Pyrido[2,3-d]pyrimidin-4-amines as SOS1 inhibitors

Abstract

The present invention relates to a pyrido[2,3-d]pyrimidine-4-amine compound of general formula (I): wherein R 1 、R 2 、R 3 , A, x and y are as defined herein; methods for preparing the compounds; intermediate compounds used to prepare the compounds; pharmaceutical compositions and combinations comprising the compounds; and the use of the compounds as a single agent or in combination with other active ingredients for the preparation of pharmaceutical compositions for treating or preventing diseases, particularly hyperproliferative diseases.

Description

[0001] The present invention relates to pyrido[2,3-d]pyrimidin-4-amine compounds of the general formula (I) as described and defined herein; methods for preparing said compounds; intermediate compounds for preparing said compounds; pharmaceutical compositions and combinations comprising said compounds; and the use of said compounds as a single agent or in combination with other active ingredients for the preparation of pharmaceutical compositions for the treatment or prevention of diseases, in particular hyperproliferative diseases. Background Art

[0002] The present invention relates to pyrido[2,3-d]pyrimidin-4-amine compounds of general formula (I) that inhibit Ras-Sos1 interaction

[0003]

[0004] US 2011 / 0054173 A1 discloses certain 1- or 2-(4-(aryloxy)-phenyl)ethylamino-, oxy-, or sulfanyl)pteridines and 1- or 2-(4-(heteroaryloxy)-phenyl)ethylamino-, oxy-, or sulfanyl)pteridines and their use as agrochemicals and animal health products.

[0005] Compounds substituted at the 2-position of quinazoline are described, for example, in EP 0326328, EP 0326329, WO 93 / 007124, WO 2003 / 087098 and US 5,236,925. These compounds are either not described as pharmaceutically active compounds or, if they are described as pharmaceutically active compounds, they are described as compounds having affinity for the epidermal growth factor receptor (EGFR).

[0006] Skin toxicity is a specific class of side effects that occurs in the majority (45-100%) of patients receiving EGFR inhibitors and typically manifests as a papulopustular rash. Skin toxicity is associated with the inhibition of EGFR in the skin, which is essential for normal development and physiology of the epidermis.

[0007] However, the prior art does not record:

[0008] The pyrido- and pyrrolopyrimidine compounds of the general formula (I) of the present invention, ie compounds having a pyrido- and pyrrolopyrimidine core, as described and defined herein, can potently and selectively inhibit the Ras-Sos1 interaction.

[0009] Ras proteins play an important role in human cancer. Mutations in Ras proteins are present in 20-30% of all human tumors and are considered to be tumorigenic drivers, particularly in lung, colorectal, and pancreatic cancers (Malumbres & Barbacid 2002 Nature Reviews Cancer, Pylayeva-Gupta et al. 2011 Nature Reviews Cancer). Three human Ras genes are known to encode four different 21 kDa Ras proteins: H-Ras, N-Ras, and two splice variants of K-Ras, K-Ras 4A and K-Ras-4B. All Ras subtypes are highly conserved within the GTP binding domain and differ primarily in the hypervariable C-terminal region. The C-termini of different Ras subtypes are post-translationally modified by lipidation (farnesylation, palmitoylation) to promote membrane anchoring. The localization of Ras proteins on the plasma membrane places them in close proximity to transmembrane growth receptors and has been shown to be crucial for transmitting growth signals from extracellular growth factors that bind to downstream pathways within the cell. Depending on the cellular context, Ras proteins can be activated by a variety of upstream signals, such as the epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), and nerve growth factor receptor (NGFR). Activated Ras can signal through various downstream pathways, such as the Raf-MEK-ERK or PI3K-PDK1-Akt pathways.

[0010] At the molecular level, Ras proteins function as molecular switches. By binding to GTP and GDP, they exist in cells in two states: activated (GTP-bound) and inactivated (GDP-bound). Ras loaded with activated GTP recruits other proteins through binding to its cognate Ras binding domain (RBD), leading to the activation of effector proteins and, in turn, triggering downstream signaling events that promote diverse functions, such as cytoskeletal rearrangements or transcriptional activation. The activation state of Ras is tightly regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). GEFs act as activators of Ras by promoting the nucleotide exchange from GDP to GTP. GAPs inactivate Ras-GTP by catalyzing the hydrolysis of bound GTP to GDP. In cancer cells, point mutations within the GTP-binding region, typically at codon 12, abolish the ability of RAS to efficiently hydrolyze bound GTP, even in the presence of GAP. Consequently, cancer cells contain increased levels of activating mutant Ras-GTP, which is believed to be a key factor driving cancer cell proliferation.

[0011] To date, three major RAS-specific GEF families have been identified (reviewed in Vigil 2010 Nature Reviews Cancer; Rojas et al. 2011, Genes & Cancer 2 (3) 298-305). There are two classes of SOS (son of sevenless) proteins (SOS1 and SOS2), four different Ras guanine nucleotide releasing protein isoforms (Ras-GRP1-4) and two Ras guanine nucleotide releasing factors (Ras-GRF1 and 2). SOS proteins are ubiquitously expressed and recruited to sites of activated growth factors. Ras-GRFs are primarily expressed in the nervous system, where they participate in the calcium-dependent activation of Ras. In contrast, Ras GRP proteins are expressed in hematopoietic cells and act in concert with non-receptor tyrosine kinases. In the context of cancer, SOS proteins have been found to be primarily involved.

[0012] Since the 1990s, targeting Ras for cancer treatment has been a dream (Downward 2002 Nature Reviews Cancer, Krens et al. 2010 Drug Discovery Today). Due to its compact nature, high affinity for GDP and GTP combined with high intracellular GTP concentrations, the Ras protein itself has been considered undruggable, and the chance of identifying small chemical molecules that will bind and inhibit the activation of Ras has been rated as extremely low. Alternative methods have been taken to reduce Ras signaling, such as by looking for more promising drug targets, such as enzymes involved in post-translational modification of Ras proteins, especially farnesyltransferase and geranylgeranyltransferase (Berndt 2011 Nature Reviews Cancer). Inhibitors of farnesyltransferase (FTI) have been identified and developed in preclinical models, and they have promising anti-tumor effects. Surprisingly, in clinical trials, the efficacy of these inhibitors is limited. Targeting the upstream and downstream kinases involved in the Ras signaling pathway has been more successful. Several drugs are in and have been in clinical trials for inhibiting different kinases, such as EGFR, Raf, MEK, Akt, PI3K (Takashima & Faller 2013 Expert Opin. Ther. Targets). Commercially available anticancer drugs are available that inhibit Raf, EGFR or MEK.

[0013] However, there is still a significant unmet need for the treatment of Ras-dependent tumors that are resistant to current treatments. Many research groups have been actively identifying small molecules that directly target Ras (Ras small molecules have been reviewed in the following literature: Cox et al. 2014 Nature Reviews Drug Discovery, Spiegel et al. 2014 Nature Chemical Biology, Cromm 2015 Angewandte Chemie, Marin-Ramos et al. Cancer Biology Symposium). One group of inhibitors includes small molecules that inhibit the interaction of Ras with its effectors Raf or PI3K. Another group of compounds acts as covalent inhibitors of specific cysteine ​​mutant forms of K-Ras (glycine to cysteine ​​point mutation G12C). Specific targeting of the Ras-G12C mutant may have the benefit of reducing side effects, as wild-type Ras protein should not be affected. In addition, several reports have shown small molecules and peptides that interrupt GEF-assisted Ras activation (Hillig et al. 2019 PNAS; Gray et al. 2019 Angewandte Chemie). There appear to be several different binding sites that may lead to this mode of action. Inhibitors may bind to Ras in an allosteric or orthosteric manner or to GEFs. All of these approaches to directly target Ras are in preclinical development. Stabilized peptides have been shown to have activity in the nanomolar range (Leshchiner et al. 2015 PNAS). Their effectiveness as drugs in the clinical setting must be awaited.

[0014] The epidermal growth factor receptor (EGFR) is a tyrosine kinase (TK) receptor that is activated upon binding to epidermal growth factor and other growth factor ligands, triggering multiple downstream pathways, including RAS / MAPK, PI3K / Akt, and STAT, which regulate diverse cellular processes, including DNA synthesis and proliferation (Russo A, Oncotarget. 4254, 2015). The HER (ErbB) receptor tyrosine kinase family consists of four members: the epidermal growth factor receptor (EGFR) (HER1 or ErbB1), HER2 (ErbB2, neu), HER3 (ErbB3), and HER4 (ErbB4). Overexpression, mutation, or aberrant activity of these receptors has been linked to various types of cancer (Feldinger K, Breast Cancer (Dove Med Press), 2015, 7, 147).

[0015] First-generation inhibitors

[0016] Erlotinib and gefitinib are small molecule inhibitors of EGFR / HER-1 (human epidermal growth factor receptor) tyrosine kinase. Erlotinib and gefitinib were developed as reversible and highly specific small molecule tyrosine kinase inhibitors that competitively block the binding of ATP to the ATP binding site in the EGFR tyrosine kinase domain, thereby inhibiting autophosphorylation and blocking downstream signaling (Cataldo VD, N Engl J Med, 2011, 364, 947).

[0017] Second-generation inhibitors

[0018] Afatinib is an oral tyrosine kinase inhibitor (TKI) approved for the first-line treatment of patients with NSCLC whose tumors are driven by activating mutations in the gene encoding epidermal growth factor receptor (EGFR). Afatinib is also an inhibitor of a specific EGFR mutation (T790M) that causes resistance to first-generation EGFR-targeted TKIs in approximately half of patients who receive these drugs. (Engle JA, Am J Health Syst Pharm 2014, 71(22), 1933).

[0019] Neratinib, a pan-HER inhibitor and irreversible tyrosine kinase inhibitor, binds to and inhibits the tyrosine kinase activity of epidermal growth factor receptors EGFR (or HER1), HER2, and HER4, which leads to reduced phosphorylation and activation of downstream signaling pathways. Neratinib has been shown to be effective in vitro and in vivo against HER2-overexpressing or mutated tumors. Neratinib is currently being studied in various clinical trials for breast cancer and other solid tumors, including those with HER2 mutations (Feldinger K, Breast Cancer (Dove Med Press), 2015, 7, 147).

[0020] Dacomitinib is an irreversible inhibitor of EGFR, HER2, and HER4. In preclinical cell line and xenograft studies, dacomitinib has shown inhibitory effects on both activating EGFR mutations and EGFR T790M (Liao BC, Curr Opin Oncol. 2015, 27(2), 94).

[0021] Third-generation inhibitors

[0022] The third-generation EGFR-TKIs are designed to inhibit EGFR T790M while sparing wild-type EGFR.

[0023] AZD9291 (AstraZeneca, Macclesfield, UK)—a monoanilinopyrimidine compound—is an irreversible, mutation-selective EGFR-TKI. This drug is structurally distinct from first- and second-generation EGFR-TKIs. In preclinical studies, it potently inhibited EGFR phosphorylation in cell lines harboring activating EGFR mutations (EGFR del19 and EGFR L858R) and EGFR T790M. AZD9291 also caused profound and sustained tumor regression in tumor xenografts and transgenic mouse models harboring activating EGFR mutations and EGFR T790M. AZD9291 was less potent in inhibiting phosphorylation in wild-type EGFR cell lines (Liao BC, Curr Opin Oncol. 2015, 27(2), 94).

[0024] Rociletinib (CO-1686) (Clovis Oncology, Boulder, Colo.)—a 2,4-disubstituted pyrimidine molecule—is an irreversible, mutation-selective EGFR-TKI. In preclinical studies, CO-1686 resulted in tumor regression in cell lines, xenograft models, and transgenic mouse models harboring activating EGFR mutations and EGFR T790M (Walter AO, Cancer Discov, 2013, 3(12), 1404).

[0025] HM61713 (Hanmi Pharmaceutical Company Ltd, Seoul, South Korea) is an orally administered selective inhibitor of activating EGFR mutations and EGFR T790M. It has low activity against wild-type EGFR (Steuer CE, Cancer. 2015, 121(8), E1).

[0026] Hillig et al. 2019 PNAS described the following compounds,

[0027]

[0028] It acts as a potent SOS1 inhibitor and serves as a tool compound for further investigation of RAS-SOS1 biology in vitro.

[0029] FR 3 066 761 (Universite d'Orleans et al.) describes the following compounds,

[0030]

[0031] It is used to treat cancer.

[0032] WO 2018 / 134685 (Eisai Management Co. Ltd. et al.) describes the following compound,

[0033]

[0034] It is used to treat and prevent filarial infections.

[0035] WO 2018 / 172250 (Bayer Pharma AG) describes the following 2-methyl-quinazoline,

[0036]

[0037] It inhibits Ras-Sos interaction.

[0038] WO 2018 / 115380 (Boehringer Ingelheim) describes the following benzylamino-substituted quinazolines,

[0039]

[0040] It acts as an SOS1 inhibitor.

[0041] WO 2019 / 122129 (Boehringer Ingelheim) describes the following benzylamino-substituted pyridopyrimidone,

[0042]

[0043] It acts as an SOS1 inhibitor.

[0044] WO 2020 / 180768 and WO 2020 / 180770 (Revolution) describe compounds of the following formula:

[0045]

[0046] It acts as an SOS1 inhibitor.

[0047] It has now been found, and this forms the basis of the present invention, that the compounds of the present invention have unexpected and advantageous properties.

[0048] In particular, it has been unexpectedly found that the compounds of the present invention potently and selectively inhibit the Ras-Sos1 interaction and are therefore useful in the treatment or prevention of hyperproliferative diseases, in particular cancer. Summary of the Invention

[0049] According to a first aspect, the present invention relates to a compound of general formula (I), or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof:

[0050]

[0051] in

[0052] A is selected from

[0053] phenyl, naphthyl, heteroaryl, and 9-10 membered bicyclic heterocyclyl;

[0054] R 1 Selected from

[0055] -H; or

[0056] -LM, where

[0057] L is selected from

[0058] single bond;

[0059] -C(R a )(R b )-;

[0060] -C(=O)-;

[0061] -S(=O)2-;

[0062] -C(=O)-NR a -;or

[0063] -S(=O)2-NR a -;and

[0064] R a and R b Can be independently

[0065] -H;

[0066] C optionally substituted by halogen or -OH 1-6 -alkyl;

[0067] C optionally substituted by halogen or -OH 3-8 -cycloalkyl; or R a and R b Together with the carbon atoms to which they are attached, they form C 3-8 - cycloalkyl or 4- to 6-membered heterocycloalkyl; and

[0068] M is selected from

[0069] C 1-6 -alkyl; C 2-6 -alkenyl; C 2-6 -alkynyl; C 1-6-alkoxy; C 3-8 -cycloalkyl; 4-6 membered heterocycloalkyl; phenyl; heteroaryl, wherein the C 1-6 -alkyl; C 2-6 -alkenyl; C 2-6 -alkynyl; C 1-6 -alkoxy; C 3-8 -cycloalkyl; 4-6 membered heterocycloalkyl; phenyl and heteroaryl are optionally substituted by one or more identical or different R selected from the following m replace:

[0070] -OH, halogen, -CN; -C 1-6 -alkyl; -C 3-6 -cycloalkyl; -NR n R n ;

[0071] -NR n -C(=O)-R n ;-NR n -S(=O)2-R n 、-OC 1-6 -alkyl;

[0072] -SR n ;-S(O)-R n 、-S(O)2-R n or a divalent oxo substituent, wherein the oxo substituent may be a substituent only in a non-aromatic ring, and wherein

[0073] Each R n are the same or different and are independently selected from C 1-6 -alkyl or C 3-8 -cycloalkyl;

[0074] C substituted by a 3- to 10-membered heterocyclic group 1-6 -haloalkyl;

[0075] Hydroxyl, halogen, -NH2, -SO2-C 1-6 - a 3- to 10-membered heterocyclic group substituted with an alkyl group and a divalent oxo substituent, wherein the oxo substituent may be the only substituent in a non-aromatic ring;

[0076] y is selected from 1 or 2;

[0077] R 2 Each independently selected from

[0078] C 1-6 -alkyl;

[0079] C 1-6 -haloalkyl;

[0080] C 2-6-alkenyl;

[0081] C 2-6 -alkynyl;

[0082] C 3-8 -cycloalkyl;

[0083] C 4-8 -cycloalkenyl;

[0084] 3-10 membered heterocyclic group;

[0085] Phenyl and

[0086] heteroaryl;

[0087] wherein the C 1-6 -alkyl, C 1-6 -haloalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl, C 4-8 -cycloalkenyl, 3-10 membered heterocyclyl, phenyl and heteroaryl are optionally substituted by one or more identical or different R c and / or R d replace;

[0088] Each R c independently selected from halogen, -CN, -C(=O)R d 、-C(=O)OR d 、-C(O)NR d R d 、-NR d R d 、-OR d 、-S(=O)2-R d 、-S(=O)2-NR d R d 、-NH-C(=O)-R d 、-N(CH3)-C(=O)-R d 、-N(C 1-6 -alkyl)C(=O)-R d 、-NH-C(=O)OR d 、-N(CH3)-C(=O)OR d 、-N(C 1-6 -alkyl)-C(═O)OR d and -NR d -S(=O)2-R d ;and

[0089] Each R d are independently selected from hydrogen, C 1-6 -alkyl, C 1-6-haloalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl, C 4-8 -cycloalkenyl, 3-10 membered heterocyclyl, phenyl and heteroaryl, wherein the C 1-6 -alkyl, C 1-6 -haloalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl, C 4-8 -cycloalkenyl, 3-10 membered heterocyclyl, phenyl and heteroaryl are optionally substituted by one or more identical or different R e and / or R f replace;

[0090] Each R e independently selected from halogen, -CN, -C(=O)-R f 、-C(=O)OR f 、-C(=O)-NR f R f 、-NR f R f 、-OR f 、-S(=O)2-R f 、-S(=O)2NR f R f 、-NHC(=O)R f 、-N(C 1-4 alkyl)C(=O)R f 、-NHC(=O)OR f and -N(C 1-4 alkyl)C(=O)OR f ; and each of R f are independently selected from hydrogen, C 1-6 -alkyl, C 1-6 -haloalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl, C 4-8 - cycloalkenyl, 3-10 membered heterocyclyl, phenyl and heteroaryl;

[0091] x is selected from 1 or 2

[0092] R 3 Selected from

[0093] -H or -CH3.

[0094] definition

[0095] The term "substituted" means that one or more hydrogen atoms on the designated atom or group is replaced with a selected one of the designated groups, provided that the normal valency of the designated atom in the existing situation is not exceeded. Combinations of substituents and / or variables are permissible.

[0096] The term "optionally substituted" means that the number of substituents may be equal to or different from zero. Unless otherwise indicated, an optionally substituted group may be substituted with as many optional substituents as possible by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon, nitrogen, or oxygen atom. Typically, the number of optional substituents, when present, may be 1, 2, 3, 4, or 5, particularly 1, 2, or 3.

[0097] As used herein, the term "one or more", for example in the definition of substituents of the compounds of general formula (I) of the present invention, means "1, 2, 3, 4 or 5, in particular 1, 2, 3 or 4, more in particular 1, 2 or 3, even more in particular 1 or 2".

[0098] When a group in the compounds of the invention is substituted, unless otherwise indicated, the group may be mono- or polysubstituted by a substituent. Within the scope of the present invention, the meanings of all groups that appear repeatedly are independent of one another. A group in the compounds of the invention may be substituted by one, two or three identical or different substituents, in particular by one substituent.

[0099] As used herein, an oxo substituent represents an oxygen atom bonded to a carbon atom or a sulfur atom via a double bond.

[0100] The term "ring substituent" refers to a substituent attached to an aromatic or non-aromatic ring which replaces an available hydrogen atom on the ring.

[0101] If a composite substituent consists of more than one part, for example (C1-C4-alkoxy)-(C1-C4-alkyl)-, the position of a given part may be at any suitable position of the composite substituent, i.e. the C1-C4-alkoxy part may be attached to any carbon atom of the C1-C4-alkyl part of the (C1-C4-alkoxy)-(C1-C4-alkyl)- group. A hyphen at the beginning or end of such a composite substituent indicates the point of attachment of the composite substituent to the rest of the molecule. If a ring comprising carbon atoms and optionally one or more heteroatoms (e.g. nitrogen, oxygen or sulphur atoms) is substituted by a substituent, the substituent may be attached to any suitable position of the ring, whether to a suitable carbon atom and / or a suitable heteroatom.

[0102] When used in the specification, the term "comprising" includes "consisting of".

[0103] If any item is referred to herein as "as referred to herein", it is meant to be referred to anywhere in the document.

[0104] As used herein, the terms have the following meanings:

[0105] The term "halogen atom" or "halogen" refers to a fluorine, chlorine, bromine or iodine atom, in particular a fluorine, chlorine or bromine atom.

[0106] The term "C1-C6-alkyl" refers to a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms, for example: methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 1,2-dimethylbutyl or 1,3-dimethylbutyl, or an isomer thereof. In particular, the radical has 1, 2, 3 or 4 carbon atoms ("C1-C4-alkyl"), for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl or tert-butyl, more particularly 1, 2 or 3 carbon atoms ("C1-C3-alkyl"), for example methyl, ethyl, n-propyl or isopropyl.

[0107] The term "C1-C6-hydroxyalkyl" refers to a linear or branched saturated monovalent hydrocarbon group, wherein the term "C1-C6-alkyl" is as defined above and wherein 1, 2 or 3 hydrogen atoms are replaced by hydroxy groups, such as: hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 1-hydroxyprop-2-yl, 2-hydroxyprop-2-yl, 2,3-dihydroxypropyl, 1,3-dihydroxyprop-2-yl, 3-hydroxy-2-methylpropyl, 2-hydroxy-2-methylpropyl, 1-hydroxy-2-methylpropyl.

[0108] The term "C1-C6-alkylsulfanyl" refers to a linear or branched saturated monovalent group of the formula (C1-C6-alkyl)-S-, wherein the term "C1-C6-alkyl" is as defined above, and the C1-C6-alkylsulfanyl group is exemplified by methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, sec-butylsulfanyl, isobutylsulfanyl, tert-butylsulfanyl, pentylsulfanyl, isopentylsulfanyl, and hexylsulfanyl.

[0109] The term "C1-C6-haloalkyl" refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the term "C1-C6-alkyl" is as defined above and wherein one or more hydrogen atoms are identically or differently substituted by a halogen atom. In particular, the halogen atom is a fluorine atom. The C1-C6-haloalkyl group is, for example, a fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or 1,3-difluoroprop-2-yl.

[0110] The term "C1-C6-alkoxy" refers to a straight-chain or branched saturated monovalent group of the formula (C1-C6-alkyl)-O-, wherein the term "C1-C6-alkyl" is as defined above, and the C1-C6-alkoxy group is, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentoxy, isopentoxy or n-hexoxy, or an isomer thereof.

[0111] The term "C1-C6-haloalkoxy" refers to a linear or branched saturated monovalent C1-C6-alkoxy group as defined above, in which one or more hydrogen atoms are replaced identically or differently by halogen atoms. In particular, the halogen atoms are fluorine atoms. The C1-C6-haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy.

[0112] The term "C2-C6-alkenyl" refers to a straight-chain or branched monovalent hydrocarbon radical containing one or two double bonds and having 2, 3, 4, 5 or 6 carbon atoms, in particular 2 or 3 carbon atoms ("C2-C3-alkenyl"), it being understood that in case the alkenyl group contains more than one double bond, the double bonds may be separated or conjugated to one another. The alkenyl group is, for example, ethenyl (or "vinyl"), prop-2-en-1-yl (or "allyl"), prop-1-en-1-yl, but-3-enyl, but-2-enyl, but-1-enyl, pent-4-enyl, pent-3-enyl, pent-2-enyl, pent-1-enyl, hex-5-enyl, hex-4-enyl, hex-3-enyl, hex-2-enyl, hex-1-enyl, prop-1-en-2-yl (or "isopropenyl"), 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methyl Prop-1-enyl, 1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, 2-methylbut-2-enyl, 1-methylbut-2-enyl, 3-methylbut-1-enyl, 2-methylbut-1-enyl, 1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl, 4-methylpent-4-enyl, 3-methylpent-4-enyl, 2-methylpent-4-enyl, 1-methyl Pent-4-enyl, 4-methylpent-3-enyl, 3-methylpent-3-enyl, 2-methylpent-3-enyl, 1-methylpent-3-enyl, 4-methylpent-2-enyl, 3-methylpent-2-enyl, 2-methylpent-2-enyl, 1-methylpent-2-enyl, 4-methylpent-1-enyl, 3-methylpent-1-enyl, 2-methylpent-1-enyl, 1-methylpent-1-enyl, 3-ethylbut-3-enyl, 2-ethylbut-3-enyl, 1-ethylbut-3-enyl, 3-ethylbut-2-enyl, 2-ethylbut-2-enyl, 1 The group is 1-ethylbut-2-enyl, 3-ethylbut-1-enyl, 2-ethylbut-1-enyl, 1-ethylbut-1-enyl, 2-propylprop-2-enyl, 1-propylprop-2-enyl, 2-isopropylprop-2-enyl, 1-isopropylprop-2-enyl, 2-propylprop-1-enyl, 1-propylprop-1-enyl, 2-isopropylprop-1-enyl, 1-isopropylprop-1-enyl, 3,3-dimethylprop-1-enyl, 1-(1,1-dimethylethyl)vinyl, buta-1,3-dienyl, penta-1,4-dienyl or hexa-1,5-dienyl. Specifically, the group is vinyl or allyl.

[0113] The term "C2-C6-alkynyl" refers to a straight-chain or branched monovalent hydrocarbon radical containing one triple bond and comprising 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C2-C3-alkynyl"). The C2-C6-ynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl (or "propargyl"), but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl. , 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethylbut-1-ynyl. Specifically, the alkynyl is ethynyl, prop-1-ynyl or prop-2-ynyl.

[0114] The term "C3-C8-cycloalkyl" refers to a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 3, 4, 5, 6, 7 or 8 carbon atoms ("C3-C8-cycloalkyl"). The C3-C8-cycloalkyl group is, for example, a monocyclic hydrocarbon ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, or a bicyclic hydrocarbon ring, such as bicyclo[4.2.0]octyl or octahydropentenyl.

[0115] The term "C4-C8-cycloalkenyl" refers to a monovalent monocyclic or bicyclic hydrocarbon ring containing 4, 5, 6, 7 or 8 carbon atoms and one double bond. In particular, the ring contains 4, 5 or 6 carbon atoms ("C4-C6-cycloalkenyl"). The C4-C8-cycloalkenyl is, for example, a monocyclic hydrocarbon ring, such as cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl, or a bicyclic hydrocarbon ring, such as bicyclo[2.2.1]hept-2-enyl or bicyclo[2.2.2]oct-2-enyl.

[0116] The term "C3-C8-cycloalkoxy" refers to a saturated monovalent monocyclic or bicyclic group of the formula (C3-C8-cycloalkyl)-O-, which contains 3, 4, 5, 6, 7 or 8 carbon atoms, wherein the term "C3-C8-cycloalkyl" is as defined above, and the C3-C8-cycloalkoxy group is, for example, a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy or cyclooctyloxy group.

[0117] The term "spiroalkyl" refers to a saturated monovalent bicyclic hydrocarbon radical wherein the two rings share a common ring carbon atom, and wherein the bicyclic hydrocarbon radical contains 5, 6, 7, 8, 9, 10 or 11 carbon atoms, and the spiroalkyl radical may be attached to the remainder of the molecule via any one carbon atom other than the spiral carbon atom. The spiroalkyl radical is, for example, a spiral [2.2] pentyl, a spiral [2.3] hexyl, a spiral [2.4] heptyl, a spiral [2.5] octyl, a spiral [2.6] nonyl, a spiral [3.3] heptyl, a spiral [3.4] octyl, a spiral [3.5] nonyl, a spiral [3.6] decyl, a spiral [4.4] nonyl, a spiral [4.5] decyl, a spiral [4.6] undecyl or a spiral [5.5] undecyl.

[0118] The terms "4- to 7-membered heterocycloalkyl" and "4- to 6-membered heterocycloalkyl" refer to monocyclic saturated heterocycles having a total of 4, 5, 6 or 7, or 4, 5 or 6 ring atoms, respectively, containing one or two identical or different ring heteroatoms from the series N, O and S, said heterocycloalkyl being attached to the rest of the molecule via any one carbon atom or nitrogen atom (if present).

[0119] The heterocycloalkyl group (but not limited thereto) can be a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl; or a 5-membered ring, such as tetrahydrofuranyl, 1,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-dioxythiolanyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl or 1,3-thiazolidinyl; or a 6-membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithiophenyl, thiomorpholinyl, piperazinyl, 1,3-dioxanyl, 1,4-dioxanyl or 1,2-oxazinyl; or a 7-membered ring, such as azepanyl, 1,4-diazepanyl or 1,4-oxepanyl.

[0120] In particular, “4- to 6-membered heterocycloalkyl” refers to a 4- to 6-membered heterocycloalkyl as defined above, which contains one ring nitrogen atom and optionally one further ring heteroatom from the following series: N, O, S. More particularly, “5- or 6-membered heterocycloalkyl” refers to a monocyclic saturated heterocycle having a total of 5 or 6 ring atoms, which contains one ring nitrogen atom and optionally one further ring heteroatom from the following series: N, O.

[0121] The term "5- to 8-membered heterocycloalkenyl" refers to a monocyclic, unsaturated, non-aromatic heterocycle having a total of 5, 6, 7 or 8 ring atoms, which contains one or two double bonds and one or two identical or different ring heteroatoms from the following series: N, O, S; said heterocycloalkenyl group may be attached to the rest of the molecule through any one carbon atom or nitrogen atom (if present).

[0122] The heterocycloalkenyl group is, for example, 4H-pyranyl, 2H-pyranyl, 2,5-dihydro-1H-pyrrolyl, [1,3]dioxolanyl, 4H-[1,3,4]thiadiazinyl, 2,5-dihydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrothienyl, 2,3-dihydrothienyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl.

[0123] The term "heterospirocycloalkyl" refers to a bicyclic saturated heterocycle having a total of 6, 7, 8, 9, 10 or 11 ring atoms, wherein the two rings share a common ring carbon atom, wherein the "heterospirocycloalkyl" contains one or two identical or different ring heteroatoms from the following series: N, O, S; the heterospirocycloalkyl may be attached to the remainder of the molecule via any one carbon atom other than the spiro carbon atom or via the nitrogen atom (if present).

[0124] The heterospirocycloalkyl group is, for example, azaspiro[2.3]hexyl, azaspiro[3.3]heptyl, oxazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl, oxazaspiro[3.3]heptyl, oxazaspiro[3.3]heptyl, oxazaspiro[5.3]nonyl, oxazaspiro[4.3]octyl, azaspiro[4,5]decyl, oxazaspiro[5.5]undecyl, diazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl, thiazaspiro[4.3]octyl, azaspiro[5.5]undecyl or one of the other homologous skeletons, for example, spiro[3.4]-, spiro[4.4]-, spiro[2.4]-, spiro[2.5]-, spiro[2.6]-, spiro[3.5]-, spiro[3.6]-, spiro[4.5]- and spiro[4.6]-.

[0125] The term "fused heterocycloalkyl" refers to a bicyclic saturated heterocycle having a total of 6, 7, 8, 9 or 10 ring atoms, wherein the two rings share two adjacent ring atoms, wherein the "fused heterocycloalkyl" contains one or two identical or different ring heteroatoms from the following series: N, O, S; said fused heterocycloalkyl may be attached to the rest of the molecule via any one carbon atom or nitrogen atom (if present).

[0126] The fused heterocycloalkyl group is, for example, azabicyclo[3.3.0]octyl, azabicyclo[4.3.0]nonyl, diazabicyclo[4.3.0]nonyl, oxazabicyclo[4.3.0]nonyl, thiazabicyclo[4.3.0]nonyl or azabicyclo[4.4.0]decyl.

[0127] The term "bridged heterocycloalkyl" refers to a bicyclic saturated heterocycle having a total of 7, 8, 9 or 10 ring atoms, wherein the two rings share two non-adjacent common ring atoms, wherein the "bridged heterocycloalkyl" comprises one or two identical or different ring heteroatoms from the following series: N, O, S; said bridged heterocycloalkyl may be attached to the rest of the molecule via any one carbon atom other than the spiro carbon atom or the nitrogen atom (if present).

[0128] The bridged heterocycloalkyl group is, for example, azabicyclo[2.2.1]heptyl, oxazabicyclo[2.2.1]heptyl, thiazabicyclo[2.2.1]heptyl, diazabicyclo[2.2.1]heptyl, azabicyclo[2.2.2]octyl, diazabicyclo[2.2.2]octyl, oxazabicyclo[2.2.2]octyl, thiazabicyclo[2.2.2]octyl, azabicyclo[3.2.1]octyl, diazabicyclo[3.2.1]octyl, oxazabicyclo[3.2.1]octyl, thiazabicyclo[3.2.1]octyl, a ... heterobicyclo[3.3.1]nonyl, diazabicyclo[3.3.1]nonyl, oxazabicyclo[3.3.1]nonyl, thiazabicyclo[3.3.1]nonyl, azabicyclo[4.2.1]nonyl, diazabicyclo[4.2.1]nonyl, oxazabicyclo[4.2.1]nonyl, thiazabicyclo[4.2.1]nonyl, azabicyclo[3.3.2]decyl, diazabicyclo[3.3.2]decyl, oxazabicyclo[3.3.2]decyl, thiazabicyclo[3.3.2]decyl or azabicyclo[4.2.2]decyl.

[0129] The term "heteroaryl" refers to a monovalent, mono-, bi- or tricyclic aromatic ring having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5, 6, 9 or 10 ring atoms ("5- to 14-membered heteroaryl"), which contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms from the following series: N, O and / or S, and which is bonded via a ring carbon atom or, if valence permits, via a ring nitrogen atom.

