TW202237585A - Cdk inhibitors - Google Patents

Abstract

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof as cyclin-dependent kinase inhibitors (one or more of CDK1, CDK2, CDK4, and CDK6), methods of preparing them, and pharmaceutical compositions containing them. The compounds of the present invention are useful in the treatment, prevention and/or amelioration of diseases or disorders associated with one or more of CDK1, CDK2, CDK4, and CDK6.

Description

CDK inhibitors

This application claims the benefit of Indian Patent Application No. 202041051646 filed on November 27, 2020, which is hereby incorporated by reference.

The present invention provides a compound of formula (I) , which is an inhibitor of cyclin-dependent kinase (one or more of CDK1, CDK2, CDK4 and CDK6) (such as an inhibitor of CDK2 and/or CDK 4/6); preparing the Methods of the compounds; pharmaceutical compositions containing the compounds; and methods of treating, preventing and/or improving diseases or conditions involving one or more of CDK1, CDK2, CDK4 and CDK6.

Cyclin-dependent kinases (CDKs) are serine/threonine kinases whose activity depends on a regulatory subunit, cyclins. Based on the sequence of the kinase domain, CDKs belong together with mitogen-activated protein kinase (MAPK), glycogen synthase kinase-3β (Gsk3β), members of the dual specificity tyrosine-regulated kinase (DYRK) family, and CDK-like kinases CMGC kinase group (named after some members' initials). In related kinases such as MAPKs, substrate specificity is conferred by a docking site separate from the catalytic site, whereas CDKs are characterized by reliance on separate protein subunits that provide the additional sequences required for enzymatic activity. To facilitate the nomenclature and analysis of CDKs, the proteins belonging to this family have been renamed Cdk1 to Cdk20.

CDKs were first discovered in genetic and biochemical studies of model organisms such as yeast and frogs. This work establishes the importance of CDKs in promoting cell cycle transitions. In addition, these studies show that the catalytic subunit CDK must associate with the regulatory subunit cyclins whose protein levels are regulated during the cell cycle (this oscillation gives these regulators their cyclin name). Since these pioneering studies in the 1980s, the importance of CDKs as a major family of eukaryotic protein kinases involved in the integration of extracellular and intracellular signals to regulate gene transcription and cell division has been clearly established.

The number of CDKs increases during evolution and is marked by a greater expansion of cell cycle-associated groups. Fungi contain 6 to 8 CDKs and 9 to 15 cyclins, while flies and echinoderms contain 11 CDKs and 14 cyclins, and human cells have 20 CDKs and 29 cyclins. Evolutionary studies have shown that CDKs are divided into eight subfamilies represented by Cdk1, Cdk4 and Cdk5 (from yeast cell cycle-associated CDKs) and Cdk7, Cdk8, Cdk9, Cdk11 and Cdk20 (functioning as transcriptional CDKs). (Marcos Malumbres , Genome Biology, 2014, 15:122) .

Cyclin-dependent kinase 1 (CDK1) is the main protein kinase that drives cells into normal mitosis. CDK1 is activated by binding to B-type cyclins, primarily cyclin B1, which in turn phosphorylates substrates critical for entry into mitosis. Disruption of cyclin B1 provides a mechanism to rapidly inactivate CDK1 and exit cells from mitosis (RYC Poon , Encyclopedia of Cell Biology, 2016 ). CDK1 is present throughout the cell cycle. In contrast, upon entry into S phase, cyclin B1 accumulates and forms a complex with CDK1. This complex remains inactive until MYT1 and WEE1 enter mitosis by phosphorylating CDK1 ^Thr14/Tyr15 . At the end of the G2 phase, the reserve of inactive cyclin B1-CDK1 is suddenly activated by members of the CDC25 phosphatase family. Cyclin B1-CDK1 catalyzes its own activation by simultaneously stimulating CDC25 activation and WEE1 inactivation (Lindqvist et al., 2009, JCB (2009), 185(2): 193-202 ). This bistable system is believed to be activated by PLK1, thereby initiating the activation of CDC25 and the inactivation of WEE1/MYT1 (Van Vugt and Medema, Oncogene , Vol. 24, pp. 2844-2859 (2005)). Activation of PLK1 in turn requires phosphorylation of PLK1 ^Thr210 by Aurora A, an event assisted by Bora. Binding of Bora to PLK1 is stimulated by cyclin B1-CDK1-dependent phosphorylation, creating another positive feedback loop in the activation of CDK1.

