of suppositories or enemas; by inhalation, for example, as a finely divided powder or liquid aerosol; or by inhalation (e.g., as a finely divided powder).

[0283] For oral administration, the compounds of the present invention can be mixed with an adjuvant or carrier (e.g., lactose, sucrose, sorbitol, mannitol; starch, such as potato starch, corn starch, or amylopectin; cellulose derivatives; binders, such as gelatin or polyvinylpyrrolidone; and / or lubricants, such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, etc.) and then compressed into tablets. If coated tablets are desired, the core material prepared as described above can be coated with a concentrated sugar solution, which may contain, for example, gum arabic, gelatin, talc, and titanium dioxide. Alternatively, the tablets can be coated with a suitable polymer dissolved in a volatile organic solvent. Thus, compositions for oral administration can contain, for example, one or more colorants, sweeteners, flavoring agents, and / or preservatives.

[0284] To prepare soft gelatin capsules, the compounds of the present invention can be mixed with, for example, vegetable oils or polyethylene glycol. Hard gelatin capsules can contain particles of the compounds using the above-described tablet excipients. Liquid or semi-solid formulations of the compounds of the present invention can also be filled into hard gelatin capsules. Oral liquid formulations can be in the form of syrups or suspensions, such as solutions containing the compounds of the present invention, with the balance being a mixture of sugar and ethanol, water, glycerol, and propylene glycol. Optionally, such liquid formulations can contain colorants, flavoring agents, sweeteners (such as saccharin), preservatives, and / or carboxymethyl cellulose as thickeners or other excipients known to those skilled in the art.

[0285] For intravenous (parenteral) administration, the compounds of the present invention can be administered as sterile aqueous solutions or oily solutions.

[0286] Based on well-known medical principles, the dosage of the compounds of the present invention used for therapeutic or preventative purposes will naturally vary depending on the nature and severity of the disease, the concentration of the compound required for effectiveness in isolated cells, the concentration of the compound required for effectiveness in experimental animals, the age and sex of the animal or patient, and the route of administration.

[0287] The dosage level, frequency of dosing, and duration of treatment of the compounds of the present invention are expected to vary depending on the formulation and clinical indication, the patient’s age, and comorbidities.

[0288] The effective amount of the compounds of the present invention used for treating conditions is sufficient to achieve relief of condition symptoms, reduction of physical manifestations of the condition, or slowing of the progression of the condition in warm-blooded animals, particularly humans.

[0289] The amount of active ingredient combined with one or more excipients to produce a single dosage form will necessarily vary depending on the host being treated and the specific route of administration. For example, formulations for oral administration in humans typically contain, for example, 0.5 mg to 0.5 g of the active ingredient (more suitably 0.5 to 100 mg, e.g., 1 to 30 mg), mixed with an appropriate and convenient amount of excipients, which may comprise about 5% to about 98% of the total composition by weight.

[0290] For the compounds of the present invention described above, the dosage will naturally vary depending on the compound used, the method of administration, the desired treatment, and the applicable disease. When using the compounds of the present invention for therapeutic or preventative purposes, they are generally administered such that the received daily dose ranges from, for example, 0.1 mg / kg to 100 mg / kg, 1 mg / kg to 75 mg / kg, 1 mg / kg to 50 mg / kg, 1 mg / kg to 20 mg / kg, or 5 mg / kg to 10 mg / kg body weight, and, if necessary, in fractionated doses. Generally, lower doses are administered when using a parenteral route. Thus, for example, for intravenous or intraperitoneal administration, doses in the range of 0.1 mg / kg to 30 mg / kg body weight are typically used. Similarly, for inhalation administration, doses in the range of, for example, 0.05 mg / kg to 25 mg / kg body weight are used. Suitably, the compounds of the present invention are administered orally, for example, in tablet or capsule form. The daily dose for oral administration can be, for example, selected from a total daily dose of 1 mg to 1000 mg, 5 mg to 1000 mg, 10 mg to 750 mg, or 25 mg to 500 mg. Typically, a unit dosage form will contain about 0.5 mg to 0.5 g of the compound of the present invention.

[0291] The compounds of this invention can be administered as part of a treatment regimen in conjunction with other active compounds. These other active compounds can be administered simultaneously, subsequently, or before the compounds of this invention. Pharmaceutical formulations that may contain the compounds of this invention also contain one or more other active compounds. These other active compounds may be anticancer, anti-inflammatory, antibacterial, antiviral, antiemetic, antithrombotic, or metabolically altering compounds.

[0292] The other active compounds may be aminoglycoside antibiotics. The other active compounds may be eRF1 modulators. The other active compounds may be inhibitors or suppressors of nonsense-mediated decay. The other active compounds may be SMG1 kinase inhibitors. The other active compounds may be ribosome binding agents.

[0293] The compounds of the present invention can be administered in combination with aminoglycoside antibiotics. In some embodiments, when administered in combination with sub-effective, sub-optimal, or sub-maximal doses of aminoglycoside antibiotics, the compounds of the present invention may allow for translational readthrough of PTC mutations.

[0294] Aminoglycoside antibiotics are compounds containing amino-modified glycosides. Aminoglycoside antibiotics can allow translational readthrough of PTC mutations. In some embodiments, when the compounds of the present invention are administered in combination with aminoglycoside antibiotics, the aminoglycoside antibiotics can increase ribosome readthrough of mRNA transcripts carrying PTC mutations in the cystic fibrosis CFTR channel.

[0295] Non-limiting examples of aminoglycoside antibiotics include kanamycin A, amikacin, tobramycin, dibekacin, gentamicin, genimycin, sisomicin, netilmicin, neomycin B, neomycin C, paromomycin, streptomycin, prazomycin, tobramycin, ELX-02, and pharmaceutically acceptable salts thereof.

[0296] Combining the compounds of the present invention with aminoglycoside antibiotics can enhance PTC readability. Furthermore, combining the compounds of the present invention with aminoglycoside antibiotics enhances PTC readability while reducing the dosage of aminoglycoside antibiotics compared to their use alone, thereby reducing the side effects associated with aminoglycoside antibiotics, such as toxicity.

[0297] Combining the compounds of this invention with aminoglycoside antibiotics can increase the efficacy and / or beneficial effects of aminoglycoside antibiotics.

[0298] Compared with the administration of aminoglycoside antibiotics alone, the combination of the compounds of the present invention with aminoglycoside antibiotics can reduce the required dose of aminoglycoside antibiotics by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more.

[0299] The compounds of the present invention can be used in combination with eRF1 modulators such as SRI-41315.

[0300] The compounds of the present invention can be administered in combination with inhibitors of nonsense-mediated decay or inhibitors such as ammoniaxol or NMD1.

[0301] The compounds of the present invention can be administered in combination with SMG1 kinase inhibitors (such as SMG1i).

[0302] The compounds of the present invention can be used in combination with ribosome binding agents (such as ZKN-013).

[0303] The compounds of the present invention can be administered in combination with antibodies, such as checkpoint inhibitor antibodies. In some embodiments, when administered in combination with checkpoint inhibitor antibodies, the compounds of the present invention can increase immune cell recognition of cancer cells used to treat cancer. In some embodiments, when administered in combination with sub-effective, sub-optimal, or sub-maximal amounts of checkpoint inhibitor antibodies, the compounds of the present invention can allow for increased immune cell recognition of cancer cells used to treat cancer.

[0304] Checkpoint inhibitor antibodies are a type of immunotherapy used in oncology. They recognize and block different checkpoint proteins, such as CTLA-4, PD-1, and PD-L1, thereby triggering immune recognition and destruction of tumors. When the compounds of this invention are administered in combination with checkpoint inhibitor antibodies, immune recognition can be enhanced, wherein the compounds promote PTC readthrough and increase the expression of neoantigens in cancer cells.

[0305] Non-limiting examples of checkpoint inhibitor antibodies include pembrolizumab, nivolumab, cemiplimab, atezolizumab, durvalumab, avelumab, relatlimab, and ipilimumab.

[0306] Combining the compounds of this invention with checkpoint inhibitor antibodies may increase the potency and / or beneficial effects of the checkpoint inhibitor antibodies.

[0307] Throughout the description and claims of this specification, the words “comprising” and “including”, and variations thereof, mean “containing but not limited to”, and are not intended to exclude other parts, additives, components, wholes, or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context requires otherwise. In particular, where the indefinite article is used, this specification should be understood to include both the plural and the singular, unless the context requires otherwise.

[0308] Features, integrals, characteristics, compounds, chemical parts, or groups described in connection with a particular aspect, embodiment, or example of the invention should be understood to be applicable to any other aspect, embodiment, or example described herein, unless incompatible therewith. All features disclosed in this specification (including any appended claims, abstract, and drawings), and / or all steps of any method or process so disclosed, may be combined in any combination, but not including combinations of at least some such features and / or steps that are mutually exclusive. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any novel one or any novel combination of features disclosed in this specification (including any appended claims, abstract, and drawings), or to any novel one or any novel combination of steps of any disclosed method or process.

[0309] It should be understood that various modifications can be made to the embodiments disclosed herein. Therefore, the above description should not be construed as restrictive, but merely as examples of preferred embodiments. For example, the functions described above and those implemented as the best mode for operating the invention are for illustrative purposes only. Other arrangements and methods can be implemented by those skilled in the art without departing from the scope and spirit of the invention. Furthermore, those skilled in the art will contemplate other modifications within the scope and spirit of the appended specification.

[0310] Readers should note that all documents and references related to this application that were submitted concurrently with or prior to this specification are publicly available together with this specification, and the contents of all such documents and references are incorporated herein by reference.

[0311] The compounds of formula (I) can be prepared according to or similar to general schemes 1 to 7 and / or the following examples.

[0312] Example

[0313] List of abbreviations:

[0314]

[0315] NMR methods:

[0316] Record on a Bruker AVANCE III HD 300, Bruker AVANCE NEO 400, or Bruker AVANCE III HD 400 spectrometer. 1 Broad-spectral 1H NMR. Chemical shifts are expressed in ppm (δ) relative to the residual protonated solvent used as an internal standard, as described, for example, in Gottlieb et al. Journal of Organic Chemistry (1997) 62 7512. NMR spectra splitting modes are represented as follows: s (singlet), br (broad), d (doublet), t (triplet), m (multiplex), or combinations thereof. Coupling constants (J) are expressed in Hz, accurate to one decimal place.

[0317] Purification method:

[0318] Record liquid chromatography-mass spectrometry (LCMS) data using the following systems and operating conditions:

[0319]

[0320] Purification performed by preparative HPLC (prep-HPLC) used the following instruments and conditions:

[0321]

[0322] SFC separation was performed using the following instruments and conditions:

[0323]

[0324]

[0325] Chiral-HPLC separation was performed using the following instruments and conditions:

[0326]

[0327] Preparation method:

[0328] Some compounds of the present invention can be synthesized according to the general methods disclosed herein. Some compounds of the present invention can be synthesized according to general schemes 1 to 7. Some compounds of the present invention can be synthesized according to or similar synthetic methods provided in the examples.

[0329] General Option 1

[0330]

[0331] General Scheme 1 illustrates the route for preparing the compound of formula (I) and is described in the following examples.

[0332] Appropriately functionalized starting materials can be activated into suitable leaving groups X using conditions well known to those skilled in the art. 1 (where X) 1 =Cl, Br, OMs, OTs, OTf), the conditions being, for example, the use of POCl3, POBr3, trifluoromethyl anhydride, methanesulfonyl chloride or toluenesulfonyl chloride, in the presence of a suitable base (e.g., TEA, DIPEA) (if necessary), in a suitable solvent (e.g., DCM, THF), and heating if necessary.

[0333] X 1 Sequential substitution can be achieved by reacting the amine in a cross-coupling reaction (where X... 1 The reaction is carried out under the following conditions: in the presence of a suitable catalyst (e.g., palladium(II) acetate, Brettphos PdG3, Pd2(dba)3), ligands (e.g., Brettphos, XantPhos) if necessary, a suitable base (e.g., Na2CO3, Cs2CO3), in a suitable solvent (e.g., 1,4-dioxane, toluene, THF), and heating if necessary (conventional heating or by microwave irradiation).

[0334] Or, X 1 Sequential substitution can be achieved by reacting the amine in a substitution reaction (where X... 1 The reaction is carried out under the following conditions: in the presence of a suitable base (e.g., TEA, KF, CsF, potassium tert-butoxide, Na2CO3, Cs2CO3), in a suitable solvent (e.g., 1,4-dioxane, DMSO, THF, NMP, or a solvent-free condition), and if necessary, heated (conventional heating or by microwave radiation).

[0335] Those skilled in the art know that whether it is two coupling reactions, two substitution reactions, or a mixture of coupling and substitution reactions, for two X... 1Sequential and regioselective substitution of functional groups may be necessary.

[0336] General Option 2

[0337]

[0338] General scheme 2 illustrates the route for preparing compounds of formula (III), and is described in the following examples.

[0339] The appropriately functionalized intermediate A (where X) 2 This involves a cross-coupling reaction of aminocyanide with substances such as Cl, Br, I, and OSO2CF3, under the following conditions: in the presence of a suitable catalyst (e.g., palladium(II) acetate, Brettphos Pd G3, Pd2(dba)3), ligands (e.g., Brettphos, XantPhos) if necessary, a suitable base (e.g., Na2CO3, Cs2CO3), in a suitable solvent (e.g., 1,4-dioxane, toluene, THF), and heating if necessary (conventional heating or microwave irradiation).

[0340] Alternatively, appropriately functionalized intermediate A (where X) 2 For example, F, Cl, OMs, OTs) undergo nucleophilic aromatic substitution with aminocyanides (S N The reaction is carried out under the following conditions: in the presence of a suitable base (e.g., TEA, KF, CsF, potassium tert-butoxide, Na2CO3, Cs2CO3), in a suitable solvent (e.g., 1,4-dioxane, DMSO, THF, NMP, or solvent-free conditions), and if necessary, heated (conventional heating or by microwave radiation).

[0341] The obtained cyanoaminocyanide product can be cyclized by reacting with a suitable nucleophile (e.g., an amine or hydroxylamine) under the following conditions: the use of a suitable base (e.g., triethylamine, DIPEA, potassium carbonate) if necessary; in a suitable solvent (e.g., DCM, DMSO, DMF, NMP, THF, 1,4-dioxane, ethanol, methanol) if necessary; and heating (conventional heating or by microwave irradiation) if necessary.

[0342] General Scheme 3

[0343]

[0344] Intermediate A may be commercially available; may be synthesized using methods similar to those previously described in, for example, WO2005097750 A1, CN109232412 A or WO2013089573 A1; or may be synthesized according to general scheme 3 and as described in the following examples.

[0345] A suitably functionalized 1,3-dialdehyde or ketone is condensed with 2-cyanoacetamide in the presence of a suitable base (e.g., piperidine, sodium hydride) in a suitable solvent (e.g., ethanol, DMSO), with heating if necessary.

[0346] The resulting pyrimidinone intermediate can be activated to a suitable leaving group X using conditions well known to those skilled in the art. 2 (where X) 2 The substances used are, for example, F, Cl, Br, I, OMs, OTs, OTf), and the conditions are: using, for example, POCl3, POBr3, trifluoromethyl anhydride, methanesulfonyl chloride or toluenesulfonyl chloride, in the presence of a suitable base (e.g., TEA, DIPEA) (if necessary), in a suitable solvent (e.g., DCM, THF), and heating if necessary.

[0347] Those skilled in the art will understand that the condensation step can produce mixtures of isomers in varying proportions, which can be separated using well-known techniques such as crystallization, positive critical, anticritical, and supercritical fluid chromatography. Separation can be performed after the condensation step or after activation of the crude mixture.

[0348] General Scheme 4

[0349]

[0350] Alternatively, intermediate B can be synthesized according to general scheme 4.

[0351] Appropriately functionalized starting materials (where X) can be used. 4 Examples include F, Cl, and X. 3 For example, Br, I) and aminocyanide undergo nucleophilic aromatic substitution (S) under the following conditions. N Ar) reaction: In the presence of a suitable base (e.g., TEA, KF, CsF, potassium tert-butoxide, Na2CO3, Cs2CO3), in a suitable solvent (e.g., 1,4-dioxane, DMSO, THF, NMP or solvent-free conditions), heating may be required (conventional heating or microwave radiation).

[0352] Appropriately functionalized starting materials (where X) can be used. 4 For example, I, X 3For example, Cl, Br) and aminocyanide undergo cross-coupling reaction under the following conditions: in the presence of a suitable catalyst (e.g., palladium(II) acetate, Brettphos Pd G3, Pd2(dba)3), ligands (e.g., Brettphos, XantPhos) if necessary, a suitable base (e.g., Na2CO3, Cs2CO3), in a suitable solvent (e.g., 1,4-dioxane, toluene, THF), and heating if necessary (conventional heating or microwave irradiation).

[0353] The cyano group can be introduced into the resulting intermediate via Negishi coupling, wherein, for example, zinc cyanide is used, in the presence of a suitable palladium catalyst (e.g., Pd2dba3), a suitable ligand (e.g., triphenylphosphine or BINAP), in a suitable solvent (e.g., 1,4-dioxane), and heating is performed if necessary.

[0354] General Plan 5

[0355]

[0356] General scheme 5 illustrates the route for preparing compounds of formula (II) and is described in the following examples.

[0357] The starting material can be cyclized to provide intermediate C under the following conditions: potassium cyanate and ammonium chloride in water, for example, with heating if necessary, as described in, for example, WO2006090167 A2 or Bioorganic & Medicinal Chemistry Letters (2009), 19(20), 5950-5953.

[0358] Alternatively, a suitably substituted starting material can be cyclized to provide intermediate C, under reaction conditions such as the use of, for example, urea (pure or in a suitable solvent such as water), in the presence of sodium hydroxide (if necessary), and heating if required, as described in, for example, Tetrahedron (2012), 68(43), 8908-8915; Journal of Medicinal Chemistry (2016), 59(4), 1370-1387; US20070281949 A1 or WO2005049033 A1.

[0359] The resulting intermediate can be activated into a suitable leaving group X using conditions well known to those skilled in the art. 5 (where X) 5=Cl, Br, OMs, OTs, OTf), the conditions being: using, for example, POCl3, POBr3, trifluoromethyl anhydride, methanesulfonyl chloride or toluenesulfonyl chloride, in the presence of a suitable base (e.g., TEA, DIPEA) (if necessary), in a suitable solvent (e.g., DCM, THF), and heating if necessary.

[0360] X 5 Sequential substitution can be achieved by reacting the amine in a cross-coupling reaction (where X... 5 The reaction is carried out under the following conditions: in the presence of a suitable catalyst (e.g., palladium(II) acetate, Brettphos PdG3, Pd2(dba)3), ligands (e.g., Brettphos, XantPhos) if necessary, a suitable base (e.g., Na2CO3, Cs2CO3), in a suitable solvent (e.g., 1,4-dioxane, toluene, THF), and heating if necessary (conventional heating or by microwave irradiation).

[0361] Or, X 5 Sequential substitution can be achieved by reacting the amine in a substitution reaction (where X... 5 The reaction is carried out under the following conditions: in the presence of a suitable base (e.g., TEA, KF, CsF, potassium tert-butoxide, Na2CO3, Cs2CO3), in a suitable solvent (e.g., 1,4-dioxane, DMSO, THF, NMP, or solvent-free conditions), and if necessary, heated (conventional heating or by microwave radiation).

[0362] Those skilled in the art know that whether it is two coupling reactions, two substitution reactions, or a mixture of coupling and substitution reactions, for two X... 5 Sequential and regioselective substitution of functional groups may be necessary.

[0363] General Plan 6

[0364]

[0365] Alternatively, intermediate C can be synthesized according to general scheme 6, as described in the following examples.

[0366] A suitable dicarbonyl starting material can be condensed with a suitable amidine ester (e.g., ethyl 3-amino-3-iminopropionate, as a free base or salt, e.g., hydrochloride) under the following reaction conditions: in the presence of a suitable base (e.g., piperidine, DIPEA, TEA, potassium tert-butoxide, Na2CO3, sodium hydroxide, pyridine), in a suitable solvent (e.g., methanol, ethanol, isopropanol, dichloroethane, acetonitrile, 1,4-dioxane, tetrahydrofuran, toluene, DMF, DMSO), and if necessary, heated (conventional heating or by microwave radiation).

[0367] Those skilled in the art will understand that the condensation step can produce mixtures of isomers in different proportions, which can be separated using well-known techniques such as crystallization, positive critical, anticritical, and supercritical fluid chromatography.

[0368] The resulting amino group can be activated by heating (conventional heating or microwave radiation) in a suitable solvent (e.g., dichloroethane, 1,4-dioxane, tetrahydrofuran, toluene) in a suitable solvent, if necessary.

[0369] The resulting compound can be cyclized under the following conditions: in the presence of ammonia, in a suitable solvent (e.g., methanol, ethanol, isopropanol), heating if necessary (conventional heating or microwave radiation), and pressurization if necessary.

[0370] General Scheme 7

[0371]

[0372] Alternatively, intermediate C can be synthesized according to general scheme 7, as described in the following examples.

[0373] Suitable starting materials (e.g., 6-aminouracil) can be condensed with suitable diketones (e.g., acetylacetone) under the following conditions: in the presence of a suitable acid (e.g., polyphosphoric acid), and if necessary, heated (either by conventional heating or by microwave radiation).

[0374] Those skilled in the art will understand that the condensation step can produce mixtures of isomers in different proportions, which can be separated using well-known techniques such as crystallization, positive critical, anticritical, and supercritical fluid chromatography.

[0375] Example 1: N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0376]

[0377] Route A

[0378] Preparation of 1–2-(cyanoamino)pyridine-3-nitrile

[0379] At room temperature, sodium aminocyanide (690 mg, 10.8 mmol) was added to a solution of 2-chloropyridin-3-onitrile (1.00 g, 7.22 mmol) in NMP (10.0 mL). The mixture was stirred overnight at 60 °C. The mixture was then purified directly by silica gel column chromatography (eluting with EtOAc / MeOH (0-100%)) to give the title compound as a yellow solid (1.0 g, crude). LCMS: m / z = 145 [M+H] + .

[0380] Preparation of 2-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0381] At room temperature, 1-methylpiperidin-4-amine (570 mg, 5.00 mmol) was added to a solution of 2-(cyanoamino)pyridin-3-onitrile (600 mg, 4.16 mmol) in 1,4-dioxane (10.0 mL). The mixture was stirred overnight at 100 °C. The resulting mixture was concentrated under reduced pressure. The concentration was determined by Prep-HPLC. G The crude product was purified to give the title compound as a yellow solid (30.7 mg, 2.8%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.62 - 8.56 (m, 1H), 8.36 - 8.30 (m, 1H), 7.39 (br, 2H), 6.98 (s, 1H), 6.56 (br, 1H), 3.87 - 3.73 (m, 1H), 2.79 - 2.70(m, 2H), 2.16 (s, 3H), 1.99 - 1.89 (m, 2H), 1.86 - 1.78 (m, 2H), 1.58 - 1.44(m, 2H).LCMS B m / z = 259 [M+H] + .

[0382] Route B

[0383] Preparation of 3–2-chloropyrido[2,3-d]pyrimidine-4-amine

[0384] At room temperature, 2,4-dichloropyrido[2,3-d]pyrimidine (500 mg, 2.50 mmol) and ammonium hydroxide (5.0 mL) were added to a 40 mL vial. The resulting mixture was stirred overnight at 80 °C. The mixture was concentrated under reduced pressure. The residue was purified by preparation with MtBE (8.0 mL). This gave the title compound as a pale yellow solid (430 mg, crude). LCMS m / z = 181 [M+H + ]

[0385] Preparation of 4-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0386] At room temperature, Cs₂CO₃ (721 mg, 2.21 mmol) and 1-methylpiperidin-4-amine (252 mg, 2.21 mmol) were added fractionally to a stirred solution of 2-chloropyrido[2,3-d]pyrimidin-4-amine (200 mg, 1.11 mmol) in DMSO (5.0 mL). The resulting mixture was stirred at 100 °C for 12 hours. The mixture was then cooled to room temperature. The resulting mixture was filtered through a diatomaceous earth sieve. The combined filtrate was purified by Prep-HPLCAS to give the title compound as a pale yellow solid (5 mg, 1.7%). 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 3.6 Hz, 1H), 8.36-8.33 (m, 1H), 7.38(br., 2H), 6.97 (s, 1H), 6.66 (br s, 1H), 3.91 – 3.64 (m, 1H), 2.75-2.70 (m,2H), 2.16 (s, 3H), 2.00 – 1.89 (m, 2H), 1.81-1.80 (m, 2H), 1.51-1.50 (m, 2H).LCMS H m / z = 259 [M+H + ]

[0387] Example 2: 5-Methyl-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0388]

[0389] Preparation of 5–N-(3-cyano-4-methylpyridin-2-yl)aminocyanide

[0390] At room temperature, sodium aminocyanide (840 mg, 13.1 mmol) was added to a stirred solution of 2-chloro-4-methylpyridin-3-onitrile (1.00 g, 6.55 mmol) in 20.0 mL of NMP. The resulting mixture was stirred at 60 °C for 1 hour. The mixture was acidified to pH 6 with concentrated hydrochloric acid. The resulting mixture was filtered, and the filter cake was washed with water (3 x 3.00 mL). The filtrate was concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. B Purification yielded the title compound as a white solid (560 mg, 54.0%). LCMS: m / z = 159 [M+H] + .

[0391] Preparation of 6–5-methyl-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0392] A solution of 2-(cyanoamino)-4-methylpyridin-3-onitrile (200 mg, 1.27 mmol) and 1-methylpiperidin-4-amine (0.19 mL, 1.52 mmol) in ethanol (4.00 mL) was stirred at 80 °C for 6 hours. The resulting mixture was concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. C Purification. The residue was purified by preparation with MTBE (10.0 mL) to give the title compound (100.4 mg, 29.2%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.38 (s, 1H),7.00 – 6.33 (m, 4H), 3.85 – 3.72 (m, 1H), 2.74 – (d, J = 11.1 Hz, 2H), 2.68(s, 3H), 2.16 (s, 3H), 2.00 – 1.86 (m, 2H), 1.89 - 1.81 (m, 2H), 1.56 - 1.46(m 2H).LCMS A m / z = 273 [M+H] + .

[0393] Example 3: 7-Methyl-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0394]

[0395] Preparation of 7–N-(3-cyano-6-methylpyridin-2-yl)aminocyanide

[0396] Sodium aminocyanide (839 mg, 13.1 mmol) was added to a mixture of 2-chloro-6-methylpyridin-3-onitrile (1.00 g, 6.55 mmol) in NMP (10.0 mL). The mixture was stirred overnight at 60 °C. The resulting mixture was diluted with water (30.0 mL) and acidified to pH 6.5 by adding an aqueous solution of HCl (1.0 M). The product was precipitated, filtered, and dried to give the title compound (555.4 mg, 53.6%) as a yellow solid. LCMS: m / z = 159 [M+H] + .

[0397] Preparation of 2:7-methyl-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0398] To a mixture of 2-(cyanoamino)-6-methylpyridin-3-onitrile (300 mg, 1.90 mmol, 1.00 equivalent) in ethanol (10.0 mL), 1-methylpiperidin-4-amine (0.28 mL, 2.28 mmol, 1.20 equivalent) was added. The mixture was stirred overnight at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. E Purification. The product was further purified by MTBE (10 mL) to give the title compound as a pale yellow solid (81 mg, 15.9%). 1 H NMR (300 MHz, DMSO-d 6 )δ 8.22 (d, J = 8.1 Hz, 1H), 7.29 (br, 2H), 6.88 (d, J= 8.1 Hz, 1H), 6.50 (br,1H), 3.87 - 3.64 (m, 1H), 2.82 - 2.62 (m, 2H), 2.45 (s, 3H), 2.16 (s, 3H), 2.00 - 1.88 (m, 2H), 1.81 - 1.73 (m, 2H), 1.53 - 1.49 (m, 2H).LCMS A m / z = 273 [M+H] + .

[0399] Example 4: 6-Methyl-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0400]

[0401] Preparation of 8–N-(3-cyano-5-methylpyridin-2-yl)aminocyanide

[0402] At room temperature, sodium aminocyanide (252 mg, 3.93 mmol) was added to a solution of 2-chloro-5-methylpyridin-3-onitrile (400 mg, 2.62 mmol) in DMSO (4.0 mL). The mixture was stirred at 60 °C for 2 hours. The reaction was quenched with water. The mixture was acidified to pH 6 with an aqueous solution of HCl (1 M). The precipitated solid was collected by filtration and washed with EtOAc (3 × 30 mL). The crude product was further purified by grinding with MTBE (5.0 mL). The precipitated solid was dried under vacuum to give the title compound as a gray solid (390 mg, 94.1%). LCMS: m / z = 159 [M+H] + .