[0130] The heteroaryl group may be a 5-membered heteroaryl group, for example, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group, for example, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl; or a tricyclic heteroaryl group, for example, carbazolyl, acridinyl or phenazinyl; or a 9-membered heteroaryl group, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, indolizinyl or purinyl; or a 10-membered heteroaryl group, for example, quinolinyl, quinazolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinoxalinyl or pteridinyl.

[0131] In general, unless otherwise indicated, a heteroaryl or heteroarylene group includes all possible isomeric forms thereof, for example, tautomers and positional isomers with respect to the point of attachment to the rest of the molecule. Thus, for some illustrative, non-limiting examples, the term pyridyl includes pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.

[0132] The terms "C1-C6", "C 1-6 ”, for example in the context of the definitions of “C1-C6-alkyl”, “C1-C6-haloalkyl”, “C1-C6-hydroxyalkyl”, “C1-C6-alkoxy” or “C1-C6-haloalkoxy” refers to an alkyl group having a limited number of 1 to 6 carbon atoms, i.e. 1, 2, 3, 4, 5 or 6 carbon atoms.

[0133] Furthermore, as used herein, the term "C3-C8" or "C 3-8 ”, for example in the context of the definition of “C3-C8-cycloalkyl”, which refers to a cycloalkyl group having a limited number of 3 to 8 carbon atoms (i.e. 3, 4, 5, 6, 7 or 8 carbon atoms).

[0134] When a range of values ​​is given, that range includes every value and sub-range within that range.

[0135] For example:

[0136] "C1-C6" includes C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5 and C5-C6;

[0137] "C2-C6" includes C2, C3, C4, C5, C6, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6;

[0138] "C3-C 10 " includes C3, C4, C5, C6, C7, C8, C9, C 10 , C3-C 10 , C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4, C4-C 10 , C4-C9, C4-C8, C4-C7, C4-C6, C4-C5, C5-C 10 , C5-C9, C5-C8, C5-C7, C5-C6, C6-C 10 , C6-C9, C6-C8, C6-C7, C7-C 10 , C7-C9, C7-C8, C8-C 10 , C8-C9, and C9-C 10 ;

[0139] "C3-C8" includes C3, C4, C5, C6, C7, C8, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4, C4-C8, C4-C7, C4-C6, C4-C5, C5-C8, C5-C7, C5-C6, C6-C8, C6-C7, and C7-C8;

[0140] "C3-C6" includes C3, C4, C5, C6, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6;

[0141] "C4-C8" includes C4, C5, C6, C7, C8, C4-C8, C4-C7, C4-C6, C4-C5, C5-C8, C5-C7, C5-C6, C6-C8, C6-C7, and C7-C8;

[0142] "C4-C7" includes C4, C5, C6, C7, C4-C7, C4-C6, C4-C5, C5-C7, C5-C6, and C6-C7;

[0143] "C4-C6" includes C4, C5, C6, C4-C6, C4-C5, and C5-C6;

[0144] "C5-C 10 " includes C5, C6, C7, C8, C9, C 10 , C5-C 10,C5-C9,C5-C8,C5-C7,C5-C6,C6-C 10 ,C6-C9,C6-C8,C6-C7,C7-C 10 、C7-C9、C7-C8、C8-C 10 , C8-C9 and C9-C 10 ;

[0145] “C6-C 10 "Including C6, C7, C8, C9, C 10 、C6-C 10 ,C6-C9,C6-C8,C6-C7,C7-C 10 、C7-C9、C7-C8、C8-C 10 , C8-C9 and C9-C 10 .

[0146] As used herein, the term "leaving group" refers to an atom or group of atoms that is substituted as a stable species in a chemical reaction, which carries bonding electrons. In particular, such leaving groups are selected from the group consisting of: halides, in particular fluorides, chlorides, bromides or iodides, (methylsulfonyl)oxy, [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl)sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy.

[0147] "Heterocyclyl" refers to a ring system which is separated by the groups -O-, -S-, -NH-, -N(C 1-4 -alkyl)-substituted hydrocarbon rings in one or more independent groups -CH2- or by replacing one or more groups =CH- with a group =N- and derived from previously defined cycloalkyl, cycloalkenyl and aryl, wherein a total of no more than five heteroatoms may be present, at least one carbon atom must be present between two oxygen atoms and between two sulfur atoms or between oxygen and sulfur atoms, and the ring as a whole must be chemically stable. Heteroatoms may optionally be present in all possible oxidation stages (sulfur → sulfoxide -SO-, sulfone -SO2-; nitrogen → N-oxide). There is no heteroaromatic ring in the heterocyclic group, i.e. no heteroatom is part of the aromatic system. Examples of heterocyclic groups are mentioned in WO 2019 / 122129, page 43, line 25 to page 47, line 5.

[0148] The heterocycle can be tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, thiazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, oxiranyl, aziridinyl, azetidinyl, 1,4-dioxanyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl 1,3-dioxolanyl, tetrahydropyranyl, tetrahydrothiopyranyl, [1,4]-oxazepanyl, tetrahydrothiophenyl, homothiomorpholinyl-S,S-dioxide, oxazolidinone, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuranyl, dihydropyranyl, tetrahydrothiophenyl-S-oxide, tetrahydrothiophenyl-S,S-dioxide compounds, homothiomorpholinyl-S-oxide, 2,3-dihydroazetyl, 2H-pyrrolyl, 4H-pyranyl, 1,4-dihydropyridyl, 8-azabicyclo[3.2.1]octyl, 8-azabicyclo[5.1.0]octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.1]heptyl, 1-azabicyclo[2. [3.2.1]octyl, 3,9-diazabicyclo[4.2.1]nonyl, 2,6-diazabicyclo[3.2.2]nonyl, 1,4-dioxaspiro[4.5]decyl, 1-oxa-3,8-diazaspiro[4.5]decyl, 2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[4.4]nonyl, 2,6-diazaspiro[3.4]octyl, 3,9-diazaspiro[5.5]undecyl, 2,8-diazaspiro[4,5]decyl, etc.

[0149] In the context of the present invention, an "oxo substituent" refers to an oxygen atom bonded to a carbon or sulfur atom via a double bond. Two oxo substituents may be bonded to a sulfur atom.

[0150] The compounds of general formula (I) may exist as isotopic variations. Therefore, the present invention includes one or more isotopic variations of the compounds of general formula (I), in particular deuterated compounds of general formula (I).

[0151] The term "isotopic variant" of a compound or agent is defined as a compound that exhibits an unnatural ratio of one or more isotopes that constitute the compound.

[0152] The term "isotopic variation of a compound of formula (I)" is defined as a compound of formula (I) that exhibits an unnatural ratio of one or more isotopes constituting the compound.

[0153] The expression "unnatural ratio" means that the ratio of this isotope is higher than its natural abundance. The natural abundance of the isotopes used in this article is described in "Isotopic Compositions of the Elements 1997", Pure Appl. Chem., 70(1), 217-235, 1998.

[0154] Examples of such isotopes include the following stable and radioactive isotopes: hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, for example 2 H (deuterium), 3 H (tritium), 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 32 P. 33 P. 33 S. 34 S. 35 S. 36 S. 18 F. 36 Cl, 82 Br, 123 I. 124 I. 125 I. 129 I and 131 I.

[0155] For the treatment and / or prevention of the diseases specified herein, isotopic variations of the compounds of formula (I) preferably contain deuterium ("deuterated compounds of formula (I)"). Isotopic variations of the compounds of formula (I) (in which one or more radioactive isotopes are incorporated, e.g. 3 H or 14 C) can be used, for example, in drug and / or substrate tissue distribution studies. These isotopes are particularly preferred because they are easy to incorporate and easy to detect. Positron emitting isotopes such as 18 F or 11 C can be incorporated into the compounds of formula (I). These isotopic variants of the compounds of formula (I) can be used for in vivo imaging applications. 13 Compound C can be used for mass spectrometry analysis in preclinical or clinical research settings.

[0156] Isotopic variants of compounds of formula (I) can generally be prepared by methods known to those skilled in the art, such as those described in the schemes and / or examples herein, by replacing a reagent with an isotopic variant of the reagent, preferably a deuterated reagent. Depending on the desired deuteration site, in some cases, deuterium from D2O can be incorporated directly into the compound or into a reagent that can be used to synthesize such compounds. Deuterium gas is also a useful reagent for incorporating deuterium into molecules. Catalytic deuteration of olefinic and acetylenic bonds is a rapid way to incorporate deuterium. Metal catalysts (i.e., Pd, Pt, and Rh) in the presence of deuterium gas can be used to directly exchange hydrogen in hydrocarbon-containing functional groups with deuterium. Various deuterated reagents and synthetic building blocks are commercially available from the following companies, such as C / D / N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA.

[0157] The term "deuterium-containing compound of formula (I)" is defined as a compound of formula (I) in which one or more hydrogen atoms are replaced by one or more deuterium atoms, and wherein the deuterium abundance of each deuterated position of the compound of formula (I) is higher than the natural abundance of deuterium, which is about 0.015%. In particular, in the deuterium-containing compound of formula (I), the deuterium abundance of each deuterated position of the compound of formula (I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% at said position, preferably higher than 90%, 95%, 96% or 97%, even more preferably higher than 98% or 99%. It should be understood that the deuterium abundance of each deuterated position is independent of the deuterium abundance of other deuterated positions.

[0158] The selective incorporation of one or more deuterium atoms into the compounds of general formula (I) may alter the physicochemical properties (e.g. acidity [CL Perrin et al., J. Am. Chem. Soc., 2007, 129, 4490], basicity [CL Perrin et al., J. Am. Chem. Soc., 2005, 127, 9641], lipophilicity [B. Testa et al., Int. J. Pharm., 1984, 19 (3), 271]) and / or the metabolic profile of the molecule and may result in a change in the ratio of parent compound to metabolite or in the amount of metabolite formed. Such a change may confer certain therapeutic advantages and may therefore be preferred in certain circumstances. It has been reported that in the case of a change in the ratio of metabolites, the rate of metabolism and metabolic conversion is reduced (AEMutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). Exposure to these changes in the parent drug and metabolites may have an important impact on the pharmacodynamics, tolerability and efficacy of the deuterated compounds of general formula (I). In some cases, deuterium substitution reduces or eliminates the formation of undesirable or toxic metabolites and enhances the formation of desired metabolites (e.g., nevirapine: AM Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Efavirenz: AEMutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). In other cases, the main effect of deuteration is to reduce systemic clearance. As a result, the biological half-life of the compound is increased. Potential clinical benefits will include the ability to maintain similar systemic exposure with reduced peak levels and increased trough levels. This may result in reduced side effects and improved efficacy based on the pharmacokinetic / pharmacodynamic relationship of a specific compound. ML-337 (CJ Wenthur et al., J. Med. Chem., 2013, 56, 5208) and Odanacatib (Odanacatib) (K. Kassahun et al., WO 2012 / 112363) are examples of this deuterium effect. Other cases have also been reported, in which reduced metabolic rate leads to increased drug exposure without changing systemic clearance (e.g., rofecoxib (Rofecoxib): F. Schneider et al., Arzneim. Forsch. / Drug. Res., 2006, 56, 295; Telaprevir (Telaprevir): F. Maltais et al., J. Med. Chem., 2009, 52, 7993). Deuterated drugs showing this effect may have reduced dosage requirements (e.g., less dosage or lower dosage to achieve the desired effect) and / or may produce lower metabolite loads.

[0159] The compound of general formula (I) may have multiple potential attack sites of metabolism. In order to optimize the above-mentioned influence on physicochemical properties and metabolic characteristics, the deuterium-containing compound of general formula (I) with one or more deuterium-hydrogen exchanges of a specific pattern can be selected. In particular, the deuterium atom of the deuterium-containing compound of general formula (I) is connected to a carbon atom and / or is located at those positions of the compound of general formula (I) that are metabolic enzymes, such as cytochrome P 450 attack site.

[0160] When the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like is used herein, this also refers to a single compound, salt, polymorph, isomer, hydrate, solvate and the like.

[0161] By "stable compound" or "stable structure" is meant a compound that is sufficiently robust that it can be isolated to a useful degree of purity from a reaction mixture, and formulated into an efficacious therapeutic agent.

[0162] The compounds of the present invention optionally contain one or more asymmetric centers, depending on the location and nature of the various substituents desired. One or more asymmetric carbon atoms may be present in the (R) or (S) configuration, which may result in racemic mixtures in the case of a single asymmetric center and diastereomeric mixtures in the case of multiple asymmetric centers. In some cases, asymmetry may also exist due to restricted rotation about a given bond, for example, a central bond adjacent to two substituted aromatic rings in a given compound.

[0163] Preferred compounds are those that produce more desirable biological activity. Isolation, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the invention are also included within the scope of the present invention. The purification and separation of these materials can be accomplished by standard techniques known in the art.

[0164] Preferred isomers are those that produce more desirable biological activity. These isolated, pure or partially purified isomers or racemic mixtures of the compounds of the invention are also included within the scope of the present invention. The purification and separation of these materials can be accomplished by standard techniques known in the art.

[0165] Optical isomers can be obtained by splitting racemic mixtures according to conventional methods, for example, by forming diastereomeric salts using optically active acids or bases, or by forming covalent diastereoisomers. Examples of suitable acids are tartaric acid, diacetyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid. A mixture of diastereoisomers can be separated into their respective diastereomers by methods known in the art (for example, by chromatography or fractional crystallization) based on their physical and / or chemical differences. The optically active base or acid is then released from the separated diastereomeric salts. The different methods for separating optical isomers involve using chiral chromatography (for example, using an HPLC column of a chiral phase), with or without conventional derivatization, optimally selected to separate enantiomers to the greatest extent possible. Suitable HPLC columns using chiral phases are commercially available, such as those manufactured by Daicel, such as Chiracel OD and Chiracel OJ, and many others, which are all conventionally selectable. Enzymatic separation - with or without derivatization - is also useful. The optically active compounds of the present invention can also be obtained by chiral synthesis using optically active starting materials.

[0166] In order to distinguish different types of isomers from each other, reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).

[0167] The present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of such stereoisomers (e.g., (R) or (S) isomers in any ratio). Isolation of single stereoisomers (e.g., single enantiomers or single diastereomers) of the compounds of the present invention can be achieved by any suitable state of the art method, such as chromatography, in particular chiral chromatography.

[0168] Furthermore, the compounds of the present invention may exist as tautomers. For example, any compound of the present invention comprising an imidazopyridine moiety as a heteroaryl group may exist as a 1H tautomer, or a 3H tautomer, or even as a mixture of two tautomers in any amount, i.e.:

[0169]

[0170] The present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers in any ratio.

[0171] Additionally, the compounds of the present invention may exist as N-oxides, which are defined as at least one nitrogen atom of the compounds of the present invention being oxidized. The present invention includes all such possible N-oxides.

[0172] The present invention also relates to useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts and / or coprecipitates.

[0173] The compounds of the present invention may exist as hydrates or solvates, wherein the compounds of the present invention contain polar solvents, particularly water, methanol or ethanol, for example as structural elements of the compound lattice. The amount of polar solvent (particularly water) may be present in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, for example, hydrates, hemi- (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates are possible respectively. The present invention includes all such hydrates or solvates.

[0174] Furthermore, the compounds of the present invention may exist in free form, for example as a free base, or as a free acid, or as a zwitterion, or in the form of a salt. The salt may be any salt, organic or inorganic addition salt, in particular any pharmaceutically acceptable organic or inorganic addition salt, which is conventionally used in pharmacy or for example for isolating or purifying the compounds of the present invention.

[0175] The term "pharmaceutically acceptable salt" refers to an inorganic or organic acid addition salt of a compound of the present invention. For example, see SM Berge et al. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19.

[0176] Suitable pharmaceutically acceptable salts of the compounds of the present invention may be acid addition salts of compounds of the present invention which carry nitrogen atoms in the chain or in the ring, for example, which have sufficient basicity, such as acid addition salts with the following inorganic acids or "mineral acids": such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, disulfuric acid, phosphoric acid or nitric acid; or acid addition salts with the following organic acids: such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)-benzoic acid, camphoric acid, cinnamic acid. acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectic acid, 3-phenylpropionic acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphate, aspartic acid, sulfosalicylic acid, or thiocyanic acid.

[0177] In addition, another suitable pharmaceutically acceptable salt of the compound of the present invention having sufficient acidity is an alkali metal salt, such as a sodium salt or a potassium salt; an alkaline earth metal salt, such as a calcium salt, a magnesium salt or a strontium salt; or an aluminum salt or a zinc salt; or an ammonium salt derived from ammonia or from an organic primary, secondary or tertiary amine having 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine, dibenzylamine, N-methyl Morpholine, arginine, lysine, 1,2-ethylenediamine, N-methylpiperidine, N-methyl-glucamine, N,N-dimethyl-glucamine, N-ethyl-glucamine, 1,6-hexanediamine, glucosamine, sarcosine, serinol, 2-amino-1,3-propanediol, 3-amino-1,2-propanediol, 4-amino-1,2,3-butanetriol; or a salt of a quaternary ammonium ion having 1 to 20 carbon atoms, such as tetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium, tetra(n-butyl)ammonium, N-benzyl-N,N,N-trimethylammonium, choline or benzalkonium chloride.

[0178] Those skilled in the art will further recognize that the acid addition salts of the claimed compounds can be prepared by any of a variety of known methods by reacting the compounds with a suitable inorganic or organic acid. Alternatively, alkali metal salts and alkaline earth metal salts of the acidic compounds of the present invention can be prepared by reacting the compounds of the present invention with a suitable base by various known methods.

[0179] The present invention includes all possible salts of the compounds of the present invention as a single salt, or as any mixture of said salts in any ratio.

[0180] In this text (especially in the experimental part), for the synthesis of intermediates and the examples of the present invention, when compounds are mentioned as salt forms with the corresponding bases or acids, the exact stoichiometric composition of said salt forms obtained by the corresponding preparation and / or purification processes is in most cases unknown.

[0181] Unless otherwise indicated, suffixes in chemical names or formulas relating to salts, such as "hydrochloride", "trifluoroacetate", "sodium salt" or "×HCl", "×CF3COOH", "×Na + ”, denotes a salt form whose stoichiometry is unspecified.

[0182] This applies analogously to the case where synthetic intermediates or exemplary compounds or salts thereof are obtained by the preparation and / or purification processes described as solvates (eg hydrates) of (if defined) unknown stoichiometric composition.

[0183] Furthermore, the present invention includes all possible crystalline forms or polymorphs of the compounds of the present invention, either as single polymorphs or as mixtures of more than one polymorph in any ratio.

[0184] Furthermore, the present invention also includes prodrugs of the compounds of the present invention. The term "prodrug" herein means that they themselves may be biologically active or inactive, but are converted (eg metabolized or hydrolyzed) into the compounds of the present invention during their residence time in the body.

[0185] According to a second embodiment of the first aspect, the present invention relates to a compound of formula (II), or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof

[0186]

[0187] in

[0188] A is a phenyl group;

[0189] R 1 Selected from

[0190] halogen, 5- to 10-membered mono- or bicyclic heterocycloalkyl or heterocycloalkenyl having 1 or 2 nitrogen as heteroatoms and substituted by -CH3, -C(=O)-CH3 or -NH-C(=O)-CH3, R 1a Selected from

[0191] Hydrogen, -CH3, CF3 or -OCH3;

[0192] R 2 Selected from

[0193] Hydrogen, halogen or C optionally substituted one or more times by halogen and / or hydroxy 1-6 -alkyl;

[0194] x is selected from 1 or 2, and

[0195] R 3 Selected from

[0196] Hydrogen or -CH3.

[0197] According to a third embodiment of the first aspect, the present invention relates to a compound of the above-mentioned general formula (II) or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein:

[0198] A is a phenyl group;

[0199] R 1 Selected from

[0200] halogen,

[0201] R 1a Selected from

[0202] Hydrogen, -CH3, CF3 or -OCH3;

[0203] R 2 Each independently selected from

[0204] -H, -CH3, -F, -CF3 or –CF2-C(CH3)2-OH;

[0205] R 3 Selected from

[0206] Hydrogen or -CH3.

[0207] According to a fourth embodiment of the first aspect, the present invention relates to a compound of formula (III) or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof

[0208]

[0209] in:

[0210] R 1 Selected from

[0211] -Br,

[0212] R 3 selected from -H and -CH3;

[0213] R 4 selected from -CH3 and -C(=O)-CH3, and

[0214] R 5 Selected from -C(=O)-CH3 and -C(=O)OC(CH3)3.

[0215] According to another embodiment of the first aspect, the present invention relates to a 1a A compound which is -H or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

[0216] According to another embodiment of the first aspect, the present invention relates to a 1a A compound which is -CH3 or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

[0217] According to another embodiment of the first aspect, the present invention relates to a 1aA compound which is -CF3 or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

[0218] According to another embodiment of the first aspect, the present invention relates to a 1a A compound which is -O-CH3 or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

[0219] According to another embodiment of the first aspect, the present invention relates to compounds wherein A is phenyl or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

[0220] According to another embodiment of the first aspect, the present invention relates to a method wherein A is naphthyl and R 2 is a compound wherein: H or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

[0221] According to another embodiment of the first aspect, the present invention relates to yes And R 2’ A compound which is -CH3 or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

[0222] According to another embodiment of the first aspect, the present invention relates to yes And R 2’ A compound which is -F or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

[0223] According to another embodiment of the first aspect, the present invention relates to yes And R 2’ A compound which is -H or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

[0224] According to another embodiment of the first aspect, the present invention relates to yes And R 2” A compound which is -CF3 or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

[0225] According to another embodiment of the first aspect, the present invention relates to yes And R 2” A compound which is -CF2H or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

[0226] According to another embodiment of the first aspect, the present invention relates to yes And R 2” A compound which is -CF2-C(CH3)2-OH or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

[0227] According to another embodiment of the first aspect, the present invention relates to yes And R 2” A compound which is -CF2-CH2-OH or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

[0228] According to another embodiment of the first aspect, the present invention relates to a 3 is a compound wherein: H or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

[0229] According to another embodiment of the first aspect, the present invention relates to a 3 A compound which is -CH3 or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

[0230] In another embodiment of the first aspect, the present invention relates to a compound of formula (I), (II) and / or (III) or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, said compound being selected from:

[0231] 6-Bromo-N-{(1R)-1-[3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3-d]pyrimidin-4-amine

[0232] N-{(3R)-1-[4-({(1R)-1-[3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]pyrrolidin-3-yl}acetamide

[0233] 6-(4-Methylpiperazin-1-yl)-N-{(1R)-1-[3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3-d]pyrimidin-4-amine

[0234] 1-{4-[4-({(1R)-1-[3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]piperazin-1-yl}ethan-1-one

[0235] 1-{4-[4-({(1R)-1-[3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one

[0236] 6-Bromo-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3-d]pyrimidin-4-amine

[0237] tert-Butyl 6-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0238] 1-{6-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one

[0239] 1-{4-[4-({(1R)-1-[3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]piperidin-1-yl}ethan-1-one

[0240] 1-{4-[4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]piperazin-1-yl}ethan-1-one

[0241] N-{(3R)-1-[4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]pyrrolidin-3-yl}acetamide

[0242] 1-{4-[4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one

[0243] 1-{6-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one-hydrogen chloride (1 / 1)

[0244] 1-{(1S,4S)-5-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]hept-2-yl}ethan-1-one

[0245] 2-Methyl-6-(4-methylpiperazin-1-yl)-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3-d]pyrimidin-4-amine

[0246] N-{(3R)-1-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]pyrrolidin-3-yl}acetamide

[0247] 1-{4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidine-6-sulfonyl]piperazin-1-yl}ethan-1-one

[0248] N-{(3R)-1-[2,7-dimethyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]pyrrolidin-3-yl}acetamide

[0249] 1-{4-[2,7-dimethyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]piperazin-1-yl}ethan-1-one

[0250] 1-{6-[7-methoxy-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one

[0251] 1-{4-[7-methoxy-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one

[0252] 1-{4-[7-methoxy-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]piperidin-1-yl}ethan-1-one

[0253] 2-[7-methoxy-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-1λ 6 ,2-thiazolidine-1,1-dione

[0254] 1-{6-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl]ethyl}amino)-2-methyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one

[0255] 1-{4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one

[0256] 1-{4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one hydrochloride (1 / 1)

[0257] 1-{7-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2-azaspiro[3.5]non-6-en-2-yl}ethan-1-one

[0258] 1-{7-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2-azaspiro[3.5]nonan-2-yl}ethan-1-one

[0259] 1-{6-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one

[0260] 1-{3-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2,5-dihydro-1H-pyrrol-1-yl}ethan-1-one

[0261] 1-{(3RS)-3-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]pyrrolidin-1-yl}ethan-1-one

[0262] 6-Methoxy-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3-d]pyrimidin-4-amine

[0263] N-Methyl-N-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]methanesulfonamide

[0264] 2-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-1λ 6 ,2-thiazolidine-1,1-dione

[0265] 1-{4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]piperazin-1-yl}ethan-1-one

[0266] 1-{4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-4-oxo-4λ 5 -piperazin-1-yl}ethan-1-one

[0267] 1-{6-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one

[0268] 6-Methoxy-2,7-dimethyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3-d]pyrimidin-4-amine

[0269] 2-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]-1λ 6 ,2-thiazolidine-1,1-dione

[0270] 1-{3-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]azetidin-1-yl}ethan-1-one

[0271] 1-{4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one

[0272] 1-{4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-6-yl]piperidin-1-yl}ethan-1-one

[0273] 1-{4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one

[0274] 1-{4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]piperidin-1-yl}ethan-1-one

[0275] 2-Methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}-6-(pyrimidin-5-yl)pyrido[2,3-d]pyrimidin-4-amine

[0276] 1-{4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one

[0277] 1-{4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]piperidin-1-yl}ethan-1-one

[0278] 6-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]heptane-2-carboxamide

[0279] 1-{3-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]-3,6-diazabicyclo[3.1.1]hept-6-yl}ethan-1-one

[0280] 1-{(1S,4S)-5-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]hept-2-yl}ethan-1-one

[0281] 1-{(1R,4R)-5-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]hept-2-yl}ethan-1-one

[0282] 1,1-Difluoro-1-{2-fluoro-3-[(1R)-1-{[2-methyl-6-(4-methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-4-yl]amino}ethyl]phenyl}-2-methylpropan-2-ol

[0283] 1-{4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]piperazin-1-yl}ethan-1-one

[0284] 1-{6-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one

[0285] N-{(3R)-1-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]pyrrolidin-3-yl}acetamide

[0286] 1-{4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one

[0287] 1-{4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]piperidin-1-yl}ethan-1-one

[0288] 2-[2,7-dimethyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-1λ 6 ,2-thiazolidine-1,1-dione

[0289] 2-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]-1λ 6 ,2-thiazolidine-1,1-dione

[0290] 1-{6-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one

[0291] 4-Acetyl-1-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]piperazin-2-one

[0292] 1-{4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]-5-methyl-3,6-dihydropyridin-1(2H)-yl}ethan-1-one

[0293] 1-{6-[2,7-dimethyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one

[0294] 1-{(1S,4S)-5-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]hept-2-yl}ethan-1-one

[0295] 1-{4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one

[0296] 1-{4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]piperidin-1-yl}ethan-1-one

[0297] 1-{4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]piperazin-1-yl}ethan-1-one

[0298] 4-Acetyl-1-[2,7-dimethyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]piperazin-2-one

[0299] 1-{6-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one

[0300] 1-{6-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one

[0301] 1-{6-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one.

[0302] In certain further embodiments of the first aspect, the invention relates to combinations of two or more of the above embodiments under the heading "Further embodiments of the first aspect of the invention".

[0303] The present invention relates to any sub-combination of compounds of the above general formula (I) within any embodiment or aspect of the present invention.

[0304] The present invention relates to any sub-combination of intermediate compounds of general formula (I) within any embodiment or aspect of the present invention.

[0305] The present invention relates to compounds of general formula (I) disclosed in the Examples section hereinafter.

[0306] The compounds of general formula (I) according to the present invention can be prepared according to the following schemes 1, 2, 3, 4, 5 and 6. The schemes and procedures described below illustrate the synthetic routes of the compounds of general formula (I) according to the present invention and are not intended to be limiting. It is clear to those skilled in the art that the order of the transformations illustrated in schemes 1, 2, 3, 4, 5 and 6 can be modified in various ways. Therefore, the order of the transformations illustrated in these schemes is not intended to be limiting. In addition, any substituent R 1 、R 1a 、R 2 、R 3 、R 4 、R a and R b The interconversions can be achieved before and / or after the exemplified conversions. These conversions can be, for example, the introduction of protecting groups, the cleavage of protecting groups, the reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to those skilled in the art. These conversions include those that introduce functionality that allows further interconversion of substituents. Suitable protecting groups and their introduction and cleavage are well known to those skilled in the art (see, for example, TW Greene and PGM Wutsin Protective Groups in Organic Synthesis, 4 th Specific embodiments will be described in the following paragraphs.

[0307] Solution 1

[0308]

[0309] LGLG is

[0310] Scheme 1 Synthetic route for preparing compounds of general formula (III), wherein R 1 、R 1a 、R 3 and A have the meanings given above for formula (I), and R a represents R in formula (I) 1 or a leaving group such as, but not limited to, a halide (preferably chlorine), an alkylsulfonyl, an alkylsulfonate, and an arylsulfonate; and R b Represents a protecting group. bExamples include, but are not limited to, hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and benzyl. LG represents a leaving group, such as a halide (preferably chlorine), alkylsulfonyl, alkylsulfonate, and arylsulfonate as described above.

[0311] Step 1 → General formula (IV) (Scheme 1)

[0312] Formation of bicyclic pyrimidines: Alternatively, halogen-substituted benzoic acid derivatives of general formula 1 (which are commercially available or described in the literature) can be converted into the corresponding bicyclic pyrimidine formation IV in a manner similar to the literature methods for synthesizing azaquinolines. Typically, derivative 1 is reacted with ammonia to form a derivative of general formula 2, preferably at elevated temperature, optionally under high pressure, in water or an organic solvent or a mixture thereof, such as 1,2-dichloroethane, THF, methanol, ethanol. For example, see WO2017069275, US20030199511 and US20030187026 and references therein. Alternatively, derivative 1 can be converted into the corresponding acid chloride in an organic solvent using, for example, thionyl chloride, oxalyl chloride, optionally with a drop of DMF in an organic solvent, optionally at elevated temperature. The corresponding acid chloride can be treated with an iminamide or a salt thereof, with an inorganic base such as cesium carbonate, sodium carbonate, potassium carbonate, or an organic base such as triethylamine, diisopropylethylamine or pyridine with or without DMAP, optionally using a metal-catalyzed reaction, optionally in the presence of a ligand, in an organic solvent such as DMF, toluene, 1,4-dioxane / water at elevated temperature. For example, see WO2007134986, Bioorg.Med.Chem.Lett., 2015, 23, 3013 and references therein.

[0313] Step 2 → General formula (IV) (Scheme 1)

[0314] Formation of bicyclic pyrimidines: Alternatively, amino-substituted benzoic acid derivatives of general formula 2 (which are commercially available or described in the literature) can be converted into the corresponding bicyclic pyrimidine formation IV in a manner similar to the literature methods for synthesizing azaquinolines. Typically, derivative 2 is reacted with acetamidine or imine amide, optionally with a base such as potassium carbonate or sodium hydroxide or triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene or pyridine in an organic solvent such as DMF at elevated temperature. For example, see WO2004071460, WO2015155306 and Chem.Med.Chem., 2014, 9, 2516.

[0315] Step 3 → General formula (IV) (Scheme 1)

[0316] Formation of bicyclic pyrimidines: Alternatively, halogen-substituted benzoate derivatives of general formula 3 (which are commercially available or described in the literature) can be converted to the corresponding bicyclic pyrimidine precursors (IV) in analogy to literature methods for the synthesis of azaquinolines. Typically, derivatives 3 can be reacted with iminamides or salts thereof, inorganic bases such as cesium carbonate, sodium carbonate, potassium carbonate, or organic bases such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, or pyridine with or without DMAP, optionally using a metal-catalyzed reaction, optionally in the presence of a ligand, in an organic solvent such as DMF, toluene, 1,4-dioxane / water at elevated temperature. For example, see Chem. Commun., 2008, 47, 6333; Bioorg. Med. Chem. Lett., 2013, 23, 3325; WO2018118735, WO2007134986, and references therein.

[0317] Step 4 → General formula (IV) (Scheme 1)

[0318] Formation of bicyclic pyrimidines: Alternatively, amino-substituted benzoate derivatives of general formula 4 (which are commercially available or described in the literature) can be converted into the corresponding bicyclic pyrimidine formation products (IV) similar to the literature methods for synthesizing azaquinolines. Typically, derivative 3 can be reacted with a nitrile, carboxylic acid chloride, carboxylic anhydride, imine amide, or a salt thereof at an elevated temperature in the presence of an acid or a base in water or an organic solvent or a mixture thereof, such as DMF, toluene, 1,4-dioxane / water. For example, see J. Med. Chem., 2018, 61, 3389; J. Med. Chem., 2019, 62, 9772; WO2004071460, WO2007134986, and references therein.

[0319] Step 5 → General formula (IV) (Scheme 1)

[0320] Formation of bicyclic pyrimidines: Alternatively, benzoxazinone derivatives of general formula 5 (which are commercially available or can be prepared similarly to literature methods) can be converted into the corresponding bicyclic pyrimidine formation (IV) similarly to the literature methods for synthesizing azaquinolines. Typically, derivative 4 can be reacted with ammonium acetate in an organic solvent at an elevated temperature. For example, see J. Med. Chem., 2019, 62, 9772; J. Med. Chem., 2011, 54, 6734; Bioorg. Med. Chem., 2014, 22, 5487 or WO2005105760 and references therein.

[0321] Step 6 → General formula (IV) (Scheme 1)

[0322] Formation of bicyclic pyrimidines: Alternatively, benzoic acid amide derivatives of general formula 6 (which are commercially available or described in the literature) can be converted to the corresponding bicyclic pyrimidine precursors (IV) similarly to literature methods for synthesizing azaquinolines. Typically, derivatives 6 can be reacted with a base such as sodium hydroxide in a solvent such as water at elevated temperature. For example, see Monatshefte Für Chemie, 1987, 118, 399; WO2007134986, WO2013016999; WO2012028578 and references therein.