CDK1 is a major cell cycle regulator. In yeast, cell cycle progression is controlled by a single CDK, called Cdc28 in Saccharomyces cerevisiae and Cdc2 in Schizosaccharomyces pombe, and this CDK binds at different stages of the cell cycle to specific cycle proteins. Systematic knockout of Cdk in the mouse germline has shown that Cdk2, Cdk4 and Cdk6 are not essential for the cell cycle of most cell types by genetic studies in mice. Only depletion of Cdk1 caused cell cycle arrest and fetal death at the two-cell stage. CDK1 activity controls M phase entry and exit. During the G2/M transition, CDK1-cyclin B1 activation leads to phosphorylation of various proteins that control chromosome compaction, nuclear envelope breakdown, and spindle assembly. At the onset of anaphase, CDK1-cyclin B1 participates in this event by controlling the activity of separase, a protease that cleaves the mucin complex that holds sister chromatids together. Regulation of CDK1 activity is controlled at multiple levels, such as binding to its regulatory subunits (cyclins A and B), interaction with cyclin-dependent kinase inhibitors (CKIs), and activation by the activating kinase CAK (CDK kinases) or by phosphorylation and dephosphorylation of specific residues by several inhibitor kinases including Wee1 and Myt1 or the phosphatase Cdc25. See also Brown et al., Nat Commun., 6, 6769 (2015) .

CDK2 overexpression is associated with abnormal cell cycle regulation, and CDK2/cyclin E is involved in the regulation of cell cycle G1 phase to S phase. At the end of the G1 phase, the CDK2/cyclin E complex can also catalyze the phosphorylation of Rb, thereby promoting the progression of the cell cycle from the G1 phase to the S phase; in the S phase, the CDK2/cyclin A complex can promote the DNA replication process. Asghar et al., Nat. Rev. Drug. Discov. , 2015;14(2):130-146. Cyclin E corresponding to CDK2 is commonly found in tumors. Amplification and overexpression of cyclin El is associated with poor prognosis in ovarian, gastric and breast cancers. Nakayama et al., Cancer , 2010, 116:2621-34); Etemadmoghadam et al., Clin cancer res, 2013, 19:5960-71; Au-Yeung et al., Clin. Cancer Res. 2017, 30:297-303) ; Ooi et al., Hum Pathol. , 2017, 61:58-67 ; Noske et al., Oncotarget , 2017, 8:14794-14805. Cyclin E2 overexpression is associated with breast cancer resistance to endocrine therapy and suppresses CDK2 cells resistant to tamoxifen. Caldon et al., Mol Cancer Ther. , 2012, 11:1488-99; Herrera-Abreu et al., Cancer Res. , 2016, 76:2301-2313. In HER2-positive breast cancer, cyclin E amplification is also associated with trastuzumab resistance. Scaltriti et al., Proc Natl Acad Sci. 2011, 108:3761-6. The discovery of CDK4 validated the hypothesis that D-type cyclins can allosterically regulate novel CDKs, revealing that CDK4 physically binds to and is enzymatically activated by any of the three D-type cyclins. Two years later, a related cyclin D-dependent kinase CDK6 with similar properties was identified. While complexes of CDK 1 and 2 with cyclins E, A and B drive cell cycle progression through S and M phases (mitosis), cyclin D-dependent CDKs act during G1 phase to drive cells that have entered Cyclic quiescent cells or proliferative cells that have completed mitosis progress to S phase. Unlike CDK 1 and 2, which phosphorylate hundreds of cellular protein substrates, CDK4 is a surprisingly finicky enzyme with limited retinoblastoma protein (RB1, hereinafter referred to as RB) and two other The propensity for phosphorylation of RB family proteins [RB2 (p130), RBL1 (p107)], and very few other substrates.