[0403] Preparation of 2:6-methyl-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0404] At room temperature, 1-methylpiperidin-4-amine (86.6 mg, 0.758 mmol, 1.20 equivalent) was added to a stirred solution of 2-(cyanoamino)-5-methylpyridin-3-onitrile (100 mg, 0.632 mmol, 1.00 equivalent) in ethanol (2.0 mL). The mixture was stirred overnight at 80 °C. The resulting mixture was concentrated under reduced pressure. The concentration was determined by Prep-HPLC. E The crude product was purified to give the title compound as a white solid (29.6 mg, 16.5%). 1 H NMR (400 MHz, MeOD) δ 8.49 (s, 1H), 8.13 (s,1H), 4.02 - 3.92 (m, 1H), 2.86 (d, J= 11.7 Hz, 2H), 2.38 (s, 3H), 2.30 (s,3H), 2.27 - 2.17 (m, 2H), 2.09 - 2.01 (m, 2H), 1.66 - 1.53 (m, 2H).LCMS B m / z = 273 [M+H] + .

[0405] Example 5: 5,7-Dimethyl-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0406]

[0407] Route A

[0408] Preparation of 9–2-(cyanoamino)-4,6-dimethylpyridine-3-nitrile

[0409] At room temperature, sodium aminocyanide (22.7 g, 360 mmol) was added to a stirred mixture of 2-chloro-4,6-dimethylpyridin-3-onitrile (30.0 g, 180 mmol) in DMSO (300 mL). The resulting mixture was stirred at 60 °C for 2 h. The reaction was terminated by adding water (600 mL). The residue was acidified to pH 6 with an aqueous solution of HCl (1 M). The precipitated solid was collected by filtration and washed with MTBE (3 x 100 mL). The filter cake was dried under vacuum to give the title compound (25.0 g, crude product) as a brown solid. LCMS: m / z = 173 [M+H] + .

[0410] Preparation of 10–5,7-dimethyl-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0411] At room temperature, 1-methylpiperidin-4-amine (15.9 g, 139 mmol) was added dropwise to a stirred mixture of 2-(cyanoamino)-4,6-dimethylpyridin-3-onitrile (20.0 g, 116 mmol) in ethanol (400 mL). The resulting mixture was stirred overnight at 80 °C. The mixture was then concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. A Purification was performed, and the product was prepared with MTBE (50 mL) to give the title compound as a brown solid (10.6 g, 31.6%). 1 H NMR (300 MHz, DMSO-d 6 ) δ 6.67 (s,3H), 6.38 (s, 1H), 3.84 - 3.69 (m, 1H), 2.74 (d, J = 11.6 Hz, 2H), 2.63 (s,3H), 2.37 (s, 3H), 2.16 (s, 3H), 2.02 - 1.88 (m, 2H), 1.81 - 1.78 (m, 2H), 1.56 - 1.48 (m, 2H).LCMS A m / z = 287 [M+H] + .

[0412] Route B

[0413] Preparation of 11–5,7-dimethylpyrido[2,3-d]pyrimidine-2,4-diol

[0414] PPA (90.5 g, 786 mmol) was added to a mixture of 50.0 g (393 mmol) of 6-aminouracil (200 mL) under stirring at room temperature. The resulting mixture was stirred at 100 °C for 1 hour. The mixture was allowed to cool to room temperature. The reaction was quenched at 0 °C with NaHCO3 (aqueous solution). The precipitated solid was collected by filtration and washed with water (2 × 300 mL). The solid was further purified by preparation with MtBE (300 mL). The title compound was given as a grayish-white solid (38.0 g, crude). LCMS m / z = 192 [M+H] +

[0415] Preparation of 12–2,4-dichloro-5,7-dimethylpyrido[2,3-d]pyrimidine

[0416] At 0 °C, N,N-diethylaniline (60.5 g, 405 mmol) was added dropwise to a mixture of 15.5 g (81.1 mmol) of 5,7-dimethylpyrido[2,3-d]pyrimidine-2,4-diol (POCl3) in 155 mL of POCl3. The resulting mixture was stirred at 60 °C for 3 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The mixture was alkalized to pH 8 with saturated sodium bicarbonate (aqueous solution). The resulting mixture was extracted with ethyl acetate (3 × 500 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na2SO4. The filtrate was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (2:1) to give the title compound as a yellow solid (9.8 g, 40.2%). LCMS: m / z = 228 [M+H] +

[0417] Preparation of 13–2-chloro-5,7-dimethylpyrido[2,3-d]pyrimidin-4-amine

[0418] A mixture of 2,4-dichloro-5,7-dimethylpyrido[2,3-d]pyrimidine (6.00 g, 26.3 mmol) in ammonium hydroxide (90.0 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. B Purification yielded the title compound as a grayish-white solid (4.45 g, 81.1%). LCMS m / z = 209 [M+H] +

[0419] Preparation of 14–5,7-dimethyl-N 2-(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0420] At room temperature, 1-methylpiperidin-4-amine (164 mg, 1.44 mmol) was added to a stirred solution of 2-chloro-5,7-dimethylpyrido[2,3-d]pyrimidin-4-amine (60.0 mg, 0.288 mmol) in dioxane (1.50 mL). The resulting mixture was stirred overnight at 80 °C. The mixture was then cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in DMF (2.00 mL). The crude product was purified by Prep-HPLCAU to give the title compound as a grayish-white solid (5.5 mg, 6.52%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 6.67 (s, 3H), 6.38 (s, 1H), 3.84 - 3.69 (m,1H), 2.74 (d, J = 11.6 Hz, 2H), 2.63 (s, 3H), 2.37 (s, 3H), 2.16 (s, 3H),2.02 - 1.88 (m, 2H), 1.81 - 1.78 (m, 2H), 1.56 - 1.48 (m, 2H).LCMS H m / z = 287 [M+H] + .

[0421] Example 6: 5,7-Dimethyl-N 2 -(3-morpholinopropyl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0422]

[0423] At room temperature, 4-morpholinopropylamine (100 mg, 0.697 mmol) was added to a stirred mixture of 2-(cyanoamino)-4,6-dimethylpyridin-3-onitrile (100 mg, 0.581 mmol) and ethanol (1.5 mL). The resulting mixture was stirred overnight at 80 °C. The mixture was then concentrated under reduced pressure. The final product was analyzed by Prep-HPLC. H The crude product was purified to give the title compound as a white solid (79 mg, 42.9%). 1H NMR (300 MHz, MeOD) δ 6.78 (s, 1H), 3.70 (t, J = 4.7 Hz, 4H), 3.48 (t, J = 6.7 Hz, 2H), 2.71 (s, 3H), 2.53 - 2.42 (m, 9H), 1.87 -1.77 (m,2H).LCMS C m / z = 317 [M+H] + .

[0424] Example 7: 5,7-DimethylN 2 -(3-(piperidin-1-yl)propyl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0425]

[0426] As described in Example 6, 3-(piperidin-1-yl)propyl-1-amine was used and analyzed by Prep-HPLC. L Purification yielded the title compound as a white solid (90 mg, 43.5%). ¹H NMR (400 MHz, MeOD) δ 6.79 (s, 1H), 3.48–3.45 (m, 2H), 2.71–2.62 (m, 9H), 2.46 (s, 3H), 1.92–1.87 (m, 2H), 1.69–1.60 (m, 4H), 1.60–1.51 (m, 2H). LCMS E m / z = 315 [M+H] + .

[0427] Example 8: 4-(3-((4-amino-5,7-dimethylpyridino[2,3-d]pyrimidin-2-yl)amino)propyl)thiomorpholine 1,1-dioxide

[0428]

[0429] As described in Example 6, 4-(3-aminopropyl)thiomorpholine 1,1-dioxide was used and analyzed by Prep-HPLC. J Purification yielded the title compound as a white solid (46.9 mg, 44.3%). 1H NMR (400 MHz, MeOD) δ 6.80(s, 1H), 3.51 (t, J = 6.0 Hz, 2H), 3.14 - 3.08 (m, 4H), 3.01 - 2.96 (m, 4H), 2.72 (s, 3H), 2.63 (t, J = 8.0 Hz, 2H), 2.47 (s, 3H), 1.86 - 1.75 (m, 2H).LCMS A m / z = 365 [M+H] +

[0430] Example 9: 6-Methyl-N 3 -(1-Methylpiperidin-4-yl)pyrimidino[4,5-c]isoquinoline-1,3-diamine

[0431]

[0432] Route A

[0433] Preparation of 15–1-methyl-3-oxo-3,4-dihydroisoquinoline-4-nitrile and 2-hydroxy-4-methylquinoline-3-nitrile

[0434] At 0 °C, NaH (16.7 g, 416 mmol, 60% wt, in mineral oil) was added fractionally to a solution of 1-(2-fluorophenyl)ethyl ketone (25.0 g, 181 mmol) and cyanoacetamide (33.5 g, 398 mmol) in DMSO (250 mL). The resulting mixture was stirred overnight at 80 °C. The mixture was allowed to cool to room temperature. The mixture was acidified to pH 3 with cold HCl (1 M aqueous solution). The precipitated solid was collected by filtration and washed with water (3 x 50 mL). The solid was dried under vacuum to give the title compound (19.0 g, crude) as a yellow solid. The crude product (6.0 g) was analyzed by Prep-HPLC. B Further purification yielded 1-methyl-3-oxo-3,4-dihydroisoquinoline-4-onitrile (1.78 g) and 2-hydroxy-4-methylquinoline-3-onitrile (756 mg). LCMS m / z = 185 [M+H] +

[0435] Preparation of 16–4-cyano-1-methylisoquinoline-3-yltrifluoromethanesulfonate

[0436] At 0 °C, Tf₂O (183 μL, 1.09 mmol) was added dropwise to a stirred solution of 1-methyl-3-oxo-3,4-dihydroisoquinoline-4-onitrile (100 mg, 0.543 mmol) and Et₃N (151 μL, 1.09 mmol) in DCM (2.0 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The mixture was then concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 10:1) to give the title compound (130 mg, 75.7%) as a yellow solid. LCMS: m / z = 315 [MH] -

[0437] Preparation of 17–N-(4-cyano-1-methylisoquinoline-3-yl)aminocyanide

[0438] Under a nitrogen atmosphere and at room temperature, Xantphos (18.3 mg, 0.032 mmol), Pd2(dba)3 (29.0 mg, 0.032 mmol), and DIEA (110 µL, 0.632 mmol) were added to a stirred solution of 4-cyano-1-methylisoquinoline-3-yltrifluoromethanesulfonate (100 mg, 0.316 mmol) and aminocyanide (26.6 mg, 0.632 mmol) in 1,4-dioxane (1.5 mL). The resulting mixture was stirred at 100 °C for 1 hour under a nitrogen atmosphere. The mixture was cooled to room temperature and diluted with water / ice (10 mL). The resulting mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give the title compound (45.0 mg, 68.4%) as a yellow solid. LCMS m / z = 209 [M+H] +

[0439] Preparation of 18–6-methyl-N 3 -(1-Methylpiperidin-4-yl)pyrimidino[4,5-c]isoquinoline-1,3-diamine

[0440] A solution of N-(4-cyano-1-methylisoquinoline-3-yl)aminocyanine (40 mg, 0.192 mmol) and 1-methylpiperidin-4-amine (43.9 mg, 0.384 mmol) in ethanol (1.0 mL) was stirred overnight at 80 °C. The mixture was allowed to cool to room temperature. The residue was analyzed by Prep-HPLC. B Purification yielded the title compound (7.70 mg, 10.9%) as a yellow solid formate. 1H NMR(400 MHz, DMSO-d6) δ 8.51 (d, J = 8.5 Hz, 1H), 8.29 (s, 1H), 8.20 (d, J = 8.2Hz, 1H), 7.77 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 6.98 (s, 2H), 6.58 (s, 1H), 3.87-3.80 (m, 1H), 2.87 (s, 3H), 2.81 (d, J = 11.6 Hz, 2H), 2.21 (s, 3H), 2.06 (t, J = 10.1 Hz, 2H), 1.92 - 1.82 (m, 2H), 1.61 - 1.46 (m, 2H).LCMS I m / z = 323 [M+H] +

[0441] Example 10: 5-Methyl-N 2 -(1-Methylpiperidin-4-yl)pyrimidino[4,5-b]quinoline-2,4-diamine

[0442]

[0443] Route A

[0444] Preparation of 19–2-chloro-4-methylquinoline-3-nitrile

[0445] At room temperature, phosphoryl chloride (8.30 g, 54.3 mmol) was added dropwise to a solution of 2-hydroxy-4-methylquinoline-3-onitrile (1.00 g, 5.43 mmol, synthesized as described in Example 9, Preparation 15) in 1,4-dioxane (15.0 mL). The resulting mixture was stirred at 100 °C for 6 hours. The mixture was allowed to cool to room temperature. The reaction was quenched at 0 °C with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with CH2Cl2 (3 × 100 mL). The combined organic layers were washed with brine (1 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to give the title compound (260 mg, 23.6%) as a white solid. LCMS: m / z = 203 [M+H] +

[0446] Preparation of 20–N-(3-cyano-4-methylquinoline-2-yl)aminocyanide

[0447] BrettPhos (61.0 mg, 0.114 mmol) and Cs₂CO₃ (740 mg, 2.27 mmol) were added to a solution of 2-chloro-4-methylquinoline-3-onitrile (230 mg, 1.14 mmol), aminocyanide (95.0 mg, 2.27 mmol), and 1,4-dioxane (6.0 mL). The mixture was stirred at 100 °C under a nitrogen atmosphere for 1 hour. The mixture was allowed to cool to room temperature. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. B Purification yielded the title compound (129 mg, 54.6%) as a yellow solid. LCMS: m / z = 209 [M+H] +

[0448] Preparation of 21–5-methyl-N 2 -(1-Methylpiperidin-4-yl)pyrimidino[4,5-b]quinoline-2,4-diamine

[0449] A mixture of N-(3-cyano-4-methylquinoline-2-yl)aminocyanine (110 mg, 0.528 mmol) and 1-methylpiperidin-4-amine (72.0 mg, 0.634 mmol) in 1,4-dioxane (2.5 mL) was stirred at 100 °C for 1 hour. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. Q Purification yielded the title compound (26.9 mg, 15.8%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 8.0 Hz, 1H),7.69 – 7.54 (m, 2H), 7.37 – 7.29 (m, 1H), 3.77 (br, 1H), 2.75 (s, 3H), 2.73 –2.63 (m, 2H), 2.17 (s, 3H), 2.10 – 1.99 (m, 2H), 1.99 – 1.87 (m, 2H), 1.60 -1.33 (m, 2H).LCMS I m / z = 323 [M+H] +

[0450] Route B

[0451] Preparation of 22–2-hydroxy-4-methylquinoline-3-nitrile

[0452] At room temperature, HOBt (497 mg, 3.69 mmol), EDCI (12.7 g, 66.1 mmol), and DIEA (9.47 g, 74.0 mmol) were added to a solution of o-aminoacetophenone (5.00 g, 37.0 mmol) and cyanoacetic acid (4.70 g, 55.2 mmol) in THF (25 mL). The resulting mixture was stirred overnight at room temperature. The mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was recrystallized from DMSO / water (200 mL, 1 / 1) to give the title compound (3.27 g, 48.0%) as a white solid. LCMS m / z: 185 [M+H] +

[0453] Preparation of 23–2-chloro-4-methylquinoline-3-nitrile

[0454] At 0 °C, POCl3 (12.5 g, 81.4 mmol) was added over 5 minutes to a solution of 2-hydroxy-4-methylquinoline-3-nitrile (1.50 g, 8.14 mmol) in dioxane (30 mL). The resulting mixture was stirred overnight at 100 °C. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM (30 mL) and quenched at 0 °C by adding saturated NaHCO3 (aqueous solution) (30 mL), and extracted with DCM (3 × 30 mL). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The title compound (1.40 g, crude) was thus given as a brown solid. LCMS m / z = 203 [M+H] + .

[0455] Preparation of 24–2-(cyanoamino)-4-methylquinoline-3-nitrile

[0456] Add sodium aminocyanide (508 mg, 7.94 mmol) to a DMSO (20 mL) solution of 2-chloro-4-methylquinoline-3-onitrile (800 mg, 3.95 mmol). Stir the reaction mixture overnight at 80 °C. Allow the mixture to cool to room temperature and dilute with water (50 mL). Extract the resulting mixture with EtOAc (50 mL × 3). Wash the combined organic phases with brine (50 mL), dry with Na₂SO₄, filter, and concentrate under reduced pressure. Residue was analyzed by Prep-HPLC. B Purification yielded the title compound (390 mg, 47.4%) as a pale yellow solid. LCMS m / z = 209 [M+H] + .

[0457] Preparation of 25–5-methyl-N 2 -(1-Methylpiperidin-4-yl)pyrimidino[4,5-b]quinoline-2,4-diamine

[0458] 1-Methylpiperidin-4-amine (937 mg, 8.23 ​​mmol) was added to a solution of 2-(cyanoamino)-4-methylquinoline-3-onitrile (390 mg, 1.87 mmol) in dioxane (20 mL). The resulting mixture was stirred at 100 °C for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. B Purification yielded the title compound (212.3 mg, 35.2%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J = 8.3 Hz, 1H), 7.68 -7.57 (m, 2H), 7.33 (t, J = 7.5 Hz, 1H), 3.78 (br, 1H), 2.75 (s, 3H), 2.69 (d,J = 10.1 Hz, 2H), 2.18 (s, 3H), 2.09 - 2.01 (m, 2H), 1.95 (d, J = 12.4 Hz,2H), 1.46 (s, 2H).LCMS I m / z = 323 [M+H] + .

[0459] Example 11: 6-Methyl-N 3 -(1-Methylpiperidin-4-yl)-8,9-dihydro-7H-cyclopentan[4,5]pyrido[2,3-d]pyrimidin-1,3-diamine

[0460]

[0461] A mixture of 26–1-methyl-3-oxo-4,5,6,7-tetrahydro-3H-cyclopenta[c]pyridine-4-onitrile and 4-methyl-2-oxo-3,5,6,7-tetrahydro-2H-cyclopenta[b]pyridine-3-onitrile was prepared.

[0462] Piperidine (1.35 g, 15.9 mmol) was added to a mixture of 2-acetylcyclopenten-1-one (2.00 g, 15.9 mmol) and 2-cyanoacetamide (1.33 g, 15.9 mmol) in ethanol (20.0 mL). The mixture was stirred at 80 °C for 6 hours. The mixture was cooled to room temperature. The precipitated solid was collected by filtration and washed with ethanol (3 × 50 mL). The solid was dried under vacuum to give the title compound (1.67 g, crude, mixture of positional isomers) as a white solid. LCMS m / z = 175 [M+H] + .

[0463] Preparation of 27–3-chloro-1-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine-4-onitrile and 2-chloro-4-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-onitrile

[0464] At 0 °C, POCl3 (7.04 g, 45.9 mmol) was added dropwise to a mixture of 1-methyl-3-oxo-4,5,6,7-tetrahydro-3H-cyclopentane[C]pyridine-4-onitrile and 4-methyl-2-oxo-3,5,6,7-tetrahydro-2H-cyclopentane[b]pyridine-3-onitrile (800 mg, 4.59 mmol) in dioxane (15.0 mL). The resulting mixture was stirred at 100 °C for 6 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting mixture was diluted with CH2Cl2 (20 mL) and quenched with saturated NaHCO3 (aqueous solution) at 0 °C. The resulting mixture was extracted with CH2Cl2 (3 × 80 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give a mixture of the two isomers (770 mg, 87.0%) as a white solid. SFC was then used to purify the residue. A Separate the mixture to give a white solid of 3-chloro-1-methyl-6,7-dihydro-5H-cyclopenta[c]pyridine-4-onitrile (390 mg, R t = 3 min) and white solid 2-chloro-4-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-onitrile (250 mg, R t = 4 min). LCMS m / z = 193[M+H] +

[0465] Preparation of 28–N-(4-cyano-1-methyl-6,7-dihydro-5H-cyclopentan[c]pyridin-3-yl)aminocyano

[0466] To a solution of 3-chloro-1-methyl-6,7-dihydro-5H-cyclopenta[c]pyridin-4-onitrile (360 mg, 1.87 mmol) and aminocyanide (86.4 mg, 2.06 mmol) in dioxane (8.0 mL), BrettPhos Pd G3 (169 mg, 0.187 mmol), BrettPhos (100 mg, 0.187 mmol), and Cs₂CO₃ (1.21 g, 3.74 mmol) were added. The mixture was stirred at 100 °C for 1 hour under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was filtered through a diatomaceous earth sieve. The sieve was washed with CH₂Cl₂ (3 × 50 mL). The combined filtrates were concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. B Purification yielded the title compound (150 mg, 40.5%) as a white solid. LCMS m / z = 199 [M+H] + .

[0467] Preparation of 29–6-methyl-N 3 -(1-Methylpiperidin-4-yl)-8,9-dihydro-7H-cyclopentan[4,5]pyrido[2,3-d]pyrimidin-1,3-diamine

[0468] A solution of N-(4-cyano-1-methyl-6,7-dihydro-5H-cyclopentan[c]pyridin-3-yl)aminocyano (60 mg, 0.303 mmol) and 1-methylpiperidin-4-amine (41.5 mg, 0.364 mmol) in EtOH (1.5 mL) was stirred at 80 °C for 3 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. B Purification yielded the title compound, a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 6.56 (s, 2H), 6.27 (s, 1H), 3.86 – 3.62(m, 1H), 2.85 – 2.70 (m, 4H), 2.37 (s, 3H), 2.16 (s, 3H), 2.13 – 2.03 (m,2H), 1.94 (t, J = 11.5 Hz, 2H), 1.87 – 1.73 (m, 2H), 1.57 – 1.44 (m, 2H).LCMS A m / z = 313 [M+H] +

[0469] Example 12: 5-Methyl-N 2-(1-Methylpiperidin-4-yl)-7,8-dihydro-6H-cyclopentan[5,6]pyrido[2,3-d]pyrimidin-2,4-diamine

[0470]

[0471] Preparation of 30–N-(3-cyano-4-methyl-6,7-dihydro-5H-cyclopentan[b]pyridin-2-yl)aminocyano

[0472] To a solution of 2-chloro-4-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-3-onitrile (230 mg, 1.194 mmol, synthesized as described in Example 11, Preparation 27) and aminocyanide (55.2 mg, 1.31 mmol) in dioxane (5.0 mL), BrettPhos Pd G3 (108 mg, 0.119 mmol), BrettPhos (64.1 mg, 0.119 mmol), and Cs2CO3 (778 mg, 2.39 mmol) were added. The mixture was stirred at 100 °C under a nitrogen atmosphere for 1 hour. The mixture was allowed to cool to room temperature. The resulting mixture was filtered through a short diatomaceous earth sieve. The sieve was washed with CH2Cl2 (2 × 10 mL). The combined filtrates were concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. B Purification yielded the title compound (120 mg, 50.7%) as a yellow solid. LCMS m / z = 199 [M+H] + .

[0473] Preparation of 31–5-methyl-N2-(1-methylpiperidin-4-yl)-7,8-dihydro-6H-cyclopentan[5,6]pyrido[2,3-d]pyrimidine-2,4-diamine

[0474] A mixture of N-(3-cyano-4-methyl-6,7-dihydro-5H-cyclopentadien[b]pyridin-2-yl)aminocyano (60.0 mg, 0.303 mmol) and 1-methylpiperidin-4-amine (51.9 mg, 0.455 mmol) in EtOH (1.5 mL) was stirred at 80 °C for 5 hours. The resulting mixture was filtered through a diatomaceous earth stencil. The stencil was washed with CH2Cl2 (3 × 10 mL). The combined filtrates were concentrated under reduced pressure. The mixture was then analyzed by Prep-HPLC. B The residue was purified to give the title compound (31.3 mg, 33.1%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 6.63 (s, 2H), 6.26 (s, 1H), 3.82 – 3.67 (m, 1H), 2.88-2.86 (m, 4H), 2.75-2.71 (m, 2H), 2.57(s, 3H), 2.16 (s, 3H), 2.07 – 1.99 (m, 2H), 1.98 – 1.87 (m, 2H), 1.86 – 1.81(m, 2H), 1.57 – 1.42 (m, 2H).LCMS O m / z = 313 [M+H] +

[0475] Example 13: 7-Methyl-N 2 -(1-Methylpiperidin-4-yl)-5-phenylpyrido[2,3-d]pyrimidin-2,4-diamine

[0476]

[0477] Preparation of 32–2-hydroxy-6-methyl-4-phenylpyridine-3-nitrile

[0478] t-BuOK (6.14 g, 54.7 mmol) was added to a DMSO (2.00 mL) solution of 4-phenylbut-3-en-2-one (2.00 g, 13.7 mmol) and cyanoacetamide (1.38 g, 16.4 mmol). The resulting mixture was stirred overnight at 60 °C. The resulting mixture was filtered through a diatomaceous earth sieve. The sieve was washed with EtOAc (10 mL). The combined filtrates were diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. A Purification yielded the title compound as a white solid (210 mg, 7.3%). LCMSm / z = 211 [M+H] + .

[0479] Preparation of 33–2-hydroxy-6-methyl-4-phenylpyridine-3-nitrile

[0480] A solution of 2-hydroxy-6-methyl-4-phenylpyridin-3-onitrile (200 mg, 0.952 mmol) in POCl3 (3.0 mL) was stirred overnight at 100 °C. The resulting mixture was concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. SPurification yielded the title compound as a yellow solid (120 mg, 55.2%). LCMS m / z = 229 [M+H] + .

[0481] Preparation of 3,4–2-(cyanoamino)-6-methyl-4-phenylpyridine-3-nitrile

[0482] At room temperature, sodium aminocyanide (61.6 mg, 0.962 mmol, 2.00 equivalents) was added to a DMSO (3.0 mL) solution of 2-chloro-6-methyl-4-phenylpyridin-3-onitrile (110 mg, 0.481 mmol). The resulting mixture was stirred overnight at 100 °C. The reaction mixture was allowed to cool to room temperature and quenched by adding water (10 mL). The mixture was extracted with EtOAc (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was further analyzed by Prep-HPLC. S Purification yielded the title compound as a white solid (60.0 mg, 53.2%). LCMS m / z = 235 [M+H] + .

[0483] Preparation of 35–7-methyl-N 2 -(1-Methylpiperidin-4-yl)-5-phenylpyrido[2,3-d]pyrimidin-2,4-diamine

[0484] At room temperature, 1-methylpiperidin-4-amine (29.2 mg, 0.260 mmol) was added to a solution of 2-(cyanoamino)-6-methyl-4-phenylpyridin-3-onitrile (50.0 mg, 0.213 mmol) in dioxane (1.5 mL). The resulting mixture was stirred overnight at 80 °C. The mixture was then concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. T Purification yielded the title compound as a white solid (18.5 mg, 24.6%). 1 H NMR (400 MHz, DMSO-d6) δ 7.63 – 7.49 (m, 3H), 7.47 –7.37 (m, 2H), 6.67 (s, 1H), 6.58 (s, 1H), 3.90 – 3.73 (m, 1H), 2.76 – 2.73(m, 2H), 2.46 (s, 3H), 2.16 (s, 3H), 1.95 – 1.92 (m, 2H), 1.83 – 1.80 (m,2H), 1.59 – 1.43 (m, 2H).LCMS m / z = 349 [M+H]+ .