[0323] Step 7 → General formula (IV) (Scheme 1)

[0324] Formation of bicyclic pyrimidines: Alternatively, aminobenzoic acid amide derivatives of general formula 6 (which are commercially available or described in the literature) can be converted into the corresponding bicyclic pyrimidine formers (IV) similar to the literature methods for synthesizing azaquinolines. Typically, derivative 7 can be reacted with an organic acid, organic acid amide or carboxylic anhydride at an elevated temperature, or using a copper-catalyzed reaction, optionally with a base, water or an organic solvent or a mixture thereof, preferably at an elevated temperature. For example, see Eur.J.Org.Chem., 2020, 2730; Polish Journal of Pharmacology and Pharmacy, 1985, 37, 541; Heterocycles, 2015, 90, 857; Yakugaku Zasshi, 1977, 97, 1022 and references therein.

[0325] For the case where LG = chlorine or bromine, phosphorus oxychloride or phosphorus oxybromide, respectively, is typically used at elevated temperature in the presence or absence of N,N-dimethylaniline or N,N-diisopropylethylamine, in the presence or absence of an organic solvent (e.g., toluene). See, for example, US 2012 / 53174, WO 2012 / 30912, or WO 2012 / 66122, and references therein.

[0326] In the case of LG=2,4,6-triisopropylsulfonate, 2,4,6-triisopropylbenzenesulfonyl chloride, a base such as triethylamine and / or DMAP are typically used in an organic solvent such as dichloromethane. See, for example, WO 2010 / 99379, US 2012 / 53176, and references therein.

[0327] In the case of LG=tosylate, 4-methylbenzene-1-sulfonyl chloride, a base such as triethylamine or potassium carbonate and / or DMAP are typically used in an organic solvent such as dichloromethane or acetonitrile. See, for example, Organic Letters, 2011, 4374 or Bioorg. Med. Chem. Lett., 2013, 2663 and references therein.

[0328] In the case of LG = trifluoromethanesulfonate, N,N-bis(trifluoromethylsulfonyl)aniline or trifluoromethanesulfonic anhydride, a base such as triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene and / or DMAP are typically used in an organic solvent such as dichloromethane. See, for example, J. Am. Chem. Soc., 2015, 13433 or WO 2014 / 100501 and references therein.

[0329] Option 2

[0330]

[0331] Scheme 2 Synthetic route for preparing compounds of general formula (II), wherein R 1 、R 1a 、R 2 、R 3 and A have the meanings given above for formula (I), and R a represents R in the general formula (I) 1 or a leaving group such as, but not limited to, a halide (preferably chlorine), an alkylsulfonyl, an alkylsulfonate, and an arylsulfonate; and R b Represents a protecting group. b Examples include, but are not limited to, hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and benzyl. LG represents a leaving group as shown in Scheme 1, such as a halide (preferably chlorine), an alkylsulfonyl group, an alkylsulfonate group, and an arylsulfonate group.

[0332] Compounds of general formula (VIII) are well known in the public domain, commercially available, or can be synthesized by known synthetic routes and are known to those skilled in the art.

[0333] Compounds of general formula (VII) are well known in the public domain, commercially available, or can be synthesized from compounds of general formula (VIII) via known synthetic routes, such as acidic or basic ester hydrolysis.

[0334] Compounds of general formula (VI) are well known in the public domain and are commercially available, or can be synthesized from compounds of general formula (VIII) by known synthetic routes, for example, by forming a nucleophilic substitution reaction (S) with a nitrogen-containing nucleophile. NAr), see the teachings of WO2017069275, US20030199511 and US20030187026.

[0335] The conversion of compounds of formula (VI) to compounds of formula (V) is well documented in the public domain, for which see J. Med. Chem., 2018, 61, 3389; J. Med. Chem., 2019, 62, 9772; WO2004071460 and WO2007134986. Compounds of formula (IV) are also commercially available.

[0336] Alternatively, compounds of formula (V) can be formed from compounds of formula (VII) and are well documented in the public domain, see the teachings of WO2004071460, WO2015155306 and Chem. Med. Chem., 2014, 9, 2516.

[0337] Other compounds of general formula (IV) can be formed by dehydration coupling methods using compounds of general formula (V) and compounds of general formula (X). Such methods using coupling agents such as benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) and benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) are known, as well as J.Org.Chem., 2007, 72, 10194; Advanced Synthesis & Catalysis, 2018, 360, 4764; Bioorg.Med.Chem., 2019, 27, 931; WO 2011028741 A1 are known in the public domain.

[0338] Alternatively, compounds of general formula (III) can be formed in a two-step process in which compounds of general formula (V) are converted to compounds of general formula (IV) using standard, well-documented methods, for example, using phosphorus oxychloride when LG = Cl, or phosphorus oxybromide when LG = Br, or using a base such as triethylamine or potassium carbonate and / or DMAP in an organic solvent such as dichloromethane or acetonitrile when LG = tosylate, typically 4-methylbenzene-1-sulfonyl chloride. See, for example, Organic Letters, 2011, 4374 or Bioorg. Med. Chem. Lett., 2013, 2663 and references therein.

[0339] Subsequently, a nucleophilic substitution reaction (S) with a compound of general formula (X) is used. N Ar), compounds of general formula (IV) can be converted into compounds of general formula (III), which is well documented in the public domain and known to those skilled in the art.

[0340] The compound of general formula (III) can be converted into the compound of general formula (II) wherein R a is a functional group that can be further modified. The scope of such transformations is very broad and is known to those skilled in the art. For example (but not limited to) when R a When it is a leaving group, such as a halide or alkylsulfonyl, it can undergo metal-catalyzed reactions such as Suzuki, Sonogashiri, Buchwald-Hartwig, Heck, Stille, and Ullman reactions. In addition, these leaving groups can be converted into other functional groups such as amines, sulfides, sulfoxides, sulfones, and sulfonamides.

[0341] Option 3

[0342]

[0343] Scheme 3 Synthetic route for preparing compounds of general formula (III), wherein R 1 、R 1a 、R 2 、R 3 and A have the meanings given above for formula (I), and R a represents R in the general formula (I) 1 or a leaving group such as, but not limited to, a halide (preferably chlorine), an alkylsulfonyl, an alkylsulfonate, and an arylsulfonate; and R b Represents a protecting group. b Examples include, but are not limited to, hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and benzyl. LG represents a leaving group as shown in Scheme 1, such as a halide (preferably chlorine), an alkylsulfonyl group, an alkylsulfonate group, and an arylsulfonate group.

[0344] Compounds of general formula (XIII) are well known in the public domain and are commercially available, or can be synthesized by known synthetic routes, for example, by reacting compounds of general formula (VIII) with urea under different conditions to form heteroaromatic rings, as taught by Luo et al., CN 102584828. Alternatively, a multi-step synthesis as described in Brogi et al., J. Med. Chem., 2018, 61, 2124; Bergeron et al., WO2010014939A1.

[0345] The conversion of compounds of general formula (XIII) to compounds of general formula (XII) is well known in the public domain and is similarly illustrated in Scheme 2 for the conversion of (V) to (IV). For example, when LG = chlorine, trichlorophosphate or thionyl chloride can typically be used at elevated temperatures, in the presence or absence of N,N-dimethylaniline or N,N-diisopropylethylamine, in the presence or absence of an organic solvent (e.g., toluene). For example, see Cantin et al., Bioorg. Med. Chem. Lett., 2012, 2565; Bayrakdarian et al., WO 2008136756 A1; Luo et al., CN 102584828; Zhou et al., J. Med. Chem., 2015, 58, 9480.

[0346] For the case where LG = bromine, phosphorus oxybromide can generally be used at elevated temperature in the presence or absence of a base in the presence or absence of an organic solvent such as toluene. See, for example, Kim et al., J. Org. Chem., 2004, 69, 5638.

[0347] The conversion of compounds of general formula (XII) to compounds of general formula (XI) is well known in the public domain and is similarly illustrated for the conversion of (IV) to (III) in Scheme 2. For example, such nucleophilic substitutions are well documented, see the teachings of Liwicki et al., WO 2018066718 A1; Gelin et al., WO 2013016197 A1; Jiang, et al., J. Med. Chem., 2016, 59, 10498.

[0348] Compounds of general formula (XI) can be converted into compounds of general formula (II) using various synthetic methods, such as Suzuki reaction (Liwicki et al., WO 2018066718 A1; Pulipati, et al., Synth. Commun., 2017, 47, 1142), Stille reaction (Johnson et al., WO 2011028741A1; Labadie et al., Bioorg. Med. Chem. Lett., 2013, 23, 5923) or other methods, see the teachings of Finlay et al., ACSMed. Chem. Letters, 2016, 7, 831.

[0349] The remaining steps in Scheme 3 follow the same routes and methods as described in Scheme 2 to generate compounds of formula (II) from compounds of formula (III).

[0350] Option 4

[0351]

[0352] Scheme 4 Synthetic route for preparing compounds of general formula (X), which are compounds of general formula (I), wherein R2, A and x have the meanings given above for general formula (I).

[0353] Step XVII→XVI (Scheme 4)

[0354] Formation of acetyl groups

[0355] In the first step (Scheme 4), the bromo derivative XVII (which is commercially available or recorded in the literature) can be converted into the corresponding acetyl group XVI similarly to many literature methods. For example, the reaction can be carried out using different chemical reactions known to those skilled in the art, such as Grignard chemistry using magnesium in an organic solvent such as THF; or palladium catalytic chemistry or static chemistry. For such conversions, see (Grignard: Fillon et al., Tetahedron 2003, 59, 8199; Leazer et al., Org. Synth. 2005, 82, 115; Palladium: WO 2005 / 5382; Stille: WO 2019 / 122129 and references therein).

[0356] Step XVI → XV (Scheme 4)

[0357] Formation of sulfinimine

[0358] In the first step (Scheme 4), the carbonyl derivative XVI (which is commercially available or described in the literature) can be converted to the corresponding sulfenyl imine XV similarly to many literature methods. For example, the reaction can be carried out at ambient temperature in an organic solvent such as THF using titanium (IV) ethoxide or titanium (IV) isopropoxide. For a review of sulfenyl imine chemistry, see, for example, Chem. Rev. 2010, 110, 3600–3740; Chem. Soc. Rev. 2009, 38, 1162–1186; Tetrahedron 2004, 60, 8003 or WO 2019 / 122129 and references therein.

[0359] Step XV→XIV (Scheme 4)

[0360] Formation of sulfenamide

[0361] In the next step (Scheme 4), sulfenyl imine XV can be converted to the corresponding sulfenamide XIV similarly to many literature methods. For example, the reaction can be carried out in a protic organic solvent such as ethanol or methanol or tetrahydrofuran using a reducing agent such as sodium borohydride or borane-THF. Such conversion is known to those skilled in the art, see Pan et al., Tetrahedron Asym., 2011, 22, 329; WO2019 / 122129; Li et al., Chem. Med. Chem., 2018, 13, 1363; Ghosh et al., Eur. J. Med. Chem., 2018, 160, 171. Alternatively, the reaction can be carried out in an aprotic solvent such as toluene using a reducing agent such as diisopropylaluminum hydride. Such conversion is known to those skilled in the art, see WO2017 / 6282; Lee et al., Synlett., 2019, 30, 401.

[0362] Step XIV → X (Scheme 4)

[0363] Amine formation

[0364] In the next step (Scheme 4), sulfenamide XIV can be converted to the corresponding amine X in a manner similar to many literature methods. For example, the reaction can be carried out using acetyl chloride in a protic organic solvent such as methanol. For a review of sulfenimine and sulfonamide chemistry, see, for example, Chem. Rev. 2010, 110, 3600–3740; Chem. Soc. Rev. 2009, 38, 1162–1186; Tetrahedron 2004, 60, 8003 or WO 2013030138 and references therein.

[0365] Option 5

[0366]

[0367] Scheme 5 Synthetic route for the preparation of compounds of general formula (X), which are compounds of general formula (I), wherein R2, A and x have the meanings given above for general formula (I).

[0368] Step XVI → XIX (Scheme 5)

[0369] Formation of ethanol

[0370] In the first step (Scheme 5), ketone derivatives XVI (which are commercially available or described in the literature) can be converted into the corresponding chiral alcohols XIX in a manner analogous to many literature methods. For example, enantioselective reduction can be carried out using catalytic hydrogenation using pressurized hydrogen using a catalyst, such as a BINAP-derived catalyst, such as (R)- or (S)-RUCY-Xyl-BINAP (see WO 2019 / 122129, page 140 or WO 2013 / 185103, page 81).

[0371] Step XIX→XVIII (Scheme 5)

[0372] Azide formation

[0373] In the next step (Scheme 5), alcohol XIX can be converted into the corresponding azide XVIII similarly to many literature methods. For example, the reaction can be carried out in an aprotic organic solvent such as toluene using diphenylphosphine azide and a base such as DBU (see the teaching of WO2019 / 122129 page 144). For a review of azide chemistry, see, for example, Chem. Rev. 1988, 88, 297.

[0374] Step XVIII→X (Scheme 5)

[0375] Amine formation

[0376] In the next step (Scheme 5), azide XVIII can be converted into the corresponding amine X similar to many literature methods. For example, the reaction can be carried out in water with various organic solvents such as methanol, ethanol or THF using Staudinger reduction conditions with phosphines such as triphenylphosphine. Alternatively, azide reduction can be carried out using a catalytic hydrogenation method (using a metal catalyst such as palladium on carbon) under a hydrogen pressurized atmosphere (see the teaching of page 144 of WO2019 / 122129). For a review of azide chemistry, see, for example, Chem.Rev.1988,88,297.

[0377] Option 6

[0378]

[0379] Scheme 6 Synthetic route for the preparation of compounds of general formula (X), which are compounds of general formula (I), wherein R2, A and X have the meanings given above for general formula (I).

[0380] For those skilled in the art, the chemical reactions described in Schemes 4 and 5 can be carried out, wherein the stereoisomers can be separated using various methods known to those skilled in the art, such as separation using chiral HPLC purification. The separation of these stereoisomers can be carried out on compounds of general formula (X).

[0381] According to another aspect, the present invention relates to intermediate compounds useful in the preparation of the compounds of the invention of general formula (I), in particular in the processes described herein.

[0382] The present invention is directed to the intermediate compounds disclosed in the Examples section hereinafter.

[0383] The present invention relates to any subcombination of the intermediate compounds of the general formula (I) described above in any embodiment or aspect of the present invention.

[0384] The compounds of the general formula (I) of the present invention can be converted into any salt by any method known to those skilled in the art, preferably a pharmaceutically acceptable salt as described herein. Similarly, any salt of the compounds of the general formula (I) of the present invention can be converted into a free compound by any method known to those skilled in the art.

[0385] The compounds of the present invention of general formula (I) exhibit an unexpectedly valuable pharmacological spectrum of action. Unexpectedly, it was found that the compounds of the present invention effectively inhibit SOS1 and therefore have the potential to be used in the treatment or prevention of diseases, preferably hyperproliferative diseases in humans and animals.

[0386] According to another aspect, the present invention relates to a compound of general formula (I) as described above, or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, in particular its pharmaceutically acceptable salts, or mixtures thereof, for use in treating or preventing diseases, in particular hyperproliferative diseases.

[0387] The compounds of the present invention can be used to inhibit, block, reduce, decrease, etc. cell proliferation and / or cell division, and / or induce cell apoptosis. The method comprises administering to a mammal (including a human) in need thereof a certain amount of a compound of the general formula (I) of the present invention or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof, which is effective for treating a disease.

[0388] Hyperproliferative diseases include, but are not limited to, for example, psoriasis, keloids and other proliferations affecting the skin, benign prostatic hyperplasia (BPH), solid tumors such as breast cancer, respiratory tract cancer, brain cancer, reproductive organ cancer, digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer and their distant metastases. These diseases also include lymphomas, sarcomas and leukemias.

[0389] Examples of breast cancer include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

[0390] Examples of respiratory tract cancers include, but are not limited to, small cell lung cancer and non-small cell lung cancer, as well as bronchial adenoma and pleuropulmonary blastoma.

[0391] Examples of brain cancer include, but are not limited to, brainstem and hypophtalmic gliomas, cerebellar and cerebral astrocytomas, medulloblastomas, ependymomas, and neuroectodermal and pineal tumors.

[0392] Tumors of the male reproductive organs include, but are not limited to, prostate cancer and testicular cancer.

[0393] Tumors of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancers, as well as uterine sarcomas.

[0394] Digestive tract cancers include, but are not limited to, anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, stomach cancer, pancreatic cancer, rectal cancer, small intestine cancer, and salivary gland cancer.

[0395] Tumors of the urinary tract include, but are not limited to, bladder cancer, penile cancer, kidney cancer, renal pelvis cancer, ureter cancer, urethral cancer, and human papillary renal carcinoma.

[0396] Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.

[0397] Examples of liver cancer include, but are not limited to, hepatocellular carcinoma (liver cell carcinoma with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.

[0398] Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

[0399] Head and neck cancers include, but are not limited to, cancers of the larynx, hypopharynx, nasopharynx, oropharynx, lip and oral cavity, and squamous cell carcinoma.

[0400] Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt's lymphoma, Hodgkin's disease, and central nervous system lymphoma.

[0401] Sarcomas include, but are not limited to, soft tissue sarcomas, osteosarcomas, malignant fibrous histiocytomas, lymphosarcoma, and rhabdomyosarcoma.

[0402] Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia.

[0403] The present invention also provides methods of treating angiogenic disorders, including diseases associated with excessive and / or abnormal angiogenesis.

[0404] Inappropriate and ectopic expression of angiogenesis can be harmful to the organism. Many pathological conditions are associated with the growth of foreign blood vessels. These include, for example, diabetic retinopathy, ischemic retinal vein occlusion, and retinopathy of prematurity [Aiello et al., New Engl. J. Med., 1994, 331, 1480; Peer et al., Lab. Invest., 1995, 72, 638], age-related macular degeneration (AMD) [Lopez et al., Invest. Opthalmol. Vis. Sci., 1996, 37, 855], neovascular glaucoma, psoriasis, retrolental fibroplasia, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, vascular graft restenosis, etc. In addition, the increased blood supply associated with cancerous and tumor tissues promotes growth, leading to rapid tumor enlargement and metastasis. Furthermore, the growth of new blood vessels and lymphatic vessels in tumors provides escape routes for mutated cells, promoting metastasis and subsequent spread of cancer. Therefore, the compounds of formula (I) of the present invention can be used to treat and / or prevent any of the above-mentioned angiogenic disorders, for example, by inhibiting and / or reducing blood vessel formation; by inhibiting, blocking, reducing, or decreasing the proliferation of endothelial cells or other types involved in angiogenesis, and by causing cell death or apoptosis of such cell types.

[0405] These diseases are well characterized in humans, but have similar etiologies in other mammals and can be treated by administering the pharmaceutical compositions of the present invention.

[0406]

[0046] The terms "treating" or "treatment" as used throughout this document are used conventionally, eg, to manage or care for a subject for the purpose of combating, alleviating, reducing, relieving, or ameliorating a disease or condition (eg, cancer).

[0407] The compounds of the present invention are particularly useful for treating and preventing (ie, prophylactically) tumor growth and metastasis, particularly in solid tumors of all indications and stages, with or without pretreatment of the tumor growth.

[0408] Typically, chemotherapeutic and / or anticancer agents used in conjunction with the compounds or pharmaceutical compositions of the present invention will help:

[0409] 1. Produce greater efficacy in reducing tumor growth or even eliminating tumors compared to either agent administered alone;

[0410] 2. Provides for administration of lower amounts of the administered chemotherapeutic agent;

[0411] 3. Provide a chemotherapy treatment that is well tolerated by patients and has fewer deleterious pharmacologic complications than those observed with single-agent chemotherapy and certain other combination therapies;

[0412] 4. Provide treatment for a wider range of different cancer types in mammals, especially humans;

[0413] 5. Provide higher response rates among treated patients;

[0414] 6. Patients who received treatment lived longer than those who received standard chemotherapy.

[0415] 7. Provide a longer time for tumor progression, and / or

[0416] 8. Compared with other cancer drug combinations where antagonism is known to occur, the combination produces efficacy and tolerability outcomes that are at least as good as the drugs used alone.

[0417] Furthermore, the compounds of general formula (I) of the present invention can also be used in combination with radiotherapy and / or surgical operation.

[0418] In another embodiment of the invention, the compounds of formula (I) of the invention can be used to sensitize cells to radiation, i.e., treating the cells with the compounds of the invention prior to subjecting the cells to radiation therapy renders the cells more susceptible to DNA damage and cell death than cells not subjected to any treatment with the compounds of the invention. In one aspect, cells are treated with at least one compound of formula (I) of the invention.

[0419] Thus, the present invention also provides a method of killing cells wherein one or more compounds of the present invention are administered to the cells in combination with conventional radiation therapy.

[0420] The present invention also provides a method for making a cell more sensitive to cell death, wherein the cell is treated with one or more compounds of formula (I) of the present invention prior to treating the cell to cause or induce cell death. In one aspect, after treating the cell with one or more compounds of formula (I) of the present invention, the cell is treated with at least one compound or at least one method, or a combination thereof, to cause DNA damage with the purpose of inhibiting normal cell function or killing the cell.

[0421] In other embodiments of the present invention, cells are killed by treating them with at least one DNA damaging agent, i.e., after treating the cells with one or more compounds of formula (I) of the present invention to sensitize them to cell death, the cells are treated with at least one DNA damaging agent to kill the cells. DNA damaging agents that can be used in the present invention include, but are not limited to, chemotherapeutic agents (e.g., cisplatin), ionizing radiation (X-rays, ultraviolet radiation), carcinogens, and mutagens.

[0422] In other cases, cells are killed by treating the cells with at least one method that causes or induces DNA damage. Such methods include, but are not limited to, activating a cell signaling pathway that causes DNA damage when the pathway is activated, inhibiting a cell signaling pathway that causes DNA damage when the pathway is inhibited, and inducing biochemical changes in the cell, wherein the changes result in DNA damage. As a non-limiting example, a DNA repair pathway in the cell can be inhibited, thereby preventing the repair of DNA damage and causing abnormal accumulation of DNA damage in the cell.

[0423] In one aspect of the invention, a compound of formula (I) of the invention is administered to a cell prior to radiation or other induction of DNA damage in the cell. In another aspect of the invention, a compound of formula (I) of the invention is administered to a cell simultaneously with radiation or other induction of DNA damage in the cell. In yet another aspect of the invention, a compound of formula (I) of the invention is administered to a cell immediately after radiation or other induction of DNA damage in the cell has begun.

[0424] In another aspect, the cell is in vitro. In another embodiment, the cell is in vivo.

[0425] According to another aspect, the present invention relates to a compound of general formula (I) as described above, or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, in particular its pharmaceutically acceptable salts, or mixtures thereof, for use in treating or preventing diseases, in particular hyperproliferative diseases.

[0426] The pharmaceutical activity of the compounds according to the invention can be explained by their activity as SOS1 inhibitors.

[0427] According to another aspect, the present invention relates to the use of a compound of formula (I) as described above or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, in particular pharmaceutically acceptable salts, or mixtures thereof for treating or preventing diseases, in particular hyperproliferative diseases, in particular cancer.

[0428] According to another aspect, the present invention relates to the use of a compound of the above formula (I) or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, in particular pharmaceutically acceptable salts, or mixtures thereof for preventing or treating diseases, in particular hyperproliferative diseases, in particular cancer.

[0429] According to another aspect, the present invention relates to the use of a compound of formula (I) as described above or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, in particular pharmaceutically acceptable salts, or mixtures thereof, in a method for treating or preventing diseases, in particular hyperproliferative diseases, in particular cancer.

[0430] According to another aspect, the present invention relates to the use of a compound of general formula (I) as described above or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, in particular pharmaceutically acceptable salts, or mixtures thereof, in the preparation of a pharmaceutical composition, preferably a medicament, for preventing or treating a disease, in particular a hyperproliferative disease, in particular cancer.

[0431] According to another aspect, the present invention relates to a method for treating or preventing diseases, in particular hyperproliferative diseases, in particular cancer, using an effective amount of a compound of general formula (I) as described above or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, in particular pharmaceutically acceptable salts, or mixtures thereof.

[0432] According to another aspect, the present invention relates to a pharmaceutical composition, in particular a medicament, comprising a compound of formula (I) as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, salt, in particular a pharmaceutically acceptable salt, or a mixture thereof, and one or more excipients, in particular one or more pharmaceutically acceptable excipients. Conventional methods can be used to prepare the pharmaceutical composition in an appropriate dosage form.

[0433] The invention also relates to pharmaceutical compositions, in particular medicaments, comprising at least one compound according to the invention, normally together with one or more pharmaceutically suitable excipients, and their use for the above-mentioned purposes.

[0434] The compounds of the present invention may have systemic and / or local activity. For this purpose, they can be administered in a suitable manner, for example, orally, parenterally, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.

[0435] For these administration routes, the compounds according to the invention can be administered in suitable administration forms.

[0436] For oral administration, the compounds of the present invention can be formulated into dosage forms known in the art that deliver the compounds of the present invention quickly and / or in an improved manner, such as tablets (uncoated or coated tablets, e.g., with delayed dissolution or insoluble enteric or controlled-release coatings), orally disintegrating tablets, films / thin sheets, films / lyophilizates, capsules (e.g., hard or soft gelatin capsules), sugar-coated tablets, granules, pills, powders, emulsions, suspensions, aerosols or solutions. The compounds of the present invention can be incorporated into the dosage forms in crystalline and / or amorphous and / or dissolved form.

[0437] Parenteral administration can be carried out with the absorption step avoided (e.g. intravenously, intraarterially, intracardially, intraspinally or intralumbarly) or with the absorption included (e.g. intramuscularly, subcutaneously, intradermally, transdermally or intraperitoneally). Suitable administration forms for parenteral administration are especially preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

[0438] Examples of suitable other routes of administration are pharmaceutical forms for inhalation [especially powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets / films / wafers / capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye washes, eye inserts, ear drops, ear sprays, ear powders, ear washes, ear plugs; vaginal capsules, aqueous suspensions (lotions, mixtures), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (e.g. patches), milks, pastes, foams, dusting powders, implants or stents.

[0439] The compounds of the invention can be incorporated into the administration forms described. This can be achieved in a manner known per se by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients include, in particular, the following substances:

[0440] Fillers and carriers (e.g. cellulose, microcrystalline cellulose (e.g. ), lactose, mannitol, starch, calcium phosphate (e.g. ));

[0441] ointment bases (e.g., petrolatum, paraffin, triglycerides, waxes, wool wax, wool alcohol, lanolin, hydrophilic ointments, polyethylene glycol);

[0442] Suppository bases (e.g., polyethylene glycol, cocoa butter, hard fat);

[0443] Solvents (e.g., water, ethanol, isopropanol, glycerol, propylene glycol, medium-chain triglyceride fatty oils, liquid polyethylene glycol, paraffin),

[0444] Surfactants, emulsifiers, dispersants or wetting agents (e.g. sodium lauryl sulfate), lecithin, phospholipids, fatty alcohols (e.g. ), sorbitan fatty acid esters (e.g. ), polyoxyethylene sorbitan fatty acid esters (e.g. ), polyoxyethylene fatty acid glycerides (e.g. ), polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (e.g. );

[0445] Buffers, acids, and bases (e.g., phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, tromethamine, triethanolamine);

[0446] Isotonic agents (e.g., glucose, sodium chloride);

[0447] Adsorbents (e.g., highly dispersed silica);

[0448] Viscosifiers, gel formers, thickeners and / or binders (e.g. polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, starch, carbomer, polyacrylic acid (e.g. ); alginate, gelatin);

[0449] Disintegrants (e.g. modified starch, sodium carboxymethyl cellulose, sodium starch glycolate (e.g. ), cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose (e.g. ));

[0450] Flow regulators, lubricants, glidants and release agents (e.g. magnesium stearate, stearic acid, talc, highly dispersed silicon dioxide (e.g. ));

[0451] Coating materials for thin or diffusion membranes (e.g. sugar, shellac) and film formers that dissolve rapidly or in a modified manner (e.g. polyvinylpyrrolidone (e.g. ), polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates, e.g. ));

[0452] capsule materials (e.g., gelatin, hydroxypropyl methylcellulose),

[0453] Synthetic polymers (e.g. polylactide, polyglycolide, polyacrylate, polymethacrylate (e.g. ), polyvinylpyrrolidone (e.g. ), polyvinyl alcohol, polyvinyl acetate, polyethylene oxide, polyethylene glycol and copolymers and block copolymers thereof);

[0454] Plasticizers (e.g. polyethylene glycol, propylene glycol, glycerol, triacetin, triacetyl citrate, dibutyl phthalate);

[0455] Penetration enhancers;

[0456] Stabilizers (e.g., antioxidants such as ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate);

[0457] Preservatives (e.g., parabens, sorbic acid, thimerosal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate);

[0458] Colorants (e.g., inorganic pigments, such as iron oxide, titanium dioxide);

[0459] • Flavorings, sweeteners, taste-masking agents, and / or odor-masking agents.

[0460] The present invention also relates to a pharmaceutical composition comprising at least one compound according to the invention, usually together with one or more pharmaceutically suitable excipients, and to their use according to the invention.

[0461] According to another aspect, the present invention relates to a drug combination, in particular a drug, comprising at least one compound of the general formula (I) according to the invention and at least one or more other active ingredients, in particular for the treatment and / or prevention of hyperproliferative diseases, such as cancer.

[0462] In particular, the present invention relates to a drug conjugate comprising:

[0463] one or more first active ingredients, in particular compounds of formula (I) as defined above, and

[0464] • One or more other active ingredients, particularly for hyperproliferative diseases such as cancer.

[0465] The term "conjugate" in the present invention is used as known to those skilled in the art, and the conjugate may be an immobilized conjugate, a non-immobilized conjugate or a kit-of-parts.

[0466] "Fixed binding" in the present invention is used as known to those skilled in the art and is defined as a binding in which, for example, the first active ingredient, such as one or more compounds of formula (I) according to the present invention, and the further active ingredient are present together in one unit dose or in one single entity. An example of a "fixed binding" is a pharmaceutical composition in which the first active ingredient and the further active ingredient are present in a mixture for simultaneous administration, such as in a formulation. Another example of a "fixed binding" is a pharmaceutical combination in which the first active ingredient and the further active ingredient are present in one unit rather than in a mixture.

[0467] In the present invention, non-fixed combinations or "kits of parts" are used as known to those skilled in the art and are defined as combinations in which the first active ingredient and the further active ingredient are present in more than one unit. An example of a non-fixed combination or kit of parts is a combination in which the first active ingredient and the further active ingredient are present separately. The components of the non-fixed combination or kit of parts can be administered separately, sequentially, simultaneously, concurrently, or chronologically staggered.

[0468] The compounds of the present invention can be administered as a single agent or in combination with one or more other pharmaceutically active ingredients, where the combination does not cause unacceptable side effects. The present invention also relates to such drug combinations. For example, the compounds of the present invention can be combined with known anti-hyperproliferative agents / antitumor agents / cancer therapeutic agents.

[0469] Examples of anti-hyperproliferative / anti-tumor / cancer therapeutic agents include:

[0470] 131I-chTNT, abarelix, abiraterone, aclarubicin, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II, antithrombin III III), aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, axitinib, azacitidine, basiliximab, belotecan, bendamustine, besilesomab, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib, buserelin, bosutinib, brentuximab vedotin), busulfan, cabazitaxel, cabozantinib, calcitonine, calcium folinate, calcium folinatelevofolinate), capecitabine, capromab, carboplatin, carboquone, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid acid, clofarabine, cobimetinib, copanlisib, crisantaspase, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daratumumab, darbepoetin alfa, darolutamide, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidiumchloride), vinblastine, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta beta), epoetinzeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, ethinylestradiol, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid acid), formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadooversetamide, gadoxetic acid, gallium nitratenitrate), ganirelix, gefitinib, gemcitabine, gemtuzumab, glutcarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony-stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, iodine-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan), ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenolmebutate, interferon-α, interferon-β, interferon-γ, iobitridol, iobenguane (123I), iomeprol, ipilimumab, irinotecan, itraconazole, ixabepilone, ixazomib, lanreotide, lansoprazole razole), lapatinib, larotrectinib, lasocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodiumsodium), lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinic acid nate), methylprednisolone, methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride hydrochloride), morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin, nelarabine, neridronic acidacid), netupitant / palonosetron, nivolumab pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, omacetaxine mepesuccinate), omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palbociclib, b), palifermin, palladium-103 seed, palonosetron, pamidronate, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alpha-2balfa-2b), pemetrexed, pentazocine, pentostatin, peplomycin, perflubutane, perfosfamide, pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiolphosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium sodium), pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib, regorafenib, risedronic acidacid), rhenium-186 etidronate, rituximab, rogaratinib, rolapitant, romidepsin, romiplostim, romurtide, roniciclib, samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, siltuximab, sipuleucel-T, sizofil ran), sobuzoxane, sodium glycididazole, sonidegib, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, talimogenelaherparepvec, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan), 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur+gimeracil+oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfaalfa), tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab, trastuzumab-emtansine emtansine), treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valatinib, valrubicin, vandetanib anib), vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, and zorubicin.

[0471] Further examples of binding partners are ATR inhibitors (e.g. BAY 1895344), DHODH inhibitors (e.g. BAY2402234), SHP2 inhibitors (e.g. SHP099, RMC-4550, TNO155) or H-, N- or K-Ras inhibitors, including inhibitors of mutants thereof, in particular K-RAS-G12C inhibitors (e.g. ARS-853, ARS-1620, AMG-510, MRTX849, MRTX1257) or farnesyltransferase inhibitors.