RB is a canonical tumor suppressor gene in retinoblastoma and in many other cancers. As cells go through the division cycle, RB proteins undergo periodic phosphorylation. RB is dephosphorylated when cells exit mitosis, and the hypophosphorylated form detected in G1 phase becomes hyperphosphorylated (inactive) in late G1 and remains so throughout progression through S phase to mitosis. Studies have highlighted the role of hypophosphorylated (active) RB in limiting proliferation and serving as a potent tumor suppressor gene, indicating that the growth inhibitory function of RB may be due to its association with DNA tumor virus oncoproteins (human papillomavirus E7, adenovirus E1A, and SV40 T antigen;) binds without activation. In mammalian cells that enter the division cycle from quiescence (G0) stimulated by mitogens, CDK4/6-mediated RB phosphorylation precedes cyclin D induction but precedes cyclin E and A-dependent CDK2 activation Detected in the middle of G1 phase. Taken together, these results suggest that the role of CDK4/6 is to phosphorylate RB, thereby priming RB for inactivation by other CDKs in late G1, and to release E2F transcription factors from RB constraints to allow them to coordinately induce a series of Activity is a common requirement for the initiation of S phase genes. Sherr et al., Cancer Discovery , 2016 April, 6(4):353-367CD-15-0894.

The CDK4 (INK4)-retinoblastoma (Rb) pathway regulates cell proliferation by controlling the G1 (pre-DNA synthesis) to S (DNA synthesis) cell cycle checkpoints. Dysregulation of the cyclin D-CDK4/6-INK4-Rb pathway is frequently observed in cancer and contributes to cell cycle progression and continued growth. CDK4/6 mediates the transition from G1 to S phase by associating with D-type cyclins and regulating the phosphorylation state of Rb. Non-phosphorylated Rb binds E2 family (E2F) transcription factors and inhibits their function; upon phosphorylation, Rb dissociates from E2F transcription factors, releasing the factors so that they can participate in DNA replication and cell division. Increased cyclin D-CDK4/6 activity promotes phosphorylation of Rb, which can occur through several mechanisms, including overexpression of D-type cyclins, mutation or amplification of CDK4/6, or negative regulation of cyclin D-CDK4/6 Factors such as p16INK4A are lost and ultimately lead to cancer cell growth. Therefore, the development of selective CDK4/6 inhibitors provides novel therapeutic approaches for patients with advanced cancer. Hamilton et al., Cancer Treatment Reviews , 45 (2016) 129-138.

Cyclin-dependent kinase 4 (CDK4) and the closely related CDK6 play key roles in mammalian cell proliferation, where these kinases help drive cell progression through the DNA synthesis (S) phase of the cell division cycle. Unlike CDK 1 and 2, which act in response to cycle oscillations of cyclins E, A, and B in late cell cycle to coordinate DNA replication with mitosis, CDK4 and CDK6 interact during the first interval (G1) of the cycle. Enzyme activity is regulated by D-type cyclins that are expressed in response to a variety of extracellular signals, including stimulatory mitogens, inhibitory cytokines, inducers of differentiation, cell-cell contacts, and other steric triggers. Three D-type cyclins (D1, D2 and D3) are differentially expressed individually or in combination in different cell lineages where they assemble with CDK4 and CDK6 to form enzymatically active holoenzyme complexes. Understanding how three distinct D-type cyclins act as environmental sensors dynamically in response to extracellular cues in various cell types helps explain how CDK4/6 activity is differentially regulated and predicts mitogens in normal and cancer cells. Basis for functional interplay between signaling pathways and CDK4/6 activity. More than two decades after the discovery of CDK4 and CDK6, drugs that inhibit their activity are now showing significant efficacy in cancer treatment.

CDK4/6 inhibitors act on G1 to S cell cycle checkpoints. This checkpoint is tightly controlled by D-type cyclins as well as CDK4 and CDK6. When CDK4 and CDK6 are activated by D-type cyclins, they phosphorylate retinoblastoma-associated protein (pRb). This releases pRb's repression of the E2F family of transcription factors and ultimately allows the cell to proceed through the cell cycle and divide. In HR+ breast cancer, cyclin D overexpression is common and pRb loss is rare, making the G1 to S checkpoint an ideal therapeutic target. CDK4/6 inhibitors prevent progression through this checkpoint, resulting in cell cycle arrest.

Hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) advanced breast cancer is rarely cured despite multiple therapies. Current treatment paradigms for HR+/HER2- advanced breast cancer involve sequencing endocrine therapy, targeted therapy, and/or chemotherapy to prolong patient life, delay disease progression, and minimize cancer-related symptoms. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are rapidly changing the treatment landscape. There are currently three CDK4/6 inhibitors approved by the U.S. Food and Drug Administration: Palbociclib, Ribociclib, and Abemaciclib.