[0485] Example 14: (R)-5,7-dimethyl-N 2 -(1-Methylpyrrolidone-3-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0486]

[0487] DIEA (150 mg, 1.16 mmol) was added to a stirred ethanol (4.0 mL) solution of 2-(cyanoamino)-4,6-dimethylpyridin-3-onitrile (100 mg, 0.581 mmol) and (3R)-1-methylpyrrolidine-3-amine dihydrochloride (121 mg, 0.697 mmol) at room temperature. The resulting mixture was stirred overnight at 80 °C. The mixture was then concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. AN Purification yielded the title compound (62.4 mg, 39.5%) as a white solid. 1 H NMR (400 MHz, methanol-d4) δ 6.81 (s, 1H), 4.67- 4.57 (m, 1H), 2.98 (t, J = 8.8 Hz, 1H), 2.92 –2.75 (m, 1H), 2.72 (s, 3H), 2.66 – 2.54 (m, 2H), 2.47 (s, 3H), 2.45 – 2.31 (m, 4H), 1.85 – 1.74 (m, 1H).LCMS H m / z = 273 [M+H] +

[0488] Example 15: (S)-5,7-dimethyl-N 2 -(1-Methylpyrrolidone-3-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0489]

[0490] As described in Example 14, (3S)-1-methylpyrrolidine-3-amine dihydrochloride was used and analyzed by Prep-HPLC. U Purification yielded the title compound (41.6 mg, 26.3%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 6.95 -6.46 (m, 4H), 4.48 - 4.35 (m, 1H), 2.88 - 2.72 (m, 1H), 2.64 (s, 3H), 2.58 -2.54 (m, 1H), 2.47 - 2.41 (m, 1H), 2.41 - 2.31 (m, 4H), 2.26 (s, 3H), 2.20 -2.08 (m, 1H), 1.78 - 1.63 (m, 1H).LCMS H m / z = 273 [M+H] + .

[0491] Example 16: 5-Methyl-N 2 -(1-Methylpiperidin-4-yl)-7-phenylpyrido[2,3-d]pyrimidin-2,4-diamine

[0492]

[0493] Preparation of 36–2-hydroxy-4-methyl-6-phenylpyridine-3-nitrile

[0494] Pd(PPh3)4 (617 mg, 0.530 mmol) and Na2CO3 (1.13 g, 10.6 mmol) were added to a solution of 2,6-dichloro-4-methylpyridin-3-onitrile (1.00 g, 5.37 mmol) and phenylboronic acid (521 mg, 4.27 mmol) in DME (5.0 mL) and H2O (1.0 mL). The mixture was irradiated with microwave at 80 °C for 1 hour under a nitrogen atmosphere. The mixture was allowed to cool to room temperature and quenched by adding water (50 mL). The resulting mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. L Purification yielded the title compound (420 mg, 34.3%) as a white solid. LCMS m / z = 229 [M+H] +

[0495] Preparation of 37–2-(cyanoamino)-4-methyl-6-phenylpyridine-3-nitrile

[0496] To a mixture of 2-chloro-4-methyl-6-phenylpyridin-3-onitrile (410 mg, 1.79 mmol) and carbamate (150 mg, 3.58 mmol) in dioxane (5.0 mL), Brettphos Pd G3 (162 mg, 0.170 mmol), Brettphos (96.2 mg, 0.170 mmol), and Cs₂CO₃ (1.16 g, 3.58 mmol) were added. The mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was filtered through a diatomaceous earth stencil. The stencil was washed with DCM (30 mL). The combined filtrates were concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. L Purification yielded the title compound (302 mg, 71.9%) as a yellow solid. LCMS m / z = 235 [M+H] + .

[0497] Preparation of 38–5-methyl-N 2 -(1-Methylpiperidin-4-yl)-7-phenylpyrido[2,3-d]pyrimidin-2,4-diamine

[0498] A solution of 2-(cyanoamino)-4-methyl-6-phenylpyridin-3-onitrile (190 mg, 0.811 mmol) and 1-methylpiperidin-4-amine (648 mg, 5.67 mmol) in DMSO (2.0 mL) was microwave-irradiated at 180 °C for 2 hours. The mixture was cooled to room temperature. The resulting mixture was filtered through a diatomaceous earth sieve. The sieve was washed with EtOAc (10 mL). The combined filtrates were concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. W Purification yielded the title compound (26.6 mg, 9.41%) as a white solid. 1 HNMR (400 MHz, DMSO-d 6 ) δ 8.19 – 8.08(m, 2H), 7.55 – 7.45 (m, 3H), 7.42 (s,1H), 6.76 (br, 2H), 6.44 (br, 1H), 3.93 – 3.78 (m, 1H), 2.82 – 2.70 (m, 5H),2.17 (s, 3H), 1.98 (t, J = 12.0 Hz, 2H), 1.82 (d, J = 12.0 Hz, 2H), 1.60 –1.45 (m, 2H).LCMS C m / z = 349 [M+H] +

[0499] Example 17: 7-Methoxy-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0500]

[0501] Preparation of 39–2-(cyanoamino)-6-methoxypyridine-3-nitrile

[0502] At room temperature, aminocyanide (118 mg, 2.82 mmol), Brettphos Pd G3 (1.28 g, 1.41 mmol), Brettphos (756 mg, 1.41 mmol), and K2CO3 (389 mg, 2.82 mmol) were added to a mixture of 2-bromo-6-methoxypyridin-3-onitrile (300 mg, 1.41 mmol) in dioxane (3.00 mL). The resulting mixture was stirred at 80 °C for 2 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was filtered through a diatomaceous earth stencil. The stencil was washed with EtOAc (5 mL). The combined filtrates were concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. B Purification yielded the title compound as a white solid (130 mg, 53.0%). LCMS m / z = 175 [M+H] +

[0503] Preparation of 40–7-methoxy-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0504] At room temperature, 1-methylpiperidin-4-amine (102 mg, 0.895 mmol) was added to a solution of 2-(cyanoamino)-6-methoxypyridin-3-onitrile (130 mg, 0.746 mmol) in dioxane (1.30 mL). The resulting mixture was stirred at 80°C for 6 hours. The mixture was then allowed to cool to room temperature. The mixture was analyzed by Prep-HPLC. I The crude product was purified to give the title compound (95.6 mg, 44.4%). 1H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J = 8.6 Hz, 1H), 7.41 – 6.99 (br,2H), 6.43 (d, J = 8.6 Hz, 2H), 3.87 (br, 4H), 2.73 (d, J = 10.5 Hz, 2H), 2.16(s, 3H), 1.96 (t, J = 11.6 Hz, 2H), 1.86 – 1.75 (m, 2H), 1.51 (m, 2H).LCMS H m / z = 289 [M+H] +

[0505] Example 18: N 2 -(1-Methylpiperidin-4-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0506]

[0507] Preparation of 41–2-(cyanoamino)-6-(trifluoromethyl)pyridine-3-nitrile

[0508] Sodium aminocyanide (619 mg, 9.68 mmol) was added to a mixture of 2-chloro-6-(trifluoromethyl)pyridin-3-onitrile (1.00 g, 4.84 mmol) in DMSO (10.0 mL). The mixture was stirred at 100 °C for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. B Purification yielded the title compound as a light brown solid (618 mg, 60.1%). LCMS m / z = 211 [MH] -

[0509] Preparation of 42 – N 2 -(1-Methylpiperidin-4-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0510] To a mixture of 2-(cyanoamino)-6-(trifluoromethyl)pyridin-3-onitrile (200 mg, 0.943 mmol, 1.00 equivalent) in dioxane (5.00 mL), 1-methylpiperidin-4-amine (215 mg, 1.88 mmol, 2.00 equivalent) was added. The mixture was stirred at 100 °C for 2 hours. The resulting mixture was concentrated under reduced pressure. The solution was analyzed by Prep-HPLC. W The crude product was purified to give the title compound as a white solid (182.9 mg, 59.5%). 1H NMR (400 MHz, methanol-d4) δ 8.49 (d, J = 8.1 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 4.84 (s, 1H), 3.98 (dt, J = 11.2, 6.7 Hz, 1H), 2.87 (d, J = 11.7 Hz, 2H), 2.45 – 2.13 (m, 5H), 2.05 (d, J = 13.7 Hz, 2H),1.60-1.59 (m, 2H).LCMS H m / z = 327 [M+H] +

[0511] Example 19: N 2 -(1-Methylpiperidin-4-yl)-6-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0512]

[0513] Preparation of 43–2-(cyanoamino)-5-(trifluoromethyl)pyridine-3-nitrile

[0514] A mixture of 2-chloro-5-(trifluoromethyl)pyridine-3-onitrile (500 mg, 2.42 mmol) and sodium aminocyanide (309 mg, 4.84 mmol) in DMSO (5.0 mL) was stirred at 100 °C for 1 hour. The mixture was allowed to cool to room temperature and acidified to pH 1 with an aqueous solution of HCl (6.0 M). The precipitate was collected by filtration and dried under vacuum to give the title compound (200 mg crude product) as a gray solid. LCMS m / z = 213 [M+H] +

[0515] Preparation of 44 – N 2 -(1-Methylpiperidin-4-yl)-6-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0516] A mixture of 2-(cyanoamino)-5-(trifluoromethyl)pyridine-3-onitrile (195 mg, 0.919 mmol) and 1-methylpiperidin-4-amine (209 mg, 1.83 mmol) in dioxane (3.0 mL) was stirred at 100 °C for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was analyzed by Prep-HPLC. Y Purification yielded the title compound (142 mg, 47.3%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6) δ 9.06 – 8.65 (m, 2H), 8.36 – 7.45 (m, 2H), 7.45 – 7.00 (m, 1H), 3.87 (s, 1H), 2.94 – 2.70 (m, 2H), 2.37 (m, 3H), 2.17 –1.96 (m, 2H), 1.93 – 1.75 (m, 2H), 1.66 – 1.47 (m, 2H).LCMS C m / z = 327 [M+H] +

[0517] Example 20: 6-Bromo-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0518]

[0519] Route A

[0520] Preparation of 45–N-(5-bromo-3-cyanopyridin-2-yl)aminocyanide

[0521] At room temperature, sodium aminocyanide (0.290 g, 4.60 mmol) was added to a solution of 5-bromo-2-chloronicotinonitrile (1.00 g, 4.60 mmol) in DMSO (10.0 mL). The resulting mixture was stirred at 80 °C for 1 hour. The reaction was quenched with water at room temperature. The resulting mixture was filtered. The analysis was performed by Prep-HPLC. P The filter cake was purified to provide the title compound (450 mg, 43.9%). LCMS m / z = 225 [M+H] +

[0522] Preparation of 46–6-bromo-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0523] At room temperature, 1-methylpiperidin-4-amine (307 mg, 2.69 mmol) was added to a solution of N-(5-bromo-3-cyanopyridin-2-yl)aminocyanine (300 mg, 1.34 mmol) in dioxane (5.0 mL). The resulting mixture was stirred at 100 °C for 1.5 hours. The mixture was then concentrated under vacuum. The final concentration was determined by Prep-HPLC. AA The residue was purified to give the title compound as a white solid (340 mg, 74.1%). 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 2H), 7.81 - 7.35 (m, 2H), 7.11 - 6.51 (m, 1H), 3.87 - 3.71 (m, 1H), 2.74 (d, J = 8.0 Hz, 2H), 2.15 (s, 3H), 1.93 (t, J = 12.0 Hz, 2H), 1.84 - 1.74 (m, 2H), 1.58 - 1.45 (m,2H).LCMS L m / z = 339 [M+H] + .

[0524] Route B

[0525] Preparation of 47–6-bromo-2-chloropyrido[2,3-d]pyrimidine-4-amine

[0526] 6-bromo-2,4-dichloropyrido[2,3-d]pyrimidine (200 mg, 0.717 mmol) and NH3 . The solution of H₂O (3.0 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum to give the title compound (200 mg, crude product) as a yellow solid. LCMS m / z = 261 [M+H] +

[0527] Preparation of 48–6-bromo-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0528] At room temperature, Cs₂CO₃ (339 mg, 1.04 mmol) was added to a solution of 6-bromo-2-chloropyrido[2,3-d]pyrimidin-4-amine (90.0 mg, 0.347 mmol) and 1-methylpiperidin-4-amine (396 mg, 3.47 mmol) in DMSO (1.0 mL). The resulting mixture was stirred at 100 °C for 3 hours. The resulting mixture was analyzed by Prep-HPLC. AK Purification yielded the title compound (14.1 mg, 12.1%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 2H), 7.87 -7.34(m, 2H), 7.06 – 6.79 (m, 1H), 3.86 – 3.72 (m, 1H), 2.74 (dd, J = 11.2, 4.3Hz, 2H), 2.15 (s, 3H), 2.01 - 1.87 (m, 2H), 1.85 - 1.73 (m, 2H), 1.59 - 1.44(m, 2H).LCMS H m / z = 339 [M+H] +

[0529] Example 21: 6-Bromo-7-methyl-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0530]

[0531] Preparation of 49–5-bromo-2-(cyanoamino)-6-methylpyridine-3-nitrile

[0532] Sodium aminocyanide (207 mg, 3.24 mmol) was added to a mixture of 5-bromo-2-chloro-6-methylpyridin-3-onitrile (500 mg, 2.16 mmol) in DMSO (5.00 mL). The mixture was stirred overnight at 80°C. The resulting mixture was analyzed by Prep-HPLC. AC Purification yielded the title compound (168 mg, crude product) as a brown solid. LCMS m / z = 239 [M+H] +

[0533] Preparation of 50–6-bromo-7-methyl-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0534] 1-Methylpiperidin-4-amine (121 mg, 1.06 mmol) was added to a mixture of 5-bromo-2-(cyanoamino)-6-methylpyridin-3-onitrile (158 mg, 0.533 mmol) in dioxane (2.50 mL). The mixture was stirred at 100 °C for 2 hours. The resulting mixture was concentrated under reduced pressure. The final product was analyzed by Prep-HPLC. AD The crude product was purified to give the title compound as a white solid (21.7 mg, 11.5%). 1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 7.78 – 7.14 (br, 2H), 6.68 (s, 1H), 3.84 – 3.72 (m, 1H), 2.74 (d, J = 11.5 Hz, 2H), 2.56 (s, 3H), 2.16(s, 3H), 1.94 (t, J = 11.5 Hz, 2H), 1.80 (d, J = 12.3 Hz, 2H), 1.58 – 1.44(m, 2H).LCMS C m / z = 353 [M+H] +

[0535] Example 22: 6-Bromo-5,7-Dimethyl-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0536]

[0537] Preparation of 51–N-(5-bromo-3-cyano-4,6-dimethylpyridin-2-yl)aminocyano

[0538] A solution of 5-bromo-2-chloro-4,6-dimethylnicotinonitrile (2.00 g, 8.14 mmol) and sodium aminocyanide (1.04 g, 16.2 mmol) in DMSO (20.0 mL) was stirred at 80 °C for 2 h. The mixture was allowed to cool to room temperature and acidified to pH 6 with an aqueous HCl (1 M) solution. The solid was collected by filtration. The solid was purified by preparation with PE / EA (2:1, 30 mL) to give the title compound as a light brown solid (1.3 g, 63.6%). LCMS m / z = 253 [M+H] +

[0539] Preparation of 52–6-bromo-5,7-dimethyl-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0540] A solution of N-(5-bromo-3-cyano-4,6-dimethylpyridin-2-yl)aminocyanine (100 mg, 0.398 mmol) and 1-methylpiperidin-4-amine (90.8 mg, 0.796 mmol) in dioxane (2.00 mL) was stirred overnight at 100 °C. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. AE Purification yielded the title compound as a white solid (21.9 mg, 15.0%).1 H NMR (400 MHz, DMSO-d6) δ 7.00 - 6.88 (br, 2H), 6.73 -6.70 (br, 1H), 3.81-3.71 (m, 1H), 2.76-2.73 (m, 5H), 2.50 (s, 3H), 2.16 (s,3H), 1.97 - 1.92 (m, 2H), 1.80 - 1.77(m, 2H), 1.56 - 1.46 (m, 2H).LCMS C m / z = 267 [M+H] +

[0541] Example 23: 7-Chloro-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0542]

[0543] Route A

[0544] Preparation of 53–2,7-dichloropyrido[2,3-d]pyrimidine-4-amine

[0545] 2,4,7-trichloropyrido[2,3-d]pyrimidine (200 mg, 0.853 mmol) in NH3 . The H2O (3.0 mL) solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure to give the title compound as a white solid (190 mg, crude product). LCMS m / z = 217 [M+H] +

[0546] Preparation of 54–7-chloro-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0547] At room temperature, DIEA (180 mg, 1.40 mmol) was added to a stirred solution of 2,7-dichloropyrido[2,3-d]pyrimidin-4-amine (150 mg, 0.698 mmol) and 1-methylpiperidin-4-amine (398 mg, 3.49 mmol) in DMSO (3.00 mL). The resulting mixture was stirred at 60°C for 1 hour. The mixture was then allowed to cool to room temperature. The mixture was analyzed by Prep-HPLC. U The crude product was purified to give 7-chloro-N 2 -(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine, is a grayish-white solid (6.9 mg, 3.34%).1 H NMR (400 MHz, DMSO-d 6 ) δ 8.40 – 8.30 (m, 1H), 8.00 – 7.37(m, 2H), 7.16 – 6.82 (m, 2H), 3.85 – 3.72 (m, 1H), 2.80 – 2.68 (m, 2H), 2.16(s, 3H), 2.00 – 1.86 (m, 2H), 1.84 – 1.73 (m, 2H), 1.58 – 1.38 (m, 2H).LCMS H m / z = 293 [M+H] + .

[0548] Route B

[0549] Preparation of 55–6-chloro-2-(cyanoamino)pyridine-3-nitrile

[0550] At room temperature, sodium aminocyanide (22.2 g, 347 mmol) was added to a solution of 30.0 g (173 mmol) of 2,6-dichloropyridin-3-onitrile in 240 mL of DMSO. The resulting mixture was stirred at 60 °C for 1 hour. The mixture was then allowed to cool to room temperature. The residue was analyzed by Prep-HPLC. B Purification yielded the title compound as a red solid (10.0 g, 32.3%). LCMS m / z = 179 [M+H] +

[0551] Preparation of 56–7-chloro-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0552] At room temperature, 1-methylpiperidin-4-amine (7.67 g, 67.2 mmol) was added to a stirred solution of 6-chloro-2-(cyanoamino)pyridin-3-onitrile (10.0 g, 56.0 mmol) in dioxane (150 mL). The resulting mixture was stirred at 100°C for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in DMF (10.0 mL). The residue was analyzed by Prep-HPLC. B Purification yielded the title compound as a yellow solid (3.00 g, 18.3%). 1H NMR (400 MHz, DMSO-d6) δ 8.40 – 8.30 (m, 1H), 8.00 – 7.37 (m, 2H), 7.16 – 6.82 (m, 2H), 3.85 –3.72 (m, 1H), 2.80 – 2.68 (m, 2H), 2.16 (s, 3H), 2.00 – 1.86 (m, 2H), 1.84 –1.73 (m, 2H), 1.58 – 1.38 (m, 2H).

[0553] Example 24: 7-(4-methoxyphenyl)-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0554]

[0555] Preparation of 57–N-(3-cyano-6-(4-methoxyphenyl)pyridin-2-yl)aminocyano

[0556] Under a nitrogen atmosphere, Pd(AMPHOS)₂Cl₂ (59.5 mg, 0.084 mmol) and K₃PO₄ (356 mg, 1.68 mmol) were added to a solution of 6-chloro-2-(cyanoamino)pyridin-3-onitrile (150 mg, 0.840 mmol, synthesized as described in Example 23, Preparation 55) and (255 mg, 1.68 mmol) boric acid (255 mg, 1.68 mmol) in 1,4-dioxane (3.0 mL) and H₂O (0.6 mL). The resulting mixture was stirred at 100 °C for 3 hours under a nitrogen atmosphere. The resulting mixture was analyzed by Prep-HPLC. B Purified to provide the title compound as a yellow solid (80.0 mg, 38.1%). LCMS m / z = 251 [M+H] +

[0557] Preparation of 58–7-(4-methoxyphenyl)-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0558] At room temperature, 1-methylpiperidin-4-amine (73.0 mg, 0.640 mmol) was added to a stirred solution of N-(3-cyano-6-(4-methoxyphenyl)pyridin-2-yl)aminocyanide (80.0 mg, 0.320 mmol) in 1,4-dioxane (1.0 mL). The resulting mixture was stirred at 80 °C for 4 hours. The mixture was then concentrated under vacuum. The residue was analyzed by Prep-HPLC. IPurification yielded the title compound as a white solid (17.0 mg, 14.2%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.37 (d,J = 8.3 Hz, 1H), 8.14 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.0 Hz, 1H), 7.32 (s,2H), 7.05 (d, J = 8.0 Hz, 2H), 6.52 (s, 1H), 3.94 - 3.76 (m, 4H), 2.75 (d, J= 11.2 Hz, 2H), 2.17 (s, 3H), 1.98 (t, J = 11.5 Hz, 2H), 1.83 (d, J = 12.2Hz, 2H), 1.60 - 1.45 (m, 2H);LCMS M m / z: 365 [M+H] + .

[0559] Example 25: N 2 -(1-Methylpiperidin-4-yl)-7-(pyridin-3-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0560]

[0561] At room temperature, 7-chloro-N 2 Pd(AMPhos)₂Cl₂ (14.5 mg, 21.0 μmol) and K₃PO₄ (87.0 mg, 0.410 mmol) were added to a solution of 1.5 mL dioxane / 0.5 mL H₂O. The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The mixture was then cooled to room temperature. The residue was analyzed by Prep-HPLC. AF Purification yielded the title compound (29.4 mg, 42.8%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.32 (d, J = 2.3 Hz, 1H), 8.67 (dd, J = 4.8, 1.6 Hz, 1H), 8.56 –8.44 (m, 2H), 7.70 (d, J = 8.2 Hz, 1H), 7.54 (dd, J = 8.0, 4.7 Hz, 1H), 7.46(br, 2H), 6.92 – 6.59 (m, 1H), 3.87 (br, 1H), 2.76 (d, J = 11.3 Hz, 2H), 2.17(s, 3H), 1.96 (d, J = 11.7 Hz, 2H), 1.83 (d, J = 12.3 Hz, 2H), 1.62 – 1.47(m, 2H).LCMS C m / z = 336 [M+H] +

[0562] Example 26: 7-(1-methyl-1H-pyrazole-4-yl)-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0563]

[0564] As described in Example 25, 1-methyl-4-(3,3,4,4-tetramethylboronen-1-yl)-1H-pyrazole was used and subjected to Prep-HPLC. N Purification yielded the title compound (14.4 mg, 24.9%) as a grayish-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.29 (d, J = 8.3 Hz, 1H), 8.06 (s, 1H), 7.57 – 7.04(m, 3H), 6.53 (br, 1H), 3.90 (s, 3H), 3.83 LCMS C m / z = 339 [M+H] +

[0565] Example 27: N 2-(1-Methylpiperidin-4-yl)-7-phenylpyrido[2,3-d]pyrimidin-2,4-diamine

[0566]

[0567] Route A

[0568] As described in Example 25, phenylboronic acid was used and analyzed by Prep-HPLC. AH Purification yielded the title compound as a white solid (22.3 mg, 39.0%). 1 H NMR (300 MHz, DMSO-d6) δ 8.43 (d, J = 9.0 Hz, 1H), 8.20– 8.13 (m, 2H), 7.62 (d, J = 9.0 Hz, 1H), 7.56 – 7.35 (m, 5H), 6.70 – 6.45(s, 1H), 3.82 (br, 1H), 2.76 (d, J = 12.0 Hz, 2H), 2.17 (s, 3H), 1.98 (t, J =12.0 Hz, 2H), 1.83 (d, J = 12.0 Hz, 2H), 1.65 – 1.45 (m, 2H).LCMS C m / z = 335[M+H] + .

[0569] Route B

[0570] Preparation of 59–7-chloro-1H,3H-pyrido[2,3-d]pyrimidine-2,4-dione

[0571] At room temperature, (COCl)₂ (3.55 g, 28.0 mmol) was added to a solution of 2-amino-6-chloropyridine-3-carboxamide (4.00 g, 23.3 mmol) in toluene (40.0 mL). The resulting mixture was stirred at 100 °C for 2 hours. The mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration and washed with toluene (3 x 5 mL). The solid was dried under vacuum to give the title compound (4.00 g, crude) as a brown solid. LCMS m / z = 198 [M+H] + .

[0572] Preparation of 60–7-phenyl-1H,3H-pyrido[2,3-d]pyrimidine-2,4-dione

[0573] At room temperature, Pd(AMPHOS)₂Cl₂ (1.08 g, 1.52 mmol) and K₃PO₄ (6.45 g, 30.4 mmol) were added to a stirred solution of 7-chloro-1H,3H-pyrido[2,3-d]pyrimidine-2,4-dione (3.00 g, 15.2 mmol) and phenylboronic acid (2.22 g, 18.2 mmol) in 1,4-dioxane (60.0 mL) and H₂O (20.0 mL). The resulting mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with H₂O (100 mL) and extracted with CH₂Cl₂ (3 × 200 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the combined filtrates were concentrated under reduced pressure. The residue was purified with Et₂O (200 mL) to give the title compound (3.50 g, crude product) as a brown solid. LCMS m / z = 240 [M+H] + .