[0472] In particular, the present invention relates to the combination of covalent inhibitors of KRAS-G12C and SOS1 inhibitors. Covalent KRAS-G12C inhibitors (e.g., ARS-853 or ARS-1620) have been shown to specifically bind to KRAS-G12C in the GDP-bound state, but not in the GTP-bound state (Patricelli 2016 Cancer Discovery; Janes et al. 2018 Cell), thereby trapping KRAS-G12C in its inactive GDP-bound state. In addition, it has been shown that certain RAS mutants that normally exist in an active GTP-bound state are undergoing slow intrinsic GTP hydrolysis, particularly the G12C and G12D mutants of KRAS (Hunter et al. 2015 Molecular Cancer Research). It can be speculated that even those mutant RAS proteins require activation by nucleotide exchange factors such as SOS1 to fully exert their activity and tumorigenesis. Treatment with SOS1 inhibitors is expected to shift the intracellular equilibrium of KRAS mutants toward the inactive GDP-bound state, which in turn favors the binding of KRAS inhibitors that preferentially bind to the GDP-bound state of RAS, as do covalent KRAS-G12C inhibitors such as ARS-853 and ARS-1620. The combination of BAY-293 and ARS-853 (Hillig 2019 PNAS) has shown synergistic antiproliferative activity in vitro.

[0473] The effective dosage of the compounds of the present invention for treating each desired indication can be readily determined based on standard laboratory techniques known for evaluating compounds useful in treating hyperproliferative diseases, by standard toxicity tests and by standard pharmacological assays to determine the treatment of the above-mentioned conditions in mammals, and by comparing these results with the results of known active ingredients or drugs used to treat these conditions. The amount of active ingredient administered in treating one of these conditions can vary widely depending on factors such as the specific compound and dosage unit used, the mode of administration, the duration of treatment, the age and sex of the patient being treated, and the nature and extent of the disease being treated.

[0474] The total amount of active ingredient to be administered is generally from about 0.001 mg / kg to about 200 mg / kg of body weight per day, preferably from about 0.01 mg / kg to about 20 mg / kg of body weight per day. Clinically useful dosing regimens range from one to three times daily to once every four weeks. In addition, a "drug holiday"—a period during which the patient does not take the drug—may be beneficial for the overall balance between pharmacological action and tolerability. A unit dose may contain from about 0.5 mg to about 1500 mg of the active ingredient and may be administered once or more times per day or less than once per day. Administration by injection, including intravenous, intramuscular, subcutaneous, and parenteral injections, as well as using infusion techniques, will preferably range from 0.01 to 200 mg / kg of total body weight. The average daily rectal dosage regimen will preferably range from 0.01 to 200 mg / kg of total body weight. The average daily vaginal dosage regimen will preferably range from 0.01 to 200 mg / kg of total body weight. The average daily topical dosage regimen will preferably range from 0.1 to 200 mg, administered 1 to 4 times per day. Transdermal concentrations will preferably be that required to maintain a daily dosage of 0.01 to 200 mg / kg.The average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg / kg of total body weight.

[0475] Of course, the specific initial and ongoing dosing regimen for each patient will vary depending on the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound used, the age and general condition of the patient, the time of administration, the route of administration, the rate of excretion of the drug, drug conjugates, etc. The desired mode of treatment and frequency of administration of a compound of the present invention, or a pharmaceutically acceptable salt or ester thereof, or composition thereof, can be determined by one skilled in the art using routine therapeutic testing.

[0476] Experimental part

[0477] The forms of NMR peaks refer to the form in which they appear in the spectrum, without taking into account possible higher-order effects.

[0478] The selected compounds 1 H-NMR data were 1 The H-NMR peak lists are presented in the form of a peak list. For each signal peak, the δ value in ppm is given, followed by the signal intensity, reported in parentheses. The δ value-signal intensity pairs for different peaks are separated by commas. Thus, the peak list is described by the following general form: δ1 (intensity 1), δ2 (intensity 2), ..., δ i (strength i ), ..., δ n (strength n ).

[0479] The intensity of a sharp signal is related to the height of the signal in the printed NMR spectrum (in centimeters). When compared with other signals, this data can be correlated to the true ratio of the signal intensities. In the case of broad signals, more than one peak or signal center is shown, along with their relative intensities, compared to the strongest signal shown in the spectrum. 1 H-NMR peak lists are similar to conventional 1 H-NMR readings therefore typically contain all peaks listed in conventional NMR interpretations. In addition, similar to conventional 1 H-NMR printouts, peak lists can show solvent signals, signals originating from stereoisomers of specific target compounds, signals of impurity peaks, 13 The signal of the C satellite peak and / or the signal of the rotating sideband. The peaks of stereoisomers and / or impurities are usually displayed with lower intensity compared to the peak of the target compound (e.g. purity>90%). Such stereoisomers and / or impurities can be unique to a particular production process, so their peaks can help identify the reproducibility of the production process based on the "by-product fingerprint". Experts who calculate the peaks of the target compound by known methods (MestReC, ACD simulation or using expected values ​​estimated empirically) can optionally use additional intensity filters to separate the peaks of the target compound as needed. This operation is similar to conventional 1 Peak picking in H-NMR analysis. A detailed description of reporting NMR data in peak list format can be found in the publication "Citation of NMR Peaklist Data within Patent Applications" (see http: / / www.researchdisclosure.com / searching-disclosures, Research Disclosure Database Number 605005, 2014, 01 August 2014). In the peak picking program, as described in Research Disclosure Database Number 605005, the parameter "Minimum Height" can be adjusted from 1% to 4%. However, depending on the chemical structure and / or the concentration of the compound being tested, it may be reasonable to set the parameter "Minimum Height" to <1%.

[0480] Chemical names were generated using ACD / Name software from ACD / Labs. In some cases, generally accepted commercial reagent names were used in place of ACD / Name-generated names.

[0481] Table 1 below lists the abbreviations used in this paragraph and the Examples section, unless they are explained in the text. Other abbreviations have the meanings customary to those skilled in the art.

[0482] Table 1: Abbreviations

[0483] The following table lists the abbreviations used in this article.

[0484]

[0485]

[0486]

[0487] Other abbreviations have the meanings customary to those skilled in the art.

[0488] Various aspects of the invention described in this application are illustrated by the following examples, which are not intended to limit the invention in any way.

[0489] The example test experiments described herein serve to illustrate the invention, and the invention is not limited to the examples given.

[0490] Experimental Section - General Section

[0491] All reagents whose synthesis is not described in the experimental section are commercially available, are known compounds, or can be formed from known compounds by methods known to those skilled in the art.

[0492] The compounds and intermediates produced according to the methods of the present invention may require purification. Purification of organic compounds is well known to those skilled in the art, and there may be several methods for purifying the same compound. In some cases, purification may not be necessary. In some cases, the compound may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compound may be purified by chromatography, particularly flash column chromatography, using, for example, pre-packed silica gel columns, such as Biotage SNAP cartidges. or Combined with Biotage autopurifier system ( or Isolera ) and eluents such as a gradient of hexane / ethyl acetate or dichloromethane / methanol. In some cases, the compound can be purified by preparative HPLC using, for example, a Waters autopurifier equipped with a diode array detector and / or an online electrospray ionization mass spectrometer in combination with a suitable pre-packed reverse phase column and an eluent gradient of, for example, water and acetonitrile, which may contain additives such as trifluoroacetic acid, formic acid, or aqueous ammonia.

[0493] In some cases, the purification methods described above can provide those compounds of the invention having sufficiently basic or acidic functional groups in the form of salts, for example, in the case where the compound of the invention is sufficiently basic, such as trifluoroacetate or formate, or in the case where the compound of the invention is sufficiently acidic, such as ammonium salts. Salts of this type can be converted to their free base or free acid forms, respectively, by various methods known to those skilled in the art, or used as salts in subsequent bioassays. It should be understood that the particular form of the compound of the invention isolated and described herein (e.g., salt, free base, etc.) is not necessarily the only form in which the compound can be used in a bioassay to quantify a particular biological activity.

[0494] Analytical methods

[0495] LC-MS Method 1:

[0496]

[0497]

[0498] LC-MS Method 3:

[0499]

[0500] Preparative HPLC

[0501] a) Automatic purifier: acidic conditions

[0502]

[0503] b) Automatic purifier: alkaline conditions

[0504]

[0505] Experimental Section - General Procedures

[0506] Experimental Part - Intermediates

[0507] Intermediate 1

[0508] 6-Bromo-2-methylpyrido[2,3-d]pyrimidin-4-ol

[0509]

[0510] A solution of 2-amino-5-bromonicotinic acid (5.00 g, 23.0 mmol), acetamidine hydrochloride (7.62 g, 81.0 mmol), and sodium acetate (6.62 g, 81.0 mmol) in 2-methoxyethanol (60 mL) was heated at 150°C for 3 days. The reaction mixture was poured into water at 0°C, and the product was collected on a sintered funnel. The title compound (4.60 g, 83%) was washed with water and dried.

[0511] LC-MS (LC-MS method 2): R t =0.43min; MS(ESIpos):m / z=242[M+H] +

[0512] 1 H-NMR (400MHz, DMSO-d6) δ [ppm]: 2.392 (16.00), 2.518 (0.46), 8.554 (3.20), 8.561 (3.45), 8.986 (3.45), 8.993 (3.08), 12.659 (0.47).

[0513] Intermediate 2

[0514] tert-Butyl (1S,4S)-5-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0515]

[0516] Using the method described in Example 7: Example 6 (6-bromo-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]pyrido[2,3-d]pyrimidin-4-amine (75.0 mg, 176 μmol), (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (69.9 mg, 353 μmol), NaOtBu (37.3 mg, 388 μmol), Pd2dba3 (13.9 mg, 17.6 μmol), XPhos (16.8 mg, 35.3 μmol) in 1,4-dioxane (1 mL) was heated at 100°C overnight to give the title compound (47.0 mg, 95% purity, 47% yield) after purification by HPLC (basic method).

[0517] LC-MS (LC-MS method 2): R t =1.38min; MS(ESIpos):m / z=543[M+H]+

[0518] 1 H NMR(DMSO-d6)δ:8.59(br s,2H),8.37(br d,2H),7.67-7.75(m,4H),7.53(d,2H),7.33(m,2H),5.70(br m,2H),4.79(br d,2H),4.52(br d,2H),3.65(br m,2H),3.36-3.43(m,3H),3.19-3.30(m,4H),2.67(m,1H),2.62(s,6H),2.52-2.53( m,1H),2.29-2.34(m,7H),1.96-2.04(m,4H),1.57(d,6H),1.41(s,9H),1.32(s,9H)

[0519] Intermediate 3

[0520] 6-(Benzylsulfanyl)-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3-d]pyrimidin-4-amine

[0521]

[0522] To a solution of Pd2(dba)3 (4.31 mg, 4.70 μmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (6.80 mg, 11.8 μmol) in 1,4-dioxane (710 μL) was added DIPEA (82 μL, 470 μmol), 6-bromo-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3-d]-pyrimidin-4-amine (Example 6, 100 mg, 235 μmol) and benzyl mercaptan (30 μL, 260 μmol). The mixture was stirred at 100 ° C overnight. Then, water and ethyl acetate were added, and the organic phase was washed with saturated NaHCO3 solution and brine, filtered and concentrated under reduced pressure. Purification by flash column chromatography (hexanes / ethyl acetate) gave the title compound (108 mg, 90% purity, 88% yield).

[0523] LC-MS (LC-MS method 2): R t =1.45min; MS(ESIpos):m / z=469.5[M+H] +

[0524] 1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.154(0.89),1.172(1.80),1.189(0.89),1.546(4.91),1 .563(4.91),1.987(3.52),2.331(0.67),2.359(16.00),2.518(3.73),2.523(2.43),2.608 (6.02),2.673(0.62),4.017(0.79),4.035(0.79),4.325(0.70),4.358(3.70),4.370(3.65),4.402(0.70),5.684(0.74),5.701(1.15),5.718(0.74),7.205(0.41),7.222(1.49),7.2 29(0.53),7.235(0.72),7.240(1.55),7.244(0.88),7.260(1.76),7.263(0.95),7.274(1.38),7.279(3.80),7.291(0.62),7.296(2.19),7.299(1.59),7.311(3.28),7.314(3.69),7 .331(1.78),7.336(1.21),7.355(0.68),7.375(1.49),7.395(0.92),7.545(1.61),7.564(1.29),7.738(1.44),7.757(1.28),8.788(1.24),8.807(2.00),8.815(8.12),8.821(1.32).

[0525] Intermediate 4

[0526] 2-Methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidine-6-sulfonyl chloride

[0527]

[0528] To a solution of 6-(benzylsulfanyl)-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]-ethyl}pyrido[2,3-d]pyrimidin-4-amine (Intermediate 3, 108 mg, 230 μmol) in MeCN (1.2 mL), acetic acid (130 μL) and water (58 μL) was added 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (227 mg, 1.15 mmol) at 0°C and the mixture was stirred at 0°C for 1 hour. The mixture was diluted with dichloromethane and water, and the organic phase was washed with saturated NaHCO solution and brine, filtered through a hydrophobic filter and concentrated under reduced pressure. The crude product (244 mg, 42% purity, 100% yield) was used in the subsequent step without further purification.

[0529] Intermediate 5

[0530] 6-Bromo-2,7-dimethyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3-d]pyrimidin-4-amine

[0531]

[0532] To a solution of 6-bromo-2,7-dimethylpyrido[2,3-d]pyrimidin-4-ol (Intermediate 39, 500 mg, 1.97 mmol), pyBOP (1.33 g, 2.56 mmol), and (1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethan-1-amine (480 mg, 2.36 mmol) in DMF (15 mL) was added DBU (1.2 mL, 7.9 mmol), and the reaction mixture was stirred at room temperature overnight. Water was added, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over Na2SO4. Purification by flash column chromatography and recrystallization from DMSO gave the title compound (460 mg, 53% yield).

[0533] LC-MS (LC-MS method 2): R t =1.36min; MS(ESIpos):m / z=439[M+H] +

[0534] 1 H NMR (chloroform-d) δ: 8.48 (s, 1H), 7.60 (d, 1H), 7.51 (d, 1H), 7.20 (m, 1H), 6.75 (brd, 1H), 5.83 (m, 1H), 2.51-2.80 (m, 16H), 1.87 (br s, 2H), 1.62 (d, 3H), 1.19-1.30 (m, 1H)

[0535] Intermediate 6

[0536] 6-Bromo-N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-2,7-dimethylpyrido[2,3-d]pyrimidin-4-amine

[0537]

[0538] To a solution of 6-bromo-2,7-dimethylpyrido[2,3-d]pyrimidin-4-ol (Intermediate 39, 500 mg, 1.97 mmol), pyBOP (1.33 g, 2.56 mmol) and (1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethan-1-amine hydrochloride (1 / 1) (511 mg, 2.26 mmol) in DMF (17 mL) was added DBU (1.2 mL, 7.9 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with water and ethyl acetate, and the organic phase was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography gave the title compound (651 mg, 95% purity, 74% yield).

[0539] 1 H NMR(DMSO-d6)δ:9.15(s,4H),8.80(br d,4H),7.68(m,4H),7.45-7.54(m,4H),7.35-7.40(m,1H),7.23-7.32(m,6H),7.10(s,1H),5.75(m,4H),4.03(m,2H), 2.67-2.70(m,11H),2.52-2.53(m,2H),2.33-2.38(m,11H),1.98-2.00(m,3H),1.59(d,11H),1.52(d,1H),1.17(m,3H)

[0540] Intermediate 7

[0541] 2-Acetamido-5-bromo-6-(trifluoromethyl)pyridine-3-carboxylic acid methyl ester

[0542]

[0543] A solution of methyl 2-amino-5-bromo-6-(trifluoromethyl)picolinate (5.00 g, 16.7 mmol) and DMAP (20.4 mg, 167 μmol) in AcO (330 mL, 3.5 mol) was heated at 100° C. for 2 days. The mixture was concentrated under reduced pressure and used in the next step without further purification (5.7 g, 16.7 mmol).

[0544] LCMS (LC-MS method 2): R t =1.13min; MS(ESIpos):m / z=343[M+H] +

[0545] Intermediate 8

[0546] 6-Bromo-2-methyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-4-ol

[0547]

[0548] A solution of methyl 2-acetamido-5-bromo-6-(trifluoromethyl)pyridine-3-carboxylate (Intermediate 7, 5.70 g, 16.7 mmol) in ammonium hydroxide (30%, 500 mL, 170 mmol) was stirred at room temperature overnight. The mixture was carefully concentrated under reduced pressure and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The title compound (3.60 g, 70% yield) was obtained by flash column chromatography (hexane / ethyl acetate).

[0549] LC-MS (LC-MS method 2): R t =0.57min; MS(ESIneg):m / z=308[MH] -

[0550] 1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.154(1.02),1.171(2.17),1.189(1.04),1.986(3.42 ),2.421(16.00),2.518(0.55),4.016(0.74),4.034(0.72),8.827(2.66),12.878(0.46).

[0551] Intermediate 9

[0552] 6-Bromo-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-4-amine

[0553]

[0554] To a solution of 6-bromo-2-methyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-4-ol (Intermediate 8, 250 mg, 812 μmol), (1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethan-1-amine (594 mg, 2.92 mmol) and pyBOP (1.65 g, 3.16 mmol) in DMF (6.3 mL) was added DBU (1.5 mL, 9.7 mmol) and the reaction mixture was heated to 50 ° C overnight. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The title compound (258 mg, 64% yield) was obtained after purification by flash column chromatography (hexane / ethyl acetate).

[0555] LC-MS (LC-MS method 2): R t =1.51min; MS(ESIpos):m / z=495[M+H] +

[0556] 1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.154(0.84),1.172(1.61),1.189(0.74),1.562(4.55),1.579(4.46),1.987(3.19),2. 323(0.53),2.327(0.73),2.331(0.51),2.406(16.00),2.518(2.68),2.523(1.91),2.605(5.08),2.665(0.54),2.669(0. 74),2.673(0.50),4.017(0.63),4.035(0.64),5.687(0.66),5.705(1.02),5.722(0.65),5.759(0.55),7.352(0.57),7.372(1.28),7.391(0.77),7.558(1.39),7.576(1.11),7.754(1.22),7.773(1.09),9.188(1.03),9.206(1.00),9.480(3.55)

[0557] Intermediate 10

[0558] 6-Bromo-N-{(1R)-1-[3-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-difluoroethyl)-2-fluorophenyl]ethyl}-2-methyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-4-amine

[0559]

[0560] Using the method described for Intermediate 9: 6-Bromo-2-methyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-4-ol (Intermediate 8, 115 mg, 373 μmol), (1R)-1-[3-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-difluoroethyl)-2-fluorophenyl]ethan-1-amine (448 mg, 1.34 mmol), pyBOP (758 mg, 1.46 mmol) and DBU (670 μL, 4.5 mmol) in DMF (2.9 mL) were purified by flash column chromatography (hexanes / ethyl acetate) to give the title compound (150 mg, 64% yield).

[0561] LC-MS (LC-MS method 2): R t =1.72min; MS(ESIpos):m / z=625[M+H] +

[0562] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:0.769(0.99),0.776(16.00),0.783(0.91),0.847(0.97),1.270(0.56),1.697(1.3 1),1.715(1.29),2.084(0.96),2.508(4.64),2.616(1.28),2.620(0.89),4.227(0.64),7.368(0.53),9.599(1.09).

[0563] Intermediate 11

[0564] tert-Butyl 6-[4-({(1R)-1-[3-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-difluoroethyl)-2-fluorophenyl]ethyl}amino)-2-methyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0565]

[0566] A solution of 6-bromo-N-{(1R)-1-[3-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-difluoroethyl)-2-fluorophenyl]ethyl}-2-methyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-4-amine (Intermediate 10, 120 mg, 192 μmol), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (45.8 mg, 231 μmol), cesium carbonate (81.5 mg, 250 μmol), palladium(II) acetate (4.32 mg, 19.2 μmol) and XPhos (14.7 mg, 30.8 μmol) in toluene (2.5 mL) was heated to 120° C. overnight. The mixture was diluted with dichloromethane, filtered and concentrated. The title compound (120 mg, 84% yield) was obtained after purification by flash column chromatography (hexane / ethyl acetate).

[0567] LC-MS (LC-MS method 2): R t =1.72min; MS(ESIpos):m / z=742[M+H] +

[0568] 1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.021(2.52),-0.015(2.53),0.037(0.53),0.049(0 .53),0.754(0.66),0.761(8.86),0.768(0.68),0.771(1.01),0.778(16.00),0.786(1 .05),0.828(1.79),0.959(0.52),0.976(0.53),1.227(0.53),1.233(0.62),1.245(0.61),1.251(1.08),1.269(0.61),1.311(1.36),1.328(1.15),1.453(0.99),1.467(11. 34),1.680(0.83),1.694(1.37),1.711(1.23),2.066(1.64),2.401(0.68),2.405(1.03),2.413(4.38),2.494(2.19),2.596(3.13),2.601(2.21),2.743(0.61),2.747(0.85 ),2.752(0.58),4.160(1.00),4.182(0.47),4.215(0.66),4.303(1.79),5.837(1.99),7.004(0.52),7.344(0.55),7.494(0.42),8.059(0.81),8.074(0.44),8.095(0.44).

[0569] Intermediate 12

[0570] tert-Butyl 4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridine-1(2H)-carboxylate

[0571]

[0572] Using the method described in Example 21: 6-bromo-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]pyrido[2,3-d]pyrimidin-4-amine (Example 6, 100 mg, 235 μmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (80.0 mg, 259 μmol), bis(triphenylphosphine)palladium(II) chloride (16.5 mg, 24 μmol), and aqueous potassium carbonate solution (180 μL, 2.0 M, 350 μmol) in 1,2-dimethoxyethane (1.0 mL) and ethanol (1.0 mL) were purified by HPLC (alkaline method) to give the title compound (80.0 mg, 64% yield).

[0573] LC-MS (LC-MS method 2): R t =1.43min; MS (ESIpos): m / z=528.7

[0574] [M+H] +

[0575] 1 H NMR(DMSO-d6)δ:9.09(d,1H),8.81(d,1H),8.78(d,1H),7.76(d,1H),7.55(d,1H),7.36(m,1H),6.44(br s,1H),5.73(m,1H),4.08(br s,2H),3.62(br m,2H),3.42(s,1H),2.59-2.66(m,5H),2.52-2.53(m,3H),2.33-2.39(m,3H),1.58(d,3H),1.35-1.46(m,11H)

[0576] Intermediate 13

[0577] tert-Butyl 7-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2-azaspiro[3.5]non-6-ene-2-carboxylate

[0578]

[0579] Using the method described in Example 21: 6-bromo-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]pyrido[2,3-d]pyrimidin-4-amine (Example 6, 100 mg, 235 μmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-azaspiro[3.5]non-6-ene-2-carboxylic acid tert-butyl ester (90.3 mg, 259 μmol), bis(triphenylphosphine)palladium(II) chloride (16.5 mg, 23.5 μmol), and aqueous potassium carbonate solution (180 μL, 2.0 M, 350 μmol) in 1,2-dimethoxyethane (1.0 mL) and ethanol (1.0 mL) were purified by flash column chromatography (dichloromethane / EtOH) to give the title compound (128 mg, 96% yield).

[0580] LC-MS (LC-MS method 2): R t =1.54min; MS(ESIpos):m / z=569[M+H] +

[0581] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:1.052(0.82),1.066(1.32),1.070(0.50),1.156(1.54),1.3 88(16.00),1.565(1.66),1.582(1.61),1.944(0.84),1.959(0.42),2.363(4.98),2.518(2.4 5),2.523(1.75),2.621(2.37),6.373(0.45),7.360(0.51),7.537(0.56),7.556(0.46),7.756(0.50),7.776(0.45),8.754(0.70),8.761(0.71),8.812(0.40),9.049(0.92),9.055(0.90).

[0582] Intermediate 14

[0583] tert-Butyl 3-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2,5-dihydro-1H-pyrrole-1-carboxylate

[0584]

[0585] Using the method described in Example 21: 6-bromo-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]pyrido[2,3-d]pyrimidin-4-amine (150 mg, 353 μmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (115 mg, 388 μmol), bis(triphenylphosphine)palladium(II) chloride (25.8 mg, 35 μmol), and aqueous potassium carbonate solution (260 μL, 2.0 M, 530 μmol) in 1,2-dimethoxyethane (1.5 mL) and ethanol (1.5 mL) were maintained at 100° C. for 4 hours and purified by flash column chromatography (hexane / ethyl acetate) to give the title compound (92.0 mg, 90% purity, 46% yield).

[0586] LC-MS (LC-MS method 2): R t =1.44min; MS(ESIpos):m / z=514[M+H] +

[0587] 1H NMR(DMSO-d6)δ:9.25(d,1H),8.82-8.93(m,1H),8.68-8.74(m,1H),7.75(brd,1H),7.52-7.65(m,2H),7.37(br m,1H),6.66(br s,1H),5.72(br m,1H),4.51-4.62(m,2H),4.30(br s,2H),2.62(s,3H),2.52-2.55(m,6H),2.33-2.42(m,3H),1.54-1.63(m,3H),1.31-1.50(m,9H)

[0588] Intermediate 15

[0589] tert-Butyl 4-hydroxy-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]piperidine-1-carboxylate

[0590]

[0591] To a solution of 6-bromo-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}-pyrido[2,3-d]pyrimidin-4-amine (200 mg, 470 μmol) in THF (5.0 mL) was added sodium hydride (60%, 28.2 mg, 705 μmol) at room temperature, and the mixture was stirred for 10 minutes. Then, n-butyllithium (2.5 M in hexane, 280 μL) was added at -40°C, and the mixture was stirred for 45 minutes. Then, a solution of tert-butyl 4-oxopiperidine-1-carboxylate (281 mg, 1.41 mmol) in THF (2.0 mL) was added dropwise at -40°C, and the mixture was stirred for 1 hour, then slowly warmed to 0°C over 2 hours. A saturated solution of NH4Cl was then carefully added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The title compound (4.90 mg, 95% purity, 2% yield) was obtained after purification by HPLC (basic method) and preparative TLC (dichloromethane / EtOH).

[0592] LC-MS (LC-MS method 2): R t =1.35min; MS(ESIpos):m / z=546[M+H] +

[0593] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:1.427(16.00),1.560(1.80),1.578(1.79),1.736(0. 44),1.771(0.53),2.363(6.12),2.518(0.61),2.523(0.42),2.625(2.32),3.166(0.7 6),5.723(0.43),7.359(0.57),7.533(0.63),7.552(0.50),7.760(0.56),7.779(0.50),8.837(0.83),8.843(0.86),8.897(0.46),8.914(0.44),9.089(1.18),9.095(1.13).

[0594] Intermediate 16

[0595] tert-Butyl 3-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]azetidine-1-carboxylate

[0596]

[0597] A solution of 6-bromo-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}-pyrido[2,3-d]pyrimidin-4-amine (150 mg, 353 μmol), Pd(dppf)Cl2·CH2Cl2 (115 mg, 141 μmol), and copper(I) iodide (13.4 mg, 70.5 μmol) in DMA (4 mL) was heated to 85°C for 5 minutes. Simultaneously, a solution of tert-butyl 3-iodoazetidine-1-carboxylate (499 mg, 1.76 mmol) and zinc (118 mg, 1.80 mmol) in DMA (4 mL) was heated at 65°C for 20 minutes. After cooling to room temperature, the two mixtures were combined and heated at 85°C overnight. The mixture was diluted with ethyl acetate, filtered, washed with water and brine, and dried over Na2SO4. The mixture was concentrated under reduced pressure. Purification by flash column chromatography and preparative TLC (dichloromethane / EtOH 95:5) afforded the title compound (7.90 mg, 95% purity, 4% yield).

[0598] LC-MS (LC-MS method 2): R t =1.40min; MS(ESIpos):m / z=503[M+H] +

[0599] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:0.484(1.44),0.504(1.61),0.523(0.53),0.884(1.73),0.904(3.57),0.924( 1.38),1.419(16.00),1.570(1.63),1.587(1.60),2.327(0.57),2.331(0.42),2.364(4.55),2.518(2.56),2.5 23(1.72),2.624(2.04),2.669(0.57),2.673(0.42),4.026(0.41),4.038(0.52),4.049(0.57),4.062(0.60),4.075(0.48),7.362(0.50),7.539(0.60),7.557(0.50),7.755(0.49),7.774(0.44),8.830(1.16),8.835(1.35).

[0600] Intermediate 17

[0601] 6-Bromo-N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]-2-methylpyrido[2,3-d]pyrimidin-4-amine

[0602]

[0603] 6-Bromo-2-methylpyrido[2,3-d]pyrimidin-4-ol (Intermediate 1, 3.89 g, 16.2 mmol) and (1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethan-1-amine (16.1 g, 40% purity, 17.8 mmol) were dissolved in DMF (120 mL). PyBop (10.96 g, 21.05 mmol) and DBU (9.7 mL, 64.78 mmol) were added, and the reaction was stirred at room temperature overnight. Ethyl acetate was added to the reaction, and the organic phase was washed twice with water and with saturated NaCl solution. The organic phase was dried, and the compound was purified by flash column chromatography, first on SiO2 and then on a basic column, to give the title compound (5.55 g, 59% yield).

[0604] LC-MS (LC-MS method 2): R t =1.72min; MS(ESIpos):m / z=583[M+H] +

[0605] 1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.384(1.14),0.387(1.21),0.405(5.21),0.417(0.57),0.425(7.62),0.434(0.56),0.444(2.69),0.6 63(7.57),0.674(0.88),0.682(16.00),0.691(1.14),0.703(5.64), 1.323(3.86),1.332(4.28),1.566(2.95),1.584(2.98),2.367(11.8 4),2.518(5.24),2.523(3.80),3.321(0.48),5.753(0.44),5.770(0.71),5.788(0.46),7.199(0.41),7.218(1.02),7.238(0.73),7.272(0.40),7.276(0.50),7.293(0.64),7.622(0.62),8.790(0.76),8.808(0.74),8.991(2.74),8.998(2.85),9.199(2.02),9.205(1.92).

[0606] Intermediate 18

[0607] 1-(3-{(1R)-1-[(6-bromo-2-methylpyrido[2,3-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol

[0608]

[0609] 6-Bromo-N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]-2-methylpyrido[2,3-d]pyrimidin-4-amine (Intermediate 17, 1.00 g, 1.71 mmol) and triethylsilane (27 μL, 170 mol) were dissolved in dichloromethane (15 mL). TFA (2.0 mL, 26 mmol) was added dropwise at room temperature. The mixture was stirred at room temperature overnight. Toluene was added to the mixture and the solvent was evaporated. The crude product was purified by silica gel flash column chromatography to give the title compound (815 mg, quantitative).

[0610] LC-MS (LC-MS method 2): R t =1.15min; MS(ESIpos):m / z=469[M+H] +

[0611] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:1.154(1.56),1.171(3.19),1.189(1.97),1.202(6.12),1.226(6.30),1.563(4.72),1.580(4.71),1.986(5.1 3),2.326(1.02),2.332(0.76),2.368(16.00),2.518(4.80),2.522(3. 15),2.669(1.03),2.673(0.74),4.017(1.18),4.034(1.19),5.338(2.2 2),5.731(0.73),5.748(1.14),5.766(0.72),7.197(0.70),7.216(1.68),7.235(1.06),7.299(0.64),7.303(0.73),7.321(1.06),7.336(0.51),7.340(0.46),7.588(0.59),7.604(1.04),7.620(0.54),8.803(1.25),8.821(1.19),8.995(3.68),9.002(3.64),9.196(3.17),9.202(2.98).

[0612] Intermediate 19

[0613] tert-Butyl 4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridine-1(2H)-carboxylate

[0614]

[0615] A mixture of 1-(3-{(1R)-1-[(6-bromo-2-methylpyrido[2,3-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (Intermediate 18, 200 mg, 426 μmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (158 mg, 511 μmol), bis(triphenylphosphine)palladium(II) dichloride (29.9 mg, 43 μmol) and potassium carbonate (88.3 mg, 639 μmol) in DME (1.9 mL) and EtOH (1.9 mL) was purged with argon and heated in a microwave at 100 °C for 6 h. The mixture was filtered through a syringe filter, concentrated under reduced pressure and purified by HPLC (basic method) to give the title compound (152 mg, 62% yield) as a white solid.

[0616] LC-MS (LC-MS method 2): R t =1.27min; MS(ESIpos):m / z=573[M+H] +

[0617] 1 H NMR(400MHz,DMSO-d6)δppm 9.10(d)8.80(d)8.72(d)7.60(t)7.32(t)7.22(t)6.44(br s)5.80(quin)5.34(s)4.09(br s)3.62(br t)2.57-2.68(m)2.52-2.57(m)2.37(s)1.60(d)1.44(s)1.22(d)

[0618] Intermediate 20

[0619] tert-Butyl 3-(4-{[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]amino}-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0620]

[0621] 6-Bromo-N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]-2-methylpyrido[2,3-d]pyrimidin-4-amine (Intermediate 17, 100 mg, 171 μmol) and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (51.0 mg, 257 μmol) were dissolved in dioxane (2.5 mL). Sodium tert-butoxide (65.9 mg, 0.034 mmol) was added, followed by XPhos (16.3 mg, 34.3 μmol). The atmosphere was changed to argon and Pd2(dba)3 (15.7 mg, 17.1 μmol) was added. The mixture was heated to 100°C overnight. The mixture was cooled to room temperature, diluted with dichloromethane and filtered. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel to give the title compound (61.1 mg, 51% yield).