CDK4/6 inhibitors as a class are generally well tolerated. The most common class-wide adverse effects included nausea, diarrhea, fatigue, neutropenia, leukopenia, anemia, and thrombocytopenia. Palbociclib and ribociclib most commonly cause neutropenia, while diarrhea is a unique gastrointestinal (GI) toxicity associated with abeciclib, possibly due to abeciclib's higher affinity for CDK4 than CDK6. Shah et al., Oncology (Williston Park) , 2018 May 15; 32(5): 216-222.

The U.S. Food and Drug Administration (FDA) warns that Ibrance (palbociclib), Kisqali (ribociclib), and Verzenio (abeciclib), used to treat certain patients with advanced breast cancer, may cause rare but serious Inflammation of the lungs. See USFDA, Drugs Safety Communications, dated September 13, 2019, titled "FDA warns about rare severe lung inflammation-Ibrance, Kisqali and Verzeni breast cancer."

Patent documents related to CDK inhibitors include, but are not limited to, International Publication Nos. WO 2000/064900, WO 2000/035908, WO 2004/031158, WO 2004/046130, WO 2004/101549, WO 2005/111019, WO 2006/105386, WO 2006/040050, WO 2006/040036, WO 2006/002828, WO 2006/040052, WO 2018/033815, WO 2020/223558, WO 2020/205560, WO 2020/180959, WO 2020/168197, WO 2020/157652, WO 2020/223469, WO 2021/072232, WO 2021/030537, WO 2021/170076, WO 2021/073593, WO 2019/161224, WO 2019/148161, WO 2019/170055, WO 2019/222521, WO 2019 /035008, WO 2018/106870, WO 2018/108167, WO 2018/113771, WO 2018/045957, WO 2018/081211, WO 2018/081204, WO 2017/ 020065, WO 2017/114512, WO 2017/177836, WO 2017/177837, WO 2017/114351, WO 2017/133701, WO 2017/193872, WO 2017/041535 No., WO 2017/054484, WO 2016/058501, WO 2016/141881, WO 2016/194831, WO 2016/014904, WO 2016/015597, WO 2015/101293 , WO 2015/180642, WO 2014/183520, WO 2011/101417, WO 2011/101409, WO 2010/132725, WO 2009/061345, WO 2006/008874, WO 2002/002550, WO 2021/030623, WO 20 19/161224, each of which is hereby incorporated by reference in its entirety for all purposes. The CDK 2/4/6 inhibitor PF-06873600 (WO 2018/033815) developed by Pfizer is selective for CDK 2/4/6 isoforms.

There remains a continuing need for CDK inhibitors having activity against CDK1, CDK2 and/or CDK4/6, such as against CDK2 and/or CDK4/6, for the treatment of various diseases and disorders associated with cell proliferation, such as cancer.

The present invention relates to compounds of formula (I) , processes for their preparation, pharmaceutical compositions containing them and methods of treatment using these compounds. Specifically, the compounds of the formula (I) and pharmaceutically acceptable salts thereof can be used to treat, prevent and/or improve diseases or conditions related to CDK1, CDK2 and/or CDK4/6.