[0574] Preparation of 61–2,4-dichloro-7-phenylpyrido[2,3-d]pyrimidine

[0575] A mixture of 7-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (2.80 g, 11.7 mmol) in phosphorus oxychloride (100 mL) was stirred overnight at 110 °C. The resulting mixture was concentrated under reduced pressure. The residue was quenched at 0 °C by adding saturated NaHCO3 (aqueous solution) (100 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (2:1) to give the title compound (640 mg, 19.9%) as a green solid. LCMS m / z = 278 [M+H] +

[0576] Preparation of 62–2-chloro-7-phenylpyrido[2,3-d]pyrimidin-4-amine

[0577] 2,4-Dichloro-7-phenylpyrido[2,3-d]pyrimidine (200 mg, 0.724 mmol) in NH3 . The H2O (3.0 mL) solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum to give the title compound (230 mg, crude product) as a white solid. LCMS m / z = 257 [M+H] +

[0578] Preparation of 63–N 2-(1-Methylpiperidin-4-yl)-7-phenylpyrido[2,3-d]pyrimidin-2,4-diamine

[0579] At room temperature, 1-methylpiperidin-4-amine (169 mg, 1.48 mmol) was added to a solution of 2-chloro-7-phenylpyrido[2,3-d]pyrimidin-4-amine (190 mg, 0.740 mmol) in dioxane (3.0 mL). The resulting mixture was stirred at 100 °C for 10 hours. The mixture was then concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. AL Purification yielded the title compound (10.1 mg, 4.03%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 8.3 Hz, 1H), 8.21 - 8.12 (m, 2H), 7.62 (d, J = 8.3 Hz, 1H), 7.56 - 7.44 (m, 5H), 6.88 -6.49 (m, 1H), 3.87 (br, 1H), 2.75 (d, J = 10.9 Hz, 2H), 2.17 (s, 3H), 2.00-1.95 (m, 2H), 1.84-1.82 (m, 2H), 1.65 - 1.45 (m, 2H).LCMS H m / z = 335 [M+H] +

[0580] Example 28: N 2 -(1-Methylpiperidin-4-yl)-6-(oxetane-3-yloxy)pyrido[2,3-d]pyrimidin-2,4-diamine

[0581]

[0582] At room temperature, to 6-bromo-N 2 Rockphos (41.7 mg, 89.0 μmol), Cs₂CO₃ (290 mg, 0.889 mmol), and bis(chloro(prop-2-en-1-yl)palladium) (10.9 mg, 30.0 μmol) were added to a solution of (1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine (200 mg, 0.593 mmol) and oxetane-3-ol (87.9 mg, 1.19 mmol) in toluene (4.0 mL). The resulting mixture was stirred at 90 °C for 2 hours under a nitrogen atmosphere. The mixture was then concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. AKPurification yielded the title compound (2.8 mg, 1.43%) as a yellow solid. 1 ¹H NMR (400 MHz, methanol-d⁴) δ 8.48 (s, 1H), 7.66 (s, 1H), 5.35–5.34 (m, 1H), 5.09–5.06 (m, 2H), 4.88–4.71 (m, 2H), 4.18 (s, 1H), 3.49–3.46 (m, 2H), 3.25–3.12 (m, 2H), 2.80 (s, 3H), 2.22–2.20 (m, 2H), 1.97–1.86 (m, 2H). LCMS H m / z = 331 [M+H] +

[0583] Example 29: N 2 -(3-(2-oxa-6-azaspiro[3.3]hept-6-yl)propyl)-5,7-dimethylpyrido[2,3-d]pyrimidine-2,4-diamine

[0584]

[0585] Preparation of 64–N 2 -(3,3-Diethoxypropyl)-5,7-dimethylpyrido[2,3-d]pyrimidin-2,4-diamine

[0586] Route A

[0587] 3,3-diethoxypropyl-1-amine (9.40 mL, 58.0 mmol) was added to a mixture of 2-(cyanoamino)-4,6-dimethylpyridin-3-onitrile (5.00 g, 29.0 mmol) in dioxane (50.0 mL). The mixture was stirred at 100 °C for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparation with EA / PE (30.0 mL / 60 mL). The solid was collected by filtration and washed with hexane and EA / PE (1:2, 3 × 10 mL). This gave the title compound as a brown solid (4.48 g, crude product). LCMS m / z = 320 [M+H] +

[0588] Route B

[0589] At room temperature, 3,3-diethoxypropyl-1-amine (4.55 g, 30.9 mmol, 1.50 equivalent) was added dropwise to a mixture of 2-chloro-5,7-dimethylpyrido[2,3-d]pyrimidin-4-amine (4.30 g, 20.6 mmol, synthesized as described in Example 5, Preparation 13) in 1,4-dioxane (86.0 mL). The resulting mixture was stirred at 100 °C for 5 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. B Purification yielded the title compound (2.33 g, 35.4%) as a yellow solid. LCMS m / z = 320 [M+H] +

[0590] Preparation of 65–3-((4-amino-5,7-dimethylpyrido[2,3-d]pyrimidin-2-yl)amino)propionaldehyde

[0591] To N 2 TFA (2.00 mL) was added to a mixture of (3,3-diethoxypropyl)-5,7-dimethylpyrido[2,3-d]pyrimidine-2,4-diamine (1.00 g, 3.13 mmol) in DCM (10.0 mL). The mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparation with EA / PE (10.0 mL / 5 mL). The crude product was collected by filtration and dried under vacuum to give the title compound as a white solid (570 mg, crude product). LCMS m / z = 246 [M+H] +

[0592] Preparation of 66–N 2 -(3-(2-oxa-6-azaspiro[3.3]hept-6-yl)propyl)-5,7-dimethylpyrido[2,3-d]pyrimidine-2,4-diamine

[0593] Et3N (131 mg, 1.30 mmol) and 2-oxa-6-azaspiro[3.3]heptane hemioxalate (188 mg, 0.652 mmol) were added to a solution of 3-((4-amino-5,7-dimethylpyridino[2,3-d]pyrimidin-2-yl)amino)propionaldehyde (80.0 mg, 0.326 mmol) in MeOH (2.0 mL). The solution was stirred at room temperature for 1 hour, and then NaBH4 (24.6 mg, 0.652 mmol) was added. The resulting mixture was stirred at room temperature for another 1 hour and concentrated under reduced pressure. The solution was analyzed by Prep-HPLC. N The crude product was purified to give the title compound as a white solid (22.2 mg, 20.7%). 1H NMR (400 MHz, DMSO-d6)δ 6.85 – 6.61 (m, 3H), 6.47(s, 1H), 4.58 (s, 4H), 3.28 – 3.21 (m, 2H), 3.21(s, 4H), 2.63 (s, 3H), 2.37 (s, 3H), 2.33 (t, J = 7.0 Hz, 2H), 1.54 – 1.45(m, 2H).LCMS H m / z = 329 [M+H] +

[0594] Example 30: N 2 -(2-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethyl)-5,7-dimethylpyrido[2,3-d]pyrimidine-2,4-diamine

[0595]

[0596] As described in Example 29, 2,2-diethoxyethane-1-amine was used and administered via Prep-HPLC. Y The final purification yielded the title compound (28.4 mg, 26.1%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 6.74 (s, 2H), 6.69 (s, 1H), 6.30 (s, 1H), 4.58 (s, 4H), 3.25 - 3.16 (m, 4H), 3.19-3.11 (m,2H), 2.63 (s, 3H), 2.49 - 2.44 (m, 2H), 2.37 (s, 3H).LCMS H m / z = 315 [M+H] +

[0597] Example 31: N 3 -(1-Methylpiperidin-4-yl)-6-phenylpyrimidino[4,5-c]isoquinoline-1,3-diamine

[0598]

[0599] Preparation of 67–1-(3-chloro-1-phenylisoquinoline-4(3H)-ylidene)-N,N-dimethylmethylamine

[0600] A solution of POCl3 (6.72 g, 43.8 mmol) in THF (15 mL) was treated with DMF (3.20 g, 43.7 mmol) at 0 °C for 30 min, followed by the addition of 1-phenyl-1,4-dihydroisoquinoline-3(2H)-one (2.47 g, 10.9 mmol). The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched by adding NaOH (2 mol / L, 20 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. This gave the title compound as a brown oil (5.3 g, crude product). LCMS m / z = 297 [M+H] +

[0601] Preparation of 68–3-chloro-1-phenylisoquinoline-4-carboxaldehyde

[0602] A solution of 1-(3-chloro-1-phenylisoquinoline-4(3H)-ylidene)-N,N-dimethylmethylamine (5.2 g, 17.5 mmol) and KMnO4 (1.50 mg) in H2SO4 (50 mL) was stirred at room temperature for 1 hour. The mixture was allowed to cool to room temperature. The reaction was quenched with water at room temperature. The precipitate was collected by filtration and washed with water (3 x 10 mL). The residue was purified by preparation with EtOAc (20 mL). The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 x 10 mL). The filtrate was concentrated under reduced pressure. The title compound (1.5 g, crude) was thus given as a brown solid. LCMS m / z = 268 [M+H] +

[0603] Preparation of 69–N-[(3-chloro-1-phenylisoquinolin-4-yl)methylene]hydroxylamine

[0604] A solution of 3-chloro-1-phenylisoquinoline-4-carboxaldehyde (1.14 g, 4.26 mmol), Et3N (764 μL, 5.50 mmol), and hydroxylamine hydrochloride (433 mg, 6.23 mmol) in ethanol (5 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The mixture was diluted with water (5 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. B Purification yielded the title compound as an orange solid (476 mg, 39.5%). LCMS m / z = 283 [M+H] +

[0605] Preparation of 70–3-chloro-1-phenylisoquinoline-4-nitrile

[0606] At room temperature, pyridine (244 μL, 3.01 mmol) was added dropwise to a stirred solution of N-[(3-chloro-1-phenylisoquinolin-4-yl)methylene]hydroxylamine (426 mg, 1.51 mmol) in 5.0 mL of DCM. The resulting mixture was stirred at 0 °C for 5 minutes. TFAA (838 μL, 6.03 mmol) was added dropwise to the mixture at room temperature. The resulting mixture was stirred overnight at room temperature. The mixture was filtered, and the filtrate was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give the title compound as a yellow solid (280 mg, 70.2%). LCMS m / z = 265 [M+H] +

[0607] Preparation of 71–3-(cyanoamino)-1-phenylisoquinoline-4-nitrile

[0608] At room temperature, 2-sodium acetonitrile (129 mg, 2.04 mmol) was added fractionally to a stirred solution of 3-chloro-1-phenylisoquinoline-4-onitrile (270 mg, 1.02 mmol) in 0.5 mL of DMSO. The resulting mixture was stirred at 60 °C for 1 hour. The mixture was allowed to cool to room temperature. The mixture was acidified to pH 3 with 1 molar HCl (aqueous solution). The precipitated solid was collected to give the title compound (270 mg, crude product) as an orange solid. LCMS m / z = 271 [M+H] +

[0609] Preparation of 72–N 3 -(1-Methylpiperidin-4-yl)-6-phenylpyrimidino[4,5-c]isoquinoline-1,3-diamine

[0610] At room temperature, 1-methylpiperidin-4-amine (126 mg, 1.11 mmol) was added dropwise to a stirred solution of 3-(cyanoamino)-1-phenylisoquinoline-4-onitrile (150 mg, 0.555 mmol) in 1,4-dioxane (5.0 mL). The resulting mixture was stirred at 100 °C for 7 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (5.0 mL). The mixture was acidified to pH 5 with 1 M HCl (aqueous solution). Then, the mixture was analyzed by Prep-HPLC. J The mixture was purified to give the title compound as a yellow solid (12.1 mg, 5.6%). 1H NMR (400 MHz, methanol-d4) δ 8.65 (d, J = 8.6 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.99 (t, J = 8.1 Hz, 1H), 7.80 – 7.73 (m, 2H), 7.70 –7.58 (m, 4H), 4.33 (s, 1H), 3.71 – 3.46 (m, 2H), 3.29 – 3.08 (m, 2H), 2.93(s, 3H), 2.35 (br., 2H), 2.03 (br. s, 2H).LCMS H m / z = 385 [M+H] +

[0611] Example 32: N 2 -(1-Methylpiperidin-4-yl)-7-phenoxypyrido[2,3-d]pyrimidin-2,4-diamine

[0612]

[0613] At room temperature, to 7-chloro-N 2 t-BuOK (38.3 mg, 0.342 mmol) was added to a stirred solution of (1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine (50.0 mg, 0.171 mmol) and phenol (32.2 mg, 0.342 mmol) in DMSO (1.0 mL). The resulting mixture was stirred at 100 °C for 2 hours. The mixture was allowed to cool to room temperature. The residue was analyzed by Prep-HPLC. Q Purification yielded the title compound (22.5 mg, 37.6%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ 8.36 (d, J = 8.6 Hz, 1H), 7.44 (t, J = 7.7 Hz, 3H), 7.31 –7.10 (m, 4H), 6.74 – 6.39 (m, 2H), 3.81 – 3.64 (m, 1H), 2.68 (d, J = 11.0 Hz, 2H), 2.13 (s, 3H), 1.91 (t, J = 11.4 Hz, 2H), 1.81 – 1.63 (m, 2H), 1.47-1.42(m, 2H).LCMS H m / z = 351 [M+H] +

[0614] Example 33: 7-Cyclobutoxy-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0615]

[0616] At 100°C, 7-chloro-N 2 A solution of (1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine (50.0 mg, 0.171 mmol) and cyclobutanol (24.6 mg, 0.342 mmol), t-BuOK (38.3 mg, 0.342 mmol) in DMSO (2.00 mL) was stirred overnight. The mixture was allowed to cool to room temperature. The mixture was then analyzed by Prep-HPLC. B The residue was purified to give the title compound as a white solid (4.90 mg, 8.74%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.21 – 8.19 (m, 1H),7.13 (br, 2H), 6.54 (br, 1H), 6.41 – 6.38 (d, J = 12.0, 1H), 5.16 (s, 1H),3.86 (s, 1H), 2.89 – 2.87 (m, 2H), 2.43 – 2.36 (m, 2H), 2.29 -2.27(m, 5H),2.09 – 1.99 (m, 2H), 1.91 – 1.74 (m, 3H), 1.68 – 1.55 (m, 3H).LCMS m / z = 329[M+H] +

[0617] Example 34: N 7 -Methyl-N2-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4,7-triamine

[0618]

[0619] At room temperature, 7-chloro-N 2 Cs₂CO₃ (66.8 mg, 0.204 mmol) was added in portions to a solution of (1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine (30.0 mg, 0.102 mmol) and methylamine hydrochloride (13.8 mg, 0.204 mmol) in DMSO (0.5 mL). The resulting mixture was stirred overnight at 100 °C. The mixture was then cooled to room temperature. The resulting mixture was filtered. The mixture was analyzed by Prep-HPLC.B The combined filtrate was purified to give the title compound (3.40 mg, 9.24%) as a pale yellow oil. 1 ¹H NMR (400 MHz, methanol-d⁴) 7.86–7.77 (m, 2H), 6.36 (d, J = 9.0 Hz, 1H), 4.04–3.94 (m, 1H), 3.05–3.02 (m, 2H), 2.88 (s, 3H), 2.58–2.48 (m, 2H), 2.45 (s, 3H), 2.04–2.02 (m, 2H), 1.73–1.60 (m, 2H). LCMS G m / z = 288[M+H] +

[0620] Example 35: N 2 -(1-Methylpiperidin-4-yl)-N 7 -Phenylidene[2,3-d]pyrimidine-2,4,7-triamine

[0621]

[0622] At room temperature, 7-chloro-N 2 A mixture of (1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine (100 mg, 0.342 mmol) and aniline (63.6 mg, 0.684 mmol) in 1,4-dioxane (2.0 mL) was supplemented with NaOTMS (76.6 mg, 0.684 mmol), EPhos Pd G4 (31.4 mg, 34.0 μmol), and EPhos (18.3 mg, 34.0 μmol). The resulting mixture was stirred at 80 °C for 1 hour under a nitrogen atmosphere. The resulting mixture was analyzed by Prep-HPLC. AM Purification yielded the title compound (8.8 mg, 7.37%) as a grayish-white solid. 1H NMR (400 MHz, DMSO-d6) δ9.27 (s, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.95-7.75 (m, 2H), 7.29 (t, J = 7.7Hz, 2H), 7.03 (s, 2H), 6.94 (t, J = 7.3 Hz, 2H), 6.47 (d, J = 8.7 Hz, 1H), 3.94 – 3.71 (m, 1H), 2.73 (d, J = 11.4 Hz, 2H), 2.16 (s, 3H), 1.96 (t, J =11.5 Hz, 2H), 1.85 – 1.74 (m, 2H), 1.49 (q, J = 11.5 Hz, 2H).LCMS H m / z = 350[M+H] +

[0623] Example 36: N 7 N 7 -dimethyl-N 2 -(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4,7-triamine

[0624]

[0625] At room temperature, Cs₂CO₃ (111 mg, 0.342 mmol) was added to a stirred solution of 7-chloro-N₂-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine (50.0 mg, 0.171 mmol) and dimethylamine hydrochloride (20.6 mg, 0.257 mmol) in DMSO (1.0 mL). The resulting mixture was stirred overnight at 100 °C. The mixture was then allowed to cool to room temperature. The mixture was analyzed by Prep-HPLC. AL The crude product was purified to give the title compound as a yellow solid (18.1 mg, 33.1%). 1H NMR(400 MHz, DMSO-d6) δ 8.01 (dd, J = 9.0, 2.4 Hz, 1H), 6.85 (s, 2H), 6.43 (d, J= 8.9 Hz, 1H), 6.13 (s, 1H), 3.86 – 3.67 (m, 1H), 3.08 LCMS H m / z = 302 [M+H] +

[0626] Example 37: N 2 -(2-(isoindololin-2-yl)ethyl)-5,7-dimethylpyrido[2,3-d]pyrimidin-2,4-diamine

[0627]

[0628] As described in Example 29, isoindoline was used and the assay was performed using Prep-HPLC. O Purification yielded the title compound as a white solid (5.6 mg, 5.78%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.31 – 7.07 (m, 4H), 6.77-6.45(m, 4H), 3.91 (s, 4H), 3.49 – 3.46 (m, 2H), 2.86 (t, J = 6.7 Hz, 2H), 2.64(s, 3H), 2.38 (s, 3H).LCMS H m / z = 335 [M+H] +

[0629] Example 38: 7-Isopropoxy-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0630]

[0631] At 100°C, 7-chloro-N 2A solution of (1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine (50.0 mg, 0.171 mmol) and isopropanol (1.00 mL, 13 mmol), Cs₂CO₃ (111 mg, 0.342 mmol) in DMSO (1.00 mL) was stirred overnight. The mixture was allowed to cool to room temperature. The mixture was then analyzed by Prep-HPLC. AL The crude product was purified to give the title compound as a white solid (6.50 mg, 12.0%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.18 – 8.16 (d, J= 8.00, 1H), 7.09 (m, 2H), 6.36 – 6.33 (m, 2H), 5.78 (br m, 1H), 3.79 (s,1H), 3.74 – 3.71 (d, J = 12.0, 2H), 2.16 (s, 3H), 1.98 – 1.93 (m, 2H), 1.79 –1.77 (m, 2H), 1.54 – 1.46 (m, 2H), 1.33 (d, J = 16.0, 6H).LCMS C m / z: 317 [M+H] +

[0632] Example 39: N 4 -Methyl-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0633]

[0634] Preparation of 73–2-chloro-N-methylpyrido[2,3-d]pyrimidin-4-amine

[0635] At room temperature, Cs₂CO₃ (1.63 g, 5.00 mmol) was added to a stirred solution of 2,4-dichloropyrido[2,3-d]pyrimidine (500 mg, 2.50 mmol) and methylamine hydrochloride (338 mg, 5.00 mmol) in DMSO (5.0 mL). The resulting mixture was stirred at 60 °C for 1 hour. The mixture was diluted with water (5 mL). The precipitated solid was collected by filtration and washed with water. This gave the title compound as a white solid (330 mg, crude product). LCMS m / z = 195 [M+H] +

[0636] Preparation of 74–N 4 -Methyl-N2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0637] At room temperature, 1-methylpiperidin-4-amine (176 mg, 1.54 mmol) was added to a stirred solution of 2-chloro-N-methylpyridino[2,3-d]pyrimidin-4-amine (150 mg, 0.771 mmol) in dioxane (3.0 mL). The resulting mixture was stirred overnight at 100 °C. The mixture was then concentrated under reduced pressure. The final product was analyzed by Prep-HPLC. AK The residue was purified to give the title compound as a white solid (4.0 mg, 1.71%). 1 H NMR (400 MHz, DMSO-d6) δ 8.57 (dd, J = 4.5, 1.9 Hz,1H), 8.27 (dd, J = 8.0, 2.0 Hz, 1H), 8.02 (s, 1H), 7.13 – 6.91 (m, 1H), 6.69(s, 1H), 3.93 – 3.72 (m, 1H), 2.94 (d, J = 4.4 Hz, 3H), 2.83 – 2.67 (m, 2H), 2.16 (s, 3H), 1.95 (td, J = 11.8, 2.5 Hz, 2H), 1.83 (d, J = 12.3 Hz, 2H),1.62 – 1.46 (m, 2H).LCMS G m / z = 273 [M+H] +

[0638] Example 40: N 4 N 4 -dimethyl-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0639]

[0640] Preparation of 75–2-chloro-N,N-dimethylpyrido[2,3-d]pyrimidin-4-amine

[0641] At room temperature, Cs₂CO₃ (977 mg, 3.00 mmol) was added to a stirred solution of 2,4-dichloropyrido[2,3-d]pyrimidine (300 mg, 1.50 mmol) and dimethylamine hydrochloride (245 mg, 3.00 mmol) in DMSO (5.0 mL). The resulting mixture was stirred at 60 °C for 1 hour. The resulting mixture was diluted with water (5.0 mL). The solution was analyzed by Prep-HPLC. B The residue was purified to give the title compound (180 mg, 57.5%). LCMS m / z = 209 [M+H] +

[0642] Preparation of 76–N 4 N 4 -dimethyl-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0643] At room temperature, 1-methylpiperidin-4-amine (87.6 mg, 0.766 mmol) was added to a stirred solution of 2-chloro-N,N-dimethylpyridino[2,3-d]pyrimidin-4-amine (80.0 mg, 0.383 mmol) in dioxane (2.0 mL). The resulting mixture was stirred overnight at 100 °C. The mixture was then allowed to cool to room temperature. The mixture was analyzed by Prep-HPLC. AK The crude product was purified to give the title compound as a grayish-white solid (31.9 mg, 26.9%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.62 (s, 1H),8.33 (s, 1H), 7.06 (s, 2H), 4.07 (s, 1H), 3.42 - 3.20 (m, 8H), 3.14 - 2.99(m, 2H), 2.70 (s, 3H), 2.19 - 2.03 (m, 2H), 1.92 - 1.72 (m, 2H).LCMS Q m / z = 287 [M+H] +

[0644] Example 41: N 7 -(2,4-Dimethoxybenzyl)-N 2 -(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4,7-triamine

[0645]

[0646] At room temperature, 7-chloro-N2 Cs₂CO₃ (1.02 g, 3.08 mmol) was added to a DMSO (8.0 mL) solution of (1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine (300 mg, 1.03 mmol) and (2,4-dimethoxyphenyl)methylamine (514 mg, 3.08 mmol). The resulting mixture was stirred at 120 °C for 5 hours. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. B Purification yielded the title product (78 mg, 17.90%) as a green solid. 1 H NMR (400 MHz, DMSO-d6)δ 7.86 (d, J = 8.8 Hz, 1H), 7.24 - 7.09 (m, 2H), 6.83 (s, 2H), 6.56 (d, J =2.4 Hz, 1H), 6.46 (dd, J = 8.3, 2.4 Hz, 1H), 6.26 (d, J = 8.7 Hz, 1H), 6.10(s, 1H), 4.42 (d, J = 5.6 Hz, 2H), 3.82 - 3.73 (m, 7H), 2.76 - 2.67 (m, 2H),2.15 (s, 3H), 2.00 - 1.90 (m, 2H), 1.81 – 1.73 (m, 2H), 1.52 – 1.41 (m, 2H).LCMSH m / z = 424 [M+H] +

[0647] Example 42: N 2 -(1-Methylpiperidin-4-yl)-6-(prop-1-yn-1-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0648]

[0649] At room temperature, under a nitrogen atmosphere, 6-bromo-N 2Pd(PPh3)4 (6.85 mg, 0.006 mmol) was added to a mixture of (1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine (40.0 mg, 0.119 mmol) and tributyl(prop-1-yn-1-yl)stanane (39.0 mg, 0.119 mmol) in toluene (0.5 mL). The resulting mixture was stirred overnight at 100 °C. The mixture was then concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. B Purification. The crude product was purified by Prep-HPLC. AT Further purification yielded the title compound as a grayish-white solid (7.2 mg, 20.3%). 1 H NMR (400 MHz, DMSO-d) 6 ) δ 8.56 (d, J = 2.3 Hz, 1H), 8.43(s, 1H), 7.79 - 7.29 (br, 2H), 7.71– 6.68 (br, 1H), 3.91 - 3.71 (m, 1H), 2.81 (d, J = 11.1 Hz, 2H), 2.22 (s,3H), 2.15 – 1.94 (m, 5H), 1.87 – 1.74 (m, 2H), 1.61 – 1.48 (m, 2H).LCMS H m / z = 297 [M+H] +

[0650] Example 43: N 2 -(1-Methylpiperidin-4-yl)-1,8-naphthidin-2,4-diamine

[0651]

[0652] Prepare 77–4-chloro-N-(1-methylpiperidin-4-yl)-1,8-naphthidine-2-amine and 2-chloro-N-(1-methylpiperidin-4-yl)-1,8-naphthidine-4-amine.

[0653] A solution of 2,4-dichloro-1,8-naphthidine (2.00 g, 10.0 mmol), 1-methylpiperidin-4-amine (13.3 mL, 12.1 mmol), and DIEA (3.50 mL, 20.1 mmol) in DMSO (10.0 mL) was stirred at 40 °C for 1 hour. The resulting mixture was analyzed by Prep-HPLC. BPurification yielded 4-chloro-N-(1-methylpiperidin-4-yl)-1,8-naphthidin-2-amine (1.62 g, 58.7%) and 2-chloro-N-(1-methylpiperidin-4-yl)-1,8-naphthidin-4-amine (1.16 g, 42.0%), as yellow solids. LCMS m / z = 277 [M+H] +

[0654] Preparation of 78–4-((diphenylmethylene)amino)-N-(1-methylpiperidin-4-yl)-1,8-naphthidin-2-amine

[0655] To a stirred solution of 4-chloro-N-(1-methylpiperidin-4-yl)-1,8-naphthidin-2-amine (1.00 g, 3.61 mmol) and diphenylmethaneimine (727 L, 4.33 mmol) in 1,4-dioxane (10.0 mL), Pd(OAc)₂ (81.1 mg, 0.361 mmol), XantPhos (209 mg, 0.361 mmol), and Cs₂CO₃ (2.35 g, 7.23 mmol) were added. The mixture was stirred at 100 °C for 1 hour under a nitrogen atmosphere. The resulting mixture was filtered through a diatomaceous earth stencil. The stencil was washed with CH₂Cl₂ (3 × 20 mL). The combined filtrates were concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH₂Cl₂ / MeOH (10:1), to give the title compound (1.1 g, 72.4%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.53(dd, J = 4.4, 1.9 Hz, 1H), 8.28 (dd, J = 8.0, 2.0 Hz, 1H), 7.02 (dd, J = 8.0,4.4 Hz, 1H), 6.80 (d, J = 7.7 Hz, 1H), 6.49 (s, 2H), 5.86 (s, 1H), 3.90 (s,1H), 2.90 - 2.75 (m, 2H), 2.26 (s, 3H), 2.22 - 2.02 (m, 2H), 1.92 (m, 2H),1.58 - 1.43 (m, 2H).LCMS H m / z = 258 [M+H] + .

[0656] Example 44: 5-Methyl-N 2 -(quininylcyclo-4-yl)-7,8-dihydro-6H-cyclopentane[5,6]pyrido[2,3-d]pyrimidine-2,4-diamine

[0657]

[0658] Preparation of 79–1-azabicyclo[2.2.2]octane-4-amine hydrochloride

[0659] At room temperature and under a nitrogen atmosphere, triethylamine (211 mg, 2.09 mmol) and DPPA (0.250 mL, 1.15 mmol) were added to a toluene (2 mL) solution of 1-azabicyclo[2.2.2]octane-4-carboxylic acid hydrochloride (200 mg, 1.04 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was heated to 100 °C and stirred for another 3 hours. The mixture was cooled to room temperature and quenched by dropwise addition of concentrated hydrochloric acid (6.00 mL) at 0 °C. The mixture was extracted with EtOAc (3 × 10 mL). The combined organic phases were concentrated under reduced pressure and then analyzed by Prep-HPLC. L The residue was purified to give the title compound as a white semi-solid (500 mg, crude product). LCMS m / z = 125 [MH] -

[0660] Preparation of 80–5-methyl-N 2 -(quininylcyclo-4-yl)-7,8-dihydro-6H-cyclopentane[5,6]pyrido[2,3-d]pyrimidine-2,4-diamine

[0661] Et3N (40.8 mg, 0.404 mmol) was added to a solution of N-(3-cyano-4-methyl-6,7-dihydro-5H-cyclopentadieno[b]pyridin-2-yl)aminocyano (40.0 mg, 0.202 mmol) and 1-azabicyclo[2.2.2]octane-4-amine hydrochloride (197 mg, 1.21 mmol) in EtOH (1.0 mL). The reaction mixture was stirred overnight at 100 °C. The mixture was cooled to room temperature and concentrated under reduced pressure. The final product was analyzed by Prep-HPLC. M The crude product (150 mg) was purified to give the title compound as a white solid (8.1 mg, 12.4%). 1 H NMR (400 MHz, DMSO-d6) δ 6.60 (s, 2H), 5.77 (s, 1H), 2.90 - 2.80(m, 10H), 2.58 (s, 3H), 2.08 - 1.98 (m, 2H), 1.94 (t, J = 7.8 Hz, 6H).LCMS L m / z = 325 [M+H] +

[0662] Example 45: N 3-(1-Methylpiperidin-4-yl)-6-phenyl-8,9-dihydro-7H-cyclopentan[4,5]pyrido[2,3-d]pyrimidin-1,3-diamine

[0663]

[0664] Preparation of 81–1,3-dihydroxy-6,7-dihydro-5H-cyclopentan[c]pyridine-4-nitrile

[0665] To a stirred solution of ethyl 2-oxocyclopentane-1-carboxylate (5.00 g, 32.0 mmol) in methanol (25.0 mL), cyanoacetamide (2.83 g, 33.6 mmol) and KOH (1.89 g, 33.6 mmol) were added. The resulting mixture was stirred at 70 °C for 1 hour. The mixture was allowed to cool to room temperature. The mixture was acidified to pH 1 with an aqueous solution of HCl (1 M). The precipitated solid was collected by filtration and washed with water (3 x 50 mL). The solid was dried under vacuum to give the title compound (1.68 g, crude) as a white solid. LCMS m / z = 177 [M+H] + .