[0622] LC-MS (LC-MS method 2): R t =1.70min; MS(ESIpos):m / z=701[M+H] +

[0623] 1 H NMR(400MHz,DMSO-d6)δppm 8.70(d)8.38(br d)7.77-7.83(m)7.55-7.65(m)7.16-7.32(m)5.77-5.87(m)4.28(br d)3.89-4.04(m)3.38-3.53(m)2.54-2.68(m)2.28-2.45(m)1.42-1.65(m)1.31-1.35(m)1.27(s)0.61-0.86(m)0.34-0.51(m)

[0624] Intermediate 21

[0625] tert-Butyl (1S,4S)-5-(4-{[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]amino}-2-methylpyrido[2,3-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0626]

[0627] 6-Bromo-N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]-2-methylpyrido[2,3-d]pyrimidin-4-amine (Intermediate 17, 100 mg, 171 μmol) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (51.0 mg, 257 μmol) were dissolved in dioxane (2.5 mL). Sodium tert-butoxide (65.9 mg, 0.685 mmol) was added, followed by XPhos (16.3 mg, 34.3 μmol). The atmosphere was changed to argon and Pd2(dba)3 (15.7 mg, 17.1 μmol) was added, and the mixture was heated to 100°C overnight. The mixture was cooled to room temperature, diluted with dichloromethane and filtered. The solvent was evaporated. The residue was purified by silica gel flash column chromatography to give the title compound (76.3 mg, 64% yield).

[0628] LC-MS (LC-MS method 2): R t =1.70min; MS(ESIpos):m / z=701[M+H] +

[0629] 1 H NMR(400MHz,DMSO-d6)δppm 8.61(br s)8.25(br d)7.71(br d)7.53-7.62(m)7.27(t)7.15-7.24(m)5.79(quin)4.76-4.83(m)4.52(br d)3.61-3.70(m)3.37-3.45(m)3.18-3.31(m)2.52-2.57(m)2.34-2.46(m)2.28-2 .31(m)1.95-2.05(m)1.44-1.65(m)1.41(s)1.29-1.36(m)0.63-0.74(m)0.42(q)

[0630] Intermediate 22

[0631] tert-Butyl (1R,4R)-5-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0632]

[0633] 1-(3-{(1R)-1-[(6-bromo-2-methylpyrido[2,3-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (Intermediate 18, 100 mg, 213 μmol) and tert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (50.7 mg, 256 μmol) were dissolved in dioxane (3.0 mL). Sodium tert-butoxide (28.7 mg, 0.298 mmol) was added, followed by XPhos (20.3 mg, 42.6 μmol). The atmosphere was replaced with argon and Pd2dba3 (19.5 mg, 21.3 μmol) was added. The mixture was heated to 100°C overnight. The mixture was cooled to room temperature, saturated brine was added, and then ethyl acetate was added. The aqueous phase was extracted with ethyl acetate. The organic phase was dried and the solvent was evaporated. The residue was purified by flash column chromatography on silica gel to give the title compound (45 mg, 36% yield).

[0634] LC-MS (LC-MS method 2): R t =1.20min; MS(ESIpos):m / z=587[M+H] +

[0635] 1 H NMR(400MHz,DMSO-d6)δppm 8.63(d)7.70-7.79(m)7.56-7.63(m)7.32(t)7.19-7.26(m)5.75-5.83(m)5.32-5.36(m)4.79(br d)4.53(br d)3.62-3.72(m)3.36-3.45(m)3.17-3.30(m)2.52-2.54(m)2.33-2.46(m)1.95-2.06(m)1.55-1.66(m)1.40(s)1.33(s)1.21(br d)

[0636] Intermediate 23

[0637] N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]-2-methyl-6-(4-methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-4-amine

[0638]

[0639] 6-Bromo-N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]-2-methylpyrido[2,3-d]pyrimidin-4-amine (Intermediate 17, 57.0 mg, 97.7 μmol) and 1-methylpiperazine (33 μL, 290 μmol) were dissolved in dioxane (1.5 mL). Sodium tert-butoxide (37.5 mg, 0.391 mmol) was added, followed by XPhos (9.31 mg, 19.5 μmol). The atmosphere was changed to argon and Pd2dba3 (8.94 mg, 9.77 μmol) was added, and the mixture was heated to 100°C overnight. The mixture was cooled to room temperature, dichloromethane was added and filtered. The solvent was evaporated. The crude product was purified by preparative TLC using dichloromethane / MeOH 1 / 1 as eluent to afford the title compound (36.0 mg, 61% yield).

[0640] LC-MS (LC-MS method 2): R t =1.61min; MS(ESIpos):m / z=603[M+H] +

[0641] 1 H NMR(400MHz,DMSO-d6)δppm 8.85(d)8.41(d)8.04(d)7.59(t)7.28(t)7.21(t)5.76-5.84(m)3.38-3.46(m)3.31-3.31(m)2.67 (dt)2.52-2.55(m)2.30-2.34(m)2.26(s)1.47-1.64(m)1.21-1.38(m)0.63-0.75(m)0.38-0.48(m)

[0642] Intermediate 24

[0643] 1-[4-(4-{[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]amino}-2-methylpyrido[2,3-d]pyrimidin-6-yl]piperazin-1-yl]ethan-1-one

[0644]

[0645] 6-Bromo-N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]-2-methylpyrido[2,3-d]pyrimidin-4-amine (Intermediate 17, 138 mg, 236 μmol) and 1-(piperazin-1-yl)ethan-1-one (60.6 mg, 473 μmol) were dissolved in dioxane (3.5 mL). Sodium tert-butoxide (90.9 mg, 946 μmol) and XPhos (22.5 mg, 47.3 μmol) were added, the atmosphere was changed to argon, and Pd2dba3 (21.7 mg, 23.6 μmol) was added. The mixture was heated to 100°C overnight. The mixture was cooled to room temperature, dichloromethane was added, and the mixture was filtered. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel to give the title compound (46.0 mg, 31% yield).

[0646] LC-MS (LC-MS method 2): R t =1.54min; MS(ESIpos):m / z=632[M+H] +

[0647] 1 H NMR(400MHz,DMSO-d6)δppm 8.89(d)8.43(d)8.09(d)7.59(br t)7.25-7.31(m)7.21(t)5.77-5.84(m)3.66(q)3.36-3.47(m)3.23-3.30( m)2.67(dt)2.52-2.52(m)2.32-2.43(m)2.32(s)2.08(s)1.59(d)1.33(br d)0.66-0.73(m)0.38-0.48(m)

[0648] Intermediate 25

[0649] tert-Butyl 6-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0650]

[0651] 1-(3-{(1R)-1-[(6-bromo-2-methylpyrido[2,3-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (Intermediate 18, 100 mg, 213 μmol) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (50.7 mg, 256 μmol) were dissolved in dioxane (3.0 mL). Sodium tert-butoxide (28.7 mg, 298 μmol) and XPhos (20.3 mg, 42.6 μmol) were added, the atmosphere was changed to argon, and Pd2dba3 (19.5 mg, 21.3 μmol) was added. The mixture was heated to 100°C overnight. Saturated brine and ethyl acetate were added. The aqueous phase was extracted with ethyl acetate. The organic phase was dried and the solvent was evaporated. The residue was purified by flash column chromatography on silica gel to give the title compound (69.0 mg, 95% purity, 52% yield).

[0652] LC-MS (LC-MS method 2): R t =1.22min; MS(ESIpos):m / z=587[M+H] +

[0653] 1 H NMR(400MHz,DMSO-d6)δppm 8.37(d)7.74(d)7.59(br t)7.32(t)7.24(t)5.76-5.85(m)5.34(s)4.12-4.19(m)4.08(br s)2.52-2.55(m)2.33-2.40(m)1.61(d)1.39(s)1.15-1.30(m)

[0654] Intermediate 26

[0655] 2-(4-{[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]amino}-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl)-1λ 6 ,2-thiazolidine-1,1-dione

[0656]

[0657] Using the method described in Example 33: 6-bromo-N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]-2,7-dimethylpyrido[2,3-d]pyrimidin-4-amine (Intermediate 40, 65.0 mg, 109 μmol), 1λ6 ,2-thiazolidine-1,1-dione (15.8 mg, 131 μmol), copper (I) iodide (4.14 mg, 21.8 μmol), trans-N,N-dimethylcyclohexane-1,2-diamine (3.09 mg, 21.8 μmol) and potassium carbonate (30.1 mg, 218 μmol) were reacted at 100 ° C overnight to give the title compound, which was used directly in the subsequent step.

[0658] Intermediate 27

[0659] 1-[6-(4-{[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]amino}-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl)-2,6-diazaspiro[3.3]hept-2-yl]ethan-1-one

[0660]

[0661] Using the method described in Example 7, intermediate 40 (6-bromo-N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]-2,7-dimethylpyrido[2,3-d]pyrimidin-4-amine, 100 mg, 167 μmol), oxalic acid / 1-(2,6-diazaspiro[3.3]heptyl)-1-[[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]-2,7-dimethylpyrido[2,3-d]pyrimidin-4-amine, 100 mg, 167 μmol) in 1,4-dioxane (2.0 ml) was added. -2-yl)ethan-1-one (1 / 2) (93.0 mg, 251 μmol), sodium tert-butoxide (80.4 mg, 837 μmol), XPhos (16.0 mg, 33.5 μmol), Pd2(dba)3 (15.3 mg, 16.7 μmol) were subjected to preparative TLC with dichloromethane / methanol (1:1) as eluent to give 49.0 mg (45% yield) of the title compound.

[0662] LC-MS (LC-MS method 2): R t =1.56min; MS(ESIpos):m / z=657[M+H] +

[0663] 1H NMR(400MHz,DMSO-d6)δppm 8.36(br d)7.65(s)7.58(t)7.24-7.31(m)7.12-7.24(m)5.74-5.84(m)4.34(s)4.12-4.26(m )4.05(s)2.52-2.62(m)2.45-2.47(m)2.26-2.32(m)1.67-1.81(m)1.58(d)1.34(br d)0.63-0.76(m)0.37-0.50(m).

[0664] Intermediate 28

[0665] tert-Butyl 4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-3-oxopiperazine-1-carboxylate

[0666]

[0667] Using the procedure described in Example 33, intermediate 6 (6-bromo-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]pyrido[2,3-d]pyrimidin-4-amine (75.0 mg, 176 μmol), tert-butyl 3-oxopiperazine-1-carboxylate (35.3 mg, 176 μmol), copper (I) iodide (10.1 mg, 52.9 μmol), trans-N,N-dimethylcyclohexane-1,2-diamine (7.53 mg, 52.9 μmol) and K3PO4 (75 mg, 353 μmol) in 1,4-dioxane (1 ml) were heated at 100°C overnight to give the title compound, which was used directly in the subsequent step.

[0668] Intermediate 29

[0669] tert-Butyl 4-(4-{[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]amino}-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl)-5-methyl-3,6-dihydropyridine-1(2H)-carboxylate

[0670]

[0671] Using the method described in Example 21, intermediate 40 (6-bromo-N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]-2,7-dimethylpyrido[2,3-d]pyrimidin-4-amine (250 mg, 418 μmol), 5-methyl-4-(4,4,5, Tert-butyl 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (149 mg, 460 μmol), bis(triphenylphosphine)-palladium(II) chloride (59 mg, 84 μmol) and potassium carbonate (86.7 mg, 628 μmol) were subjected to silica gel flash column chromatography using dichloromethane and ethanol (9:1) as eluent to give the title compound (41.1 mg (14% yield).

[0672] LC-MS (LC-MS method 2): R t =1.83min; MS(ESIpos):m / z=714[M+H] +

[0673] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:0.381(0.44),0.385(0.48),0.391(0.55),0 .395(0.61),0.402(1.68),0.413(1.92),0.423(2.45),0.433(2.59),0.442( 1.25),0.452(1.09),0.665(3.39),0.668(3.40),0.684(6.38),0.687(6.59) ,0.704(2.44),0.707(2.40),1.322(3.32),1.335(1.66),1.412(1.48),1.42 4(1.63),1.448(16.00),1.541(1.91),1.559(1.89),2.270(0.59),2.323(0.59),2.327(0.84),2.331(0.77),2.339(3.74),2.345(3.51),2.440(5.75),2.518(2.78),2.523(1.90),2.665(0.68),2.669(0.71),2.673(0.49),7.204(0.40),7.218(0.41),7.278(0.42),7.595(0.40),8.477(0.93),8.493(0.90).

[0674] Intermediate 30

[0675] 1-[4-(4-{[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]amino}-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]piperazin-1-yl]ethan-1-one

[0676]

[0677] Using the method described in Example 7, intermediate 40 (6-bromo-N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]-2,7-dimethylpyrido[2,3-d]pyrimidin-4-amine (100 mg, 167 μmol), 1-(piperazin-1-yl)ethan-1-one (32.2 mg, 251 μmol), sodium tert-butoxide (69.5 mg, 723 μmol), XPhos (16.0 mg, 33.5 μmol), Pd2(dba)3 (15.3 mg, 16.7 μmol) in 1,4-dioxane (1.5 ml) was subjected to preparative TLC using dichloromethane / ethanol (9:1) as eluent to give the title compound (31.0 mg, 29% yield).

[0678] LC-MS (LC-MS method 2): R t =1.59min; MS(ESIpos):m / z=645[M+H] +

[0679] 1 H NMR(400MHz,DMSO-d6)δppm 8.45(d)8.32(s)7.54-7.61(m)7.12-7.31(m)5.74-5.84(m)3.60-3.71(m)3.37-3.49(m)3.16-3.30(m)2 .87-3.00(m)2.67(dt)2.60(s)2.52-2.52(m)2.29-2.36(m)2.07(s)2.01-2.07(m)1.46-1.64(m)1.33(br d)0.64-0.73(m)0.36-0.49(m).

[0680] Intermediate 31

[0681] tert-Butyl (1S,4S)-5-(4-{[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]amino}-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0682]

[0683] Using the method described in Example 7, intermediate 40 (6-bromo-N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]-2,7-dimethylpyrido[2,3-d]pyrimidin-4-amine (135 mg, 244 μmol), (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (72.6 mg, 366 μmol), sodium tert-butoxide (93.8 mg, 976 μmol), XPhos (23.3 mg, 48.8 μmol), and Pd2(dba)3 (22.3 mg, 24.4 μmol) in 1,4-dioxane (2.5 ml) was purified by silica gel flash column chromatography (ethyl acetate / hexane) to give the title compound (28.0 mg, 16% yield).

[0684] LC-MS (LC-MS method 2): Rt = 1.72 min; MS (ESIpos): m / z = 715 [M+H] +

[0685] 1H NMR(400MHz,DMSO-d6)δppm 8.28-8.39(m)7.55(br t)7.08-7.33(m)5.75-5.86(m)4.44-4.50(m)4.43(br s)3.63-3.71(m)3.36-3.51(m)2.67(dt)2.52-2.58(m)2.27-2.35(m)1 .90-2.00(m)1.45-1.62(m)1.21-1.44(m)0.61-0.85(m)0.31-0.53(m).

[0686] Intermediate 32

[0687] tert-Butyl 4-(4-{[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]amino}-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0688]

[0689] Using the procedure described in Example 21, intermediate 31 (6-bromo-N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]-2,7-dimethylpyrido[2,3-d]pyrimidin-4-amine (200 mg, 335 μmol), 4-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (114 mg, 368 μmol), bis(triphenylphosphine)-palladium(II) chloride (23 mg, 33 μmol) and potassium carbonate (69.4 mg, 502 μmol) were obtained after silica gel flash column chromatography (ethyl acetate / hexane) to give the title compound (116 mg, 50% yield).

[0690] LC-MS (LC-MS method 2): R t =1.76min; MS(ESIpos):m / z=701[M+H] +

[0691] 1 H NMR(400MHz, DMSO-d6)δppm 8.51-8.60(m)7.52-7.65(m)7.25-7.30(m)7.21(t)5.75-5.83(m)4.00-4.06(m)3.61(br t)2.52-2.68(m)2.40(br s)2.31-2.36(m)1.56(d)1.45(s)1.33(br d)0.65-0.73(m)0.38-0.48(m).

[0692] Intermediate 33

[0693] tert-Butyl 6-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0694]

[0695] Using the method described in Example 2, intermediate 33 (6-bromo-N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-2-methyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-4-amine (100 mg, 209 μmol), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (45.5 mg, 230 μmol), cesium carbonate (81.6 mg, 250 μmol), Xphos (7.96 mg, 16.7 μmol), palladium(II) acetate (2.34 mg, 10.4 μmol) in toluene (2.7 ml) was subjected to silica gel flash column chromatography (ethyl acetate / hexane) to give the title compound (40.0 mg, 32% yield).

[0696] LC-MS (LC-MS method 2): R t =1.44min; MS(ESIpos):m / z=598[M+H] +

[0697] Intermediate 34

[0698] tert-Butyl 6-[4-{[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]amino}-2-methyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0699]

[0700] Using the method described in Example 2, intermediate 34 (6-bromo-N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]-2-methyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-4-amine (70.0 mg, 107 μmol), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (23.4 mg, 118 μmol), cesium carbonate (42.0 mg, 129 μmol), XPhos (4.10 mg, 8.59 μmol), palladium(II) acetate (1.21 mg, 5.37 μmol) in toluene (1.4 ml) gave the title compound (80 mg) which was used directly in the subsequent step.

[0701] Intermediate 35

[0702] tert-Butyl 6-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0703]

[0704] Using the method described in Example 2, intermediate 35 (6-bromo-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-4-amine (60.0 mg, 122 μmol), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (36.2 mg, 182 μmol), cesium carbonate (63.4 mg, 195 μmol), XPhos (4.64 mg, 9.73 μmol), palladium(II) acetate (1.37 mg, 6.08 μmol) in toluene (1.6 ml) was subjected to preparative HPLC (basic method) to give the title compound (20.0 mg, 27% yield).

[0705] LC-MS (LC-MS method 2): R t =1.53min; MS(ESIpos):m / z=612[M+H] +

[0706] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:1.390(16.00),1.577(1.66),1.594(1.65),2. 323(0.97),2.328(6.13),2.518(3.37),2.523(2.45),2.608(2.12),2.665(0.6 7),2.669(0.96),2.673(0.68),4.080(1.35),4.227(1.96),7.367(0.54),7.54 6(0.59),7.565(0.47),7.738(0.51),7.757(0.46),7.970(1.18),8.891(0.41).

[0707] Intermediate 36

[0708] 2-Amino-5-bromo-6-methoxynicotinamide

[0709]

[0710] To a solution of 2-amino-6-methoxynicotinamide (CAS 1298123-77-9, 30 g, 175 mmol) in N,N-dimethylformamide was added N-bromosuccinimide at 25° C., and the reaction mixture was stirred for 2 hours at 25° C. The mixture was concentrated, and the residue was washed with water (200 ml) and dried under reduced pressure to give the title compound (19 g, 65%) as a brown solid.

[0711] LC-MS (LC-MS method 3): R t =0.80min; MS(ESIpos):m / z=244.0 / 246.0[M+H] +

[0712] Intermediate 37

[0713] 6-Bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4-ol

[0714]

[0715] A mixture of intermediate 36 (5 g, 20.3 mmol), 2-methoxyethanol (3 ml), and 1,1,1-triethoxyethane (50 ml) was stirred at 120°C for 2 hours. The mixture was cooled to room temperature and the resulting suspension was filtered. The filter cake was washed with methanol to give the title compound (2.9 g, 53%) as a brown solid.

[0716] LC-MS (LC-MS method 3): R t =0.67min; MS(ESIpos):m / z=269.8 / 271.8[M+H] +

[0717] Intermediate 38

[0718] 6-Bromo-7-methoxy-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3-d]pyrimidin-4-amine

[0719]

[0720] To a solution of 6-bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4-ol (Intermediate 37, 2.5 g, 9.3 mmol), (1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethan-1-amine (1.2 g, 11.1 mmol), and pyBOP (6.3 g, 12.0 mmol) in DMF (47 mL) was added DBU (5.5 mL, 37.0 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with dichloromethane. The organic phase was washed with water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The title compound (4.2 g, 99% yield) was obtained after purification by flash column chromatography (hexane / ethyl acetate).

[0721] LC-MS (LC-MS method 2): R t =0.67min; MS(ESIpos):m / z=453.4 / 455.4[M+H] +

[0722] 1 H NMR(400MHz,DMSO-d6)δppm 9.10(s)8.49-8.65(m)8.42-8.47(m)7.86(d)7.74(d)7.43-7.62(m)7.32-7.42(m)5.65(quin)4.32(q)3.99-4.08(m)3.99(s)3.7 0-3.83(m)3.48-3.69(m)3.05-3.31(m)2.57-2.61(m)2.36-2.48(m)2.32(s)1.89-1.96(m)1.66-1.88(m)1.52(d)1.14-1.43(m).

[0723] Intermediate 39

[0724] 6-Bromo-2,7-dimethylpyrido[2,3-d]pyrimidin-4-ol

[0725]

[0726] Step 1: 2-Amino-5-bromo-6-methylnicotinic acid

[0727] To a solution of methyl-2-amino-5-bromo-6-methylnicotinate trifluoroacetate (15.1 g, 92% purity, 38.7 mmol) in methanol (77 ml) was added aqueous sodium hydroxide solution (5%, 147 ml, 193 mmol), and the mixture was stirred at room temperature overnight. The methanol was then removed under reduced pressure, and the residue was stirred with 2.5 M hydrochloric acid until the pH was adjusted to pH 7-8. The pH was then adjusted to pH 4-5 with acetic acid, and the resulting precipitate was filtered, washed with water and tert-butyl methyl ether, and dried in vacuo at 70°C. The crude product was used directly in the subsequent reaction.

[0728] Step 2: 6-Bromo-2,7-dimethylpyrido[2,3-d]pyrimidin-4-ol

[0729] To a solution of the crude product from the previous reaction and acetamidine hydrochloride (1:1) (11 g, 116 mmol) in sulfolane (20 ml) and 2-methoxyethanol (80 ml) was added sodium acetate (8.5 g, 104 mmol), and the mixture was stirred at 140°C for 3 days. The 2-methoxyethanol was removed under reduced pressure, and sulfolane (80 ml), acetamidine hydrochloride (1:1) (8.7 g, 93 mmol), and sodium acetate (6.6 g, 81 mmol) were added. The mixture was stirred at 140°C overnight, at 160°C for 1 day, and at 175°C for 2 days. After cooling to room temperature, the mixture was poured into ice water (1.5 L), and the resulting precipitate was filtered, washed with water, and dried in a vacuum oven at 70°C overnight to yield 3.1 g (51%) of the title compound. The filtrate of the reaction mixture was concentrated under reduced pressure until further solid precipitation occurred. The solid was filtered, washed, and dried as above to afford another crop of the desired product (1.78 g, 30%).

[0730] LC-MS (LC-MS method 1): R t =0.71min; MS(ESIpos):m / z=254.0 / 256.0[M+H] +

[0731] 1 H NMR(400MHz,DMSO-d6)δppm 12.59(br s)8.48(s)2.68(s)2.52-2.58(m)2.38(s)

[0732] Intermediate 40

[0733] 6-Bromo-N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]-2,7-dimethylpyrido[2,3-d]pyrimidin-4-amine

[0734]

[0735] To a solution of 6-bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4-ol (Intermediate 37, 2.5 g, 9.3 mmol), (1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethan-1-amine (1.14 g, 3.1 mmol), and pyBOP (1.4 g, 2.7 mmol) in DMF (16 mL) was added DBU (1.25 mL, 8.4 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with dichloromethane. The organic phase was washed with water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The title compound (784 mg, 63% yield) was obtained after purification by flash column chromatography (hexane / ethyl acetate).

[0736] LC-MS (LC-MS method 2): R t =1.76min; MS(ESIpos):m / z=597.5 / 599.5[M+H] +

[0737] 1 H NMR(400MHz,DMSO-d6)δppm 9.15(s)8.72(d)7.67-7.84(m)7.61(br t)7.36-7.47(m)7.26-7.31(m)7.21(t)5.76(quin)4.62(q)2.68-2.69(m)2.52-2.52(m) 2.33-2.35(m)1.56(d)1.46(d)1.28-1.37(m)0.76-0.83(m)0.66-0.71(m)0.39-0.54(m).

[0738] Intermediate 41

[0739] 6-Bromo-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3-d]pyrimidin-4-amine

[0740]

[0741] To a suspension of 6-bromo-4-chloropyrido[2,3-d]pyrimidine (970 mg, 3.97 mmol) in DMA (6 mL) was added EtN (1.1 mL, 7.9 mmol), followed by (1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethan-1-amine (887 mg, 4.36 mmol). The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with H2O and extracted with ethyl acetate. The organic phase was washed with brine, filtered through a hydrophobic filter, and concentrated under reduced pressure. The title compound (1.46 g, 95% purity, 85% yield) was isolated after flash column chromatography (hexane / ethyl acetate).

[0742] LC-MS (LC-MS method 2): R t =1.25min; MS (ESIpos): m / z=411.3, 413.1[M+H] +

[0743] 1 H NMR(DMSO-d6)δ:9.27(d,1H),9.06(d,1H),8.94(d,1H),8.58(s,1H),7.77(d ,1H),7.57(d,1H),7.37(m,1H),5.73(m,1H),2.52-2.56(m,3H),1.56(d,3H)

[0744] Intermediate 42

[0745] 6-Bromo-N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-2-methylpyrido[2,3-d]pyrimidin-4-amine

[0746]

[0747] To a solution of 6-bromo-2-methylpyrido[2,3-d]pyrimidin-4-ol (Intermediate 1, 200 mg, 833 μmol), (1R)-1-[2-methyl-3-(difluoromethyl)-2-fluorophenyl]ethanamine hydrochloride (226 mg, 1.0 mmol), and pyBOP (564 mg, 1.1 mmol) in DMF (6 mL) was added DBU (497 μl, 3.3 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The title compound (267 mg, 78%) was obtained after purification by flash column chromatography (ethyl acetate / hexane).

[0748] LC-MS (LC-MS method 2): R t=1.17min; MS(ESIpos):m / z=411.2 / 413.2[M+H] +

[0749] 1H NMR(DMSO-d6)δ:9.19(d,4H),9.00(d,4H),8.82(d,4H),7.69(br m,4H),7.51(br m,4H),7.37(s,1H),7.23-7.33(m,6H),7.10(s,1H),5.75(m,4H),4.03(m,1H),3.37-3.4 3(m,3H),3.21-3.31(m,2H),2.38(s,13H),1.99(s,2H),1.60(d,12H),1.15-1.24(m,2H)

[0750] Experimental Section - Examples

[0751] Example 1

[0752] 6-Bromo-N-{(1R)-1-[3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3-d]pyrimidin-4-amine

[0753]

[0754] To a suspension of 6-bromo-4-chloropyrido[2,3-d]pyrimidine (200 mg, 818 μmol) in 2 ml of DMA was added EtN (230 μl, 1.6 mmol), followed by (1R)-1-[3-(trifluoromethyl)phenyl]ethan-1-amine (170 mg, 900 μmol). The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with H2O and extracted with ethyl acetate. The organic phase was washed with H2O, filtered through a hydrophobic filter, and concentrated under reduced pressure. The title compound (160 mg, 47%) was isolated after silica gel chromatography (hexane / ethyl acetate).

[0755] LC-MS (LC-MS method 2): R t =1.18min; MS (ESIpos): m / z=397.3, 399.3[M+H] +

[0756] 1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.595(14.95),1.613(14.89),1.987(0.52),2.518(3.53),2.523 (2.31),5.576(0.47),5.593(1.98),5.611(3.01),5.628(1.94),5.646(0.43),7.544(1.32),7.56 3(3.94),7.582(4.05),7.596(4.48),7.616(1.63),7.742(3.30),7.760(2.62),7.798(5.26),8.579(16.00),8.896(2.87),8.914(2.77),9.065(10.03),9.071(11.73),9.230(9.87),9.236(9.10).

[0757] Example 2

[0758] N-{(3R)-1-[4-({(1R)-1-[3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]pyrrolidin-3-yl}acetamide

[0759]

[0760] To a suspension of Example 1 (50.0 mg, 126 μmol) and N-[(3R)-pyrrolidin-3-yl]acetamide (48.4 mg, 378 μmol) in toluene (1 mL) under argon was added Pd2dba3 (11.5 mg, 12.6 μmol), 2-(dicyclohexylphosphino)-2',4',6'-tri-isopropyl-1,1'-biphenyl (18 mg, 37.8 μmol), and cesium carbonate (164 mg, 504 μmol). The reaction mixture was stirred at 105°C overnight. The mixture was filtered through a hydrophobic filter, H2O was added, and the aqueous phase was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. The title compound (10 mg, 17%) was obtained after purification by preparative HPLC (basic method).

[0761] LC-MS (LC-MS method 2): R t =1.01min; MS(ESIpos):m / z=445.5[M+H] +

[0762] 1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.610(5.57),1.627(5.56),1.830(16.00),1.951(0.4 7),1.968(0.75),1.981(0.81),1.998(0.58),2.216(0.64),2.233(0.77),2.249(0.70) ,2.264(0.54),3.228(0.94),3.238(0.99),3.254(1.14),3.263(1.16),3.451(0.43),3.475(0.83),3.488(0.90),3.509(0.53),3.558(0.51),3.576(1.12),3.599(0.83),3.6 41(0.94),3.657(1.10),3.666(1.01),3.682(0.86),4.433(0.82),4.446(0.79),5.632(0.84),5.650(1.26),5.668(0.84),7.544(0.51),7.563(1.69),7.581(3.31),7.605(0 .71),7.621(2.21),7.627(2.16),7.721(1.52),7.740(1.24),7.763(2.68),8.215(1.43),8.232(1.39),8.278(5.92),8.415(1.44),8.434(1.39),8.569(2.71),8.575(2.63).

[0763] Example 3

[0764] 6-(4-Methylpiperazin-1-yl)-N-{(1R)-1-[3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3-d]pyrimidin-4-amine

[0765]

[0766] Using the procedure described in Example 2: Example 1 (50 mg, 126 μmol) and 1-methylpiperazine (25.2 mg, 252 μmol) were used to give the title compound (10 mg, 18%) after purification by preparative HPLC (acidic method).

[0767] LC-MS (LC-MS method 2): R t =1.06min; MS(ESIpos):m / z=417.5[M+H] +

[0768] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:1.613(7.03),1.631(7.07),2.262(16.00),2.336(0.75),2.453(0.46),2.518(12.36 ),2.523(10.80),2.534(5.57),2.546(3.96),2.678(0.78),3.344(4.53),3.358(4.75),3.370(3.51),5.627(0.98),5. 644(1.45),5.662(0.95),7.544(0.63),7.564(1.97),7.582(2.70),7.589(2.72),7.609(0.69),7.725(1.71),7.743(1.33),7.766(2.81),8.025(2.60),8.033(2.59),8.352(7.93),8.503(1.57),8.522(1.53),8.925(3.41),8.933(3.28).

[0769] Example 4

[0770] 1-{4-[4-({(1R)-1-[3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]piperazin-1-yl}ethan-1-one

[0771]

[0772] Using the procedure described in Example 2: Example 1 (50 mg, 126 μmol) and 1-(piperazin-1-yl)ethan-1-one (32.3 mg, 252 μmol) gave the title compound (6.0 mg, 10%) after purification by preparative HPLC (basic method).

[0773] LC-MS (LC-MS method 2): R t =1.01min; MS(ESIpos):m / z=445.5[M+H] +

[0774] 1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.230(0.46),1.627(5.18),1.644(5.16),2.075(16.00),2.523(4.31),2. 673(1.13),3.397(2.59),3.410(2.80),3.422(2.24),3.651(3.20),3.664(3.28),5.627(0.74),5.645(1.1 4),5.663(0.75),7.540(0.52),7.559(1.52),7.578(2.34),7.584(2.27),7.604(0.58),7.754(1.31),7.772(1.08),7.792(2.25),8.185(1.47),8.363(6.27),8.711(0.73),8.728(0.76),8.941(2.53),8.948(2.45).

[0775] Example 5

[0776] 1-{4-[4-({(1R)-1-[3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one

[0777]

[0778] To a solution of Example 1 (110 mg, 277 μmol) and 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl]ethan-1-one (188 mg, 748 μmol) in 1,4-dioxane (3.2 mL) under argon was added K 3 PO 4 solution (830 μl, 0.50 M, 420 μmol) and XPhosPdG 2 (32.7 mg, 41.5 μmol). The reaction mixture was stirred at 100° C. overnight. The mixture was diluted with CH 2 Cl 2 , and the organic phase was filtered through a hydrophobic filter and concentrated under reduced pressure. The title compound (73.7 mg, 57%) was obtained after purification by preparative HPLC (basic method).

[0779] LC-MS (LC-MS method 2): R t =1.06min; MS (ESIpos): m / z=442.5[M+H] +

[0780] 1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.626(9.99),1.644(9.90),2.069(12.40),2.1 08(16.00),2.185(0.48),2.327(0.53),2.518(1.96),2.523(1.30),2.624(0.84 ),2.665(0.59),2.669(0.74),2.673(0.57),2.708(1.19),3.697(1.65),3.711(3.52),3.725(2.39),3.738(2.48),3.752(1.16),4.185(2.42),4.192(2.43),4.2 32(1.98),4.240(1.95),5.648(1.40),5.666(2.09),5.684(1.33),6.502(2.51),6.506(2.36),7.550(0.95),7.570(2.90),7.588(3.44),7.598(3.69),7.618(1. 12),7.743(2.50),7.761(1.98),7.785(4.09),8.517(12.56),8.835(3.87),8.840(4.30),8.860(1.23),9.154(2.87),9.160(2.85),9.184(2.31),9.190(2.20).

[0781] Example 6

[0782] 6-Bromo-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3-d]pyrimidin-4-amine

[0783]

[0784] To a solution of 6-bromo-2-methylpyrido[2,3-d]pyrimidin-4-ol (Intermediate 1, 140 mg, 583 μmol), (1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethan-1-amine (142 mg, 700 μmol), and pyBOP (395 mg, 758 μmol) in DMF (4.5 mL) was added DBU (350 μl, 2.3 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with CHCl. ​​The organic phase was dried over NaSO and concentrated under reduced pressure. Purification by silica gel chromatography followed by recrystallization from CHCl / EtO afforded the title compound (76.0 mg, 31%).