(I)或其互變異構物、其前藥、其N-氧化物、其立體異構物、其醫藥學上可接受之酯或其醫藥學上可接受之鹽， 其中 Y ¹選自CR ^a或N； Y ²選自CR ^b或N；條件係Y ¹及Y ²中之至少一者為N； R ^a、R ^b、R ^c、R ^d、R ^e、R ^f及R ^g在每次出現時獨立地選自氫、鹵素、羥基、經取代或未經取代之烷基、經取代或未經取代之烯基、經取代或未經取代之鹵烷基、經取代或未經取代之烷氧基、經取代或未經取代之胺基烷基、經取代或未經取代之羥基烷基、經取代或未經取代之環烷基、經取代或未經取代之環烷基烷基、經取代或未經取代之雜環基或經取代或未經取代之雜環基烷基； Y選自CR ^h或N； Z選自CR ⁱ或N；條件係Y及Z中之至少一者為N； R ^h及R ⁱ在每次出現時獨立地選自氫、鹵素、經取代或未經取代之C _(1-3)烷基或經取代或未經取代之C _(1-3)鹵烷基； X ¹選自CR ¹或N； X ²選自CR ²或N； X ³選自CR ³或N； X ⁴選自CR ⁴或N； R ¹、R ²、R ³、R ⁴、R ⁵及R ⁶在每次出現時獨立地選自氫、鹵素、羥基、經取代或未經取代之烷基、經取代或未經取代之鹵烷基、經取代或未經取代之烷氧基、經取代或未經取代之環烷基、經取代或未經取代之環烷基烷基、經取代或未經取代之雜環基或經取代或未經取代之雜環基烷基； L為不存在、NH、O、-S-、-SO-、-SO ₂-、-C(=O)-或經取代或未經取代之烷基； 環A為經取代或未經取代之雜環基環； R ⁷在每次出現時獨立地選自氫、羥基、鹵素、經取代或未經取代之烷基、經取代或未經取代之烷氧基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之環烷基、經取代或未經取代之環烯基、經取代或未經取代之環烷基烷基、經取代或未經取代之環烯基烷基、經取代或未經取代之雜環基、經取代或未經取代之雜環基烷基、經取代或未經取代之芳基、經取代或未經取代之芳基烷基、經取代或未經取代之雜芳基、經取代或未經取代之雜芳基烷基、側氧基(=O)、-C(=O)OR ^z、-C(=O)R ^z、-C(=S)R ^z、-C(=O)NR ^zR ^z、-C(=O)ONR ^zR ^z、-NR ^zR ^z、-NR ^zC(=O)NR ^zR ^z、-NR ^zS(=O)R ^z、-NR ^zS(=O) ₂R ^z、-N=NR ^z、-NR ^zC(=O)OR ^z、-NR ^zC(=O)R ^z、-NR ^xC(=S)R ^y、-NR ^zC(=S)NR ^zR ^z、-SONR ^zR ^z、-SO ₂NR ^zR ^z、-OR ^z、-OC(=O)NR ^zR ^z、-OC(=O)OR ^z、-OC(=O)R ^z、-OC(=O)NR ^zR ^z、-CR ^xR ^y-NR ^zC(=O)R ^z、-CR ^xR ^y-OR ^z、-CR ^xR ^y-C(=O)OR ^z、-CR ^xR ^y-C(=O)NR ^zR ^z、-CR ^xR ^y-OC(=O)R ^z、-SR ^z、-SOR ^z、-SO ₂R ^z、-CR ^xR ^yC(=O)R ^z或-CR ^xR ^yC(=S)R ^z； R ^z選自氫、經取代或未經取代之烷基、經取代或未經取代之烷氧基、經取代或未經取代之烯基、經取代或未經取代之炔基、經取代或未經取代之芳基、經取代或未經取代之芳基烷基、經取代或未經取代之雜芳基、經取代或未經取代之雜芳基烷基、經取代或未經取代之環烷基、經取代或未經取代之環烷基烷基、經取代或未經取代之環烯基、經取代或未經取代之雜環基、經取代之雜環基烷基或經取代或未經取代之胺基，或任兩個R ^z在結合至共用原子時可連結以形成(i)經取代或未經取代之飽和或不飽和3員至14員環，其可視情況包括一或多個雜原子，該(等)雜原子可相同或不同且選自O、NR ^za及S，或(ii) 側氧基(=O)、硫基(=S)或亞胺基(=NR ^za)；其中R ^za、R ^x及R ^y在每次出現時獨立地選自 氫、鹵基、羥基、胺基、烷氧基、C _1-5烷基、C _3-7環烷基、C _5-7芳基、 C _5-7雜芳基或C _3-7雜環烷基；且 n為選自0、1、2、3及4之整數。 In one aspect, the present invention relates to compounds of formula (I) :