[0666] Preparation of 82–4-cyano-6,7-dihydro-5H-cyclopenta[c]pyridine-1,3-dimethylbis(trifluoromethanesulfonate)

[0667] At 0 °C, Tf₂O (2.88 g, 10.2 mmol) was added dropwise to a mixture of 1,3-dihydroxy-6,7-dihydro-5H-cyclopenta[c]pyridine-4-onitrile (600 mg, 3.40 mmol) and DIEA (1.32 g, 10.2 mmol) in DCM (10.0 mL). The resulting mixture was stirred at room temperature for 1 hour and quenched by the addition of H₂O (30 mL). The mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give the title compound as a grayish-white liquid (1.30 g, crude product). LCMSm / z = 439 [MH] -

[0668] Preparation of 83–4-cyano-1-phenyl-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl trifluoromethanesulfonate

[0669] Pd(dppf)Cl₂∙CH₂Cl₂ (190 mg, 0.273 mmol) and K₃PO₄ (1.16 g, 5.45 mmol) were added to a mixture of 4-cyano-6,7-dihydro-5H-cyclopenta[c]pyridine-1,3-dimethylbis(trifluoromethanesulfonate) (1.20 g, 2.72 mmol) and phenylboronic acid (270 mg, 2.18 mmol) in dioxane (12.0 mL) and H₂O (4.0 mL). The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The resulting mixture was diluted with H₂O (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give the title compound as a white solid (310 mg, 30.8%). LCMS m / z = 369 [M+H] +

[0670] Preparation of 84–N-(4-cyano-1-phenyl-6,7-dihydro-5H-cyclopentan[c]pyridin-3-yl)aminocyano

[0671] At room temperature, Brettphos Pd G3 (73.8 mg, 0.081 mmol), Brettphos (43.7 mg, 0.081 mmol), and Cs2CO3 (530 mg, 1.62 mmol) were added to a mixture of 4-cyano-1-phenyl-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yltrifluoromethanesulfonate (300 mg, 0.814 mmol) and aminocyanide (68.4 mg, 1.62 mmol) in 1,4-dioxane (5.0 mL). The resulting mixture was stirred at 100 °C for 1 hour under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was filtered through a diatomaceous earth sieve. The sieve was washed with MeOH (20 mL × 3). The combined filtrates were concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. C Purification yielded the title compound (150 mg, 70.7%) as a yellow solid. LCMS m / z = 261 [M+H] +

[0672] Preparation of 85–N 3 -(1-Methylpiperidin-4-yl)-6-phenyl-8,9-dihydro-7H-cyclopentan[4,5]pyrido[2,3-d]pyrimidin-1,3-diamine

[0673] A mixture of N-(4-cyano-1-phenyl-6,7-dihydro-5H-cyclopentan[C]pyridin-3-yl)aminocyano (60.0 mg, 0.231 mmol) and 1-methylpiperidin-4-amine (52.6 mg, 0.462 mmol) in 1,4-dioxane (3.0 mL) was stirred overnight at 60 °C. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The concentration was determined by Prep-HPLC. AB The crude product was purified to give the title compound as a pale yellow solid (11.6 mg, 13.4%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.79-7.77(m, 2H), 7.55 – 7.40 (m, 3H), 6.71 (br, 2H), 6.38 (br, 1H), 3.89 – 3.75 (m,1H), 3.45 – 3.36 (m, 2H), 3.00 (t, J = 8.0 Hz, 2H), 2.74 (d, J = 12.0 Hz,2H), 2.16 (s, 3H), 2.13 – 2.03 (m, 2H), 1.96 (t, J = 12.0 Hz, 2H), 1.86 –1.76 (m, 2H), 1.60 – 1.45 (m, 2H).LCMS H m / z: 375 [M+H] +

[0674] Example 46: 6-Methyl-N 3 -(3-morpholinopropyl)-8,9-dihydro-7H-cyclopentane[4,5]pyrido[2,3-d]pyrimidine-1,3-diamine

[0675]

[0676] A solution of N-(4-cyano-1-methyl-6,7-dihydro-5H-cyclopentan[c]pyridin-3-yl)aminocyanocyanate (60.0 mg, 0.30 mmol) and 4-morpholinopropylamine (43.7 µL, 0.30 mmol) in ethanol (1.20 mL) was stirred overnight at 80 °C. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. V Purification yielded the title compound as a white solid (33.0 mg, 31.8%). 1H NMR (400 MHz, DMSO-d6) δ 6.58-6.54 (m, 3H), 3.58-3.56(m, 4H), 3.31-3.28 (m, 4H), 2.83-2.79 (m, 2H), 2.51-2.31 (m, 9H), 2.15-2.09(m, 2H), 1.72-1.65 (m, 2H).LCMS O m / z = 343 [M+H] +

[0677] Example 47: 5-Methyl-N 2 -(3-morpholinopropyl)-7,8-dihydro-6H-cyclopentane[5,6]pyrido[2,3-d]pyrimidine-2,4-diamine

[0678]

[0679] At room temperature, 4-morpholinopropylamine (43.7 μL, 0.303 mmol) was added to a solution of N-(3-cyano-4-methyl-6,7-dihydro-5H-cyclopentadieno[b]pyridin-2-yl)aminocyanide (60.0 mg, 0.303 mmol) in ethanol (1.00 mL). The resulting mixture was stirred overnight at 80°C. The mixture was then allowed to cool to room temperature. The mixture was analyzed by Prep-HPLC. N The crude product was purified to give the title compound as a white solid (17.1 mg, 16.5%). 1 H NMR (400 MHz, DMSO-d6) δ 6.84-6.32 (br,3H), 3.57 (t, J = 4.7 Hz, 4H), 3.30 (t, J = 8.0 Hz, 2H), 2.88- 2.82 (m, 4H),2.57 (s, 3H), 2.33-2.30 (m, 6H), 2.02-2.01 (m, 2H), 1.68 -1.64 (m, 2H).LCMS H m / z = 343 [M+H] +

[0680] Example 48: 6-Chloro-5-methyl-N 2 -(1-Methylpiperidin-4-yl)-7-phenylpyrido[2,3-d]pyrimidin-2,4-diamine

[0681]

[0682] Preparation of 86–2-hydroxy-6-methyl-4-phenylpyridine-3-nitrile

[0683] At room temperature, cyanoacetamide (2.59 g, 30.8 mmol) and 1,4-diazabicyclo[2.2.2]octane (34.6 g, 308 mmol) were added dropwise to a solution of 3-oxo-3-phenylpropanal (5.00 g, 30.8 mmol) in ethanol (50.0 mL). The resulting mixture was stirred at 80 °C for 6 hours. The mixture was allowed to cool to room temperature. The resulting mixture was stirred overnight at room temperature. The precipitated solid was collected by filtration and washed with MeCN (3 mL) to give the title compound as a white solid (3.20 g, crude product). LCMSm / z = 211 [M+H] +

[0684] Preparation of 87–5-chloro-2-hydroxy-6-methyl-4-phenylpyridine-3-nitrile

[0685] NCS (0.950 g, 7.14 mmol) was added to a solution of 2-hydroxy-6-methyl-4-phenylpyridin-3-onitrile (1.00 g, 4.76 mmol) in THF (5.00 mL) and methanol (5.00 mL) at room temperature. The resulting mixture was stirred at 40 °C for 1 hour. The mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration and washed with PE (10 mL). The solid was purified by silica gel column chromatography, eluting with CH2Cl2, to give the title compound as a pale yellow solid (780 mg, 67.0%). LCMS m / z = 245 [M+H] +

[0686] Preparation of 88–5-chloro-3-cyano-6-methyl-4-phenylpyridin-2-yltrifluoromethanesulfonate

[0687] Et3N (0.870 mL, 6.29 mmol) and Tf2O (1.06 mL, 6.29 mmol) were added dropwise to a solution of 5-chloro-2-hydroxy-6-methyl-4-phenylpyridin-3-onitrile (770 mg, 3.15 mmol) in DCM (7.00 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 hour. The mixture was extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (27:73), to give the title compound as a yellow solid (910 mg, 76.8%). LCMS m / z = 375 [MH] -

[0688] Preparation of 89–5-chloro-2-(cyanoamino)-6-methyl-4-phenylpyridine-3-nitrile

[0689] Under a nitrogen atmosphere and at room temperature, XantPhos (120 mg, 0.133 mmol), Pd2(dba)3 (71.2 mg, 0.133 mmol), and DIEA (865 mg, 2.65 mmol) were added to a stirred mixture of 5-chloro-3-cyano-6-methyl-4-phenylpyridin-2-yltrifluoromethanesulfonate (500 mg, 1.33 mmol) and aminocyanide (223 mg, 5.31 mmol) in 1,4-dioxane (6.50 mL). The resulting mixture was stirred at 120°C for 1 hour under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (6:1) to give the title compound as a yellow oil (200 mg, 56.1%). LCMS m / z = 269 [M+H] +

[0690] Preparation of 90–6-chloro-5-methyl-N 2 -(1-Methylpiperidin-4-yl)-7-phenylpyrido[2,3-d]pyrimidin-2,4-diamine

[0691] At room temperature, 1-methylpiperidin-4-amine (76.5 mg, 0.670 mmol) was added to a solution of 5-chloro-2-(cyanoamino)-6-methyl-4-phenylpyridin-3-onitrile (150 mg, 0.558 mmol) in 1,4-dioxane (1.50 mL). The resulting mixture was stirred at 100°C for 1 hour. The mixture was allowed to cool to room temperature. The residue was purified by preparation with DMF (4 mL) to provide the title compound (19.4 mg, 9.08%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.60 -7.59(m, 2H), 7.52 – 7.43 (m, 3H), 7.01 (br, 2H), 6.67 (br, 1H), 3.79 (br, 1H),2.80 (s, 3H), 2.74 (d, J = 8.3 Hz, 2H), 2.15 (s, 3H), 1.93 (t, J = 11.3 Hz, 2H), 1.79 (d, J = 12.6 Hz, 2H), 1.52-1.50 (m, 2H).LCMS P m / z = 383 [M+H] +

[0692] Example 49: N 2-(1-Methylpiperidin-4-yl)-7-(m-tolyl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0693]

[0694] At room temperature, 3-methylphenylboronic acid (20.4 mg, 0.151 mmol), CataCXium-A-Pd-G3 (5 mg, 0.007 mmol), CataCXium (6 mg, 0.017 mmol), and K3PO4 (87 mg, 0.411 mmol) were added to a stirred mixture of Example 23 (40 mg, 0.137 mmol) in 1,4-dioxane / H2O (5 / 1, 2 mL). The resulting mixture was stirred at 100 °C for 6 hours under a nitrogen atmosphere. The solution was cooled to room temperature, treated with a mercaptoalkyl-functionalized silica scavenger, and then filtered. The filtrate was passed through an Agela MP-Flash200 filter. 库 Purification yielded the title compound in solid form (13.7 mg, 27.46%). 1 H NMR (300 MHz, DMSO-d6) δ 8.42 (d, J = 8.3 Hz, 1H), 8.01(s, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.50 – 7.23 (m,4H),6.58 (s, 1H), 3.99-3.70 (m, 1H), 2.85 – 2.69 (m, 2H), 2.43 (s, 3H), 2.18(s, 3H), 2.09 – 1.92 (m, 2H), 1.90 – 1.76 (m, 2H), 1.64 – 1.44 (m, 2H).LCMS 库G m / z = 349 [M+H] + .

[0695] Examples 50 – 114

[0696] The following examples were synthesized using suitable boric acid or ester reagents in a manner similar to that described in Example 49:

[0697]

[0698] Example 115: 7-(2-chlorophenyl)-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0699]

[0700] At room temperature, 2-chlorophenylboronic acid (23.5 mg, 0.151 mmol), Xphos G2 (5 mg, 0.006 mmol), and K3PO4 (87.00 mg, 0.411 mmol) were added to a stirred mixture of Example 23 (40 mg, 0.137 mmol) in 1,4-dioxane / H2O (5 / 1, 2 mL). The resulting mixture was stirred at 110 °C for 6 hours under a nitrogen atmosphere. The solution was cooled to room temperature, treated with a mercaptoalkyl-functionalized silica scavenger, and then filtered. The filtrate was passed through an Agela MP-Flash200 filter. 库 Purification yielded the title compound (3.3 mg, 6.55%) in solid form. LCMS 库C m / z = 369 [M+H] + .

[0701] Examples 116 – 118

[0702] The following examples were synthesized using suitable boric acid or ester reagents in a manner similar to that described in Example 115:

[0703]

[0704] Example 119: N 2 -(1-Methylpiperidin-4-yl)-7-(azol-2-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0705]

[0706] At room temperature, 2-(tributyltinyl)-1,3-oxazole (53.82 mg, 0.151 mmol) and Pd(PPh3)4 (5 mg, 0.004 mmol) were added to a stirred mixture of Example 23 (40 mg, 0.137 mmol) in toluene (2 mL). The resulting mixture was stirred at 110 °C for 6 hours under a nitrogen atmosphere. The solution was cooled to room temperature, treated with a mercaptoalkyl-functionalized silica scavenger, and then filtered. The filtrate was passed through an Agela MP-Flash200 filter. 库 Purification yielded the title compound (3.9 mg, 8.77%) in solid form. LCMS 库C m / z = 326 [M+H] + .

[0707] Example 120: 5-Methyl-N 2 -(3-morpholinopropyl)-7-phenylpyrido[2,3-d]pyrimidin-2,4-diamine

[0708]

[0709] Preparation of 91–2-chloro-4-methyl-6-phenylnicotine

[0710] At room temperature, Pd(dppf)Cl2 (7.82 g, 10.7 mmol) and K3PO4 (45.4 g, 214 mmol) were added to a solution of 2,6-dichloro-4-methylnicotinonitrile (20.0 g, 107 mmol) and phenylboronic acid (10.4 g, 85.6 mmol) in 1,4-dioxane (150 mL) and H2O (150 mL). The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. The mixture was filtered, and the filter cake was washed with water (3 × 50 mL). The title compound (22.3 g, crude product) was purified by preparation with MeOH (3 × 100 mL) to give a red solid. LCMS m / z = 229 [M+H] +

[0711] Preparation of 92–N-(3-cyano-4-methyl-6-phenylpyridin-2-yl)aminocyanide

[0712] At room temperature, Brettphos Pd G3 (0.790 g, 0.875 mmol), and Brettphos (0.470 g, 0.875 mmol) were added to a solution of 2-chloro-4-methyl-6-phenylnicotinitrogen (2.00 g, 8.75 mmol), Cs₂CO₃ (5.70 g, 17.5 mmol), and aminocyanide (0.740 g, 17.5 mmol) in 1,4-dioxane (30.0 mL). The mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was filtered, and the filter cake was washed with DCM (3 × 100 mL). The combined filtrates were concentrated under reduced pressure. The residue was analyzed by HPLC. B Purification yielded the title compound (600 mg, 29.30%) as a yellow-green solid. LCMS m / z = 235 [M+H] + .

[0713] Preparation of 93–5-methyl-N 2 -(3-morpholinopropyl)-7-phenylpyrido[2,3-d]pyrimidin-2,4-diamine

[0714] At room temperature, 3-morpholinopropyl-1-amine (185 mg, 1.28 mmol) was added to a solution of N-(3-cyano-4-methyl-6-phenylpyridin-2-yl)aminocyanine (100 mg, 0.427 mmol) in ethanol (2.0 mL). The resulting mixture was stirred at 100 °C for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. AF Purification yielded the title compound (72.8 mg, 45.10%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.19 - 8.11 (m,2H), 7.55 - 7.40 (m, 4H), 7.04 - 6.51 (m, 3H), 3.59 (t, J = 4.6 Hz, 4H), 3.41- 3.36 (m, 2H), 2.77 (s, 3H), 2.41 - 2.30 (m, 6H), 1.77 - 1.65 (m, 2H).LCMS C m / z = 379 [M+H] +

[0715] Example 121: 5,6,7-Trimethyl-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0716]

[0717] Preparation of 94–N-(3-cyano-4,5,6-trimethylpyridin-2-yl)aminocyano.

[0718] A solution of 2-chloro-4,5,6-trimethylnicotinonitrile (200 mg, 1.10 mmol) and sodium aminocyanide (141 mg, 2.21 mmol) in DMSO (0.5 mL) was stirred at 100 °C for 2 hours. The mixture was cooled to room temperature. The residue was purified by Prep-HPLCB to give the title compound as a pale yellow solid (110 mg, 53.3%). LCMS m / z = 187 [M+H] +

[0719] Preparation of 95–5,6,7-trimethyl-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0720] A solution of N-(3-cyano-4,5,6-trimethylpyridin-2-yl)aminocyano (90.0 mg, 0.483 mmol) and 1-methylpiperidin-4-amine (110 mg, 0.966 mmol) in ethanol (5.00 mL) was stirred at 100 °C for 2.5 h. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The solution was analyzed by Prep-HPLC. AU The residue was purified to give the title compound as a white solid (78.7 mg, 54.2%). 1 H NMR (400 MHz, DMSO-d6) δ 6.68 (br, 2H), 6.23 (br, 1H), 3.81 – 3.68 (m, 1H), 2.74-2.72 (m, 2H), 2.57 (s, 3H), 2.44 (s, 3H), 2.17 (s,3H), 2.16 (s, 3H), 1.96-1.91 (m, 2H), 1.81-1.78 (m, 2H), 1.57 – 1.42 (m, 2H).LCMS C m / z = 301 [M+H] +

[0721] Example 122: Methyl 4-amino-2-[(1-methylpiperidin-4-yl)amino]pyrido[2,3-d]pyrimidine-6-carboxylic acid

[0722]

[0723] Pd(dppf)Cl2 was added to the stirred solution of Example 20 (1.50 g, 4.45 mmol) in methanol (200 mL) and DMF (4.0 mL). . CH₂Cl₂ (362 mg, 0.445 mmol) and Et₃N (1.24 mL, 8.90 mmol). The resulting mixture was stirred overnight at 100 °C under a carbon monoxide atmosphere (10 atm). The mixture was allowed to cool to room temperature. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. B Purification yielded the title compound (900 mg, 63.8%) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (s,1H), 8.96 (s, 1H), 7.75 (br, 2H), 7.35 – 7.00 (m, 1H), 3.87 (s, 3H), 3.86-3.83 (m, 1H), 2.75-2.73 (m, 2H), 2.16 (s, 3H), 1.96-1.91 (m, 2H), 1.85 – 1.72(m, 2H), 1.61 – 1.39 (m, 2H).LCMS C m / z = 317 [M+H] +

[0724] Example 123: {4-amino-2-[(1-methylpiperidin-4-yl)amino]pyrido[2,3-d]pyrimidin-6-yl}methanol

[0725]

[0726] At 0°C, LiAlH4 (474 ​​µL, 0.948 mmol, 2.0 M, in THF) was added dropwise to a stirred mixture of Example 122 (200 mg, 0.632 mmol) in THF (4.0 mL). The resulting mixture was stirred at 0°C for 1 hour. The reaction was quenched with water at 0°C. The resulting mixture was concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. AU Purification yielded the title compound (22.8 mg, 12.5%) as a grayish-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.29(s, 1H), 7.37 (br, 2H), 6.52 (br, 1H), 5.22 (t, J = 5.4 Hz, 1H), 4.50 (d, J =5.2 Hz, 2H), 3.98 – 3.61 (m, 1H), 2.79 – 2.70 (m, 2H), 2.16 (s, 3H), 1.99 – 1.89 (m, 2H), 1.86 – 1.78 (m, 2H), 1.65 – 1.32 (m, 2H).LCMS C m / z = 289 [M+H] +

[0727] Example 124: 5-Methyl-7-phenyl-N 2 -(quininylcyclo-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0728]

[0729] Quinine cyclo-4-amine hydrochloride (160 mg, 1.28 mmol) and Et3N (534 µL, 3.84 mmol) were added to a stirred solution of N-(3-cyano-4-methyl-6-phenylpyridin-2-yl)aminocyanide (50.0 mg, 0.213 mmol) in ethanol (1.0 mL). The resulting mixture was stirred at 100 °C for 4 days. The mixture was then concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. AS Purification yielded the title compound (19.4 mg, 25.30%) as a white solid. 1 H NMR (400 MHz, DMSO-d6)δ 8.19 - 8.10 (m, 2H), 7.56 - 7.46 (m, 3H), 7.43 (s, 1H), 6.86 (s, 2H), 6.06(s, 1H), 2.96 - 2.82 (m, 6H), 2.77 (s, 3H), 2.07 - 1.87 (m, 6H).LCMS O m / z = 361 [M+H] +

[0730] Example 125: 1-{4-amino-2-[(1-methylpiperidin-4-yl)amino]pyrido[2,3-d]pyrimidin-6-yl}ketene

[0731]

[0732] Pd(PPh3)4 (206 mg, 0.178 mmol) was added to a DMF (9.0 mL) solution of Example 20 (600 mg, 1.78 mmol) and tributyl(1-ethoxyvinyl)stanane (1.29 g, 3.56 mmol) under stirring. The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. At room temperature, an aqueous solution of HCl (1.0 M, 9.0 mL) was added to the mixture, and the mixture was stirred for another 1 hour at room temperature. The mixture was alkalized to pH 9 with saturated sodium bicarbonate (aqueous solution) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. B Purification yielded the title compound (400 mg, 74.7%) as a yellow solid. 1 H NMR(400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.95 (s, 1H), 7.76 (br, 2H), 7.39 – 6.95(m, 1H), 4.02 – 3.72 (m, 1H), 2.77-2.74 (m, 2H), 2.56 (s 3H), 2.16 (s, 3H), 1.97-1.94 (m, 2H), 1.81-1.79 (m, 2H), 1.57-1.49 (m, 2H).LCMS H m / z = 301 [M+H] +

[0733] Example 126: 1-{4-amino-2-[(1-methylpiperidin-4-yl)amino]pyrido[2,3-d]pyrimidin-6-yl}ethanol

[0734]

[0735] At room temperature, NaBH4 (37.8 mg, 0.999 mmol) was added to a methanol (3.0 mL) solution of Example 125 (150 mg, 0.499 mmol) under stirring. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with water at 0 °C, and the resulting mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with brine, filtered, and concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. AS Purification yielded the title compound (20.4 mg, 13.5%) as a grayish-white solid. 1H NMR (400MHz, DMSO-d6) δ 8.60 (s, 1H), 8.30 (s, 1H), 7.38 (br, 2H), 6.48 (br, 1H), 5.25 (d, J = 4.0 Hz, 1H), 4.78 – 4.75 (m, 1H), 3.80 – 3.79 (m, 1H), 2.75 –2.72 (m, 2H), 2.16 (s, 3H), 1.99 – 1.89 (m, 2H), 1.86 – 1.77 (m, 2H), 1.60 –1.42 (m, 2H), 1.40 (d, J = 6.4 Hz, 3H).LCMS H m / z = 303 [M+H] +

[0736] Example 127: 6-Phenyl-N 3 -(quininylcyclo-4-yl)-8,9-dihydro-7H-cyclopentano[4,5]pyrido[2,3-d]pyrimidin-1,3-diamine

[0737]

[0738] Et3N (175 mg, 1.73 mmol) was added to a stirred solution of N-(4-cyano-1-phenyl-6,7-dihydro-5H-cyclopentan[c]pyridin-3-yl)aminocyano (30 mg, 0.115 mmol) and quinine cyclo-4-amine hydrochloride (87.2 mg, 0.690 mmol) in EtOH (1.0 mL) at room temperature. The resulting mixture was stirred at 100°C for 30 hours. The mixture was then concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. B Purification yielded the title compound (5.3 mg, 10.67%) as a white solid formate. 1 H NMR(400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.82 - 7.72 (m, 2H), 7.54 - 7.41 (m, 3H), 6.78 (br, 2H), 6.23 (br, 1H), 3.40 - 3.35 (m, 2H), 3.10 - 2.96 (m, 8H), 2.18- 2.10 (m, 8H).LCMS R m / z = 387 [M+H] +

[0739] Example 128: 6-Chloro-5-methyl-N 2-(3-morpholinopropyl)-7-phenylpyrido[2,3-d]pyrimidin-2,4-diamine

[0740]

[0741] A solution of Example 120 (25.0 mg, 0.066 mmol) and 1-chloropyrrolidine-2,5-dione (26.5 mg, 0.198 mmol) in THF (1.0 mL) and methanol (1.0 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (5 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. G Purification yielded the title compound (3.3 mg, 12.1%) as a yellow solid. 1 ¹H NMR (400 MHz, methanol-d⁴) δ 7.68–7.60 (m, 2H), 7.51–7.41 (m, 3H), 3.70 (t, J = 4.7 Hz, 4H), 3.48 (t, J = 6.8 Hz, 2H), 2.89 (s, 3H), 2.53–2.43 (m, 6H), 1.89–1.77 (m, 2H). LCMS C m / z = 413 [M+H] +

[0742] Example 129: N 3 -(3-morpholinopropyl)-6-phenyl-8,9-dihydro-7H-cyclopentano[4,5]pyrido[2,3-d]pyrimidin-1,3-diamine

[0743]

[0744] Preparation of 96–1,3-dihydroxy-6,7-dihydro-5H-cyclopentan[c]pyridine-4-nitrile

[0745] To a stirred solution of ethyl 2-oxocyclopentane-1-carboxylate (25.0 g, 160 mmol) in methanol (125 mL), cyanoacetamide (14.1 g, 168 mmol) and KOH (9.43 g, 168 mmol, 1.05 equivalents) were added. The resulting mixture was stirred at 70 °C for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure. The precipitate was collected by filtration and washed with water (200 mL). The solid was dried under vacuum to give the title compound (9.5 g, 33.6%) as a white solid.

[0746] Preparation of 97–4-cyano-6,7-dihydro-5H-cyclopenta[c]pyridine-1,3-dimethylbis(trifluoromethanesulfonate)

[0747] At 0 °C, Tf₂O (38.4 g, 136 mmol) was added dropwise to a solution of 1,3-dihydroxy-6,7-dihydro-5H-cyclopentano[c]pyridine-4-nitrile (4.00 g, 22.7 mmol) and DIEA (8.80 g, 68.1 mmol) in DCM (40.0 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (3 × 100 mmol). The combined organic layers were washed with brine (3 x 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (3:1) to give the title compound (6.4 g, 64.0%) as a brown oil. LCMS m / z = 441 [M+H] +

[0748] Preparation of 98–4-cyano-1-phenyl-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yltrifluoromethanesulfonate

[0749] Pd(dppf)Cl2 (830 mg, 1.13 mmol) and K3PO4 (4.82 g, 22.7 mmol) were added to a stirred solution of 4-cyano-6,7-dihydro-5H-cyclopenta[c]pyridine-1,3-dimethylbis(trifluoromethanesulfonate) (5.00 g, 11.3 mmol) and phenylboronic acid (692 mg, 5.67 mmol) in 1,4-dioxane (30.0 mL) and H2O (10.0 mL). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was filtered through a diatomaceous earth sieve. The sieve was washed with CH2Cl2 (2 × 20 mL). The combined filtrates were concentrated under reduced pressure. The resulting mixture was diluted with water (200 mL) and extracted with CH2Cl2 (3 × 200 mL). The combined organic layers were washed with brine (2 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (9:1) to give the title compound (1.50 g, 35.9%) as a white solid. LCMS m / z = 369 [M+H] +

[0750] Preparation of 99–N-(4-cyano-1-phenyl-6,7-dihydro-5H-cyclopentan[c]pyridin-3-yl)aminocyano

[0751] To a mixture of 4-cyano-1-phenyl-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yltrifluoromethanesulfonate (1.35 g, 3.66 mmol) and aminocyanide (360 mg, 8.56 mmol) in dioxane (23.0 mL), Brettphos PdG3 (332 mg, 0.367 mmol), Brettphos (197 mg, 0.367 mmol), and Cs₂CO₃ (2.39 g, 7.33 mmol) were added. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 1 hour. The mixture was allowed to cool to room temperature. The resulting mixture was filtered through a diatomaceous earth stencil. The stencil was washed with MeOH (3 × 20 mL). The combined filtrates were concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. B Purification yielded the title compound (340 mg, 35.6%) as a brown solid. LCMS m / z = 261 [M+H] +

[0752] Preparation of 100–N 3 -(3-morpholinopropyl)-6-phenyl-8,9-dihydro-7H-cyclopentane[4,5]pyrido[2,3-d]pyrimidin-1,3-diamine

[0753] 4-morpholinopropanolamine (220 µL, 1.52 mmol) was added to a stirred solution of N-(4-cyano-1-phenyl-6,7-dihydro-5H-cyclopentan[c]pyridin-3-yl)aminocyanine (150 mg, 0.576 mmol) in ethanol (7.50 mL). The resulting mixture was stirred at 100 °C for 1 hour. The mixture was then concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. B Purification yielded the title compound (36.1 mg, 15.5%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.85 – 7.68 (m, 2H),7.65 – 7.37 (m, 3H), 6.75 (br, 2H), 6.57 (br, 1H), 3.58 (t, J = 4.6 Hz, 4H),3.39 – 3.31 (m, 4H), 3.01 (t, J = 7.4 Hz, 2H), 2.40 – 2.27 (m, 6H), 2.14 –2.02 (m, 2H), 1.77 – 1.60 (m, 2H).LCMS C m / z = 405 [M+H] +

[0754] Example 130: 6-Chloro-5,7-Dimethyl-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0755]

[0756] The solution of Example 5 (100 mg, 0.349 mmol) and 1-chloropyrrolidine-2,5-dione (93.3 mg, 0.698 mmol) in THF (1.0 mL) and methanol (1.0 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (5 mL) and extracted with EtOAc (3 × 10 mL). The combined organic phases were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. AN Purification yielded the title compound (48.2 mg, 45.2%) as a grayish-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 6.88 (br, 2H), 6.55(br, 1H), 3.83 - 3.68 (m, 1H), 2.80 - 2.69 (m, 5H), 2.53 (s, 3H), 2.16 (s,3H), 2.00 - 1.87 (m, 2H), 1.86 - 1.74 (m, 2H), 1.59 - 1.44 (m, 2H).LCMS C m / z = 321 [M+H] + .