[0785] LC-MS (LC-MS method 2): R t =1.32min; MS(ESIpos):m / z=425.3[M+H] +

[0786] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:1.543(4.61),1.560(4.53),2.375(16.00),2.518(1. 54),2.523(1.00),2.610(5.18),5.675(0.68),5.692(1.04),5.710(0.66),7.341(0.5 7),7.361(1.28),7.381(0.74),7.543(1.42),7.561(1.13),7.751(1.23),7.770(1.10),8.903(0.94),8.920(0.91),8.982(3.32),8.988(3.53),9.176(3.04),9.182(2.80).

[0787] Example 7

[0788] tert-Butyl 6-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0789]

[0790] To a solution of Example 6 (45 mg, 106 μmol), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (42 mg, 212 μmol), and XPhos (10.1 mg, 21.2 μmol) in 1,4-dioxane (0.6 mL) was added NaOtBu (22.4 mg, 233 μmol) followed by Pd2dba3 (8.33 mg, 10.6 μmol) under argon. The reaction mixture was stirred at 100°C for 2 hours. The mixture was filtered through a syringe filter and concentrated under reduced pressure. The title compound (26.2 mg, 43%) was obtained after purification by preparative HPLC (basic method).

[0791] LC-MS (LC-MS method 2): R t =1.39min; MS(ESIpos):m / z=543.8[M+H] +

[0792] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:1.390(16.00),1.546(1.91),1.563(1.89),2.305(5. 45),2.327(0.40),2.522(1.13),2.615(2.48),4.073(1.69),4.107(0.42),4.128(3.3 0),5.694(0.46),7.348(0.62),7.523(0.66),7.542(0.54),7.661(0.87),7.669(0.87),7.736(0.60),7.756(0.54),8.316(1.19),8.323(1.15),8.485(0.50),8.503(0.48).

[0793] Example 8

[0794] 1-{6-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one

[0795]

[0796] To a solution of Example 7 (21.0 mg, 38.7 μmol) in CHCl (0.2 mL) at 0°C was added EtSiH (0.62 μl, 3.9 μmol) followed by trifluoroacetic acid (38 μl). The mixture was stirred at room temperature for 6 hours. Toluene (1 mL) was added, and the mixture was concentrated under reduced pressure. The residue was dissolved in CHCl (0.2 mL), DIPEA (14.5 μl, 85.1 μmol) and AcO (4.02 μl, 42.6 μmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. Toluene (1 mL) was added, and the mixture was concentrated under reduced pressure. The title compound (14.0 mg, 67%) was obtained after purification by preparative TLC (CHCl / EtOH 9:1).

[0797] LC-MS (LC-MS method 2): R t =1.16min; MS(ESIpos):m / z=485.5[M+H] +

[0798] 1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.222(0.72),1.240(3.66),1.255(4.29),1.271(2.32),1.557(4.84),1.575(4.88),1.767(16.00) ,1.907(1.05),2.330(12.93),2.518(4.29),2.523(2.86),2.612(6.19),2.660(0.42),2.665(0.88),2.669(1.22),2.673(0.84),4.0 61(4.76),4.131(0.76),4.156(7.28),4.181(0.76),4.339(4.93),5.699(0.72),5.716(1.09),5.734(0.67),7.338(0.72),7.358(1.52),7.377(0.88),7.534(1.68),7.552(1.35),7.702(1.98),7.709(1.98),7.744(1.52),7.763(1.35),8.347(3.28),8.354(3.28).

[0799] Example 9

[0800] 1-{4-[4-({(1R)-1-[3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]piperidin-1-yl}ethan-1-one

[0801]

[0802] To a solution of 1-{4-[4-({(1R)-1-[3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one (Example 5, 65.0 mg, 147 μmol) in MeOH (3 mL) was added Pd / C (10%, 15.7 mg, 14.7 μmol), and the mixture was stirred at room temperature under H2 atmosphere for 3 hours. The mixture was filtered and concentrated under reduced pressure. Purification by HPLC (acidic method) gave the title compound (6.4 mg, 9% yield).

[0803] LC-MS (LC-MS method 1): R t =0.90min; MS(ESIpos):m / z=444.7[M+H] +

[0804] 1H NMR(DMSO-d6)δ:8.95(d,1H),8.71-8.79(m,2H),8.51(s,1H),7.72-7.79(m,2H),7.55-7.62(m,2H),5.65(m,1H),4.62(br d,1H),4.00(br d,1H),3.15-3.23(m,1H),3.03(m,1H),2.60-2.68(m,1H),1.88-2.07(m,5H),1.59-1.73(m,5H),1.23(br s,1H)

[0805] Example 10

[0806] 1-{4-[4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]piperazin-1-yl}ethan-1-one

[0807]

[0808] Using the method described in Example 7: Intermediate 41 (6-bromo-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]pyrido[2,3-d]pyrimidin-4-amine (100 mg, 243 μmol), 1-(piperazin-1-yl)ethan-1-one (93.5 mg, 730 μmol), NaOtBu (46.7 mg, 486 μmol), Pd2dba3 (11.1 mg, 12.2 μmol), XPhos (11.6 mg, 24.3 μmol) in 1,4-dioxane (2 mL) was purified by HPLC (MeCN / H2O) to give the title compound (56.2 mg, 95% purity, 48% yield).

[0809] LC-MS (LC-MS method 2): R t =1.08min; MS(ESIpos):m / z=459.6[M+H] +

[0810] 1H NMR(DMSO-d6)δ:8.95(d,1H),8.56(d,1H),8.37(s,1H),8.10(d,1H),7.76(d,1H),7.57(d,1H),7.37(m,1H),5.76 (m,1H),3.66(m,4H),3.35-3.43(m,2H),3.26-3.31(m,1H),2.52-2.56(m,4H),2.08(s,3H),1.57(d,3H),1.23(br s,1H)

[0811] Example 11

[0812] N-{(3R)-1-[4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]pyrrolidin-3-yl}acetamide

[0813]

[0814] Using the method described in Example 7: intermediate 41 (6-bromo-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]pyrido[2,3-d]pyrimidin-4-amine (75.0 mg, 182 μmol), N-[(3R)-pyrrolidin-3-yl]acetamide (70.1 mg, 547 μmol), NaOtBu (35.1 mg, 365 μmol), Pd2dba3 (8.35 mg, 9.12 μmol), XPhos (8.69 mg, 18.2 μmol) in 1,4-dioxane (1.5 mL) was purified by HPLC (alkaline method) to give the title compound (9.50 mg, 95% purity, 11% yield).

[0815] LC-MS (LC-MS method 2): R t =1.09min; MS(ESIpos):m / z=459.6[M+H] +

[0816] 1H NMR(DMSO-d6)δ:8.56(d,1H),8.45(d,1H),8.27(s,1H),8.22(d,1H),7.75 (d,1H),7.65(d,1H),7.56(d,1H),7.37(m,1H),5.76(m,1H),4.40-4.47(m, 1H),3.55-3.69(m,2H),3.36-3.51(m,1H),3.22-3.31(m,1H),2.52-2.56(m ,3H),2.18-2.29(m,1H),1.93-2.02(m,1H),1.80-1.86(m,3H),1.57(d,3H)

[0817] Example 12

[0818] 1-{4-[4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one

[0819]

[0820] Using the method described in Example 5: intermediate 41 (6-bromo-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]pyrido[2,3-d]pyrimidin-4-amine (100 mg, 243 μmol), 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl]ethan-1-one (165 mg, 657 μmol), XPhosPdG2 (28.7 mg, 36.5 μmol), K3PO4 solution (730 μL, 0.50 M, 360 μmol) in 1,4-dioxane (2.5 mL) was purified by HPLC (alkaline method) to give the title compound (41.0 mg, 95% purity, 35% yield).

[0821] LC-MS (LC-MS method 2): R t =1.12min; MS(ESIpos):m / z=456.6[M+H] +

[0822] 1H NMR(DMSO-d6)δ:9.16(m,1H),8.84-8.89(m,2H),8.51(s,1H),7.77(d,1H),7.58(d,1H),7.38(m,1H),6.50(br s,1H),5.77(m,1H),4.21(br m,2H),3.69-3.76(m,2H),2.58-2.75(m,2H),2.52-2.56(m,4H),2.09(d,3H),1.58(d,3H)

[0823] Example 13

[0824] 1-{6-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one-hydrogen chloride (1 / 1)

[0825]

[0826] To a solution of Example 8 (1-{6-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one (20.5 mg, 42.3 mol) in dichloromethane (1.0 mL) and MeOH (510 μL) was added HCl / 1,4-dioxane (12 μL, 4.0 M, 47 μmol), and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure and dried at 50°C to give the title compound (22.0 mg, 95% purity, 95% yield).

[0827] LC-MS (LC-MS method 2): R t =1.13min; MS(ESIpos):m / z=485[M+H] +

[0828] 1H NMR(DMSO-d6)δ:14.52(br s,1H),10.40(br s,1H),8.41(d,1H),8.14(d,1H),7.90(d,1H),7.60(d,1H),7.42(m,1H),5.88(m,1H),4.35(s,2H),4.18-4.27 (m,4H),4.04-4.11(m,2H),3.38-3.60(m,1H),2.59(s,3H),2.52-2.54(m,1H),1.77(s,3H),1.61-1.72(m,3H)

[0829] Example 14

[0830] 1-{(1S,4S)-5-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]hept-2-yl}ethan-1-one

[0831]

[0832] To a solution of Intermediate 2 (tert-butyl 5-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (45.2 mg, 83.3 μmol) and Et3SiH (1.3 μL, 8.3 μmol) in dichloromethane (340 μL) was added TFA (81 μL, 400 μmol) dropwise. The reaction mixture was stirred for 2 h. The mixture was stirred at room temperature for 6 hours, toluene (1 mL) was added, and the mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (420 μL), and DIPEA (32 μL, 180 μmol) and Ac2O (8.7 μL, 92 μmol) were added sequentially at 0 ° C. The mixture was stirred at room temperature overnight. Then, toluene (1 mL) was added and the mixture was concentrated under reduced pressure. The title compound (26.0 mg, 95% purity, 61% yield) was obtained by HPLC (alkaline method).

[0833] LC-MS (LC-MS method 2): R t =1.15min; MS(ESIpos):m / z=486[M+H] +

[0834] 1H NMR(DMSO-d6)δ:8.60(d,1H),8.56(d,1H),8.37(m,2H),7.67-7.76(m,4H),7. 53(d,2H),7.35(m,2H),5.66-5.74(m,2H),4.89(s,1H),4.84(s,1H),4.76(br d,2H),3.72(m,1H),3.60-3.66(m,2H),3.37-3.45(m,2H),3.20(d,1H),2.61-2.68(m, 7H),2.52-2.54(m,1H),2.29-2.34(m,6H),1.93-2.09(m,7H),1.82(s,3H),1.56(m,6H)

[0835] Example 15

[0836] 2-Methyl-6-(4-methylpiperazin-1-yl)-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3-d]pyrimidin-4-amine

[0837]

[0838] Using the method described in Example 7: Example 6 (6-bromo-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]pyrido[2,3-d]pyrimidin-4-amine, 50.0 mg, 118 μmol), 1-methylpiperazine (35.3 mg, 353 μmol), NaOtBu (45.2 mg, 470 μmol), Pd2dba3 (10.8 mg, 11.8 μmol), XPhos (11.2 mg, 23.5 μmol) in 1,4-dioxane (1.2 mL) was heated at 100° C. overnight to give the title compound (13.8 mg, 95% purity, 25% yield) after purification by HPLC and preparative TLC (dichloromethane / MeOH).

[0839] LC-MS (LC-MS method 2): R t =1.20min; MS(ESIneg):m / z=443[MH] -

[0840] 1H NMR(DMSO-d6)δ:8.84(d,1H),8.54(d,1H),8.02(d,1H),7.75(d,1H),7.54(d,1H),7.35(m,1H),5.71( m,1H),3.26-3.31(m,2H),2.60-2.68(m,3H),2.52-2.56(m,4H),2.32(s,3H),2.26(s,3H),1.56(d,3H)

[0841] Example 16

[0842] N-{(3R)-1-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]pyrrolidin-3-yl}acetamide

[0843]

[0844] Using the procedure described in Example 7: Example 6 (6-bromo-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]pyrido[2,3-d]pyrimidin-4-amine, 40.0 mg, 94.1 μmol), N-[(3R)-pyrrolidin-3-yl]acetamide (24.1 mg, 188 μmol), NaOtBu (18.1 mg, 188 μmol), Pd2dba3 (4.31 mg, 4.70 μmol), XPhos (4.48 mg, 9.41 μmol) in 1,4-dioxane (890 μL) was maintained at 100°C for 6 hours to give the title compound (6.00 mg, 95% purity, 13% yield) after purification by HPLC (basic method) and preparative TLC (dichloromethane / MeOH 9:1).

[0845] LC-MS (LC-MS method 2): R t =1.16min; MS(ESIpos):m / z=474[M+H] +

[0846] 1H NMR(DMSO-d6)δ:8.49(d,1H),8.44(d,1H),8.21(d,1H),7.75(d,1H),7.62(d,1H),7.5 3(d,1H),7.36(m,1H),5.72(m,1H),4.39-4.47(m,1H),3.53-3.68(m,2H),3.36-3.49( m,1H),3.20-3.30(m,1H),2.60-2.68(m,4H),2.52-2.54(m,3H),2.19-2.34(m,5H),1. 92-2.01(m,1H),1.70-1.88(m,4H),1.56(d,3H),1.06-1.30(m,2H),0.71-0.90(m,1H)

[0847] Example 17

[0848] 1-{4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidine-6-sulfonyl]piperazin-1-yl}ethan-1-one

[0849]

[0850] To a solution of 2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidine-6-sulfonyl chloride (Intermediate 4, 244 mg, 42% purity, 230 μmol) in dichloromethane (2.7 mL) were added 1-(piperazin-1-yl)ethan-1-one (88.6 mg, 691 μmol) and triethylamine (96 μL), and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with dichloromethane, and the organic phase was washed with water, saturated NaHCO3 solution and brine, filtered through a hydrophobic filter and concentrated under reduced pressure. Purification by HPLC (acidic method) gave the title compound (8.00 mg, 90% purity, 6% yield).

[0851] LC-MS (LC-MS method 1): R t =1.10min; MS(ESIpos):m / z=537.6[M+H] +

[0852] 1H NMR(DMSO-d6)δ:9.39(d,1H),9.35(d,1H),9.11(d,1H),7.76(d,1H),7.56(d,1H),7.37(m,1H),5.69-5.76(m,1H),4.03(m,2H) ,3.38-3.61(m,5H),2.94-3.08(m,4H),2.52-2.63(m,4H),2.37-2.43(m,3H),1.91-2.02(m,6H),1.59(d,3H),1.15-1.42(m,3H)

[0853] Example 18

[0854] N-{(3R)-1-[2,7-dimethyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]pyrrolidin-3-yl}acetamide

[0855]

[0856] Using the method described in Example 7: 6-bromo-2,7-dimethyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]pyrido[2,3-d]pyrimidin-4-amine (Intermediate 5, 75.0 mg, 171 μmol), N-[(3R)-pyrrolidin-3-yl]acetamide (43.8 mg, 341 μmol), NaOtBu (34.5 mg, 359 μmol), Pd2dba3 (15.6 mg, 17.1 μmol), XPhos (16.3 mg, 34.1 μmol) in 1,4-dioxane (890 μL) was heated at 100°C overnight and purified by HPLC (basic method) to give the title compound (24.0 mg, 95% purity, 27% yield).

[0857] LC-MS (LC-MS method 2): R t =1.17min; MS(ESIpos):m / z=488[M+H] +

[0858] 1H NMR(DMSO-d6)δ:8.52(d,1H),8.21(d,1H),7.88(s,1H),7.75(d,1H),7.53(d,1H),7.35(m,1H),5.71(m,1H),4.35-4.43(m,1 H),3.39-3.53(m,2H),3.22-3.31(m,1H),3.09(m,1H),2.52-2.68(m,7H),2.18-2.34(m,4H),1.82-1.91(m,4H),1.55(d,3H)

[0859] Example 19

[0860] 1-{4-[2,7-dimethyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]piperazin-1-yl}ethan-1-one

[0861]

[0862] Using the method described in Example 7: 6-bromo-2,7-dimethyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]pyrido[2,3-d]pyrimidin-4-amine (Intermediate 5, 75.0 mg, 171 μmol), 1-(piperazin-1-yl)ethan-1-one (65.7 mg, 512 μmol), NaOtBu (50.9 mg, 529 μmol), Pd2dba3 (7.82 mg, 8.54 μmol), XPhos (8.14 mg, 17.1 μmol) in 1,4-dioxane (1.7 mL) was kept at 100°C for 24 hours and purified by preparative TLC (dichloromethane / EtOH) to give the title compound (14.0 mg, 95% purity, 16% yield).

[0863] LC-MS (LC-MS method 2): R t =1.19min; MS(ESIpos):m / z=487[M+H] +

[0864] 1H NMR(DMSO-d6)δ:8.56(d,1H),8.30(s,1H),7.75(d,1H),7.54(d,1H),7.36(m,1H),5.71(m,1H),3.62-3.7 0(m,4H),2.89-3.00(m,4H),2.58-2.63(m,6H),2.52-2.54(m,2H),2.33(s,3H),2.08(s,3H),1.56(d,3H)

[0865] Example 20

[0866] 1-{6-[7-methoxy-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one

[0867]

[0868] Using the method described in Example 7: 6-bromo-7-methoxy-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]pyrido[2,3-d]pyrimidin-4-amine (Intermediate 38, 75.0 mg, 165 μmol), 1-(2,6-diazaspiro[3.3]hept-2-yl)ethan-1-one oxalate (1 / 2) (45.8 mg, 124 μmol), sodium tert-butoxide (63.3 mg, 659 μmol), Pd2dba3 (25.9 mg, 32.9 μmol), XPhos (31.4 mg, 65.9 μmol) in 1,4-dioxane (1.9 mL) were heated at 100°C overnight and purified by HPLC (basic method) to give the title compound (22.2 mg, 98% purity, 26% yield).

[0869] LC-MS (LC-MS method 2): R t =1.22min; MS(ESIpos):m / z=515[M+H] +

[0870] 1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.529(4.36),1.546(4.36),1.762(13.67),1.907(0.50),2.279(14.34),2.337(0.59 ),2.518(6.72),2.523(4.82),2.612(5.46),2.678(0.61),3.926(16.00),4.026(4.29),4.072(0.78),4.095(3.19),4. 101(5.90),4.107(3.10),4.130(0.77),4.307(4.40),5.669(0.67),5.687(1.04),5.704(0.67),7.329(0.63),7.349(1.39),7.369(0.81),7.475(3.82),7.519(1.50),7.537(1.21),7.738(1.33),7.758(1.20),8.211(1.14),8.229(1.11).

[0871] Example 21

[0872] 1-{4-[7-methoxy-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one

[0873]

[0874] A mixture of 6-bromo-7-methoxy-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]-ethyl}pyrido[2,3-d]pyrimidin-4-amine (Intermediate 38, 150 mg, 329 μmol), 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl]ethan-1-one (99.3 mg, 395 μmol), bis(triphenylphosphine)palladium(II) chloride (23.1 mg, 33 μmol) and potassium carbonate (68.3 mg, 494 μmol) in 1,2-dimethoxyethane (1.4 mL) and ethanol (1.4 mL) was purged with argon and heated in a microwave at 100° C. for 6 hours. The mixture was filtered and concentrated under reduced pressure. Purification by HPLC (basic method) and preparative TLC (dichloromethane / EtOH) afforded the title compound (51.9 mg, 95% purity, 30% yield).

[0875] LC-MS (LC-MS method 2): R t =1.29min; MS(ESIpos):m / z=500[M+H] +

[0876] 1H NMR(DMSO-d6)δ:8.58(d,1H),8.55(d,1H),7.76(d,1H),7.54(d,1H),7.35(m,1H),6.04-6.09(m,1H),5.70(m,1H),4.11-4.19(m,2H), 3.95(s,3H),3.60-3.72(m,2H),2.61(s,3H),2.52-2.58(m,2H),2.40-2.46(m,1H),2.30-2.34(m,4H),2.05-2.10(m,3H),1.53(d,3H)

[0877] Example 22

[0878] 1-{4-[7-methoxy-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]piperidin-1-yl}ethan-1-one

[0879]

[0880] To a solution of 1-{4-[7-methoxy-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)-phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one (Example 21, 70.0 mg, 140 μmol) in EtOH (3 mL) was added Pd / C (10%, 14.9 mg, 14.0 μmol), and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. The mixture was diluted with dichloromethane, filtered, and concentrated under reduced pressure. Purification by preparative TLC (dichloromethane / EtOH) gave the title compound (54.3 mg, 95% purity, 73% yield).

[0881] LC-MS (LC-MS method 2): R t =1.29min; MS(ESIpos):m / z=502[M+H] +

[0882] 1H NMR(DMSO-d6)δ:8.49(s,2H),7.74(d,1H),7.54(d,1H),7.36(m,1H),5.70(brm,1H),4.61(br d,1H),3.97(s,4H),3.27-3.32(m,1H),3.06-3.22(m,2H),2.67(br d,1H),2.61(s,4H),2.32(s,4H),2.05(s,3H),1.80-1.93(m,2H),1.51-1.67(m,5H)

[0883] Example 23

[0884] 2-[7-methoxy-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-1λ 6 ,2-thiazolidine-1,1-dione

[0885]

[0886] To a solution of 6-bromo-7-methoxy-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]-ethyl}pyrido[2,3-d]pyrimidin-4-amine (Intermediate 38, 125 mg, 275 μmol) and 1,1-dioxoisothiazolidine (49.9 mg, 412 μmol) in 1,4-dioxane (3.1 mL) were added potassium phosphate (117 mg, 549 μmol), N,N-dimethylethylenediamine (48 μL, 440 μmol) and copper(I) iodide (41.8 mg, 220 μmol), and the mixture was stirred at 90° C. overnight. Purification by HPLC (basic method) gave the title compound (12.5 mg, 98% purity, 9% yield).

[0887] LC-MS (LC-MS method 2): R t =1.25min; MS(ESIpos):m / z=496[M+H] +

[0888] 1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.527(3.91),1.544(3.96),2.318(0.44) ,2.342(14.32),2.451(0.85),2.455(0.83),2.468(1.58),2.473(1.68),2. 518(4.39),2.523(3.33),2.615(4.84),2.660(0.44),3.373(1.13),3.377( 1.03),3.392(2.27),3.396(2.20),3.410(1.00),3.414(1.06),3.713(0.51 ),3.721(0.72),3.737(1.15),3.753(0.94),3.769(1.33),3.775(0.44),3.786(0.70),3.793(0.62),3.970(16.00),5.678(0.59),5.696(0.94),5.713(0.59),7.343(0.57),7.362(1.21),7.382(0.71),7.533(1.33),7.551(1.05),7.752(1.17),7.772(1.04),8.683(1.06),8.701(1.17),8.706(5.02).

[0889] Example 24

[0890] 1-{6-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl]ethyl}amino)-2-methyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one

[0891]

[0892] To a solution of tert-butyl 6-[4-({(1R)-1-[3-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-difluoroethyl)-2-fluorophenyl]ethyl}amino)-2-methyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 11, 130 mg, 175 μmol) and triethylsilane (2.8 μL, 18 μmol) in dichloromethane (1.1 mL) was added trifluoroacetic acid (270 μL, 3.5 mmol), and the mixture was stirred at room temperature overnight. Then, toluene (1 mL) was added, and the solution was concentrated under reduced pressure. The residue was dissolved in dichloromethane (2 mL), N,N-diisopropylethylamine (67 μL, 390 μmol) and acetic anhydride (18 μL, 190 μmol) were added, and the mixture was stirred at room temperature for 2 hours. Toluene was added, and the mixture was concentrated under reduced pressure. The title compound (24.0 mg, 95% purity, 23% yield) was obtained after purification by HPLC (alkaline method).

[0893] LC-MS (LC-MS method 2): R t =1.02min; MS(ESIpos):m / z=569[M+H] +

[0894] 1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.286(0.44),1.304(0.43),1.615(4.82),1.633 (4.80),1.762(15.29),2.322(0.64),2.326(0.83),2.332(0.68),2.347(16.00),2 .518(2.40),2.522(1.62),2.664(0.53),2.668(0.73),2.673(0.51),3.894(0.64),3.910(0.70),3.930(1.18),3.946(1.25),3.966(0.57),3.982(0.56),4.059(4.7 6),4.218(0.58),4.244(5.80),4.268(0.56),4.343(4.89),5.710(1.24),5.718(0.41),5.726(2.97),5.742(1.19),5.775(0.77),5.794(1.20),5.812(0.75),7.24 5(0.91),7.264(2.05),7.283(1.29),7.414(0.80),7.431(1.19),7.448(0.56),7.611(0.62),7.629(1.10),7.646(0.57),7.991(3.48),8.798(1.28),8.816(1.21).

[0895] Example 25

[0896] 1-{4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one

[0897]

[0898] Using the method described in Example 24: tert-butyl 4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridine-1(2H)-carboxylate (Intermediate 12, 80.7 mg, 153 μmol), triethylsilane (2.4 μL, 15 μmol), trifluoroacetic acid (180 μL, 2.3 mmol), N,N-diisopropylethylamine (59 μL, 340 μmol) and acetic anhydride (16 μL, 170 μmol) in dichloromethane (1 mL) were purified by preparative TLC (dichloromethane / ethanol) to give the title compound (58.1 mg, 95% purity, 77% yield).

[0899] LC-MS (LC-MS method 2): R t =1.19min; MS(ESIneg):m / z=468[MH] -

[0900] 1H NMR(DMSO-d6)δ:9.09(m,1H),8.79-8.87(m,2H),7.77(d,1H),7.55(d,1H),7.36(m,1H),6.45-6.48(m,1H),5.70-5.77(m,1H),4.20(br m,2H),3.69-3.77(m,2H),2.59-2.75(m,5H),2.52-2.58(m,1H),2.32-2.38(m,3H),2.09(d,3H),1.58(d,3H)

[0901] Example 26

[0902] 1-{4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one hydrochloride (1 / 1)

[0903]

[0904] To a solution of 1-{4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)-pyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one (Example 25, 15.0 mg, 31.9 μmol) in 1,4-dioxane (500 μL) was added HCl in 1,4-dioxane (8.8 μL, 4.0 M, 35 μmol), and the mixture was stirred at room temperature for 10 minutes. The mixture was concentrated under reduced pressure and dried under reduced pressure at 60° C. to give the title compound (15.9 mg, 95% purity, 93% yield).

[0905] 1 H NMR(DMSO-d6)δ:10.71(br s,1H),9.27(br s,1H),9.20(m,1H),7.92(d,1H),7.61(d,1H),7.43(m,1H),6.58-6.63(m,1H),5.92(m,1H),4.22(br m,2H),3.72(m,2H),3.56(s,1H),2.63-2.75(m,2H),2.52-2.62(m,7H),2.09(d,3H),1.68(d,3H)

[0906] Example 27

[0907] 1-{7-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2-azaspiro[3.5]non-6-en-2-yl}ethan-1-one

[0908]

[0909] Using the method described in Example 24: tert-butyl 7-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2-azaspiro[3.5]non-6-ene-2-carboxylate (Intermediate 13, 128 mg, 225 μmol), trifluoroacetic acid (260 μL, 3.4 mmol), N,N-diisopropylethylamine (86 μL, 500 μmol) and acetic anhydride (23 μL, 250 μmol) in dichloromethane (1.5 mL) were purified by HPLC (basic method) to give the title compound (19.7 mg, 97% purity, 17% yield).

[0910] LC-MS (LC-MS method 2): R t=1.25min; MS(ESIpos):m / z=510[M+H] +

[0911] 1 H NMR(DMSO-d6)δ:9.07(m,1H),8.83(d,1H),8.77(d,1H),7.77(d,1H),7.5 5(d,1H),7.36(m,1H),6.38-6.42(m,1H),5.73(m,1H),3.93(d,1H),3.84( d,1H),3.66(d,1H),3.57(d,1H),2.58-2.68(m,5H),2.52-2.54(m,1H),2. 32-2.39(m,4H),1.91-2.01(m,2H),1.77(s,3H),1.57(d,3H),1.23(s,1H)

[0912] Example 28

[0913] 1-{7-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2-azaspiro[3.5]nonan-2-yl}ethan-1-one

[0914]

[0915] Using the method described in Example 22: 1-{7-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2-azaspiro[3.5]non-6-en-2-yl}ethan-1-one (Example 27, 140 mg, 275 μmol) and Pd / C (10%, 29.2 mg, 27.5 μmol) in ethanol (6.0 mL) were maintained for 3 hours and purified by HPLC (basic method) to give the title compound (35.0 mg, 90% purity, 22% yield).

[0916] LC-MS (LC-MS method 2): R t =1.24min; MS(ESIpos):m / z=512[M+H] +

[0917] 1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.533(0.70),1.561(6.63),1.579(6.32),1.602(1.53),1.635(1. 45),1.668(0.56),1.765(8.18),1.771(1.48),1.785(10.05),1.862(1.18),1.894(1.16),1.988(1. 29),2.016(1.01),2.318(0.45),2.322(1.01),2.326(1.46),2.331(1.04),2.336(0.57),2.354(16.00),2.364(1.17),2.518(5.11),2.522(3.46),2.621(7.43),2.660(0.79),2.664(1.41),2.668(1.6 6),2.673(1.27),2.678(0.78),2.684(0.63),2.692(0.68),3.515(3.68),3.637(3.32),3.786(3.75),3.910(3.82),5.702(0.88),5.720(1.38),5.737(0.87),7.341(0.80),7.361(1.76),7.381(1.02 ),7.535(1.97),7.554(1.57),7.760(1.77),7.780(1.59),8.592(2.05),8.597(2.06),8.709(0.80),8.717(0.94),8.726(0.88),8.735(0.84),8.853(2.08),8.856(2.49),8.858(2.46),8.862(1.90).

[0918] Example 29

[0919] 1-{6-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one

[0920]

[0921] Using the method described in Example 7: 6-bromo-N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-2-methylpyrido[2,3-d]pyrimidin-4-amine (Intermediate 42, 100 mg, 243 μmol), 1-(2,6-diazaspiro[3.3]hept-2-yl)ethan-1-one oxalate (1 / 2) (180 mg, 486 μmol), sodium tert-butoxide (117 mg, 1.22 mmol), Pd2dba3 (19.1 mg, 24.3 μmol), XPhos (23.2 mg, 48.6 μmol) in 1,4-dioxane (3.0 mL) were heated at 100° C. overnight and purified by HPLC and preparative TLC (dichloromethane / EtOH) to give the title compound (12.4 mg, 95% purity, 10% yield).

[0922] LC-MS (LC-MS method 2): R t =1.02min; MS(ESIneg):m / z=469[MH] -

[0923] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:1.231(0.50),1.595(5.70),1.612(5.67),1.766(15.42),2.314(16.00),2.327(1.73),2.331(1.18),2.52 3(4.87),2.665(1.02),2.669(1.35),2.673(0.98),4.060(5.65),4.1 26(0.86),4.149(9.66),4.174(0.80),4.338(5.82),5.754(0.90),5.7 72(1.38),5.790(0.90),7.101(1.24),7.236(2.60),7.267(1.00),7.286(2.17),7.305(1.25),7.372(1.11),7.481(0.81),7.498(1.34),7.516(0.66),7.628(0.76),7.646(1.36),7.664(0.71),7.687(2.60),7.694(2.61),8.356(3.44),8.363(3.29),8.387(1.55),8.405(1.47).

[0924] Example 30

[0925] 1-{3-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2,5-dihydro-1H-pyrrol-1-yl}ethan-1-one

[0926]

[0927] Using the method described in Example 24: tert-butyl 3-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2,5-dihydro-1H-pyrrole-1-carboxylate (265 mg, 516 μmol), triethylsilane (8.2 μL, 52 μmol), trifluoroacetic acid (600 μL, 7.7 mmol), N,N-diisopropylethylamine (200 μL, 1.1 mmol) and acetic anhydride (54 μL, 570 μmol) in dichloromethane (4 mL) were purified by HPLC (basic method) to give the title compound (167 mg, 95% purity, 68% yield).

[0928] LC-MS (LC-MS method 2): R t =1.17min; MS(ESIneg):m / z=454[MH] -

[0929] 1H NMR(DMSO-d6)δ:9.32(d,2H),9.19(d,1H),8.94(d,2H),8.82(d,1H),8.76(d,1H),8.68(d,2H),7.72-7 .79(m,3H),7.55(d,3H),7.37(m,3H),6.70-6.76(m,3H),5.68-5.77(m,3H),4.75-4.81(m,2H),4.59(br s,4H),4.50-4.56(m,4H),4.31(br s,2H),2.62(s,9H),2.52-2.59(m,1H),2.33-2.42(m,9H),2.12(s,3H),2.05(s,6H),1.55-1.62(m,9H)

[0930] Example 31

[0931] 1-{(3RS)-3-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]pyrrolidin-1-yl}ethan-1-one

[0932]

[0933] Using the method described in Example 22: 1-{3-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2,5-dihydro-1H-pyrrol-1-yl}ethan-1-one (134 mg, 294 μmol) and Pd / C (10%, 31.3 mg, 29.4 μmol) in ethanol (5.0 mL) were maintained for 6 hours to give the title compound (62.0 mg, 95% purity, 44% yield) after purification by HPLC (basic method) and preparative TLC (dichloromethane / ethanol).