[0757] Example 131: 4-((4-amino-5,7-dimethylpyridino[2,3-d]pyrimidin-2-yl)amino)azacycloheptan-1-carboxylic acid tert-butyl ester

[0758]

[0759] At room temperature, 4-aminoazacyclohexane-1-carboxylic acid tert-butyl ester (92.45 mg, 0.432 mmol) and CsF (130.46 mg, 0.864 mmol) were added to a stirred mixture of 2-chloro-5,7-dimethylpyrido[2,3-d]pyrimidin-4-amine (60 mg, 0.288 mmol) in 1,4-dioxane (2 mL). The resulting mixture was stirred at 110 °C for 16 hours. The solution was cooled to room temperature and tested using an Agela MP-Flash200. 库 Purification yielded the title compound in solid form (50 mg, 44.90%). LCMS 库Am / z = 387 [M+H] + .

[0760] Examples 132 – 139

[0761] The following examples were synthesized using a suitable amine reagent in a manner similar to that described in Example 131:

[0762]

[0763] Example 140: N 2 -(azacyclopentan-4-yl)-5,7-dimethylpyrido[2,3-d]pyrimidin-2,4-diamine

[0764]

[0765] At room temperature, 4.0 M HCl dissolved in 0.5 mL of 1,4-dioxane was added to a 2 mL solution of DCM (50 mg, 0.129 mmol) from Example 131 under stirring. The resulting mixture was stirred at room temperature for 2 hours. The solvent was removed under pressure to give the title compound (22.8 mg, 54.88%) in solid hydrochloride form. LCMS 库E m / z = 287 [M+H] + .

[0766] Example 141: 5,7-Dimethyl-N 2 -(piperidin-4-ylmethyl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0767]

[0768] The LCMS was synthesized from Example 133 in a manner similar to that described in Example 140. 库B m / z = 287 [M+H] + .

[0769] Example 142: N 2 -(2-(dimethylamino)ethyl)-5,7-dimethylpyrido[2,3-d]pyrimidin-2,4-diamine

[0770]

[0771] At room temperature, N was added to a stirred mixture of 2-chloro-5,7-dimethylpyrido[2,3-d]pyrimidin-4-amine (50 mg, 0.240 mmol) in 1,4-dioxane (2 mL). 1 N 1-Dimethylethane-1,2-diamine (31.73 mg, 0.360 mmol) and CsF (108.72 mg, 0.72 mmol). The resulting mixture was stirred at 110 °C for 16 hours. The solution was cooled to room temperature and passed through an Agela MP-Flash200. 库 Purification yielded the title compound in solid form (24.7 mg, 39.58%). LCMS 库A m / z = 261 [M+H] + .

[0772] Examples 143 – 218

[0773] The following examples were synthesized using a suitable amine reagent in a manner similar to that described in Example 142:

[0774]

[0775] Example 219: N 2 -(1-((dimethylamino)methyl)cyclopropyl)-5,7-dimethylpyrido[2,3-d]pyrimidin-2,4-diamine

[0776]

[0777] At room temperature, 1-((dimethylamino)methyl)cyclopropyl-1-amine (98.7 mg, 0.86 mmol) was added to a mixture of 2-chloro-5,7-dimethylpyrido[2,3-d]pyrimidin-4-amine (60 mg, 0.29 mmol) in ethanol (1 mL) under stirring. The solvent was removed under reduced pressure, and the resulting pure mixture was then stirred at 110 °C for 6–12 hours. The solution was cooled to room temperature and passed through an Agela MP-Flash200 filter. 库 Purification yielded the title compound (3.7 mg, 4.5%) in solid form. LCMS 库B m / z = 287 [M+H] + .

[0778] Example 220 – Example 222

[0779] The following examples were synthesized using a suitable amine reagent in a manner similar to that described in Example 142:

[0780]

[0781] Example 223: (R)-N 2 -(1-(2-methoxyethyl)pyrrolidine-3-yl)-5,7-dimethylpyrido[2,3-d]pyrimidin-2,4-diamine

[0782]

[0783] Preparation of 101–tert-butyl(R)-(1-(2-methoxyethyl)pyrrolidine-3-yl)carbamate

[0784] At room temperature, K₂CO₃ (1.86 g, 13.4 mmol) and KI (446 mg, 2.68 mmol) were added to a stirred solution of (R)-pyrrolidine-3-ylcarbamate tert-butyl ester (500 mg, 2.68 mmol) and 1-bromo-2-methoxyethane (448 mg, 3.22 mmol) in ACN (75.0 mL). The resulting mixture was stirred overnight at 80 °C. The mixture was allowed to cool to room temperature. The resulting mixture was filtered, and the filter cake was washed with ACN (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA:MeOH = 10:1) to give the title compound as a yellow oil (520 mg, 79.3%). LCMS m / z = 245 [M+H] +

[0785] Preparation of 102–(R)-1-(2-methoxyethyl)pyrrolidine-3-amine hydrogen chloride

[0786] A mixture of (R)-(1-(2-methoxyethyl)pyrrolidine-3-yl)carbamate tert-butyl ester (520 mg, 2.13 mmol) and 4.0 M HCl in 1,4-dioxane (4.0 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. This gave the title compound as a yellow oil (470 mg, crude product). LCMS m / z = 145 [M+H] +

[0787] Preparation of 103–(R)-N 2 -(1-(2-methoxyethyl)pyrrolidine-3-yl)-5,7-dimethylpyrido[2,3-d]pyrimidin-2,4-diamine

[0788] At room temperature, Et3N (919 µL, 6.61 mmol) was added to a stirred solution of (R)-1-(2-methoxyethyl)pyrrolidine-3-amine hydrogen chloride (458 mg, 2.54 mmol) and 2-chloro-5,7-dimethylpyrido[2,3-d]pyrimidin-4-amine (230 mg, 1.10 mmol) in dioxane (8.00 mL). The resulting mixture was stirred overnight at 100°C. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. AV Purification yielded the title compound as a yellow solid (170 mg, 16.2%, ee>99%). 1 ¹H NMR (400 MHz, methanol-d⁴) δ 6.79 (s, 1H), 4.67–4.57 (m, 1H), 3.53 (t, J = 5.6 Hz, 2H), 3.34 (s, 3H), 3.01–2.80 (m, 2H), 2.75–2.67 (m, 5H), 2.65–2.52 (m, 2H), 2.50–2.43 (m, 3H), 2.39–2.29 (m, 1H), 1.80–1.62 (m, 1H). LCMS R m / z = 317 [M+H] +

[0789] Example 224: (R)-2-(3-((4-amino-5,7-dimethylpyridino[2,3-d]pyrimidin-2-yl)amino)pyrrolidine-1-yl)ethanol

[0790]

[0791] The mixture of Example 223 (145 mg, 0.458 mmol) and 1 M BBr3 in DCM (3.0 mL) was stirred at room temperature for 1 hour. The reaction was quenched with water / ice at 0 °C. The resulting mixture was concentrated under reduced pressure. The solution was analyzed by Prep-HPLC. V The residue was purified to give the title compound as a white solid (27.9 mg, 20.1%, ee > 99%). 1¹H NMR (400 MHz, methanol-d⁴) δ 6.80 (s, 1H), 4.68–4.55 (m, 1H), 3.68 (t, J = 6.1 Hz, 2H), 3.05–2.83 (m, 2H), 2.71 (s, 3H), 2.69–2.52 (m, 4H), 2.47 (s, 3H), 2.41–2.30 (m, 1H), 1.78–1.65 (m, 1H). LCMS S m / z = 303 [M+H] +

[0792] Example 225: (R)-5,7-dimethyl-N 2 -(piperidin-3-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0793]

[0794] Preparation of 104–tert-butyl(R)-3-((4-amino-5,7-dimethylpyridino[2,3-d]pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester

[0795] A mixture of 2-chloro-5,7-dimethylpyrido[2,3-d]pyrimidin-4-amine (300 mg, 1.43 mmol) and (R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester (345 mg, 1.72 mmol) in DMSO (5.00 mL) was stirred overnight at 120 °C. The mixture was allowed to cool to room temperature. The residue was analyzed by Prep-HPLC. AW Purification yielded the title compound as a yellow oil (340 mg, 63.4%). LCMS m / z = 373 [M+H] + .

[0796] Preparation of 105–(R)-5,7-dimethyl-N 2 -(piperidin-3-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0797] A mixture of (R)-3-((4-amino-5,7-dimethylpyridino[2,3-d]pyrimidin-2-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (340 mg, 0.913 mmol) and HCl in dioxane (5.00 M, 4.0 M) was stirred at room temperature for 20 min. The resulting mixture was concentrated under reduced pressure. The residue was diluted with methanol and alkalized to pH 7 with NH3·H2O. The residue was analyzed by Prep-HPLC. LPurification yielded the title compound as a white solid (24.2 mg, 9.70%, ee > 99%). 1 H NMR (400MHz, DMSO-d6) δ 6.89 - 6.55 (m, 3H), 6.25 (s, 1H), 3.91 - 3.79 (m, 1H), 3.23- 3.11 (m, 1H), 3.00 (d, J = 11.4 Hz, 1H), 2.76 LCMS S m / z = 273 [M+H] + .

[0798] Example 226: (3S,4S)-4-((4-amino-5,7-dimethylpyridino[2,3-d]pyrimidin-2-yl)amino)-1-methylpyrrolidine-3-ol

[0799]

[0800] Preparation of 106–(3S,4S)-3-((4-amino-5,7-dimethylpyridino[2,3-d]pyrimidin-2-yl)amino)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester

[0801] At room temperature, (3S,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (1.94 g, 9.60 mmol, 2.00 equivalent) was added to a stirred solution of 2-chloro-5,7-dimethylpyrido[2,3-d]pyrimidin-4-amine (1.00 g, 4.79 mmol) in dioxane (15.0 mL). The resulting mixture was stirred at 60 °C for 4 hours. The mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration and washed with EtOAc (3 × 10 mL). The title compound was given as a grayish-white solid (1.40 g, crude product). LCMS m / z = 375 [M+H] + .

[0802] Preparation of 107–(3S,4S)-4-((4-amino-5,7-dimethylpyridino[2,3-d]pyrimidin-2-yl)amino)-1-methylpyrrolidine-3-ol

[0803] At 0 °C, a solution of 1 M LiAlH4 in 21.4 mL of THF was added dropwise to a stirred solution of (3S,4S)-3-((4-amino-5,7-dimethylpyridino[2,3-d]pyrimidin-2-ylamino)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (1.00 g, 2.67 mmol) in 25 mL of THF. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with methanol at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. AS Purification yielded the title compound as a white solid (54.1 mg, 6.7%, ee > 99%). 1 H NMR (400 MHz, DMSO-d6) δ 6.96 - 6.78 (m, 3H),6.75 (s, 1H), 6.02 (s, 1H), 4.08 - 3.82 (m, 2H), 2.85 (t, J = 8.3 Hz, 1H),2.76 - 2.68 (m, 1H), 2.66 (s, 3H), 2.48 - 2.40 (m, 2H), 2.39 (s, 3H), 2.21(s, 3H).LCMS T m / z = 289 [M+H] + .

[0804] Example 227: N 2 -((3S,4S)-4-methoxypyrrolidine-3-yl)-N 4 5,7-Trimethylpyrido[2,3-d]pyrimidine-2,4-diamine

[0805]

[0806] Preparation of 108–2-chloro-N,5,7-trimethylpyrido[2,3-d]pyrimidin-4-amine

[0807] At 0 °C, methylamine hydrochloride (1.72 g, 26.3 mmol) was added fractionally to a mixture of 2,4-dichloro-5,7-dimethylpyrido[2,3-d]pyrimidine (3.00 g, 13.2 mmol) and triethylamine (2.66 g, 26.3 mmol) in THF (60.0 mL). The resulting mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure. The residue was diluted with water (100 mL). The precipitated solid was collected by filtration and washed with water (3 x 10 mL). The title compound (1.60 g, 54.6%) was thus given as a pink solid. LCMS m / z = 223 [M+H] + .

[0808] Preparation of 109–(3S,4S)-3-((5,7-dimethyl-4-(methylamino)pyrido[2,3-d]pyrimidin-2-yl)amino)-4-methoxypyrrolidine-1-carboxylic acid tert-butyl ester

[0809] To a solution of 2-chloro-N,5,7-trimethylpyrido[2,3-d]pyrimidin-4-amine (200 mg, 0.89 mmol) in 1,4-dioxane (2.00 mL), tert-butyl (3S,4S)-3-amino-4-methoxypyrrolidine-1-carboxylic acid (233 mg, 1.07 mmol) was added. The resulting mixture was stirred overnight at 100 °C. The mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. AV Purification yielded the title compound (362 mg, crude product) as a grayish-white solid. LCMSm / z = 403 [M+H] + .

[0810] Preparation of 110–N 2 -((3S,4S)-4-methoxypyrrolidine-3-yl)-N 4 5,7-Trimethylpyrido[2,3-d]pyrimidine-2,4-diamine

[0811] A solution of 4 M HCl in MeOH (3.00 mL) was added to a solution of (3S,4S)-3-([5,7-dimethyl-4-(methylamino)pyrido[2,3-d]pyrimidin-2-yl]amino-4-methoxypyrrolidine-1-carboxylic acid tert-butyl ester (340 mg, 0.840 mmol) in 1,4-dioxane (3.40 mL). The resulting mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in methanol (2.00 mL) and alkalized to pH 9 with Et3N. The residue was analyzed by Prep-HPLC. AV Purification yielded the title compound (130.8 mg, 50.3%, ee>99%) as a grayish-white solid. 1 H NMR (400 MHz, DMSO - d6) δ 6.96 -6.72 (m, 2H), 6.69 (s, 1H), 4.36 - 4.25 (m, 1H), 3.76 - 3.71 (m, 1H), 3.32(s, 3H), 3.12 - 3.00 (m, 2H), 2.95 (s, 3H), 2.71 - 2.62 (m, 5H), 2.38 (s,3H).LCMS U m / z = 303 [M+H] + .

[0812] Example 228: N 2 -((3S,4S)-4-methoxy-1-methylpyrrolidine-3-yl)-N 4 5,7-Trimethylpyrido[2,3-d]pyrimidine-2,4-diamine

[0813]

[0814] The solution of Example 227 (95.0 mg, 0.314 mmol) in DCM (1.00 mL) was treated with paraformaldehyde (47.1 mg, 1.57 mmol) at room temperature for 30 minutes, followed by the addition of STAB (532 mg, 2.51 mmol) in portions at room temperature. The resulting mixture was stirred overnight at room temperature. The reaction was terminated by adding water (2 mL). The solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. AV Purification yielded the title compound (21.7 mg, 21.0%, ee>99%) as a grayish-white solid. 1 HNMR (400 MHz, DMSO-d6) δ 6.95 - 6.59 (m, 3H), 4.40 - 4.274 (m, 1H), 3.89 -3.77 (m, 1H), 3.25 (s, 3H), 3.00 - 2.83 (m, 4H), 2.73 - 2.59 (m, 4H), 2.49 -2.43 (m, 1H), 2.37 (s, 3H), 2.27 - 2.16 (m, 4H).LCMS U m / z = 317 [M+H] + .

[0815] Example 229: N 2 -(1-Benzylpiperidin-4-yl)-5-methyl-7,8-dihydro-6H-cyclopentan[5,6]pyrido[2,3-d]pyrimidin-2,4-diamine

[0816]

[0817] At room temperature, 1-benzylpiperidin-4-amine (192 mg, 1.01 mmol) was added to a stirred mixture of N-(3-cyano-4-methyl-6,7-dihydro-5H-cyclopentadieno[b]pyridin-2-yl)aminocyanide (100 mg, 0.504 mmol) in ethanol (5.0 mL). The resulting mixture was stirred at 100 °C for 1 hour. The mixture was then concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. LPurification yielded the title compound as a white solid (24.7 mg, 12.6%). 1 H NMR (300 MHz, DMSO-d6) δ 7.38 - 7.19 (m, 5H), 6.64 (s, 2H), 6.30 (s, 1 H), 3.89 - 3.70 (m, 1H), 3.46 (s, 2H), 2.94 - 2.73 (m, 6H), 2.57 (s, 3H), 2.10 - 1.93 (m, 4H), 1.87 -1.73 (m, 2H), 1.57 - 1.39 (m, 2H).LCMS V m / z = 389 [M+H] + .

[0818] Example 230: (R)-5-methyl-N 2 -(pyrrolidone-3-yl)-7,8-dihydro-6H-cyclopentan[5,6]pyrido[2,3-d]pyrimidin-2,4-diamine

[0819]

[0820] Preparation of a mixture of ethyl 111–3-amino-1-methyl-6,7-dihydro-5H-cyclopentyl[c]pyridine-4-carboxylate and ethyl 2-amino-4-methyl-6,7-dihydro-5H-cyclopentyl[b]pyridine-3-carboxylate.

[0821] At room temperature, acetylcyclopentanone (50.0 g, 396 mmol) was added dropwise to a mixture of ethyl 2-aminoamide hydrochloride (66.0 g, 396 mmol) and piperidine (101 g, 1190 mmol) in ethanol (1.00 L). The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was diluted with PE (100 mL). The precipitate was collected by filtration and purified by silica gel column chromatography with ethyl acetate / petroleum ether (3:1) to give ethyl 3-amino-1-methyl-6,7-dihydro-5H-cyclopentan[c]pyridine-4-carboxylic acid (35.0 g, 40.1%) as a white solid. The filtrate was concentrated under reduced pressure. The filtrate was analyzed by Prep-HPLC. AW The residue was purified to give ethyl 2-amino-4-methyl-6,7-dihydro-5H-cyclopentadieno[b]pyridine-3-carboxylate (21.0 g, 24.0%) as a grayish-white solid. LCMS m / z = 221 [M+H] + .

[0822] Preparation of ethyl 112–4-methyl-2-(3-(2,2,2-trichloroacetyl)ureido)-6,7-dihydro-5H-cyclopentadieno[b]pyridine-3-carboxylate

[0823] At 0 °C, trichloroethane carbonyl isocyanate (26.8 g, 142 mmol) was added dropwise to a stirred solution of ethyl 2-amino-4-methyl-6,7-dihydro-5H-cyclopentadieno[b]pyridine-3-carboxylate (21.0 g, 95.0 mmol) in THF (210 mL). The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate / petroleum ether (3:1) to give the title compound as a white solid (38.0 g, 98.0%). LCMS m / z = 408 [M+H] + .

[0824] Preparation of 113–5-methyl-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3-d]pyrimidine-2,4-diol

[0825] At room temperature, ethyl 1-methyl-3-(3-(2,2,2-trichloroacetyl)ureido)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carboxylate (38.0 g, 93.1 mmol) and a solution of 7.0 M NH3 in methanol (70.0 mL) in ethanol (460 mL) were added to a pressure vessel reactor. The resulting mixture was stirred overnight at 80 °C. The mixture was then cooled to 0 °C. The precipitated solid was collected by filtration and washed with ethanol (3 × 20 mL). The title compound (19.2 g, 95.0%) was thus given as a white solid. LCMS m / z = 218 [M+H] + .

[0826] Preparation of 114–2,4-dichloro-5-methyl-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3-d]pyrimidine

[0827] At 0 °C, POCl3 (21.5 mL, 23.0 mmol) was added dropwise to a stirred mixture of 5-methyl-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3-d]pyrimidine-2,4-diol (5.0 g, 2.30 mmol) and DIEA (20.0 mL, 11.5 mmol) in ACN (90.0 mL). The resulting mixture was stirred at 60 °C for 2 h. The mixture was allowed to cool to room temperature. At 0 °C, a solution of 1,4-dioxane (25.0 mL) in 4 M HCl was added dropwise to the mixture over 30 minutes. The resulting mixture was stirred at room temperature for another 2 h. The resulting mixture was concentrated under reduced pressure. The reaction was quenched at 0 °C by adding saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (3.8 g, crude product). The crude product was used directly in the next step without further purification. LCMS m / z = 254 [M+H] + .

[0828] Preparation of 115–2-chloro-5-methyl-7,8-dihydro-6H-cyclopentan[5,6]pyrido[2,3-d]pyrimidine-4-amine

[0829] 2,4-Dichloro-5-methyl-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3-d]pyrimidine (3.00 g, 11.8 mmol, 1.00 equivalent) and NH3 . The mixture of H2O (60.0 mL) was stirred at room temperature for 2 days. The precipitated solid was collected by filtration and washed with water (3 x 30 mL). The solid was purified by preparation with ethyl acetate (30 mL). The title compound (1.30 g, crude product) was thus given as a black solid. LCMS m / z = 235 [M+H] + .

[0830] Preparation of 116–(R)-3-((4-amino-5-methyl-7,8-dihydro-6H-cyclopentan[5,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester

[0831] A mixture of 2-chloro-5-methyl-7,8-dihydro-6H-cyclopentane[5,6]pyrido[2,3-d]pyrimidin-4-amine (900 mg, 3.84 mmol) and (R)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (2.86 g, 15.3 mmol) in dioxane (9.00 mL) was stirred overnight at 100 °C. The mixture was cooled to room temperature and concentrated under reduced pressure. The amber-colored crude product (800 mg) was used directly for the next step without further purification. LCMS m / z = 385 [M+H] + .

[0832] Preparation of 117–(R)-5-methyl-N 2 -(pyrrolidine-3-yl)-7,8-dihydro-6H-cyclopentan[5,6]pyrido[2,3-d]pyrimidine-2,4-diaminess

[0833] A mixture of (R)-3-((4-amino-5-methyl-7,8-dihydro-6H-cyclopentane[5,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (800 mg, 2.08 mmol) and 4.0 M HCl in 1,4-dioxane (8.00 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure and diluted with MeOH (8.00 mL). The residue was alkalized to pH 9 with TEA. The residue was analyzed by Prep-HPLC. AV Purification yielded the title compound (377.8 mg, 63.8%, ee>99%) as a light orange solid. 1 H NMR (400 MHz, DMSO-d6) δ 6.90 - 6.32 (m, 3H), 4.44 - 4.27(m, 1H), 2.98 - 2.79 (m, 6H), 2.79 - 2.69 (m, 1H), 2.64 (dd, J = 11.2, 4.6Hz, 1H), 2.58 (s, 3H), 2.14 - 1.92 (m, 3H), 1.68 - 1.54 (m, 1H).LCMS W m / z = 285 [M+H] + .

[0834] Example 231: (R)-N 4 5-Dimethyl-N 2 -(pyrrolidone-3-yl)-7,8-dihydro-6H-cyclopentan[5,6]pyrido[2,3-d]pyrimidin-2,4-diamine

[0835]

[0836] Preparation of 118–2-chloro-N,5-dimethyl-7,8-dihydro-6H-cyclopentan[5,6]pyrido[2,3-d]pyrimidine-4-amine

[0837] A mixture of 2,4-dichloro-5-methyl-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3-d]pyrimidine (1.00 g, crude product) and methylamine (10.0 mL, 2.0 M in THF) was stirred at room temperature for 1 hour, and the resulting mixture was concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. AV Purification yielded the title compound as a brown solid (210 mg, 18.5% in two steps). LCMS m / z = 249 [M+H] + .

[0838] Preparation of 119–(R)-3-((5-methyl-4-(methylamino)-7,8-dihydro-6H-cyclopentan[5,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester

[0839] A mixture of 2-chloro-N,5-dimethyl-7,8-dihydro-6H-cyclopentane[5,6]pyrido[2,3-d]pyrimidin-4-amine (300 mg, 1.20 mmol) and (R)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (447 mg, 2.40 mmol) in 1,4-dioxane (6.0 mL) was stirred at 100 °C for 1 hour. The mixture was cooled to room temperature. The residue was analyzed by Prep-HPLC. B Purification yielded the title compound (200 mg, 41.6%) as a yellow oil. LCMS m / z = 399 [M+H] + .

[0840] Preparation of 120–(R)-N4,5-dimethyl-N 2 -(pyrrolidone-3-yl)-7,8-dihydro-6H-cyclopentan[5,6]pyrido[2,3-d]pyrimidin-2,4-diamine

[0841] A mixture of (R)-3-((5-methyl-4-(methylamino)-7,8-dihydro-6H-cyclopentane[5,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 0.502 mmol) and 4.0 M HCl in 1,4-dioxane (4.00 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. It was then diluted with methanol (2.00 mL) and alkalized to pH 9 with NH3·H2O. The residue was analyzed by Prep-HPLC. AVPurification yielded the title compound (115.9 mg, 77.4%, ee>99%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 6.93 - 6.64 (m, 2H), 4.46 -4.30(m, 1H), 3.65 - 3.50 (m, 1H), 3.15 - 3.02 (m, 2H), 2.94 (d, J = 4.1 Hz, 3H),2.92 - 2.76 (m, 5H), 2.59 (s, 3H), 2.11 - 1.96 (m, 3H), 1.84 - 1.69 (m, 1H).LCMS W m / z = 299 [M+H] + .

[0842] Example 232: (3S,4S)-1-methyl-4-((5-methyl-4-(methylamino)-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyrrolidine-3-ol

[0843]

[0844] Preparation of 121–(3S,4S)-3-hydroxy-4-((5-methyl-4-(methylamino)-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester

[0845] At room temperature, (3S,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (1.95 g, 9.65 mmol) was added to a stirred solution of 2-chloro-N,5-dimethyl-7,8-dihydro-6H-cyclopentane[5,6]pyrido[2,3-d]pyrimidin-4-amine (1.50 g, 6.03 mmol) in dioxane (10.0 mL). The resulting mixture was stirred overnight at 100°C. The mixture was concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. AW Purification yielded the title compound as a yellow solid (950 mg, 38.0%). LCMS m / z = 415 [M+H] + .

[0846] Preparation of 122–(3S,4S)-4-((5-methyl-4-(methylamino)-7,8-dihydro-6H-cyclopentan[5,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyrrolidine-3-ol

[0847] At room temperature, a solution of 1,4-dioxane (7.0 mL, 4.0 M) in HCl was added to a stirred solution of (3S,4S)-3-hydroxy-4-((5-methyl-4-(methylamino)-7,8-dihydro-6H-cyclopentane[5,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (450 mg, 1.09 mmol) in dioxane (3.0 mL). The resulting mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to give the title compound as a pale yellow solid (300 mg, crude product).

[0848] Preparation of 123–(3S,4S)-1-methyl-4-((5-methyl-4-(methylamino)-7,8-dihydro-6H-cyclopentan[5,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyrrolidine-3-ol

[0849] At room temperature, paraformaldehyde (516 mg, 5.72 mmol) was added to a stirred solution of (3S,4S)-4-((5-methyl-4-(methylamino)-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyrrolidine-3-ol (300 mg, 0.954 mmol) and Et3N (265 µL, 1.91 mmol) in DCM (6.0 mL). The resulting mixture was stirred at room temperature for 40 minutes. STAB (1.21 g, 5.72 mmol) was added to the mixture at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched at room temperature by adding water (15 mL). The resulting mixture was filtered, and the filter cake was washed with water (1 × 10 mL). The filtrate was concentrated under reduced pressure. The mixture was alkalized to pH 9 with Et3N. The residue was analyzed by Prep-HPLC. M Purification yielded the title compound as a yellow solid (145 mg, 46.3%). 1 ¹H NMR (400 MHz, methanol-d⁴) δ 4.33–4.12 (m, 2H), 3.18–3.00 (m, 4H), 3.03–2.88 (m, 5H), 2.64 (s, 3H), 2.60–2.49 (m, 2H), 2.37 (s, 3H), 2.13 (p, J = 7.6 Hz, 2H). LCMS R m / z = 329 [M+H] + .

[0850] Example 233: N 2 -((3S,4R)-4-fluoro-1-methylpyrrolidone-3-yl)-N 45-Dimethyl-7,8-dihydro-6H-cyclopentane[5,6]pyrido[2,3-d]pyrimidine-2,4-diamine

[0851]

[0852] Preparation of 124–(3R,4S)-3-fluoro-4-((5-methyl-4-(methylamino)-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester

[0853] At room temperature, 2-chloro-N,5-dimethyl-7,8-dihydro-6H-cyclopentane[5,6]pyrido[2,3-d]pyrimidin-4-amine (1.00 g, 4.03 mmol) and tert-butyl(3S,4R)-3-amino-4-fluoropyrrolidine-1-carboxylic acid ester (987 mg, 4.84 mmol) dissolved in dioxane (20.0 mL) were added to a 100 mL round-bottom flask. The resulting mixture was stirred at 100 °C for 5 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (12:1), to give the title compound (600 mg, 35.8%) as a brown solid. LCMS m / z = 417 [M+H] + .

[0854] Preparation of 125–N 2 -((3S,4R)-4-fluoro-1-methylpyrrolidone-3-yl)-N 4 5-Dimethyl-7,8-dihydro-6H-cyclopentane[5,6]pyrido[2,3-d]pyrimidine-2,4-diamine

[0855] A mixture of (3R,4S)-3-fluoro-4-((5-methyl-4-(methylamino)-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3-d]pyrimidin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (270 mg, 0.648 mmol) and 37 wt% formaldehyde solution (0.270 mL) in formic acid (2.70 mL) was stirred at 100 °C for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting mixture was diluted with methanol (4.00 mL) and alkalized to pH 9 with TEA. The residue was analyzed by Prep-HPLC. AX Purification yielded the title compound (87.4 mg, 40.9%, ee>98%) as a light orange solid. 1H NMR (400 MHz, DMSO-d6) δ6.99 - 6.33 (m, 2H), 5.15 (d, J = 55.9 Hz, 1H), 4.61 - 4.44 (m, 1H), 3.24 -3.10 (m, 1H), 3.02 - 2.82 (m, 8H), 2.69 - 2.63 (m, 1H), 2.60 (s, 3H), 2.57 -2.54 (m, 1H), 2.31 (s, 3H), 2.03 (p, J = 7.6 Hz, 2H). 19 F NMR (376 MHz, DMSO-d6) δ -187.85.LCMS U m / z = 331 [M+H] + .

[0856] Example 234: (R)-N 4 -Ethyl-5-methyl-N 2 -(1-Methylpyrrolidone-3-yl)-7,8-dihydro-6H-cyclopentan[5,6]pyrido[2,3-d]pyrimidin-2,4-diamine

[0857]

[0858] Preparation of 126–2-chloro-N-ethyl-5-methyl-7,8-dihydro-6H-cyclopentan[5,6]pyrido[2,3-d]pyrimidine-4-amine

[0859] Ethylamine (950 mL, 9.84 mmol, 70% wt. in H2O) was added to a mixture of 1.00 g (3.94 mmol) of 2,4-dichloro-5-methyl-7,8-dihydro-6H-cyclopenta[5,6]pyrido[2,3-d]pyrimidine (20 mL) under stirring. The resulting mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration and washed with water (3 × 10 mL). The title compound (600 mg, crude product) was thus obtained as a brownish-yellow solid, which was used directly for the next step without further purification. LCMS m / z = 263 [M+H] + .

[0860] Preparation of 127–(R)-N 4 -Ethyl-5-methyl-N 2 -(1-Methylpyrrolidone-3-yl)-7,8-dihydro-6H-cyclopentan[5,6]pyrido[2,3-d]pyrimidin-2,4-diamine

[0861] A mixture of 2-chloro-N-ethyl-5-methyl-7,8-dihydro-6H-cyclopentane[5,6]pyrido[2,3-d]pyrimidin-4-amine (300 mg, 1.14 mmol) and (R)-1-methylpyrrolidine-3-amine (229 mg, 2.28 mmol) in 1,4-dioxane (3.00 mL) was stirred overnight at 100 °C. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. AN Purification yielded the title compound (18.2 mg, 4.88%, ee>99%) as a pink solid. 1 ¹H NMR (400 MHz, methanol-d⁴) δ 4.68 - 4.56 (m, 1H), 3.61 (q, J = 7.0 Hz, 2H), 3.06 - 2.90 (m, 5H), 2.87 - 2.71 (m, 1H), 2.70 - 2.52 (m, 5H), 2.46 - 2.33 (m, 4H), 2.13 (p, J = 7.7 Hz, 2H), 1.86 - 1.73 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H). LCMS O m / z = 327 [M+H] + .

[0862] Example 235: Methyl 4-amino-2-((1-methylpiperidin-4-yl)amino)pyrido[2,3-d]pyrimidine-7-carboxylic acid

[0863]

[0864] At room temperature, 7-chloro-N 2 Pd(dppf)Cl2 (250 mg, 0.342 mmol) and Et3N (691 mg, 6.83 mmol) were added to a solution of 1.00 g (100 mL) of 1-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine (1.00 g, 3.42 mmol) in methanol (100 mL) and DMF (2.00 mL). The resulting mixture was stirred overnight at 100°C under a carbon monoxide atmosphere. The mixture was cooled to room temperature and filtered, and the filter cake was washed with methanol (3 × 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparation with EtOAc (30 mL). The title compound (1.64 g, crude product) was thus given as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 8.2 Hz, 1H), 7.80 - 7.30 (m,3H), 6.88 (d, J = 7.2 Hz, 1H), 3.98 - 3.80 (m, 4H), 2.97 - 2.85 (m, 2H), 2.34- 2.04 (m, 5H), 1.98 - 1.78 (m, 2H), 1.66 - 1.49 (m, 2H).LCMS m / z = 317 [M+H] +

[0865] Example 236: 4-amino-2-((1-methylpiperidin-4-yl)amino)pyrido[2,3-d]pyrimidine-7-carboxylic acid

[0866]

[0867] At room temperature, LiOH was added to a stirred solution of methyl 4-amino-2-((1-methylpiperidin-4-yl)amino)pyrido[2,3-d]pyrimidin-7-carboxylic acid (50.0 mg, 0.158 mmol) in THF (500 µL) and H₂O (500 µL). . H₂O (66.3 mg, 1.58 mmol). The resulting mixture was stirred at room temperature for 1 hour, then acidified to pH 5 with 1.0 M HCl (aqueous solution). The resulting mixture was filtered, and the filter cake was washed with water (3 × 2 mL). The filtrate was concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. AV Purification yielded the title compound (25.1 mg, two-step yield 79.6%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 8.41 (d, J = 8.1 Hz, 1H), 7.74 - 7.27 (m, 3H), 6.63 (d, J =8.3 Hz, 1H), 4.01 - 3.78 (m, 1H), 2.81 - 2.66 (m, 2H), 2.16 (s, 3H), 1.92 (t,J = 11.7, 2H), 1.85 - 1.70 (m, 2H), 1.65 - 1.45 (m, 2H).LCMS X m / z = 303 [M+H] +

[0868] Example 237: 7-(methoxymethyl)-N 2-(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0869]

[0870] At room temperature, Pd(PPh3)4 (39.5 mg, 0.030 mmol) was added to a stirred NMP (3.00 mL) solution of Example 23 (100 mg, 0.342 mmol) and tributyl(methoxymethyl)stanane (229 mg, 0.684 mmol). The resulting mixture was stirred at 130 °C for 2 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and analyzed by Prep-HPLC. AV Purification yielded the title compound as a pale yellow solid (3.0 mg, 2.90%). 1 H NMR (400 MHz, DMSO-d6) δ 8.35(d, J = 8.2 Hz, 1H), 7.71 - 7.17 (br, 2H), 7.03 (d, J = 8.1 Hz, 1H), 6.70 -6.49 (br, 1H), 4.46 (s, 2H), 3.89 LCMS Y m / z = 303 [M+H] + .

[0871] Example 238: N 2 -(1-Methylpiperidin-4-yl)-7-(prop-1-en-2-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0872]

[0873] To a stirred solution of Example 23 (300 mg, 1.03 mmol) in dioxane (5.00 mL) and H₂O (1.00 mL), propionic acid (123 mg, 1.54 mmol), Pd(dppf)Cl₂ (75.0 mg, 0.100 mmol), and K₃PO₄ (435 mg, 2.04 mmol) were added. The resulting mixture was stirred at 100 °C for 1 hour under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The concentration was determined by Prep-HPLC. AVThe residue was purified to give the title compound as a white solid (190 mg, 62.0%). 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 8.1 Hz, 1H), 7.79 - 7.08(m, 3H), 6.88 - 6.37 (m, 1H), 5.96 (s, 1H), 5.42 (s, 1H), 3.98 - 3.70 LCMSm / z = 299[M+H] + .

[0874] Example 239: 7-Isopropyl-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0875]

[0876] The mixture of Example 238 (50.0 mg, 0.168 mmol) and Pd / C (25.0 mg, 10% wt) in methanol (3.00 mL) was stirred at room temperature for 1 hour under a hydrogen atmosphere. The mixture was filtered through a short diatomaceous earth filter, and the filter cake was washed with methanol (3 × 5 mL). The filtrate was concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. AU Purification yielded the title compound as a white solid (11.1 mg, 22.0%). 1 H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J = 8.2 Hz, 1H), 7.28(s, 2H), 6.92 (d, J = 8.2 Hz, 1H), 6.47 (s, 1H), 3.91 - 3.73 (m, 1H), 3.07 -2.90 (m, 1H), 2.74 (d, J = 11.1 Hz, 2H), 2.16 (s, 3H), 1.96 (t, J = 11.5 Hz,2H), 1.86 - 1.73 (m, 2H), 1.57 - 1.43 (m, 2H), 1.23 (d, J = 6.9 Hz, 6H).LCMS Z m / z = 301 [M+H] +.

[0877] Example 240: 2-(4-amino-2-((1-methylpiperidin-4-yl)amino)pyrido[2,3-d]pyrimidin-7-yl)prop-1-ol

[0878]

[0879] Preparation of 128–2-(4-amino-2-((1-methylpiperidin-4-yl)amino)pyrido[2,3-d]pyrimidin-7-yl)prop-1-ol

[0880] At 0°C and under a nitrogen atmosphere, 9-boronbicyclo[3.3.1]nonane (2.11 mL, 1.05 mmol, 0.5 M, in THF) was added to a stirred solution of Example 238 (90.0 mg, 0.302 mmol) in THF (0.50 mL). The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. A second batch of 9-boronbicyclo[3.3.1]nonane (1.2 mL, 0.60 mmol) was added to the mixture at 0°C. The mixture was stirred at room temperature for 1 hour, and then a third batch of 9-boronbicyclo[3.3.1]nonane (1.2 mL, 0.60 mmol) was added at 0°C. The resulting mixture was stirred overnight at room temperature. The reaction mixture was cooled to 0°C and 30% H2O2 (1.03 g, 9.06 mmol) and 1 M NaOH (0.45 mL) aqueous solution were added at 0°C. The resulting mixture was stirred at room temperature for another 2 hours. The reaction was quenched by adding 10 mL of Na₂SO₃ at 0 °C, followed by concentration under reduced pressure. The residue was analyzed by Prep-HPLC. AV Purification yielded the title compound (7.60 mg, 8.0%). 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 8.2 Hz, 1H), 7.33 (br, 2H), 6.91 (d, J = 8.2 Hz, 1H), 6.48 (s, 1H), 4.85 - 4.56 (m, 1H), 3.93 - 3.75 (m, 1H), 3.73 - 3.63 (m, 1H), 3.60 - 3.50 (m, 1H), 3.00 - 2.87 (m, 1H), 2.79 (d, J = 11.2 Hz, 2H), 2.20 (s,3H), 2.11 - 1.97 (m, 2H), 1.87 - 1.77 (m, 2H), 1.62 - 1.45 (m, 2H), 1.20 (d,J = 6.9 Hz, 3H).LCMSW m / z = 317 [M+H] + .

[0881] Example 241: 6-Methoxy-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0882]

[0883] At room temperature, di-tert-butyl((2-[2,4,6-tris(prop-2-yl)phenyl)phosphine) (25.2 mg, 0.060 mmol) and Cs₂CO₃ (387 mg, 1.19 mmol) were added to a stirred mixture of Example 20 (200 mg, 0.593 mmol) and Pd(PPh₃)₄ (68.5 mg, 0.060 mmol) in methanol (2.00 mL) and dioxane (2.00 mL). The resulting mixture was stirred at 100 °C for 6 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. N Purification yielded the title compound as a yellow solid (5.6 mg, 3.25%). 1 H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 3.0 Hz, 1H), 7.93 (d, J = 3.2 Hz, 1H), 7.34 (s, 2H), 6.35 (s, 1H), 3.81 (s, 3H), 3.78 – 3.70 (m, 1H), 2.74 (d, J = 11.4 Hz, 2H), 2.16 (s, 3H), 2.00 - 1.89 (m, 2H), 1.86 - 1.76 (m, 2H), 1.56 - 1.42 (m, 2H).LCMS Z m / z = 289 [M+H] + .

[0884] Example 242: 6-(methoxymethyl)-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0885]

[0886] Preparation of 129–6-(chloromethyl)-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0887] The mixture of Example 123 (50.0 mg, 0.173 mmol) in SOCl2 (1.00 mL) was stirred at 80 °C for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure. The title compound (50 mg, crude product) was thus obtained as a black solid, which was used directly in the next step without further purification. LCMS m / z: 307 [M+H] +

[0888] Preparation of 130–6-(methoxymethyl)-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0889] 6-(chloromethyl)-N 2 A mixture of 1-(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine (50.0 mg, 0.163 mmol) and NaOMe in MeOH (30% wt, 1.50 mL) was stirred at 0 °C for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. L Purification yielded a yellow solid product (38 mg, crude product). The crude product was analyzed by Prep-HPLC. AU Further purification yielded the title compound (2.6 mg, 5.3%) as a white oyster-like solid. 1 H NMR(400 MHz, DMSO-d6) δ 8.55 (d, J = 2.3 Hz, 1H), 8.33 (d, J = 2.4 Hz, 1H), 7.40(br, 2H), 6.58 (br, 1H), 4.40 (s, 2H), 3.85 – 3.73 (m, 1H), 3.29 (s, 3H), 2.74 (d, J = 11.1 Hz, 2H), 2.16 (s, 3H), 1.94 (t, J = 11.7 Hz, 2H), 1.81 (d,J = 12.3 Hz, 2H), 1.59 – 1.39 (m, 2H).LCMS V m / z: 303 [M+H] +

[0890] Example 243: 6-Cyclopentyl-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0891]

[0892] A mixture of nickel acetylacetone (7.62 mg, 0.030 mmol), ([4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′)bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium hexafluorophosphate (III) (3.33 mg, 0.003 mmol), 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine (7.96 mg, 0.030 mmol), and MgCl2 (28.2 mg, 0.297 mmol) in DMF (4.00 mL) was stirred for 5 minutes at room temperature under a nitrogen atmosphere. Then, a mixture of Example 20 (100 mg, 0.297 mmol), bromocyclopentane (221 mg, 1.49 mmol), and Et3N (124 µL, 0.891 mmol) in DMF (4.00 mL) was added to the above mixture. The resulting mixture was stirred for 5 hours at room temperature under a nitrogen atmosphere and under a blue LED. The mixture was analyzed by Prep-HPLC. L The solution was purified to give the title compound as a light red solid (53.0 mg, crude product). The crude product was analyzed by Prep-HPLC. AY Further purification yielded the title compound as a grayish-white solid (17.6 mg, 18.2%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.52 (d, J = 2.4 Hz, 1H), 8.23 ​​(d, J =2.5 Hz, 1H), 7.38 (s, 2H), 6.44 (s, 1H), 3.84 - 3.69 (m, 1H), 3.04 - 2.94 (m,1H), 2.74 (d, J = 11.4 Hz, 2H), 2.16 (s, 3H), 2.09 - 1.99 (m, 2H), 1.98 -1.89 (m, 2H), 1.86 - 1.74 (m, 4H), 1.72 - 1.61 (m, 2H), 1.60 - 1.43 (m, 4H).LCMS AA m / z = 327 [M+H] + .

[0893] Example 244: 4-amino-2-((1-methylpiperidin-4-yl)amino)pyrido[2,3-d]pyrimidin-5-ol

[0894]

[0895] Preparation of 131–N-(3-cyano-4-methoxypyridin-2-yl)aminocyano

[0896] At room temperature, BrettPhos (2.39 g, 4.45 mmol), aminocyanide (1.88 g, 44.5 mmol), and BrettPhos Pd G3 (4.03 g, 4.45 mmol) were added to a stirred mixture of 2-chloro-4-methoxypyridin-3-onitrile (3.75 g, 22.2 mmol) and K₂CO₃ (6.15 g, 44.5 mmol) in dioxane (40.0 mL). The resulting mixture was stirred at 60 °C for 1 hour under a nitrogen atmosphere. The mixture was filtered, and the filter cake was washed with methanol (5 × 100 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with water (200 mL) and acidified to pH 5 with 1 M HCl. The precipitated solid was collected by filtration and washed with water (3 × 100 mL) to give the title compound as a white solid (3.20 g, 82.6%). LCMS m / z = 175 [M+H] + .

[0897] Preparation of 132–5-methoxy-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0898] A mixture of 2-(cyanoamino)-4-methoxypyridine-3-onitrile (3.20 g, 18.4 mmol) and 1-methylpiperidin-4-amine (4.20 g, 36.8 mmol) in dioxane (60.0 mL) was stirred overnight at 120 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparation with EtOAc (200 mL) to give the title compound (2.48 g, 46.8%) as a yellow solid. LCMS m / z = 289 [M+H] + .

[0899] Preparation of 133–4-amino-2-((1-methylpiperidin-4-yl)amino)pyrido[2,3-d]pyrimidin-5-ol

[0900] At room temperature, add 5-methoxy-N to a 100 mL round-bottom flask 2 -(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine (2.38 g, 8.25 mmol) and hydrochloric acid (25.0 mL, 6.0 M) aqueous solution. The resulting mixture was stirred at 100°C for 2 hours. The resulting mixture was concentrated under reduced pressure to give the title compound as a yellow solid (3.00 g, crude product). 1H NMR (400 MHz, DMSO-d6) δ 11.41 - 10.83 (m, 1H), 9.52 - 9.13 (m, 1H), 7.59 -7.00 (m, 2H), 6.78 (d, J = 8.2 Hz, 1H), 5.80 (d, J = 7.6 Hz, 1H), 3.81 - 3.63(m, 1H), 2.73 (d, J = 11.1 Hz, 2H), 2.12 (s, 3H), 1.88 (t, J = 13.2, 2H), 1.76 (d, J = 12.2 Hz, 2H), 1.56 - 1.28 (m, 2H).LCMS m / z = 275 [M+H] + .

[0901] Example 245: N 2 -(1-Methylpiperidin-4-yl)-5-(prop-1-en-2-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0902]

[0903] Preparation of 134–5-chloro-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0904] At room temperature, 2.50 g (9.11 mmol) of 4-amino-2-[(1-methylpiperidin-4-yl)amino]pyrido[2,3-d]pyrimidin-5-ol and POCl3 (30.0 mL) were added to a 100 mL round-bottom flask. The resulting mixture was heated to 80 °C. o The mixture was stirred at C for 1 hour. The resulting mixture was concentrated under reduced pressure. The reaction was quenched at 0°C with water / ice. The mixture was alkalized to pH 8 with saturated sodium bicarbonate (aqueous solution). The aqueous layer was extracted with CH₂Cl₂ / MeOH (10:1, 3 × 100 mL) to give the title compound as a yellow solid (1.05 g, 39.4%). LCMS m / z = 293 [M+H] + .

[0905] Preparation of 135-N 2 -(1-Methylpiperidin-4-yl)-5-(prop-1-en-2-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0906] At room temperature, 5-chloro-N 2Pd(dppf)Cl2 (45.0 mg, 0.0610 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxoborane (225 μL, 1.21 mmol) were added to a mixture of (1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine (150 mg, 0.512 mmol) and K3PO4 (285 mg, 1.34 mmol) in dioxane (5.00 mL) and H2O (1.00 mL). The resulting mixture was stirred at 100 °C for 1 hour under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with methanol (2 × 5 mL). The filtrate was concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. AV Purification yielded the title compound as a white solid (100 mg, 65.4%). 1 H NMR (400 MHz, DMSO-d6) δ 8.52(d, J = 4.5 Hz, 1H), 7.34 - 6.20 (m, 4H), 5.43(s, 1H), 5.15 (s, 1H), 3.87 -3.70 (m, 1H), 2.79 - 2.64 (m, 2H), 2.16 (s, 3H), 2.09 (s, 3H), 1.94 (t, J =11.5 Hz, 2H), 1.87 - 1.69 (m, 2H), 1.64 - 1.42 (m, 2H).LCMS m / z = 299 [M+H] + .

[0907] Example 246: 5-Isopropyl-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0908]

[0909] The mixture of Example 245 (40.0 mg, 0.135 mmol) and 10% Pd / C (40 mg) in EA (16.0 mL) was stirred at room temperature under a hydrogen atmosphere for 8 hours. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH / Et3N (10:1:0.06) to give the title compound as a white solid (17.5 mg, 43.4%). 1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J= 4.9 Hz, 1H), 7.91 - 7.25 (m, 1H), 7.14 -6.52 (m, 3H), 4.12 - 3.93 (m, 1H), 3.85 - 3.69 (m, 1H), 3.08 - 2.81 (m, 2H), 2.67 (s, 3H), 2.13 - 1.97 (m, 2H), 1.92 - 1.69 (m, 2H), 1.34 - 1.08 (m, 7H), 0.98 - 0.73 (m, 1H).LCMS E m / z = 301[M+H] + .

[0910] Example 247: N 5 -Methyl-N 2 -(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4,5-triamine

[0911]

[0912] Preparation of 136–N 5 -(4-Methoxybenzyl)-N 5 -Methyl-N 2 -(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4,5-triamine

[0913] 5-chloro-N 2 A mixture of (1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine (150 mg, 0.512 mmol) and 1-(4-methoxyphenyl)-N-methylmethylamine (2.00 mL) was stirred at 100 °C for 1 hour. The mixture was cooled to room temperature and analyzed by Prep-HPLC. AV Purification yielded the title compound (150 mg, 71.8%) as a yellow solid. LCMS m / z = 408 [M+H] + .

[0914] Preparation of 137–N 5 -Methyl-N 2 -(1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4,5-triamine

[0915] N 5 -(4-Methoxybenzyl)-N 5 -Methyl-N 2A solution of (1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4,5-triamine (150 mg, 0.368 mmol) in TFA (2.00 mL) was stirred at 100 °C for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was alkalized to pH 9 with NH3·H2O. The residue was analyzed by Prep-HPLC. AV Purification yielded the title compound (44.0 mg, 41.6%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.07 - 9.69(m, 2H), 7.47 - 6.45 (m, 2H), 6.27 (s, 1H), 5.95 (s, 1H), 3.76 - 3.59 (m,1H), 2.89 (s, 3H), 2.72 (d, J = 11.1 Hz, 2H), 2.14 (s, 3H), 1.90 (t, J = 11.6Hz, 2H), 1.77 (d, J = 11.8 Hz, 2H), 1.55 - 1.39 (m, 2H).LCMS AB m / z = 288 [M+H] + .

[0916] Example 248: 5-(methoxymethyl)-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0917]

[0918] To the stirred 5-chloro-N 2 Pd(PPh3)2Cl2 (16.7 mg, 0.0240 mmol) and 4 Å MS (140 mg) were added to a mixture of (1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine (70.0 mg, 0.239 mmol) and tributyl(methoxymethyl)stanane (160 mg, 0.478 mmol) in NMP (8.00 mL). The resulting mixture was stirred at 120 °C for 4 hours under nitrogen atmosphere. The mixture was cooled to room temperature and then diluted with saturated KF (aqueous solution) (20 mL). The mixture was extracted with CH2Cl2 (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. AV Purification yielded the title compound as a brown solid (6.5 mg, 8.99%). 1¹H NMR (400 MHz, methanol-d⁴) δ 8.64–8.51 (m, 1H), 7.03 (d, J = 4.7 Hz, 1H), 4.71 (s, 2H), 4.04–3.93 (m, 1H), 3.45 (s, 3H), 2.88 (d, J = 11.8 Hz, 2H), 2.31 (s, 3H), 2.28–2.19 (m, 2H), 2.09–2.01 (m, 2H), 1.68–1.54 (m, 2H). LCMS AC m / z = 303 [M+H] + .

[0919] Example 249: 5-ethynyl-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0920]

[0921] To the stirred 5-chloro-N 2 Pd(dppf)Cl2 (50.0 mg, 0.0680 mmol) and Et3N (346 mg, 3.415 mmol) were added to a mixture of (1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine (200 mg, 0.683 mmol) and CuI (13.0 mg, 0.0680 mmol) in DMF (4.0 mL). Trimethylsilylacetylene (335 mg, 3.42 mmol) was added to the mixture at room temperature. The resulting mixture was stirred at 80°C for 3 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and filtered, and the filter cake was washed with methanol (3 × 5 mL). The filtrate was concentrated under reduced pressure. The filtrate was analyzed by Prep-HPLC. AV The residue was purified to give the title compound as a white solid, and as an off-white solid (3.2 mg, 1.62%). 1 H NMR(400 MHz, DMSO-d6) δ 8.21 - 7.56 (m, 2H), 6.89 (d, J = 7.8 Hz, 1H), 6.55 (s,2H), 3.93 - 3.73 (m, 1H), 3.05 - 2.81 (m, 2H), 2.41 - 2.19 (m, 4H), 1.91 (d,J = 12.8 Hz, 2H), 1.67 - 1.53 (m, 2H), 1.27 - 1.16 (m, 2H).LCMSAD m / z = 283 [M+H] + .

[0922] Example 250: 4-amino-2-((1-methylpiperidin-4-yl)amino)pyrido[2,3-d]pyrimidin-5-nitrile

[0923]

[0924] To the stirred 5-chloro-N 2 Zn(CN)₂ (64.1 mg, 0.546 mmol), Zn (35.7 mg, 0.546 mmol), Pd₂(dba)₃ (25.0 mg, 0.0270 mmol), and dppf (15.0 mg, 0.0270 mmol) were added to a solution of (1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine (80.0 mg, 0.273 mmol) in NMP (2.00 mL). The resulting mixture was stirred at 100 °C for 1 hour under a nitrogen atmosphere. The mixture was filtered, and the filter cake was washed with methanol (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. AX Purification yielded the title compound as a pale yellow solid (21.0 mg, 27.1%). 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 4.5 Hz, 1H), 7.57 - 7.30 (m, 2H), 7.27 - 7.02 (m, 2H), 3.86 - 3.70 (m, 1H), 2.75 (d, J = 11.1 Hz, 2H),2.16 (s, 3H), 1.94 (t, J = 11.6 Hz, 2H), 1.80 (d, J = 12.2 Hz, 2H), 1.61 -1.46 (m, 2H).LCMS AE m / z = 284 [M+H] + .

[0925] Example 251: N 2 -(1-Methylpiperidin-4-yl)-5-(prop-1-yn-1-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0926]

[0927] To the stirred 5-chloro-N 2A mixture of (1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine (100 mg, 0.342 mmol) and Pd(dppf)Cl2 (25.0 mg, 0.034 mmol) in DMF (4.00 mL) was added to tributyl(prop-1-yn-1-yl)stanane (562 mg, 1.71 mmol). The mixture was stirred at 120 °C for 1 hour under a nitrogen atmosphere. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. AV Purification yielded the title compound (20.1 mg, 19.9%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.41(br, 1H), 7.52(br, 1H), 6.65 (s, 1H), 6.40 (s, 2H), 3.86 - 3.72 (m, 1H), 2.76 (d, J = 11.4Hz, 2H), 2.29 (s, 3H), 2.17 (s, 3H), 2.06 - 1.88 (m, 2H), 1.83 (d, J = 12.3Hz, 2H), 1.59 - 1.44 (m, 2H).LCMS AF m / z = 297 [M+H] + .

[0928] Example 252: 5-(1-Methoxyethyl)-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0929]

[0930] Preparation of 138–5-(1-methoxyvinyl)-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0931] At room temperature, 5-chloro-N 2A mixture of (1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine (100 mg, 0.342 mmol) and Pd(PPh3)4 (39.5 mg, 0.0340 mmol) in NMP (2.00 mL) was added to tributyl(1-methoxyvinyl)stanane (237 µL, 0.684 mmol). The resulting mixture was stirred overnight at 120 °C under nitrogen atmosphere. The reaction was quenched with saturated KF (aqueous solution) at room temperature. The resulting mixture was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH / NH3·H2O (10:1:0.1) to give the title compound as a brown semi-solid (60.0 mg, 55.8%). LCMS m / z = 315 [M+H] + .