[0934] LC-MS (LC-MS method 2): R t =1.15min; MS(ESIpos):m / z=458[M+H] +

[0935] 1H NMR(DMSO-d6)δ:8.87-8.92(m,2H),8.73-8.82(m,4H),7.76(br m,2H),7.55(br d,2H),7.36(m,2H),5.69-5.77(m,3H),3.97-4.05(m,2H),3.66-3.78(m,2H),3.44-3.64(m,4H),3.35-3.39(m, 1H),2.60-2.71(m,7H),2.53-2.57(m,4H),2.30-2.44(m,9H),1.98-2.16(m,9H),1.90-1.97(m,1H),1.57(d,6H)

[0936] Example 32

[0937] 6-Methoxy-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3-d]pyrimidin-4-amine

[0938]

[0939] To a solution of 6-bromo-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]pyrido[2,3-d]pyrimidin-4-amine (75.0 mg, 176 μmol) and copper(I) iodide (16.8 mg, 88.2 μmol) in DMF (1.0 mL) was added a solution of sodium methoxide in methanol (130 μL, 5.4 M, 710 μmol), and the mixture was stirred at 105° C. for 2 hours. The title compound (21.0 mg, 95% purity, 30% yield) was obtained after purification by HPLC (basic method).

[0940] LC-MS (LC-MS method 2): R t =1.21min; MS(ESIpos):m / z=377[M+H] +

[0941] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:1.567(4.41),1.584(4.39),2.074(0.55),2.331(1.33),2.337(0.73),2.3 50(15.55),2.518(6.72),2.523(4.67),2.625(4.93),2.673(1.21),2.678(0.54),3.960(16.00),5.703(0.6 3),5.720(0.99),5.737(0.63),7.343(0.56),7.362(1.23),7.381(0.71),7.537(1.30),7.555(1.06),7.755(1.18),7.774(1.05),8.275(2.10),8.283(2.14),8.618(0.99),8.636(0.98),8.683(3.34),8.691(3.26).

[0942] Example 33

[0943] N-Methyl-N-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]methanesulfonamide

[0944]

[0945] To a solution of 6-bromo-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}-pyrido[2,3-d]pyrimidin-4-amine (100 mg, 235 μmol) and N-methylmethanesulfonamide (38.5 mg, 353 μmol) in 1,4-dioxane (1 mL) was added potassium carbonate (65.0 mg, 470 μmol), trans-N,N-dimethylcyclohexane-1,2-diamine (7.4 μL, 47 μmol) and copper (I) iodide (8.96 mg, 47.0 μmol) and the mixture was stirred at 110 ° C overnight. The mixture was diluted with dichloromethane, filtered, and concentrated under reduced pressure. The title compound (18.0 mg, 95% purity, 16% yield) was obtained by flash column chromatography and preparative TLC (dichloromethane / EtOH).

[0946] LC-MS (LC-MS method 2): R t =1.19min; MS(ESIpos):m / z=454[M+H] +

[0947] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:1.154(0.40),1.172(0.82),1.564(3.78),1.582(3.78),1.988(1.29),2.331(1.24), 2.336(0.56),2.382(9.74),2.518(6.85),2.523(4.84),2.620(4.57),2.673(1.22),2.678(0.55),3.119(13.93),3.37 8(16.00),5.700(0.56),5.717(0.86),5.735(0.56),5.759(3.19),7.345(0.52),7.364(1.13),7.384(0.64),7.544(1.22),7.562(0.99),7.750(1.08),7.769(0.99),8.853(1.64),8.860(2.02),8.881(0.82),8.960(1.03),8.965(0.96).

[0948] Example 34

[0949] 2-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-1λ 6 ,2-thiazolidine-1,1-dione

[0950]

[0951] To a solution of 6-bromo-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}-pyrido[2,3-d]pyrimidin-4-amine (100 mg, 235 μmol) and 1,1-dioxoisothiazolidine (42.7 mg, 353 μmol) in 1,4-dioxane (2.0 mL) was added cesium carbonate (115 mg, 353 μmol), Xantphos (20.4 mg, 35.3 μmol) and palladium (II) acetate (5.28 mg, 23.5 μmol) and the mixture was stirred at 100 ° C overnight. The mixture was diluted with dichloromethane, filtered, and concentrated under reduced pressure. The title compound (15.0 mg, 95% purity, 13% yield) was obtained by purification by HPLC (basic method) and preparative TLC (dichloromethane / MeOH).

[0952] LC-MS (LC-MS method 2): R t =1.19min; MS(ESIpos):m / z=466[M+H] +

[0953] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:1.052(0.79),1.232(0.62),1.569(4.58),1.586(4.49),2.331(1.12),2.336(0.50),2.371(16.00),2.518(7. 94),2.523(4.72),2.619(5.47),2.673(1.08),2.678(0.48),3.604(2. 03),3.623(3.83),3.641(1.87),3.875(0.55),3.882(0.89),3.898(2.2 7),3.915(2.24),3.931(0.82),3.937(0.56),5.710(0.68),5.727(1.06),5.744(0.68),5.760(1.60),7.344(0.60),7.363(1.36),7.383(0.79),7.543(1.48),7.561(1.18),7.750(1.31),7.769(1.20),8.471(2.33),8.479(2.34),8.837(1.13),8.854(1.12),8.932(3.68),8.939(3.65).

[0954] Example 35

[0955] 1-{4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]piperazin-1-yl}ethan-1-one

[0956]

[0957] The method described in Example 7 was used: 6-bromo-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]pyrido[2,3-d]pyrimidin-4-amine (40.0 mg, 94.1 μmol), 1-(piperazin-1-yl)ethan-1-one (24.1 mg, 188 μmol), sodium tert-butoxide (18.1 mg, 188 μmol), Pd2dba3 (4.31 mg, 4.70 μmol), XPhos (4.48 mg, 9.41 μmol) in 1,4-dioxane (890 μL) was kept at 100° C. for 24 hours and purified by HPLC (alkaline method) to give the title compound (17.0 mg, 95% purity, 36% yield).

[0958] LC-MS (LC-MS method 2): R t =1.17min; MS(ESIpos):m / z=474[M+H] +

[0959] 1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.557(4.73),1.575(4.70),2.075(16.00),2.328(15.81),2.518(2.49),2.523(1.58),2.540(5.74),2 .620(5.98),2.665(0.48),2.669(0.65),2.673(0.46),3.254(0.73) ,3.266(1.34),3.278(1.39),3.287(0.96),3.363(1.77),3.637(1.4 2),3.651(2.99),3.663(3.23),3.677(1.21),5.699(0.72),5.716(1.11),5.734(0.71),7.336(0.68),7.355(1.47),7.375(0.85),7.532(1.60),7.550(1.30),7.743(1.43),7.762(1.28),8.065(1.95),8.073(1.93),8.543(1.23),8.561(1.25),8.870(2.59),8.878(2.54).

[0960] Example 36

[0961] 1-{4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-4-oxo-4λ 5 -piperazin-1-yl}ethan-1-one

[0962]

[0963] To a solution of 1-{4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)-pyrido[2,3-d]pyrimidin-6-yl]piperazin-1-yl}ethan-1-one (115 mg, 243 μmol) in dichloromethane (5.0 mL) was added 3-chlorobenzene-1-carboperoxyacid (75%, 168 mg, 730 μmol) and the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The aqueous phase was basified with Et3N and extracted with dichloromethane / MeOH 9:1. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by HPLC (basic method) gave the title compound (32.3 mg, 95% purity, 26% yield).

[0964] LC-MS (LC-MS method 2): R t =1.00min; MS(ESIpos):m / z=489[M+H] +

[0965] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:1.564(5.44),1.582(5.37),2.109(16.00),2.323(0.9 6),2.327(1.43),2.332(1.02),2.401(13.76),2.518(7.82),2.523(4.97),2.624(7.60 ),2.665(1.00),2.669(1.34),2.673(0.99),3.057(1.40),3.079(1.41),3.382(0.51),3.595(0.46),3.624(0.88),3.654(0.59),3.880(0.89),3.909(0.93),3.980(0.48),4.0 09(0.80),4.038(0.41),4.085(0.80),4.117(1.86),4.149(0.88),4.437(0.85),4.469(0.78),5.711(0.82),5.729(1.24),5.746(0.81),7.343(0.82),7.363(1.80),7.383(1 .05),7.542(1.98),7.561(1.62),7.787(1.75),7.806(1.59),9.141(0.79),9.150(0.96),9.157(0.92),9.167(0.78),9.631(2.02),9.637(4.06),9.649(2.99),9.655(1.64).

[0966] Example 37

[0967] 1-{6-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one

[0968]

[0969] Using the method described in Example 7: 6-bromo-N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-2,7-dimethylpyrido[2,3-d]pyrimidin-4-amine (Intermediate 6, 100 mg, 235 μmol), 1-(2,6-diazaspiro[3.3]hept-2-yl)ethan-1-one oxalate (1 / 2) (174 mg, 470 μmol), sodium tert-butoxide (90.4 mg, 941 μmol), Pd2dba3 (18.5 mg, 23.5 μmol), XPhos (22.4 mg, 47.0 μmol) in 1,4-dioxane (2.2 mL) were purified by preparative TLC (dichloromethane / MeOH 9:1) to give the title compound (15.3 mg, 95% purity, 13% yield).

[0970] LC-MS (LC-MS method 2): R t =1.02min; MS(ESIpos):m / z=485[M+H] +

[0971] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:1.595(4.82),1.612(4.83),1.719(0.73),1.772(14.88),2.303(16.00),2.318(0.53),2 .463(15.06),2.518(4.30),2.523(3.00),4.052(4.70),4.113(0.88),4.135(5.83),4.141(5.56),4.162(0.81),4.332(4. 89),5.763(0.75),5.781(1.14),5.799(0.73),7.102(1.12),7.238(2.40),7.268(0.85),7.287(1.82),7.306(1.05),7.374(0.98),7.481(0.63),7.497(1.05),7.516(0.51),7.634(4.31),7.652(1.07),7.669(0.53),8.375(1.24),8.393(1.20).

[0972] Example 38

[0973] 6-Methoxy-2,7-dimethyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3-d]pyrimidin-4-amine

[0974]

[0975] Using the method described in Example 32: 6-bromo-2,7-dimethyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]pyrido[2,3-d]pyrimidin-4-amine (75.0 mg, 171 μmol), copper(I) iodide (16.3 mg, 85.4 μmol) and sodium methoxide in methanol (130 μL, 5.4 M, 680 μmol) in DMF (1.0 mL) were purified by HPLC (basic method) to give the title compound (17.0 mg, 95% purity, 24% yield).

[0976] LC-MS (LC-MS method 2): R t =1.27min; MS(ESIneg):m / z=389[MH] -

[0977] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:1.560(3.85),1.577(3.83),2.326(16.00),2.481(14.47),2.518(5 .85),2.522(3.85),2.621(4.31),2.660(0.41),2.664(0.94),2.669(1.26),2.673(0.92),2.678(0.4 0),3.970(12.12),5.694(0.56),5.712(0.86),5.730(0.56),7.338(0.50),7.358(1.09),7.378(0.63),7.532(1.17),7.549(0.94),7.749(1.03),7.768(0.94),8.135(3.18),8.508(0.88),8.526(0.85).

[0978] Example 39

[0979] 2-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]-1λ 6 ,2-thiazolidine-1,1-dione

[0980]

[0981] Using the procedure described in Example 33: 6-bromo-N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-2,7-dimethylpyrido[2,3-d]pyrimidin-4-amine (100 mg, 235 μmol), 1,1-dioxoisothiazolidine (42.7 mg, 353 μmol), copper(I) iodide (8.96 mg, 47.0 μmol), trans-N,N-dimethylcyclohexane-1,2-diamine (7.3 μL, 47 μmol) and potassium carbonate (65.0 mg, 470 μmol) in 1,4-dioxane (1 mL) at 110° C. overnight, the title compound was obtained after purification by HPLC (basic method) and preparative TLC (dichloromethane / EtOH 9:1) (7.00 mg, 95% purity, 6% yield).

[0982] LC-MS (LC-MS method 2): R t =1.07min; MS(ESIpos):m / z=466[M+H] +

[0983] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:1.232(1.26),1.606(3.69),1.624(3.66),2.332(3.05),2.336(1.33),2.374(13.83),2.518(16. 00),2.522(10.42),2.629(12.04),2.673(3.07),2.678(1.31),3.499(1.68),3.518(2.35),3.537(1.40),3.750(0.89),3.767(1. 79),3.786(0.87),5.766(0.54),5.784(0.86),5.801(0.56),7.107(0.82),7.242(1.82),7.287(0.59),7.307(1.37),7.326(0.78),7.378(0.76),7.497(0.45),7.514(0.75),7.651(0.41),7.668(0.74),7.687(0.41),8.775(0.92),8.794(0.88),8.857(3.62).

[0984] Example 40

[0985] 1-{3-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]azetidin-1-yl}ethan-1-one

[0986]

[0987] Using the method described in Example 24: tert-butyl 3-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]azetidine-1-carboxylate (62.0 mg, 124 μmol), triethylsilane (2.0 μL, 12 μmol), trifluoroacetic acid (191 μL), N,N-diisopropylethylamine (110 μL, 620 μmol) and acetic anhydride (13 μL, 140 μmol) in dichloromethane (1.5 mL) were purified by HPLC (basic method) to give the title compound (26.6 mg, 95% purity, 46% yield).

[0988] LC-MS (LC-MS method 2): R t =1.13min; MS(ESIpos):m / z=444[M+H] +

[0989] 1 H NMR(DMSO-d6)δ:8.90(m,1H),8.80-8.86(m,2H),7.76(d,1H),7.55(d,1H),7.36(m,1H),5.72(m,1H),4.56-4.61(m,1H), 4.21-4.34(m,2H),4.03-4.14(m,2H),2.62(s,3H),2.52-2.54(m,1H),2.34-2.38(m,3H),1.82-1.85(m,3H),1.58(d,3H)

[0990] Example 41

[0991] 1-{4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one

[0992]

[0993] Using the method described in Example 5: 6-bromo-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-4-amine (70.0 mg, 142 μmol), 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl]ethan-1-one (53.5 mg, 213 μmol), XPhosPdG2 (5.58 mg, 7.10 μmol) and aqueous K3PO4 solution (570 μL, 0.50 M, 280 μmol) in 1,4-dioxane (3.5 mL) were purified by flash column chromatography to give the title compound (63.1 mg, 95% purity, 83% yield).

[0994] LC-MS (LC-MS method 2): R t =1.35min; MS(ESIpos):m / z=538[M+H] +

[0995] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:1.052(0.48),1.065(16.00),1.556(0.78),1.574(0.77),2.070(1.0 5),2.081(0.47),2.103(1.42),2.409(2.78),2.518(1.68),2.523(1.08),2.614(1.21),3.939(2.65).

[0996] Example 42

[0997] 1-{4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-6-yl]piperidin-1-yl}ethan-1-one

[0998]

[0999] Using the procedure described in Example 22: 1-{4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one (50.0 mg, 93.0 μmol) and Pd / C (10%, 9.90 mg, 9.30 μmol) in EtOH (2.0 mL) for 16 h gave the title compound (22.0 mg, 95% purity, 42% yield) after purification by preparative TLC (dichloromethane / MeOH 9:1).

[1000] LC-MS (LC-MS method 2): R t =1.35min; MS(ESIpos):m / z=540[M+H] +

[1001] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:1.230(0.70),1.585(4.27),1.602(4.29),1.745(0.49 ),1.777(0.85),1.802(1.72),1.822(1.66),1.854(0.45),2.078(16.00),2.318(0.68) ,2.323(1.53),2.327(2.14),2.331(1.50),2.337(0.67),2.382(8.28),2.388(8.11),2.409(0.69),2.518(8.30),2.523(5.74),2.614(7.02),2.660(1.08),2.665(1.92),2.6 69(2.49),2.673(1.77),2.678(0.91),3.166(0.76),3.198(0.77),3.230(0.43),4.015(0.67),4.047(0.61),4.642(0.71),4.673(0.67),5.695(0.46),5.713(0.78),5.725(0 .77),5.741(0.46),7.360(0.72),7.379(1.55),7.399(0.93),7.552(1.28),7.571(1.03),7.728(1.75),7.747(1.63),9.076(4.29),9.094(0.85),9.102(0.89),9.119(0.70).

[1002] Example 43

[1003] 1-{4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one

[1004]

[1005] Using the procedure described in Example 21: 6-bromo-N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-2-methylpyrido[2,3-d]pyrimidin-4-amine (Intermediate 42, 175 mg, 426 μmol), 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1-[ ... To the reaction mixture of 1,4-dihydropyridin-1(2H)-yl]ethan-1-one (128 mg, 511 μmol), bis(triphenylphosphine)palladium(II) chloride (29.9 mg, 43 μmol) and potassium carbonate (88.2 mg, 638 μmol) was maintained at 100° C. for 6 hours and purified by flash column chromatography (dichloromethane / EtOH) to give the title compound (153 mg, 90% purity, 71% yield).

[1006] LC-MS (LC-MS method 2): R t =1.07min; MS(ESIneg):m / z=454[MH] -

[1007] 1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.797(0.49),0.814(0.54),0.821(0.54),0.904(0.62),1.066(1.11),1 .156(0.40),1.620(5.82),1.638(5.77),2.068(7.77),2.107(9.64),2.323(0.61),2.327(0.87),2.332( 0.61),2.393(16.00),2.518(3.33),2.523(2.43),2.599(0.50),2.614(0.50),2.660(0.40),2.665(0.74),2.669(1.00),2.673(0.80),2.679(0.54),2.705(0.77),2.729(0.89),2.888(0.93),3.691(1.02),3.7 06(2.19),3.719(1.57),3.732(1.63),3.746(0.76),4.176(1.53),4.184(1.56),4.224(1.26),4.231(1.25),5.759(2.94),5.795(0.83),5.813(1.26),5.831(0.81),6.474(1.62),7.107(1.33),7.242(2.84),7 .283(0.99),7.302(2.18),7.321(1.25),7.378(1.18),7.500(0.75),7.517(1.27),7.534(0.63),7.669(0.69),7.687(1.27),7.706(0.64),8.820(2.47),9.097(1.63),9.103(1.64),9.129(1.34),9.135(1.29).

[1008] Example 44

[1009] 1-{4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]piperidin-1-yl}ethan-1-one

[1010]

[1011] Using the method described in Example 22: 1-{4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one (Example 43, 52.0 mg, 114 μmol) and Pd / C (10%, 12.1 mg, 11.4 μmol) in EtOH (2.5 mL) for 4 hours to give the title compound (35.1 mg, 95% purity, 64% yield) after purification by HPLC (basic method).

[1012] LC-MS (LC-MS method 2): R t =1.06min; MS(ESIpos):m / z=458[M+H] +

[1013] 1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.602(4.60),1.619(4.91),1.640(0.88),1.650(0.69),1.672(0.68 ),1.682(0.44),1.866(0.60),1.905(0.83),1.943(0.46),2.057(16.00),2.323(0.78),2.327(1.13) ,2.331(0.80),2.367(12.55),2.518(4.28),2.523(3.03),2.608(0.43),2.634(0.75),2.640(0.73),2.660(0.47),2.665(1.16),2.669(1.45),2.673(1.08),2.982(0.43),2.991(0.74),3.000(0.42),3.1 54(0.46),3.181(0.76),3.214(0.45),3.973(0.58),4.008(0.52),4.597(0.55),4.630(0.52),5.768(0.69),5.786(1.05),5.803(0.67),7.106(1.17),7.241(2.49),7.279(0.83),7.299(1.83),7.318(1 .06),7.377(1.03),7.491(0.61),7.509(1.02),7.526(0.49),7.650(0.56),7.668(1.03),7.686(0.51),8.637(0.71),8.643(0.74),8.655(0.73),8.689(1.68),8.693(1.73),8.873(3.08),8.878(2.80).

[1014] Example 45

[1015] 2-Methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}-6-(pyrimidin-5-yl)pyrido[2,3-d]pyrimidin-4-amine

[1016]

[1017] To a solution of 6-bromo-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}-pyrido[2,3-d]pyrimidin-4-amine (Example 6, 50.0 mg, 118 μmol) and pyrimidin-5-ylboronic acid (39.3 mg, 317 μmol) in 1,4-dioxane (1.4 mL) was added K3PO4 aqueous solution (350 μL, 0.50 M, 180 μmol) and XPhosPdG2 (13.9 mg, 17.6 μmol), and the mixture was stirred at 100 ° C overnight. The mixture was filtered, diluted with ethyl acetate, and washed with water. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with brine, filtered through a hydrophobic filter, and concentrated under reduced pressure. Purification by HPLC (basic method) gave the title compound (35.0 mg, 95% purity, 67% yield).

[1018] LC-MS (LC-MS method 2): R t =1.18min; MS(ESIpos):m / z=425[M+H] +

[1019] 1 H NMR(400MHz,DMSO-d6)δppm 9.41(d)9.36(s)9.29(d)9.28(s)8.90(d)7.79(d)7.56(d)7.37(t)5.76(quin)2.63(s)2.52-2.52(m)2.42(s)1.60(d)

[1020] Example 46

[1021] 1-{4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one

[1022]

[1023] Tert-butyl 4-(4-{[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]-amino}-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (Intermediate 19, 188 mg, 274 μmol) and triethylsilane (4.4 μL, 27 μmol) were dissolved in dichloromethane (2.0 mL) and cooled to 0°C. TFA (320 μL, 4.1 mmol) was added dropwise. The mixture was warmed to room temperature and stirred overnight. Toluene was added and the solvent was evaporated. The residue was dissolved in dichloromethane (1.2 mL), N,N-diisopropylethylamine (110 μL, 600 μmol) was added at room temperature, followed by acetic anhydride (28 μL, 300 μmol), and the mixture was stirred overnight. Toluene was added and the solvent was evaporated. Purification by HPLC (alkaline method) gave the title compound (79.5 mg, 95% purity, 54% yield).

[1024] LC-MS (LC-MS method 2): R t =1.05min; MS(ESIpos):m / z=514[M+H] +

[1025] 1 H NMR(400MHz,DMSO-d6)δppm 9.07-9.13(m)8.80-8.83(m)8.71-8.78(m)7.60(brt)7.31(t)7.22(t)6.45-6.51(m)5.80(quin)5.34(s)4.20(br) dd)3.72(dt)3.38-3.45(m)3.21-3.30(m)2.98(t)2.67-2.75(m)2.52-2.64(m)2.33-2.40(m)2.06-2.12(m)1.60(d)1.22(d)

[1026] Example 47

[1027] 1-{4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]piperidin-1-yl}ethan-1-one

[1028]

[1029] 1-{4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one (Example 46, 58.0 mg, 113 μmol) was dissolved in EtOH (2.0 mL) and THF. Pd on carbon (12.0 mg, 10 wt%, 11.3 μmol) was added under argon. The atmosphere was replaced with hydrogen, and the mixture was stirred at room temperature for 6 hours. The mixture was diluted with dichloromethane and filtered. The solvent was evaporated and the residue was purified by HPLC (basic method) to give the title compound (13.5 mg, 22% yield).

[1030] LC-MS (LC-MS method 2): R t =0.97min; MS(ESIpos):m / z=516[M+H] +

[1031] 1 H NMR(400MHz,DMSO-d6)δppm 8.87(d)8.70(d)8.64(dd)7.58(t)7.32(t)7.22(t)5.78(quin)5.34(s)4.59-4.65(m)3.96-4.02(m)3.15-3. 23(m)2.99(tt)2.60-2.65(m)2.52-2.55(m)2.33-2.37(m)2.06(s)1.85-1.95(m)1.54-1.72(m)1.17-1.26(m)

[1032] Example 48

[1033] 6-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]heptane-2-carboxamide

[1034]

[1035] Tert-butyl 6-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (Example 7, 60.0 mg, 111 μmol) and triethylsilane (1.8 μL, 11 μmol) were dissolved in dichloromethane (0.8 mL) and cooled to 0°C. TFA (130 μL, 1.7 mmol) was added dropwise. The mixture was warmed to room temperature and stirred for 7 hours. Toluene was added and the solvent was evaporated. N,N-diisopropylethylamine (42 μL, 240 μmol) was added to the residue, followed by trimethylsilyl isocyanate (16 μL, 0.122 mmol). The mixture was stirred at room temperature overnight. Toluene was added and the solvent was evaporated. The residue was purified by HPLC and preparative TLC using dichloromethane / MeOH 9:1 as eluent to afford the title compound (2.8 mg, 95% purity, 5% yield).

[1036] LC-MS (LC-MS method 2): R t =1.10min; MS(ESIpos):m / z=486[M+H] +

[1037] 1H NMR(400MHz,DMSO-d6)δppm 8.49(d)8.33(d)7.76(d)7.67(d)7.53(d)7.35(t)5.92(s)5.70(quin)4.11-4. 16(m)4.00(s)2.60-2.68(m)2.52-2.55(m)2.29-2.36(m)1.56(d)1.17-1.30(m)

[1038] Example 49

[1039] 1-{3-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]-3,6-diazabicyclo[3.1.1]hept-6-yl}ethan-1-one

[1040]

[1041] Tert-butyl 3-(4-{[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]-amino}-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (Intermediate 20, 59.0 mg, 84.2 μmol) and triethylsilane (1.3 μL, 8.4 μmol) were dissolved in dichloromethane (0.6 mL) and cooled to 0°C. TFA (97 μL, 1.3 mmol) was added dropwise, and the mixture was warmed to room temperature and stirred overnight. Toluene (1 mL) was added, the solvent was evaporated, and the residue was redissolved in dichloromethane (0.6 mL). N, N-diisopropylethylamine (32 μL, 190 μmol) was added, followed by acetic anhydride (8.7 μL, 93 μmol). The mixture was stirred at room temperature overnight. The crude product was purified by HPLC and preparative TLC using dichloromethane / EtOH 9:1 as eluent to give the title compound (16.2 mg, 95% purity, 35% yield).

[1042] LC-MS (LC-MS method 2): R t =0.98min; MS (ESIpos): m / z=529

[1043] [M+H] +

[1044] 1 H NMR(400MHz,DMSO-d6)δppm 8.67(d)8.39(t)7.77(d)7.57(q)7.27-7.33(m)7.17-7.24(m)5.74-5.84(m)5.34(s)4.71(br s)4.44-4.50(m)3.87-3.96(m)3.67-3.85(m)3.46-3.56(m)2.62-2.73(m)2.52-2.52(m)2.26-2.45(m)1.86(d)1.67(d)1.59(d)1.22(brd)

[1045] Example 50

[1046] 1-{(1S,4S)-5-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]hept-2-yl}ethan-1-one

[1047]

[1048] Tert-butyl (1S,4S)-5-(4-{[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)-ethyl]amino}-2-methylpyrido[2,3-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (Intermediate 21, 74.0 mg, 106 μmol) and triethylsilane (1.7 μL, 11 μmol) were dissolved in dichloromethane (0.7 mL) and cooled to 0°C. TFA (120 μL, 1.6 mmol) was added dropwise, and the mixture was warmed to room temperature and stirred overnight. Toluene (1 mL) was added, and the solvent was evaporated. The residue was dissolved in dichloromethane (1.2 mL) at room temperature, N, N-diisopropylethylamine (40 μL, 230 μmol) was added, followed by acetic anhydride (11 μL, 120 μmol). The mixture was stirred overnight. Toluene was added and the solvent was evaporated. The crude product was passed through HPLC and purified by preparative TLC using dichloromethane / MeOH 1:1 as eluent to give the title compound (13.9 mg, 95% purity, 24% yield).

[1049] LC-MS (LC-MS method 2): R t =0.96min; MS(ESIpos):m / z=529[M+H] +

[1050] 1 H NMR(400MHz,DMSO-d6)δppm 8.61(d)8.57(s)8.24-8.32(m)7.74(d)7.71(d)7.57(q)7.27-7.33(m)7.21(td)5.73-5.81(m)5.34(s)4.89(s)4.84(s)4.76(br d)3.73(dd)3.59-3.67(m)3.37-3.46(m)3.29-3.30(m)3.18-3.29(m)2.67(dt)2. 52-2.52(m)2.38-2.45(m)2.26-2.35(m)1.87-2.09(m)1.82(s)1.59(dd)1.22(br d)

[1051] Example 51

[1052] 1-{(1R,4R)-5-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]hept-2-yl}ethan-1-one

[1053]

[1054] Tert-butyl (1R,4R)-5-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}-amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (Intermediate 22, 43.0 mg, 73.3 μmol) and triethylsilane (1.2 μL, 7.3 μmol) were dissolved in dichloromethane and cooled to 0°C. TFA (85 μL, 1.1 mmol) was added dropwise. The mixture was warmed to room temperature and stirred overnight. Toluene (1 mL) was added and the solvent was evaporated. The residue was dissolved in dichloromethane (1.2 mL) at room temperature. N, N-diisopropylethylamine (51 μL, 290 μmol) was added, followed by acetic anhydride (7.6 μL, 81 μmol). The mixture was stirred overnight. Toluene was added and the solvent was evaporated. The crude product was passed through HPLC and purified by preparative TLC using dichloromethane / MeOH 1: 1 as eluent to give the title compound (14.1 mg, 95% purity, 35% yield).

[1055] LC-MS (LC-MS method 2): R t =0.96min; MS(ESIpos):m / z=529[M+H] +

[1056] 1 H NMR(400MHz,DMSO-d6)δppm 8.62(d)8.57(d)8.29(br d)8.25(br d)7.73(brd)7.70(br d)7.58(br t)7.31(br t)7.21(t)5.74-5.81(m)5.34(s)4.89(s)4.83(s)4.75(br d)3.73(dd)3.63(td)3.37-3.46(m)3.18-3.31(m)2.67(dt)2.52-2.55(m)2.28-2.34(m)1.93-2.08(m)1.82(s)1.58(dd)1.22(br d)

[1057] Example 52

[1058] 1,1-Difluoro-1-{2-fluoro-3-[(1R)-1-{[2-methyl-6-(4-methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-4-yl]amino}ethyl]phenyl}-2-methylpropan-2-ol

[1059]

[1060] N-[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]-2-methyl-6-(4-methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-4-amine (Intermediate 23, 34.0 mg, 56.4 μmol) and triethylsilane (0.90 μL, 5.6 μmol) were dissolved in dichloromethane (0.4 mL) and cooled to 0°C. TFA (65 μL, 850 μmol) was added dropwise. The mixture was warmed to room temperature and stirred overnight. Toluene was added and the solvent was evaporated. The residue was purified by HPLC to give the title compound (13.0 mg, 95% purity, 45% yield).

[1061] LC-MS (LC-MS method 2): R t =1.05min; MS(ESIpos):m / z=489

[1062] [M+H] +

[1063] 1 H NMR(400MHz,DMSO-d6)δppm 8.86(d)8.43(d)8.04(d)7.58(t)7.31(t)7.21(t)5.75-5.82(m)5.34(s)3.27- 3.32(m)2.52-2.59(m)2.32-2.34(m)2.31(s)2.26(s)1.58(d)1.23(s)1.20(s)

[1064] Example 53

[1065] 1-{4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]piperazin-1-yl}ethan-1-one

[1066]

[1067] 1-[4-(4-{[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]amino}-2-methylpyrido[2,3-d]pyrimidin-6-yl]piperazin-1-yl]ethan-1-one (Intermediate 24, 45.0 mg, 71.3 μmol) and triethylsilane (1.1 μL, 7.1 μmol) were dissolved in dichloromethane (0.7 mL) and cooled to 0°C. TFA (82 μL, 1.1 mmol) was added dropwise. The mixture was warmed to room temperature and stirred overnight. Toluene was added and the solvent was evaporated. The residue was purified by HPLC to give the title compound (27.5 mg, 95% purity, 71% yield).

[1068] LC-MS (LC-MS method 2): R t =0.98min; MS(ESIpos):m / z=517[M+H] +

[1069] 1 H NMR(400MHz,DMSO-d6)δppm 8.89(d)8.45(d)8.08(d)7.58(t)7.31(t)7.21(t)5.79(quin)5.34(s)3.66(q)3.37-3.42(m) 3.23-3.30(m)2.67(dt)2.52-2.55(m)2.33-2.34(m)2.32(s)2.08(s)1.59(d)1.23(s)1.20(s)

[1070] Example 54

[1071] 1-{6-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one

[1072]

[1073] Tert-butyl 6-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 25, 59.0 mg, 101 μmol) and triethylsilane (1.6 μL, 10 μmol) were dissolved in dichloromethane (0.75 mL) and cooled to 0°C. TFA (120 μL, 1.5 mmol) was added dropwise. The mixture was warmed to room temperature and stirred overnight. Toluene (1 mL) was added and the solvent was evaporated. The residue was dissolved in dichloromethane (1.2 mL) at room temperature. N,N-diisopropylethylamine (39 μL, 220 μmol) was added, followed by acetic anhydride (10 μL, 110 μmol). The mixture was stirred at room temperature for 3 days. Toluene was added and the solvent was evaporated. The crude product was purified by HPLC to give the title compound (22.9 mg, 95% purity, 41% yield).

[1074] LC-MS (LC-MS method 2): R t =0.98min; MS(ESIpos):m / z=529[M+H] +

[1075] 1 H NMR(400MHz,DMSO-d6)δppm 8.39(d)8.36(d)7.70(d)7.56(t)7.30(t)7.20(t)5.77(quin)5.34(s)4.34(s)4.11- 4.18(m)4.06(s)2.52-2.55(m)2.27-2.46(m)1.77(s)1.58(d)1.17-1.26(m)1.22(d)

[1076] Example 55

[1077] N-{(3R)-1-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]pyrrolidin-3-yl}acetamide

[1078]

[1079] 1-(3-{(1R)-1-[(6-bromo-2-methylpyrido[2,3-d]pyrimidin-4-yl)amino]ethyl}-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (Intermediate 18, 50.0 mg, 107 μmol) and N-[(3R)-pyrrolidin-3-yl]acetamide (16.4 mg, 128 μmol) were dissolved in dioxane (1.0 mL). Sodium tert-butoxide (13.3 mg, 139 μmol) and XPhos (10.2 mg, 21.3 μmol) were added, the atmosphere was changed to argon, and Pd2dba3 (9.76 mg, 10.7 μmol) was added. The mixture was heated to 100°C overnight. The mixture was cooled to room temperature and saturated brine and ethyl acetate were added. The aqueous phase was extracted with ethyl acetate. The organic phase was dried and the solvent was evaporated. The residue was purified by HPLC and additionally by preparative TLC using dichloromethane / MeOH 9:1 as eluent to afford the title compound (13.0 mg, 95% purity, 24% yield).