[0932] Preparation of 139–5-(1-methoxyethyl)-N 2 -(1-Methylpiperidin-4-yl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0933] 5-(1-methoxyvinyl)-N 2 A solution of (1-methylpiperidin-4-yl)pyrido[2,3-d]pyrimidine-2,4-diamine (56.0 mg, 0.178 mmol) and 20% Pd(OH)₂ / C (56.0 mg) in MeOH (5.00 mL) was stirred overnight at room temperature under a hydrogen atmosphere. The resulting mixture was filtered through a diatomaceous earth sieve, and the filter cake was washed with methanol (3 × 10⁻⁶ mL). The filtrate was concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. AV Purification yielded the title compound as a grayish-white solid (5.6 mg, 9.70%). 1 H NMR (400 MHz, methanol-d4) δ 8.58 (d, J = 4.7 Hz, 1H), 7.07 (d, J = 4.7Hz, 1H), 4.73 (q, J = 6.8 Hz, 1H), 4.16 - 4.03 (m, 1H), 3.36 (s, 3H), 3.25 -3.10 (m, 2H), 2.80 - 2.63 (m, 2H), 2.59 (s, 3H), 2.23 - 2.11 (m, 2H), 1.81 -1.68 (m, 2H), 1.58 (d, J = 6.8 Hz, 3H).LCMSY m / z = 317 [M+H] + .

[0934] Example 253: 5-Methyl-N 2 -(3-morpholinopropyl)-7-(m-tolyl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0935]

[0936] Preparation of methyl 140–2-amino-4,6-dihydroxypyridine-3-carboxylate

[0937] Nickel acetylacetonate (150 mg, 0.574 mmol) was added to a stirred solution of 1,5-dimethyl-3-oxoglutarate (20.0 g, 115 mmol) and carbamate (5.79 g, 138 mmol) in 200 mL of DME at room temperature. The resulting mixture was stirred overnight at 80°C. The mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration and washed with DME (3 × 2 mL). The resulting solid was diluted with methanol (100 mL) and stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration and washed with MeOH (3 × 10 mL). The solid was dried under vacuum. The title compound (8.80 g, 41.6%) was thus given as a brown solid. LCMS m / z = 185 [M+H] + .

[0938] Preparation of methyl 141–2-amino-4,6-dichloronicotinate

[0939] At room temperature, DIEA (9.00 mL) was added to a mixture of methyl 2-amino-4,6-dihydroxypyridine-3-carboxylic acid (3.00 g, 16.3 mmol) in POCl3 (45.0 mL). The resulting mixture was stirred overnight at 60 °C. The mixture was cooled to room temperature and concentrated under vacuum. The residue was added dropwise to an aqueous sodium bicarbonate solution at 0 °C. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The title compound (2.0 g, crude product) was thus given as a brown solid. LCMS m / z = 221 [M+H] + .

[0940] Preparation of methyl 142–2-amino-4-chloro-6-(m-tolyl)nicotinic acid

[0941] At room temperature, Pd(dppf)Cl3 (1.06 g, 0.918 mmol) and K3PO4 (2.92 g, 13.8 mmol) were added to a stirred mixture of methyl 2-amino-4,6-dichloropyridine-3-carboxylic acid (2.03 g, 9.18 mmol) and 3-methylphenylboronic acid (1.50 g, 11.0 mmol) in 1,4-dioxane (40.0 mL) and H2O (4.00 mL). The resulting mixture was stirred at 60 °C for 3 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and diluted with H2O (100 mL). The resulting mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (10:1) to give the title compound (1.38 g, 54.3%) as a yellow solid. LCMS m / z = 277 [M+H] + .

[0942] Preparation of methyl 143–2-amino-4-methyl-6-(m-tolyl)nicotinic acid

[0943] At room temperature, Pd(dppf)Cl2 was added to a stirred mixture of methyl 2-amino-4-chloro-6-(m-tolyl)nicotinic acid (1.24 g, 4.48 mmol) and methylboronic acid (805 mg, 13.4 mmol) in 1,4-dioxane (18.0 mL). . CH₂Cl₂ (365 mg, 0.448 mmol) and K₃PO₄ (2.85 g, 13.4 mmol). The resulting mixture was stirred at 110°C for 1 hour under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with H₂O (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (2:1) to give the title compound (606 mg, 52.7%) as a yellow solid. LCMS m / z = 257 [M+H] + .

[0944] Preparation of 144–5-methyl-7-(m-tolyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

[0945] A solution of methyl 2-amino-4-methyl-6-(m-tolyl)nicotinic acid (576 mg, 2.25 mmol) and 2,2,2-trichloroethane carbonyl isocyanate (423 mg, 2.25 mmol) in THF (9.00 mL) was stirred at room temperature for 30 min under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. A methanol solution of 7.0 M NH3 (9.00 mL) was added to the mixture at room temperature. The mixture was stirred again at room temperature for 30 min. The resulting mixture was concentrated under reduced pressure. The residue was purified by MTBE (20 mL). The title compound (570 mg, 94.8%) was thus given as a white solid. LCMS m / z = 268 [M+H] + .

[0946] Preparation of 145–2,4-dichloro-5-methyl-7-(m-tolyl)pyrido[2,3-d]pyrimidine

[0947] A mixture of 5-methyl-7-(m-tolyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (500 mg, 1.87 mmol) and DIEA (2.00 mL) in POCl3 (10 mL) was stirred at 100 °C for 1 hour. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was used directly for the next step without further purification. LCMS m / z = 304 [M+H] + .

[0948] Preparation of 146–2-chloro-5-methyl-7-(m-tolyl)pyrido[2,3-d]pyrimidin-4-amine

[0949] At 0°C, NH3 was added to a stirred mixture of 2,4-dichloro-5-methyl-7-(m-tolyl)pyrido[2,3-d]pyrimidine (300 mg, 0.986 mmol) in 12.0 mL of ACN. . H2O (3.00 mL). The resulting mixture was stirred at 0°C for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (20 mL). The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 2 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in ACN (20 mL). The resulting mixture was filtered, and the filter cake was washed with methanol (3 × 2 mL). The filtrate was concentrated under reduced pressure. The title compound (166 mg, crude product) was thus obtained as a brown solid. LCMS m / z = 285 [M+H] + .

[0950] Preparation of 147–5-methyl-N 2-(3-morpholinopropyl)-7-(m-tolyl)pyrido[2,3-d]pyrimidin-2,4-diamine

[0951] CsF (74.7 mg, 0.492 mmol) was added to a stirred mixture of 2-chloro-5-methyl-7-(m-tolyl)pyrido[2,3-d]pyrimidin-4-amine (70.0 mg, 0.246 mmol) and 4-morpholinopropanolamine (70.9 mg, 0.492 mmol) in 1,4-dioxane (4.00 mL). The resulting mixture was stirred overnight at 100 °C. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under vacuum. The residue was analyzed by Prep-HPLC. AY Purification yielded the title compound as a brownish-yellow solid (7.2 mg, 7.46%). 1 H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.93 (d, J = 7.8 Hz,1H), 7.50 - 7.21 (m, 2H), 7.29 (d, J = 7.5 Hz, 1H), 6.80 (s, 2H), 6.62 LCMS AE m / z = 393 [M+H] + .

[0952] Example 254: N 2 -(4-(dimethylamino)butyl)-5,7-dimethyl-1,8-naphthidium-2,4-diamine

[0953]

[0954] Preparation of 148–2-amino-4,6-dimethylnicotinic acid ethyl ester

[0955] To a stirred solution of ethyl 3-amino-3-iminopropionic acid hydrochloride (10.0 g, 60.0 mmol) in ethanol (90.0 mL) at room temperature, piperidine (15.3 g, 180 mmol) and pentane-2,4-dione (9.01 g, 90.0 mmol) were added dropwise. The resulting mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (300 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (2 x 200 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (10:1), to give the title compound as a pale yellow solid (8.0 g, 68.6%). LCMS m / z = 195 [M+H] + .

[0956] Preparation of 149–5,7-dimethyl-1,8-naphthidine-2,4-diol

[0957] At room temperature, NaH (8.94 g, 223 mmol, 60% in oil) was added fractionally to a stirred solution of ethyl 2-amino-4,6-dimethylnicotinate (6.20 g, 31.9 mmol) in 200 mL of ethyl acetate. The resulting mixture was stirred at 80 °C for 3 hours. The mixture was allowed to cool to room temperature. The reaction was quenched at 0 °C with water / ice and extracted with EtOAc (100 mL × 3). The aqueous layer was acidified to pH 6 with AcOH. The precipitated solid was collected by filtration and washed with water (30 mL × 3). The solid was dried under vacuum. The title compound was given as a grayish-white solid (4.8 g, 79.1%). LCMS m / z = 191 [M+H] +

[0958] Preparation of 150–2,4-dichloro-5,7-dimethyl-1,8-naphthidine

[0959] At 0 °C, POCl3 (21.1 mL, 226 mmol) and DIEA (11.8 mL, 67.8 mmol) were added dropwise to a mixture of 5,7-dimethyl-1,8-naphthidine-2,4-diol (4.30 g, 22.6 mmol) in toluene (130 mL). The resulting mixture was stirred at 100 °C for 8 hours. The mixture was allowed to cool to room temperature. At 0 °C, the resulting mixture was added to a saturated aqueous solution of sodium bicarbonate. The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (2 x 300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give the title compound as a red solid (3.7 g, 72.1%). LCMS m / z = 227 [M+H] + .

[0960] Preparation of 151–2-chloro-5,7-dimethyl-1,8-naphthidine-4-amine

[0961] 2,4-Dichloro-5,7-dimethyl-1,8-naphthidine (600 mg, 2.64 mmol) and CsF (1.20 g, 7.93 mmol) were reacted with NH3. . The solution of H2O (20.0 mL) and dioxane (20.0 mL) was stirred at 100 °C for 34 hours. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The concentration was then determined by Prep-HPLC. AV The residue was purified to give 2-chloro-5,7-dimethyl-1,8-naphthidine-4-amine (555 mg, crude product) and 4-chloro-5,7-dimethyl-1,8-naphthidine-2-amine (430 mg, crude product, isomer) as yellow solids. LCMS m / z = 208 [M+H] + .

[0962] Preparation of 152–N 2 -(4-(dimethylamino)butyl)-5,7-dimethyl-1,8-naphthidium-2,4-diamine

[0963] At room temperature, Cs₂CO₃ (157 mg, 0.480 mmol) and Pd-PEPPSI-IHeptCl 3-chloropyridine (23.5 mg, 0.020 mmol) were added to a stirred solution of 2-chloro-5,7-dimethyl-1,8-naphthyl-4-amine (50.0 mg, 0.240 mmol) and (4-aminobutyl)dimethylamine (280 mg, 2.41 mmol) in dioxane (1.00 mL). The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (EA / MeOH = 1:2) to give the title compound (1.8 mg, 2.36%). 1 H NMR (400 MHz, DMSO-d6)δ 6.62 (s, 1H), 6.54 (s, 1H), 5.82 (s, 1H), 5.73 (s, 2H), 3.28 - 3.24(m, 2H),2.69 (s, 3H), 2.37 (s, 3H), 2.21 (t, J = 6.9 Hz, 2H), 2.11 (s, 6H), 1.58 -1.41 (m, 4H).LCMS AB m / z = 288 [M+H] + .

[0964] Example 255: (R)-5,7-dimethyl-N 2 -(pyrrolidone-3-yl)-1,8-naphthyl-2,4-diamine

[0965]

[0966] Preparation of 153–tert-butyl(R)-3-((4-amino-5,7-dimethyl-1,8-naphthid-2-yl)amino)pyrrolidine-1-carboxylic acid ester

[0967] At room temperature, Cs₂CO₃ (1.57 g, 4.82 mmol) and (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (203 mg, 0.241 mmol) were added to a stirred mixture of 2-chloro-5,7-dimethyl-1,8-naphthyl-4-amine (500 mg, 2.41 mmol) and (R)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (897 mg, 4.82 mmol) in dioxane (10.0 mL). The resulting mixture was stirred at 100 °C for 1 hour under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was analyzed by Prep-HPLC. AV Purification yielded the title compound (80.0 mg, 9.29%) as a white solid. LCMS m / z = 358 [M+H] + .

[0968] Preparation of 154–(R)-5,7-dimethyl-N 2 -(pyrrolidone-3-yl)-1,8-naphthyl-2,4-diamine

[0969] A mixture of (R)-3-((4-amino-5,7-dimethyl-1,8-naphthidin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (75.0 mg, 0.210 mmol) and 4.0 M HCl in 1,4-dioxane (1.00 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure and dissolved in MeOH (1.00 mL). The mixture was alkalized to pH 9 with NH3·H2O. The residue was analyzed by Prep-HPLC. AV Purification yielded the title compound (22.9 mg, 42.4%, ee>99%) as a grayish-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.88 (br, 1H), 6.95 (d, J = 5.9 Hz, 1H), 6.71 (s,1H), 5.97 (s, 2H), 5.85 (s, 1H), 4.54 - 4.31 (m, 1H), 3.47 - 3.38 (m, 2H),3.19 - 3.03 (m, 2H), 2.71 (s, 3H), 2.39 (s, 3H), 2.26 - 2.17 (m, 1H), 1.92 -1.81 (m, 1H).LCMS T m / z = 258 [M+H] + .

[0970] Example 256: (R)-N 4 5,7-Trimethyl-N 2 -(pyrrolidone-3-yl)-1,8-naphthyl-2,4-diamine

[0971]

[0972] Preparation of 155–2-chloro-N,5,7-trimethyl-1,8-naphthidine-4-amine

[0973] At room temperature, CH3NH2 was added to a stirred mixture of 2,4-dichloro-5,7-dimethyl-1,8-naphthidine (3.00 g, 13.2 mmol) in DMSO (30.0 mL). . HCl (1.34 g, 20.0 mmol) and DIEA (3.41 g, 26.4 mmol). The resulting mixture was stirred at 100°C for 4 h. The resulting mixture was analyzed by Prep-HPLC. AV Purification yielded the title compound (1.10 g, 37.6%) as a white solid. LCMS m / z = 222 [M+H] +

[0974] Preparation of 156–(R)-3-((5,7-dimethyl-4-(methylamino)-1,8-naphthid-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester

[0975] A mixture of 2-chloro-N,5,7-trimethyl-1,8-naphthidine-4-amine (300 mg, 1.35 mmol) and (R)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (3.00 mL) was stirred at 140 °C for 5 hours. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with DMF (5 mL). The residue was analyzed by Prep-HPLC. AV Purification yielded the title compound (408 mg, 81.0%) as a green solid. LCMS m / z = 372 [M+H] +

[0976] Preparation of 157–(R)-N 4 5,7-Trimethyl-N 2 -(pyrrolidone-3-yl)-1,8-naphthyl-2,4-diamine

[0977] At room temperature, a solution of HCl (gas) in 1,4-dioxane (4.00 mL, 4.0 M) was added dropwise to a stirred mixture of (R)-3-((5,7-dimethyl-4-(methylamino)-1,8-naphthid-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (390 mg, 1.05 mmol) in 1,4-dioxane (4.00 mL). The resulting mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in DMSO (4 mL) and alkalized to pH 9 with NH3·H2O. The residue was analyzed by Prep-HPLC. AZ Purification yielded the title compound (41.1 mg, 11.7%, ee>99%) as a white solid TFA salt. 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.40 - 7.15 (m, 1H), 6.71 (s, 1H), 6.01 - 5.88 (m, 1H), 5.64 (s, 1H), 4.63 - 4.50 (m, 1H), 3.40 - 3.33 (m, 1H), 3.32 -3.24 (m, 1H), 3.20 - 3.11 (m, 1H), 3.07 - 3.00 (m, 1H), 2.76 (d, J = 4.6 Hz, 3H), 2.72 (s,3H), 2.40 (s, 3H), 2.26 - 2.10 (m, 1H), 1.93 - 1.80 (m, 1H).LCMS AA m / z = 272[M+H] +

[0978] Example 257: N 4 3,5,7-Tetramethyl-N 2 -(1-Methylpiperidin-4-yl)-1,8-naphthidin-2,4-diamine

[0979]

[0980] Preparation of 158–3,5,7-trimethyl-1,8-naphthidine-2,4-diol

[0981] At room temperature, t-BuOK (48.5 g, 433 mmol) was added to a stirred solution of ethyl 2-amino-4,6-dimethylnicotinate (14.0 g, 72.2 mmol) and ethyl propionate (174 mL, 1.80 M) in THF (200 mL). The resulting mixture was stirred at room temperature for 40 min, then at 100 °C for 3 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting mixture was diluted with water (150 mL). The residue was alkalized to pH 7 with HCl (aqueous solution). The precipitated solid was collected by filtration and washed with water (3 x 10 mL). The title compound was thus given as a grayish-white solid (5.70 g, 38.7%). LCMS m / z = 205 [M+H] + .

[0982] Preparation of 159–2,4-dichloro-3,5,7...

Claims

1. A compound of formula (I) or its tautomer form or its pharmaceutically acceptable salt or N-oxide: (I) in X is N or CR 6 ; R 1 Independently selected from C0-C6-alkylene-R 1a and C2-C6-alkylene-R 1b ; R 1a Independently selected from C3-C8 cycloalkyl, C5-C8 cycloalkenyl, 3- to 10-membered heterocyclic alkyl, and 5- to 10-membered heterocyclic alkenyl; wherein R 1a Optionally covered by C0-C6-alkylene-R 9a And / or 1 to 6 R 9 Group substitution; wherein when R 1a When the group is a heterocyclic alkyl or heterocyclic alkenyl group, the heterocyclic alkyl or heterocyclic alkenyl group is optionally fused with a benzene ring, wherein the benzene ring is optionally surrounded by 1 to 4 R groups. 10 Group substitution; R 1b Independently selected from NR 7a R 8a and OR 7 ; Where R 1 It contains at least one nitrogen atom; R 2a Each occurrence is independently selected from H and C1-C4 alkyl groups; R 2b Each occurrence is independently selected from H, C1-C4 alkyl, C1-C4-haloalkyl, C0-C4 alkyl-R. 2c C2-C4-alkylene-R 2d C(O)-C1-C4-alkyl, S(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl; R 2c Independently selected from C3-C8 cycloalkyl, C5-C8 cycloalkenyl, phenyl, 3-8-membered heterocycloalkyl, 5-8-membered heterocycloalkenyl, and 5- or 6-membered heteroaryl; wherein R 2c When it is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, R 2c Choose from 1 to 4 Rs 9 Group substitution; and when R 2c When it is phenyl or heteroaryl, R 2c Choose from 1 to 5 Rs 10 Group substitution; R 2d Independently selected from NR 7 R 8 and OR 7 ; R 3 Independently selected from H, cyano, C1-C4-alkylene-NR 7 R 8 NR 7 R 8 C1-C4-alkylene-OR 7 OR 7 SR 7 SOR 7 S(O)2R 7 S(O)2NR 7 R 7 CO2R 7 C(O)R 7 C(O)NR 7 R 7 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, NR 7 -C0-C4-alkylene-R 3c O-C0-C4-alkylene-R 3c and C0-C4-alkylene-R 3c ; R 3c Independently selected from C3-C8 cycloalkyl, C5-C8 cycloalkenyl, phenyl, 3-10-membered heterocycloalkyl, 5-10-membered heterocycloalkenyl, and 5- or 6-membered heteroaryl; wherein when R 3c When it is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, R 3c Choose from 1 to 4 Rs 9 Group substitution; and when R 3c When it is phenyl or heteroaryl, R 3c Choose from 1 to 5 Rs 10 Group substitution; R 4 Independently selected from H, halogen, cyano, NR 7b R 8 OR 7 SR 7 SOR 7 S(O)2R 7 S(O)2NR 7 R 7 、 CO2R 7 C(O)R 7 C(O)NR 7 R 7 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-ynyl, C1-C4-haloalkyl, O-C0-C4-alkylene-R 4c and C0-C4-alkylene-R 4c ; R 4c Independently selected from C3-C8 cycloalkyl, C5-C8 cycloalkenyl, 3-10-membered heterocycloalkyl, 5-10-membered heterocycloalkenyl and 5-membered heteroaryl; wherein when R 4c When it is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, R 4c Choose from 1 to 4 Rs 9 Group substitution; and when R 4c When it is a heteroaryl group, R 4c Choose from 1 to 5 Rs 10 Group substitution; R 5 Independently selected from H, halogen, cyano, C1-C4-alkylene-NR 7 R 8 NR 7 R 8 C1-C4-alkylene-OR 7 OR 7b SR 7 SOR 7 S(O)2R 7 S(O)2NR 7 R 7 CO2R 7 C(O)R 7 C(O)NR 7 R 7 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, NR 7 -C0-C4-alkylene-R 5c O-C0-C4-alkylene-R 5c and C0-C4-alkylene-R 5c ; R 5c Independently selected from C3-C8 cycloalkyl, C5-C8 cycloalkenyl, phenyl, 3-10-membered heterocycloalkyl, 5-10-membered heterocycloalkenyl, and 5- or 6-membered heteroaryl; wherein when R 5c When it is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, R 5c Choose from 1 to 4 Rs 9 Group substitution; and when R 5c When it is phenyl or heteroaryl, R 5c Choose from 1 to 5 Rs 10 Group substitution; Or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a ring selected from phenyl, C5-C7-cycloalkyl, 5-7-membered heterocycloalkyl, and 5- or 6-membered heteroaryl; wherein when the ring is cycloalkyl or heterocycloalkyl, it is optionally bounded by 1 to 6 R atoms. 9 Group substitution, where the ring is phenyl or heteroaryl, is optionally replaced by 1 to 4 R groups. 10 Group substitution; Or R 4 and R 5 Together with the carbon atoms to which they are attached, they form a ring selected from phenyl, C5-C7-cycloalkyl, 5-7-membered heterocycloalkyl, and 5- or 6-membered heteroaryl; wherein when the ring is cycloalkyl or heterocycloalkyl, it is optionally bounded by 1 to 6 R atoms. 9 Group substitution, where the ring is phenyl or heteroaryl, is optionally replaced by 1 to 4 R groups. 10 Group substitution; R 6 Independently selected from H, halogens, C1-C6-alkyl groups, and C1-C6-haloalkyl groups; R 7 and R 7a Each of the two groups is independently selected from H and C1-C4-alkyl groups in each occurrence; R 7b Each occurrence is independently selected from C1-C4 alkyl groups; R 8 Each occurrence is independently selected from H, C1-C4-alkyl, C1-C4-haloalkyl, and C(O)-C1-C4-alkyl. R 8a Each occurrence is independently selected from H, C1-C4 alkyl, C1-C4-haloalkyl, C(O)-C1-C4-alkyl, and optionally surrounded by 1 to 5 R. 10 Phenyl groups substituted with radicals; Or, R 7a and R 8a Together with the nitrogen atoms to which they are attached, they form 5- to 8-membered heterocyclic alkyl rings; which are optionally bounded by 1 to 4 R atoms. 9 Group substitution; R 9 Each time it appears, it is independently selected from =O, =S, halogen, nitro, cyano, and NR. 7 R 8 OR 7 SR 7 SOR 7 S(O)2R 7 SO2NR 7 R 7 、 CO2R 7 C(O)R 7 CONR 7 R 7 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C1-C3-alkylene-OR 7 and C1-C3-alkylene-NR 7 R 8 ; R 9a Each time it appears, it is independently selected from C3-C8 cycloalkyl, C5-C8 cycloalkenyl, phenyl, 3-8-membered heterocycloalkyl, 5-8-membered heterocycloalkenyl, and 5- or 6-membered heteroaryl; wherein when R 9a When it is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, R 9a Choose from 1 to 4 Rs 9 Group substitution; and when R 9a When it is phenyl or heteroaryl, R 9a Choose from 1 to 5 Rs 10 Group substitution; R 10 Each time it appears, it is independently selected from halogen, nitro, cyano, and NR. 7 R 8 OR 7 SR 7 SOR 7 S(O)2R 7 SO2NR 7 R 7 、 CO2R 7 C(O)R 7 CONR 7 R 7 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, C1-C3-alkylene-NR 7 R 8 and C1-C3-alkylene-OR 7 ;and Any of the aforementioned alkyl, alkylene, alkenyl, or cycloalkyl groups may optionally be substituted with 1 to 5 substituents, wherein each substituent is independently selected from the group consisting of: C1-C4-alkyl, oxo, halogen, nitro, cyano, NR. a R b OR a SR a CO2R a C(O)R a CONR a R a S(O)R a and S(O)2R a ;where R a Each time it appears, it is independently selected from H and C1-C4-alkyl; and R b Each time it appears, it is independently selected from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl.

2. The compound according to claim 1, wherein X is N.

3. The compound according to claim 1 or claim 2, wherein R 2a and R 2b Each is represented by H.

4. The compound according to any one of claims 1 to 3, wherein R 1 It contains at least one amine nitrogen.

5. The compound according to any one of claims 1 to 4, wherein R 1 It is C0-C6-alkylene-R 1a .

6. The compound according to claim 5, wherein R 1 It is R 1a .

7. The compound according to claim 5 or claim 6, wherein R 1a It is a 3- to 10-membered heterocyclic alkyl group having nitrogen in the ring system, wherein R 1a Optionally divided by 1 to 6 R 9 Group substitution.

8. The compound according to any one of claims 1 to 7, wherein R 3 It is H.

9. The compound according to any one of claims 1 to 7, wherein R 3 It is a C1-C4-alkyl group.

10. The compound according to any one of claims 1 to 9, wherein R 4 It is H.

11. The compound according to any one of claims 1 to 9, wherein R 4 It is a C1-C4-alkyl group.

12. The compound according to any one of claims 1 to 11, wherein R 5 It is R 5c .

13. The compound according to any one of claims 1 to 12, wherein R 5c It can be selected from 1 to 5 Rs. 10 A phenyl group substituted with a radical.

14. The compound according to any one of claims 1 to 12, wherein R 5c It can be selected from 1 to 5 Rs. 10 A 6-membered heteroaryl group substituted with a functional group.

15. The compound according to any one of claims 1 to 11, wherein R 5 It is H.

16. The compound according to any one of claims 1 to 11, wherein R 5 It is a C1-C4-alkyl group.

17. The compound according to any one of claims 1 to 9, wherein R 4 and R 5 Together with the carbon atoms to which they are attached, they form a C5-C7 cycloalkyl ring; optionally, said ring is surrounded by 1 to 6 R atoms. 9 Group substitution.

18. The compound according to claim 1, wherein the compound of formula (I) is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ¸ , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

19. A pharmaceutical composition comprising the compound of any one of claims 1 to 18 and one or more pharmaceutically acceptable excipients.

20. The compound according to any one of claims 1 to 18 or the pharmaceutical composition according to claim 19, used as a medicine.

21. The compound according to any one of claims 1 to 18 or the pharmaceutical composition according to claim 19, for the treatment of: musculoskeletal disorders, skin diseases, metabolic diseases, nervous system diseases, cardiovascular diseases, endocrine disorders, eye diseases, diseases affecting the genitourinary system, blood or lymphatic diseases, respiratory diseases, inflammatory or autoimmune diseases, gastrointestinal diseases, tumors, cancer, or selected from amelioration, dentition, tooth dysplasia, gill-oto-kidney syndrome, Sothos syndrome, and Waardenburg syndrome.

22. The compound according to any one of claims 1 to 18 or the pharmaceutical composition according to claim 19, for the treatment of diseases selected from: subclinical dystrophic epidermolysis bullosa, junctional epidermolysis bullosa, xeroderma pigmentosum, Natherton syndrome, Duchenne muscular dystrophy, Becker muscular dystrophy, cystic fibrosis, Dlavit syndrome, aniridia, methylmalonic acidemia, colorectal cancer, endometrial cancer, breast cancer, ovarian cancer, squamous cell carcinoma of the lung, squamous cell carcinoma of the head and neck, familial adenomatous polyposis, hemophilia A, hemophilia B, choroidal agenesis, pulmonary hypertension, ataxia-telangiectasia, Shwachman-Diamond syndrome, mucopolysaccharidosis type I, mucopolysaccharidosis type VI, mucopolysaccharidosis type III, Niemann-Pick disease, primary ciliary dyskinesia, Usher syndrome, and retinitis pigmentosa.

23. A method of using the compound of any one of claims 1 to 18 or the pharmaceutical composition of claim 19 for treating a condition or symptom associated with PTC mutation in a subject.

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