[1080] LC-MS (LC-MS method 2): R t =0.99min; MS(ESIpos):m / z=517[M+H] +

[1081] 1 H NMR(400MHz,DMSO-d6)δppm 8.51(d)8.34(d)8.22(d)7.63(d)7.56(t)7.30(t)7.21(t)5.75-5.83(m)5.34(s)4.40-4.47(m)3.53-3 .67(m)3.39-3.49(m)3.21-3.30(m)2.52-2.56(m)2.19-2.34(m)1.92-2.01(m)1.83(s)1.58(d)1.27(br d)1.22(d)

[1082] Example 56

[1083] 1-{4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one

[1084]

[1085] 6-Bromo-N-{(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}-2,7-dimethylpyrido[2,3-d]pyrimidin-4-amine (Intermediate 6, 167 mg, 393 μmol), 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl]ethan-1-one (118 mg, 471 μmol), and bis(triphenylphosphine)palladium(II) dichloride (27.6 mg, 0.039 mmol) were dissolved in DME (1.7 mL) and EtOH (1.7 mL). Potassium carbonate (81.4 mg, 589 μmol) was added, and the atmosphere was replaced with argon. The mixture was heated to 100°C in a microwave oven for 6 hours. The mixture was cooled to room temperature, and ethyl acetate and saturated brine were added. The aqueous phase was extracted with ethyl acetate and the organic phase was dried. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel to give the title compound (131 mg, 90% purity, 64% yield).

[1086] LC-MS (LC-MS method 2): R t =1.07min; MS(ESIneg):m / z=468[MH] -

[1087] 1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.797(0.48),0.814(0.52),0.821(0.53),0.903(0.60) ,1.066(0.76),1.572(3.77),1.589(3.80),2.075(6.37),2.102(8.20),2.332(0.46),2.3 59(16.00),2.387(0.70),2.392(0.75),2.518(2.64),2.523(1.84),2.560(6.29),2.673(0.41),3.672(0.86),3.686(1.74),3.701(1.15),3.717(0.84),3.721(0.81),3.731(0.4 1),3.736(0.41),4.121(1.34),4.127(1.36),4.164(1.05),4.171(1.05),5.758(2.16),5.777(1.16),5.795(0.75),5.820(1.55),7.099(1.14),7.235(2.35),7.271(0.79),7.29 0(1.73),7.309(0.99),7.371(1.00),7.485(0.64),7.502(1.07),7.520(0.52),7.651(0.58),7.668(1.06),7.687(0.53),8.533(2.39),8.543(1.82),8.622(0.82),8.640(0.80).

[1088] Example 57

[1089] 1-{4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]piperidin-1-yl}ethan-1-one

[1090]

[1091] Under argon, 1-{4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one (Example 56, 51.0 mg, 109 μmol) was dissolved in EtOH (2.3 mL) and THF. Pd on carbon (11.6 mg, 10 wt%, 10.9 μmol) was added, and the atmosphere was replaced with hydrogen, and the mixture was stirred for 4 hours. The mixture was diluted with dichloromethane and then filtered. The solvent was evaporated and the residue was purified by HPLC to give the title compound (28.4 mg, 95% purity, 53% yield).

[1092] LC-MS (LC-MS method 2): R t =1.08min; MS(ESIneg):m / z=470[MH] -

[1093] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:1.594(4.04),1.612(4.07),1.633(0.46),1.644(0.41 ),1.653(0.59),1.684(0.53),1.807(0.60),1.839(0.44),1.862(0.57),1.900(0.45), 2.062(14.73),2.322(0.70),2.333(9.23),2.335(9.43),2.518(2.31),2.523(1.54),2.638(0.47),2.663(16.00),2.696(0.40),3.100(0.59),3.192(0.44),3.220(0.77),3.2 52(0.45),3.347(0.46),3.974(0.59),4.008(0.54),4.619(0.57),4.651(0.54),5.757(0.61),5.775(0.92),5.792(0.59),7.102(1.23),7.238(2.62),7.276(0.89),7.295(1 .93),7.314(1.10),7.374(1.07),7.483(0.61),7.501(1.03),7.518(0.50),7.627(0.59),7.645(1.06),7.663(0.52),8.557(3.29),8.571(0.83),8.577(0.77),8.588(0.63).

[1094] Example 58

[1095] 2-[2,7-dimethyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-1λ 6 ,2-thiazolidine-1,1-dione

[1096]

[1097] 6-Bromo-2,7-dimethyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]pyrido[2,3-d]pyrimidin-4-amine (Intermediate 5, 50.0 mg, 114 μmol) and 1λ 6 ,2-thiazolidine-1,1-dione (13.8 mg, 114 μmol) was dissolved in dioxane (1.0 mL). Potassium phosphate (48.3 mg, 228 μmol), N,N'-dimethylethylenediamine (10 μL, 91 μmol) and copper (I) iodide (8.67 mg, 45.5 μmol) were added, the atmosphere was replaced with argon, and the mixture was heated to 100 ° C overnight. The mixture was cooled to room temperature, dichloromethane was added, and then filtered. The solvent was evaporated and the residue was purified by HPLC to give the title compound (12.0 mg, 95% purity, 21% yield).

[1098] LC-MS (LC-MS method 2): R t =1.21min; MS(ESIpos):m / z=480[M+H] +

[1099] 1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.232(0.99),1.559(4.25),1.577(4.25),2.085(0.47),2.327(1.87),2.331(1.33),2.366(13.79) ,2.518(9.33),2.523(6.01),2.620(16.00),2.669(1.93),2.673(1.35),3.501(1.82),3.520(2.96),3.539(1.52),3.745(0.89),3.7 53(0.88),3.763(1.63),3.769(1.58),3.779(0.84),3.786(0.82),5.699(0.66),5.716(1.03),5.733(0.65),5.760(4.49),7.351(0.62),7.370(1.32),7.390(0.78),7.543(1.46),7.562(1.16),7.743(1.30),7.762(1.15),8.852(4.18),8.866(1.21),8.883(1.13).

[1100] Example 59

[1101] 2-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]-1λ 6 ,2-thiazolidine-1,1-dione

[1102]

[1103] 2-(4-{[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]amino}-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl)-1λ6,2-thiazolidine-1,1-dione (Intermediate 26, 70.0 mg, 110 μmol) and triethylsilane (1.8 μL, 11 μmol) were dissolved in dichloromethane (0.87 mL) and cooled to 0°C. TFA (170 μL, 2.2 mmol) was added dropwise. The mixture was warmed to room temperature and stirred for 3 days. Toluene was added and the solvent was evaporated. The crude product was purified by HPLC and also by preparative TLC using dichloromethane / MeOH 1:1 as eluent to give the title compound (2.0 mg, 95% purity, 3% yield).

[1104] LC-MS (LC-MS method 2): R t =1.01min; MS(ESIpos):m / z=524[M+H] +

[1105] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:1.154(1.96),1.172(4.07),1.190(2.35),1. 203(2.80),1.229(4.03),1.582(1.92),1.599(1.90),1.987(7.86),2.084(0.6 5),2.327(0.49),2.359(6.05),2.518(2.79),2.523(1.53),2.629(5.70),2.66 9(0.47),3.159(15.59),3.171(16.00),3.499(0.98),3.504(1.02),3.518(1.3 7),3.537(0.77),3.756(0.51),3.773(0.96),3.792(0.48),3.999(0.60),4.017(1.80),4.035(1.78),4.053(0.60),4.089(1.15),4.102(3.19),4.115(3.13),4.128(1.08),5.342(0.53),5.758(9.79),5.779(0.49),7.224(0.72),7.243(0.47),7.320(0.47),7.589(0.46),8.803(0.55),8.822(0.52),8.883(1.84).

[1106] Example 60

[1107] 1-{6-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one

[1108]

[1109] To a solution of intermediate 27 (1-[6-(4-{[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]amino}-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl)-2,6-diazaspiro[3.3]hept-2-yl]ethan-1-one, 47.0 mg, 71.6 μmol) and triethylsilane (1.1 μl, 7.2 μmol) in dichloromethane (600 μl) was added trifluoroacetic acid (83 μl, 1.1 mmol), and the mixture was stirred at room temperature overnight. The mixture was then triturated with toluene and concentrated under reduced pressure. The crude product obtained was purified by preparative HPLC (basic method) to give the title compound (17.4 mg, 95% purity, 43% yield).

[1110] LC-MS (LC-MS method 2): R t =0.97min; MS(ESIpos):m / z=543[M+H] +

[1111] 1 H NMR(400MHz,DMSO-d6)δppm 8.37(d)7.64(s)7.57(t)7.30(t)7.21(t)5.78(quin)5.34(s)4.33(s)4.11-4.17 (m)4.05(s)2.52-2.56(m)2.43-2.47(m)2.29(s)1.77(s)1.58(d)1.17-1.27(m).

[1112] Example 61

[1113] 4-Acetyl-1-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]piperazin-2-one

[1114]

[1115] Using the method described in Example 24, intermediate 28 (tert-butyl 4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-3-oxopiperazine-1-carboxylate (109 mg, 200 μmol), triethylsilane (not used in this example), trifluoroacetic acid (200 μl, 1.3 mmol), acetic anhydride (21 μl, 220 μmol) and N,N-diisopropylethylamine (77 μl, 440 μmol) were subjected to preparative HPLC (basic method) to give 28.4 mg (95% purity, 28% yield) of the title compound.

[1116] LC-MS (LC-MS method 2): R t =1.10min; MS(ESIpos):m / z=487[M+H] +

[1117] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:1.550(5.14),1.568(5.10),2.090(6.15 ),2.121(8.14),2.390(16.00),2.518(2.80),2.523(1.85),2.616(7.13) ,3.312(0.72),3.391(0.69),3.399(0.64),3.819(0.49),3.841(1.17),3 .853(1.05),3.873(0.72),3.884(0.75),3.908(1.39),3.917(2.39),3.9 28(2.36),3.946(0.72),4.257(3.91),4.360(3.22),5.708(0.81),5.725(1.23),5.742(0.77),7.338(0.78),7.357(1.71),7.377(0.98),7.542(1.91),7.561(1.52),7.746(1.68),7.765(1.48),8.791(3.32),8.798(3.84),8.814(0.81),8.939(1.74),8.946(1.70),8.955(1.40),8.962(1.21).

[1118] Example 62

[1119] 1-{4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]-5-methyl-3,6-dihydropyridin-1(2H)-yl}ethan-1-one

[1120]

[1121] Using the method described in Example 24, intermediate 29 (tert-butyl 4-(4-{[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]amino}-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl)-5-methyl-3,6-dihydropyridine-1(2H)-carboxylate (39.5 mg, 55.3 μmol), triethylsilane (0.88 μl, 5.5 μmol), trifluoroacetic acid (64 μl, 830 μmol), acetic anhydride (5.7 μl, 61 μmol) and N,N-diisopropylethylamine (21 μl, 120 μmol) were subjected to preparative HPLC (basic method) to give 19.7 mg (95% purity, 62% yield) of the title compound.

[1122] LC-MS (LC-MS method 2): R t =1.06min; MS(ESIpos):m / z=542[M+H] +

[1123] 1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.197(7.61),1.223(6.30),1.433(3.67),1.539(5.48),1.556(5. 50),2.091(14.10),2.263(0.88),2.323(1.18),2.327(1.72),2.343(9.68),2.347(9.68),2.454(16 .00),2.518(5.62),2.523(3.66),2.665(0.80),2.669(1.08),2.673(0.78),3.298(0.49),3.548(0.53),3.566(0.44),3.582(0.41),3.589(0.41),3.601(0.45),3.730(0.53),3.740(0.54),3.839(0.6 7),3.850(0.66),3.882(0.75),4.040(1.44),4.127(0.44),4.144(0.44),5.334(3.01),5.340(4.27),5.739(0.71),5.757(1.03),5.770(0.69),7.183(0.56),7.203(1.29),7.215(1.30),7.221(0.92 ),7.234(0.77),7.288(1.02),7.305(1.49),7.324(0.66),7.550(0.70),7.572(1.32),7.590(1.23),7.606(0.56),7.621(0.41),8.472(2.00),8.486(2.95),8.532(0.92),8.551(1.35),8.563(0.72).

[1124] Example 63

[1125] 1-{6-[2,7-dimethyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one

[1126]

[1127] Using the method described in Example 7, intermediate 5 (6-bromo-2,7-dimethyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]pyrido[2,3-d]pyrimidin-4-amine, 75.0 mg, 171 μmol), oxalic acid / 1-(2,6-diazaspiro[3.3]hept-2-yl)ethan-1-one (1 / 2) (94.9 mg, 256 μmol), sodium tert-butoxide (65.6 mg, 683 μmol), XPhos (16.3 mg, 34.1 μmol), and Pd2(dba)3 (13.4 mg, 17.1 μmol) in 1,4-dioxane (1.9 ml) were subjected to preparative TLC using dichloromethane / methanol (9:1) as eluent to give the title compound (12.0 mg, 90% purity, 13% yield).

[1128] LC-MS (LC-MS method 2): R t =1.16min; MS(ESIpos):m / z=499[M+H] +

[1129] 1 H NMR(400MHz,DMSO-d6)δppm 8.47(d)7.76-7.80(m)7.75(s)7.63(s)7.54(d)7.35(t)5.67-5.76(m)4.33(s)4.07-4.17( m)4.05(s)2.61(s)2.52-2.55(m)2.44-2.46(m)2.30(s)1.77(s)1.56(d)1.34(d)1.23(s).

[1130] Example 64

[1131] 1-{(1S,4S)-5-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]hept-2-yl}ethan-1-one

[1132]

[1133] Using the method described in Example 24, Intermediate 31 (tert-butyl 5-(4-{[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]amino}-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (27.0 mg, 37.8 μmol) was reacted with triethylsilane (0.60 μl, 3.8 μmol) and trifluoroacetic acid (44 μl, 570 μmol) in dichloromethane (400 μl). 1) at room temperature overnight. The mixture was triturated with toluene and concentrated. The treatment with triethylsilane (0.60 μl, 3.8 μmol) and trifluoroacetic acid (44 μl, 570 μmol) in dichloromethane (400 μl) was repeated overnight at room temperature. The mixture was then triturated with toluene again, concentrated, and then treated with acetic anhydride (3.9 μl, 42 μmol) and N,N-diisopropylethylamine (14 μl, 83 μmol) according to the procedure described in Example 24 to give the title compound (5.30 mg (95% purity, 25% yield) after preparative HPLC (basic method).

[1134] LC-MS (LC-MS method 2): R t =0.97min; MS(ESIpos):m / z=543[M+H] +

[1135] 1 H NMR(400MHz,DMSO-d6)δppm 8.36(t)7.87(s)7.55(t)7.31(t)7.20(t)5.78(quin)5.34(s)4.64(s)4.44(s)3.72(dd)3.55-3. 62(m)3.38-3.42(m)3.25-3.30(m)2.52-2.57(m)2.29(d)1.99-2.04(m)1.87(s)1.60(dd)1.22(br d).

[1136] Example 65

[1137] 1-{4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one

[1138]

[1139] Using the method described in Example 24, intermediate 32 (tert-butyl 4-(4-{[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]amino}-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (116 mg, 166 μmol), triethylsilane (2.6 μl, 17 μmol), trifluoroacetic acid (190 μl, 2.5 mmol), acetic anhydride (17 μl, 180 μmol) and N,N-diisopropylethylamine (64 μl, 360 μmol) were subjected to preparative TLC using dichloromethane / ethanol (9:1) as eluent to give the title compound (44.1 mg, 95% purity, 48% yield).

[1140] LC-MS (LC-MS method 2): R t =1.02min; MS(ESIpos):m / z=528[M+H] +

[1141] 1 H NMR(400MHz,DMSO-d6)δppm 8.60(d)8.54(d)7.58(br t)7.31(br t)7.21(t)5.73-5.83(m)5.34(s)4.15(br dd)3.66-3.74(m)2.58-2.68(m)2.54-2.57(m)2.37-2.42(m)2.34(s)2.32-2.34(m)2.09(d)1.55(d)1.21(br d).

[1142] Example 66

[1143] 1-{4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]piperidin-1-yl}ethan-1-one

[1144]

[1145] Using the method described in Example 22, intermediate 32 (1-{4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one (24.8 mg, 47.0 μmol) in EtOH (1 ml) was hydrogenated with Pd / C (5.00 mg, 10% purity, 4.70 μmol) under H2 atmosphere at room temperature for 6 hours. The crude product was purified by preparative HPLC (basic method) to obtain the title compound (16.2 mg, 95% purity, 62% yield).

[1146] LC-MS (LC-MS method 2): R t =1.00min; MS(ESIpos):m / z=530[M+H] +

[1147] 1 H NMR(400MHz,DMSO-d6)δppm 8.53-8.60(m)7.56(t)7.31(t)7.22(t)5.73-5.81(m)5.30-5.40(m)4.64(br d)3.99(br d)3.18-3.30(m)3.06-3.14(m)2.63-2.70(m)2.52-2.56(m)2.31-2.34(m)2.06(s)1.79-1.90(m)1.54-1.75(m)1.23(s)1.20(s).

[1148] Example 67

[1149] 1-{4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]piperazin-1-yl}ethan-1-one

[1150]

[1151] To a solution of intermediate 30 (1-[4-(4-{[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]amino}-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl)piperazin-1-yl]ethan-1-one, 30.0 mg, 46.5 μmol) and triethylsilane (0.74 μl, 4.7 μmol) in dichloromethane (0.4 ml) was added trifluoroacetic acid (54 μl, 700 μmol), and the mixture was stirred at room temperature overnight. Toluene was then added, and the mixture was concentrated. The residue was purified by HPLC (basic method) to give the title compound (14.8 mg, 95% purity, 57% yield).

[1152] LC-MS (LC-MS method 2): R t =0.99min; MS(ESIpos):m / z=531[M+H] +

[1153] 1 H NMR(400MHz,DMSO-d6)δppm 8.47(d)8.31(s)7.57(t)7.31(t)7.21(t)5.77(quin)5.34(s)3.60-3.70(m)2.89-3.01(m)2. 67(dt)2.60(s)2.52-2.59(m)2.33-2.35(m)2.32(s)2.08(s)1.58(d)1.21(d)1.17-1.28(m).

[1154] Example 68

[1155] 4-Acetyl-1-[2,7-dimethyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]piperazin-2-one

[1156]

[1157] Using the procedure described for Intermediate 28, Intermediate 5 (6-bromo-2,7-dimethylpyrido[2,3-d]pyrimidin-4-ol, 75 mg, 171 μmol), tert-butyl-oxopiperazine-1-carboxylate (34 mg, 171 μmol), copper iodide (13 mg, 68 μmol) and potassium phosphate (72 mg, 341 μmol) in DMF (0.8 ml) gave tert-butyl 6-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (100 mg), which was used directly in the subsequent step.

[1158] Using the method described in Example 24, the crude product from the previous step (tert-butyl 6-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (196 mg, 350 μmol), triethylsilane (not used in this example), trifluoroacetic acid (350 μl, 2.3 mmol), acetic anhydride (36 μl, 390 μmol) and N,N-diisopropylethylamine (130 μl, 770 μmol) were subjected to preparative HPLC (basic method) to give the title compound (28.0 mg, 95% purity, 15% yield).

[1159] LC-MS (LC-MS method 2): R t =1.10min; MS(ESIpos):m / z=501[M+H] +

[1160] 1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.531(6.38),1.549(6.64),2.105(6.19),2.145( 10.75),2.336(1.45),2.371(11.13),2.374(11.10),2.394(1.07),2.453(11.08), 2.518(16.00),2.523(12.48),2.613(6.76),2.679(1.39),3.658(0.52),3.720(0.88),3.744(1.02),3.765(0.85),3.814(0.53),3.833(0.51),3.860(0.67),3.891(0 .54),3.903(0.49),3.967(0.71),4.019(0.48),4.130(0.72),4.174(1.16),4.347(0.96),4.366(1.76),4.379(1.31),4.392(0.70),4.404(0.54),5.688(0.84),5.7 03(1.05),5.720(0.86),7.339(0.91),7.359(1.93),7.377(1.15),7.540(2.65),7.559(2.24),7.738(2.24),7.758(2.07),8.670(1.37),8.683(2.60),8.693(3.39).

[1161] Example 69

[1162] 1-{6-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one

[1163]

[1164] Using the method described in Example 24, intermediate 33 (tert-butyl 6-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (40.0 mg, 67.0 μmol), triethylsilane (1.1 μl, 6.7 μmol), trifluoroacetic acid (100 μl, 1.3 mmol), acetic anhydride (7.0 μl, 74 μmol) and N,N-diisopropylethylamine (26 μl, 150 μmol) gave the title compound (17.0 mg, 95% purity, 45% yield) after preparative HPLC (basic method).

[1165] LC-MS (LC-MS method 2): R t =1.18min; MS(ESIpos):m / z=540[M+H] +

[1166] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:1.232(0.46),1.627(4.72),1.644(4.72),1.763(14.40),2.332(2.19),2.341(16.00),2.51 8(7.60),2.523(5.44),2.673(1.72),2.678(0.75),4.059(4.56),4.217(0.51),4.242(5.61),4.268(0.50),4.343(4.70),5.7 75(0.73),5.793(1.15),5.810(0.72),7.106(1.12),7.242(2.39),7.284(0.82),7.303(1.81),7.322(1.03),7.378(0.98),7.502(0.63),7.518(1.01),7.537(0.51),7.646(0.56),7.664(1.03),7.683(0.51),7.993(3.36),8.808(1.18),8.825(1.12).

[1167] Example 70

[1168] 1-{6-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one

[1169]

[1170] Using the method described in Example 24, intermediate 34 (tert-butyl 6-[4-{[(1R)-1-(3-{1,1-difluoro-2-methyl-2-[(triethylsilyl)oxy]propyl}-2-fluorophenyl)ethyl]amino}-2-methyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (80.0 mg, 104 μmol), triethylsilane (1.7 μl, 10 μmol), trifluoroacetic acid (160 μl, 2.1 mmol), acetic anhydride (11 μl, 110 μmol) and N,N-diisopropylethylamine (40 μl, 230 μmol) were subjected to preparative HPLC (basic method) to give the title compound (13.5 mg, 95% purity, 21% yield).

[1171] LC-MS (LC-MS method 2): R t =1.12min; MS(ESIpos):m / z=598[M+H] +

[1172] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:1.206(6.44),1.232(7.09),1.601(4.56),1.619(4.55),1.764(14.21),2.328(16.00),2.518(9 .19),2.523(6.27),2.660(0.69),2.665(1.56),2.669(2.20),2.673(1.56),2.678(0.69),4.060(4.67),4.220(0.48),4.244(6.7 1),4.268(0.50),4.345(4.76),5.346(6.83),5.772(0.75),5.789(1.16),5.807(0.73),7.204(0.73),7.224(1.73),7.243(1.12),7.310(0.77),7.328(1.13),7.343(0.53),7.566(0.61),7.581(1.09),7.597(0.56),7.999(3.33),8.799(1.25),8.817(1.20).

[1173] Example 71

[1174] 1-{6-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one

[1175]

[1176] Using the method described in Example 24, intermediate 35 (tert-butyl 6-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (20.0 mg, 32.8 μmol), triethylsilane (0.52 μl, 3.3 μmol), trifluoroacetic acid (50 μl, 660 μmol), acetic anhydride (3.4 μl, 36 μmol) and N,N-diisopropylethylamine (13 μl, 72 μmol) were subjected to preparative HPLC (basic method) to give the title compound (11.0 mg, 95% purity, 58% yield).

[1177] LC-MS (LC-MS method 2): R t =1.28min; MS(ESIneg):m / z=551[MH] -

[1178] 1 H NMR(400MHz,DMSO-d6)δppm 8.90(d)7.99(s)7.75(d)7.56(d)7.37(t)5.72(t)4.34(s)4.21-4.27(m) 4.06(s)2.67(dt)2.61(s)2.52-2.52(m)2.32-2.34(m)1.76(s)1.59(d).

[1179] Experimental part - bioassay

[1180] The examples were tested one or more times in the selected biological assays. When tested more than once, the data are reported as mean or median values, where:

[1181] The average, also called the arithmetic mean, which represents the sum of the values ​​obtained divided by the number of tests, and

[1182] The median value represents the middle value of a set of values ​​when arranged in ascending or descending order. If the number of values ​​in the data set is odd, the median is the middle value. If the number of values ​​in the data set is even, the median is the arithmetic mean of the two middle values.

[1183] The examples were synthesized one or more times. When synthesized multiple times, data from the bioassays represent mean or median values ​​calculated using data sets obtained from testing of one or more synthetic batches.

[1184] Biochemical assay: hK-RasG12C interaction assay with hSOS1

[1185] This assay quantifies the interaction of human SOS1 (SOS1) with human K-Ras G12C Equilibrium interaction of GST-K-RasG12C with anti-GST-Europium (FRET donor) was detected by measuring homogeneous time-resolved fluorescence resonance energy transfer (HTRF) from anti-GST-Europium bound to GST-K-RasG12C (FRET donor) to anti-6His-XL665 bound to His-tagged hSOS1 (FRET acceptor).

[1186] The assay buffer contained 5 mM HEPES pH 7.4 (Applichem), 150 mM NaCl (Sigma), 10 mM EDTA (Promega), 1 mM DTT (Thermofisher), 0.05% BSA Fraction V, pH 7.0, (ICN Biomedicals), 0.0025% (v / v) Igepal (Sigma), and 100 mM KF (FLUKA).

[1187] The following describes the expression and purification of N-terminally GST-tagged K-RasG12C and N-terminally His-tagged SOS1. The concentrations of the protein batches used were optimized to be within the linear range of the HTRF signal. A Ras working solution was prepared in assay buffer typically containing 10 nM GST-hK-RasG12C and 2 nM anti-GST-Eu(K) (Cisbio, France). An SOS1 working solution was prepared in assay buffer typically containing 20 nM His-hSOS1 and 10 nM anti-6His-XL665 (Cisbio, France). An inhibitor control solution was prepared in assay buffer containing 10 nM anti-6His-XL665 but without SOS1.

[1188] 50 nl of a 100-fold concentrated solution of the test compound in DMSO were transferred to a black microtiter assay plate (384 or 1536, Greiner Bio-One, Germany) using a Hummingbird liquid handler (Digilab, MA, USA) or an Echo acoustic system (Labcyte, CA, USA).

[1189] All steps of the assay were performed at 20°C. 2.5 μl of Ras working solution was added to all wells of the test plate using a Multidrop dispenser (Thermo Labsystems). After a 2-minute pre-incubation, 2.5 μl of SOS1 working solution was added to all wells (except those on the side of the test plate), which were then filled with 2.5 μl of inhibitor control solution. After a 60-minute incubation, fluorescence was measured using a Pherastar (BMG, Germany) using an HTRF module (excitation 337 nm, emission 1: 620 nm, emission 2: 665 nm).

[1190] Ratio data (emission 2 divided by emission 1) were normalized using controls (DMSO = 0% inhibitor, inhibition control wells with inhibitor control solution = 100% inhibitor). Compounds were tested in duplicate at up to 11 concentrations (e.g., 20 μM, 5.7 μM, 1.6 μM, 0.47 μM, 0.13 μM, 38 nM, 11 nM, 3.1 nM, 0.89 nM, 0.25 nM, and 0.073 nM). 50 The values ​​were calculated by 4-parameter fitting using a commercial software package (Genedata Screener, Switzerland).

[1191]

[1192]

Claims

1. A compound of formula (II), or a stereoisomer, tautomer, hydrate or salt thereof, or a mixture thereof in A is a phenyl group; R 1 Selected from R 1a Selected from Hydrogen, -CH3, CF3 or -OCH3; R 2 Selected from Hydrogen, halogen or C optionally substituted one or more times by halogen and / or hydroxy 1-6 -alkyl; x is selected from 1 or 2, and R 3 Selected from Hydrogen or -CH3.

2. The compound according to claim 1, or a stereoisomer, tautomer, hydrate or salt thereof, or a mixture thereof, wherein A is a phenyl group; R 1 Selected from R 1a Selected from Hydrogen, -CH3, CF3 or -OCH3; R 2 Each independently selected from -H, -CH3, -F, -CF3 or -CF2-C(CH3)2-OH; R 3 Selected from Hydrogen or -CH3.

3. A compound of formula (III), or a stereoisomer, tautomer, hydrate or salt thereof, or a mixture thereof in R 1 Selected from R 3 selected from -H and -CH3; R 4 selected from -CH3 and -C(=O)-CH3, and R 5 Selected from -C(=O)-CH3 and -C(=O)OC(CH3)3.

4. A compound, or a stereoisomer, tautomer, hydrate or salt thereof, or a mixture thereof, selected from: N-{(3R)-1-[4-({(1R)-1-[3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]pyrrolidin-3-yl}acetamide 6-(4-Methylpiperazin-1-yl)-N-{(1R)-1-[3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3-d]pyrimidin-4-amine 1-{4-[4-({(1R)-1-[3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]piperazin-1-yl}ethan-1-one 1-{4-[4-({(1R)-1-[3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one tert-Butyl 6-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate 1-{6-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one 1-{4-[4-({(1R)-1-[3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]piperidin-1-yl}ethan-1-one 1-{4-[4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]piperazin-1-yl}ethan-1-one N-{(3R)-1-[4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]pyrrolidin-3-yl}acetamide 1-{4-[4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one 1-{6-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one-hydrogen chloride (1 / 1) 1-{(1S,4S)-5-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]hept-2-yl}ethan-1-one 2-Methyl-6-(4-methylpiperazin-1-yl)-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3-d]pyrimidin-4-amine N-{(3R)-1-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]pyrrolidin-3-yl}acetamide 1-{4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidine-6-sulfonyl]piperazin-1-yl}ethan-1-one N-{(3R)-1-[2,7-dimethyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]pyrrolidin-3-yl}acetamide 1-{4-[2,7-dimethyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]piperazin-1-yl}ethan-1-one 1-{6-[7-methoxy-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one 1-{4-[7-methoxy-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one 1-{4-[7-methoxy-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]piperidin-1-yl}ethan-1-one 2-[7-methoxy-2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-1λ 6 ,2-thiazolidine-1,1-dione 1-{6-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl]ethyl}amino)-2-methyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one 1-{4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one 1-{4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one hydrochloride (1 / 1) 1-{7-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2-azaspiro[3.5]non-6-en-2-yl}ethan-1-one 1-{7-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2-azaspiro[3.5]nonan-2-yl}ethan-1-one 1-{6-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one 1-{3-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2,5-dihydro-1H-pyrrol-1-yl}ethan-1-one 1-{(3RS)-3-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]pyrrolidin-1-yl}ethan-1-one 6-Methoxy-2-methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3-d]pyrimidin-4-amine N-Methyl-N-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]methanesulfonamide 2-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-1λ 6 ,2-thiazolidine-1,1-dione 1-{4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]piperazin-1-yl}ethan-1-one 1-{4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-4-oxo-4λ 5 -piperazin-1-yl}ethan-1-one 1-{6-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one 6-Methoxy-2,7-dimethyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}pyrido[2,3-d]pyrimidin-4-amine 2-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]-1λ 6 ,2-thiazolidine-1,1-dione 1-{3-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]azetidin-1-yl}ethan-1-one 1-{4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one 1-{4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-6-yl]piperidin-1-yl}ethan-1-one 1-{4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one 1-{4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]piperidin-1-yl}ethan-1-one 2-Methyl-N-{(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}-6-(pyrimidin-5-yl)pyrido[2,3-d]pyrimidin-4-amine 1-{4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one 1-{4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]piperidin-1-yl}ethan-1-one 6-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]heptane-2-carboxamide 1-{3-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]-3,6-diazabicyclo[3.1.1]hept-6-yl}ethan-1-one 1-{(1S,4S)-5-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]hept-2-yl}ethan-1-one 1-{(1R,4R)-5-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]hept-2-yl}ethan-1-one 1,1-Difluoro-1-{2-fluoro-3-[(1R)-1-{[2-methyl-6-(4-methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-4-yl]amino}ethyl]phenyl}-2-methylpropan-2-ol 1-{4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]piperazin-1-yl}ethan-1-one 1-{6-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one N-{(3R)-1-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl]pyrrolidin-3-yl}acetamide 1-{4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one 1-{4-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]piperidin-1-yl}ethan-1-one 2-[2,7-dimethyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-1λ 6 ,2-thiazolidine-1,1-dione 2-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]-1λ 6 ,2-thiazolidine-1,1-dione 1-{6-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one 4-Acetyl-1-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]piperazin-2-one 1-{4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]-5-methyl-3,6-dihydropyridin-1(2H)-yl}ethan-1-one 1-{6-[2,7-dimethyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one 1-{(1S,4S)-5-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]-2,5-diazabicyclo[2.2.1]hept-2-yl}ethan-1-one 1-{4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydropyridin-1(2H)-yl}ethan-1-one 1-{4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]piperidin-1-yl}ethan-1-one 1-{4-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2,7-dimethylpyrido[2,3-d]pyrimidin-6-yl]piperazin-1-yl}ethan-1-one 4-Acetyl-1-[2,7-dimethyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[2,3-d]pyrimidin-6-yl]piperazin-2-one 1-{6-[4-({(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl}amino)-2-methyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one 1-{6-[4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl}amino)-2-methyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one 1-{6-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-6-yl]-2,6-diazaspiro[3.3]hept-2-yl}ethan-1-one.

5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 and one or more pharmaceutically acceptable excipients.

6. A drug conjugate comprising: one or more first active ingredients, which are compounds according to any one of claims 1 to 4, and One or more other active ingredients.

7. The combination according to claim 6, wherein the other active ingredient is an anti-hyperproliferative agent and / or an anticancer agent.

8. Use of a compound according to any one of claims 1 to 4 for the preparation of a medicament for the treatment or prevention of a disease responsive to inhibition of the Ras-Sos1 interaction.

9. The use according to claim 8, wherein the disease is a hyperproliferative disease.

10. The use according to claim 9, wherein the hyperproliferative disease is cancer.

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