(I) or its tautomer, its prodrug, its N ^- oxide, its stereoisomer, its pharmaceutically acceptable ester or its pharmaceutically acceptable salt, wherein Y is selected from CR ^a or N; Y ² is selected from CR ^b or N; proviso that at least one of Y ¹ and Y ² is N; R ^a , R ^b , R ^c , R ^d , ^Re , R ^f and R ^g are in each The second occurrence is independently selected from hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted Alkoxy, substituted or unsubstituted aminoalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkane group, substituted or unsubstituted heterocyclyl or substituted or unsubstituted heterocyclylalkyl; Y is selected from CR ^h or N; Z is selected from CR ⁱ or N; the proviso is that at least one of Y and Z One is N; R ^h and R ⁱ are independently selected from each occurrence of hydrogen, halogen, substituted or unsubstituted C _(1-3) alkyl or substituted or unsubstituted C ₍ 1-3) ₃₎ Haloalkyl; X ¹ is selected from CR ¹ or N; X ² is selected from CR ² or N; X ³ is selected from CR ³ or N; X ⁴ is selected from CR ⁴ or N; R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from hydrogen, halogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted Substituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heterocyclic L is absent, NH, O, -S-, -SO-, -SO ₂ -, -C(=O)-, or substituted or unsubstituted alkyl; Ring A is substituted or Unsubstituted heterocyclyl ring ^; each occurrence of R is independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or Unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkane substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, Substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, side oxy (=O), -C(=O)OR ^z , -C(=O)R ^z , -C(=S)R ^z , -C(=O)NR ^z R ^z , -C(=O)ONR ^z R ^z , -NR ^z R ^z , -NR ^z C(=O)NR ^z R ^z , -NR ^z S(=O)R ^z , -NR ^z S(=O) ₂ R ^z , -N=N R ^z , -NR ^z C(=O)OR ^z , -NR ^z C(=O)R ^z , -NR ^x C(=S)R ^y , -NR ^z C(=S)NR ^z R ^z , - SONR ^z R ^z , -SO ₂ NR ^z R ^z , -OR ^z , -OC(=O)NR ^z R ^z , -OC(=O)OR ^z , -OC(=O)R ^z , -OC(= O)NR ^z R ^z , -CR ^x R ^y -NR ^z C(=O)R ^z , -CR ^x R ^y -OR ^z , -CR ^x R ^y -C(=O)OR ^z , -CR ^x R ^y -C(=O)NR ^z R ^z , -CR ^x R ^y -OC(=O)R ^z , -SR ^z , -SOR ^z , -SO ₂ R ^z , -CR ^x R ^y C(=O) R ^z or -CR ^x R ^y C (= S) R ^z ; R ^z is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted Alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Substituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted A heterocyclyl group, a substituted heterocyclylalkyl group or a substituted or unsubstituted amino group, or any two R ^z may be linked when bound to a common atom to form (i) a substituted or unsubstituted A saturated or unsaturated 3- to 14-membered ring, which optionally includes one or more heteroatoms, the (etc) heteroatoms may be the same or different and are selected from O, NR ^za and S, or (ii) side oxy ( =O), thio (=S) or imino (=NR ^za ); wherein R ^za , R ^x and R ^y are independently selected from each occurrence of hydrogen, halo, hydroxyl, amine, alkoxy base, C _1-5 alkyl, C _3-7 cycloalkyl, C _5-7 aryl, C _5-7 heteroaryl or C _3-7 heterocycloalkyl; and n is selected from 0, 1, Integers of 2, 3 and 4.

Another preferred compound is the compound of formula (I) , wherein X ¹ , X ² , X ³ and X ⁴ are independently selected from CH or N.

Another preferred compound is the compound of formula (I) , wherein X ¹ and X ² are N.

Another preferred compound is the compound of formula (I) , wherein X ¹ is N.

Another preferred compound is the compound of formula (I) , wherein X ² , X ³ and X ⁴ are CH.

Another preferred compound is a compound of formula (I) , wherein Y and Z are independently selected from CH or N.

Another preferred compound is the compound of formula (I) , wherein Y and Z are N.

(IA)                                                          (IB)

(IC)                                                            (ID)或其互變異構物、其前藥、其N-氧化物、其立體異構物、其醫藥學上可接受之酯或其醫藥學上可接受之鹽， 其中所有變數(包括環A、L、R ⁵、R ⁶、R ⁷、R ^c、R ^d、R ^e、R ^f、R ^g、Y ¹、Y ²及n)係如上文關於式 (I)化合物所定義。 In another aspect, the present invention relates to compounds of formula (IA) , (IB) , (IC) or (ID) :

(IA) (IB)

(IC) (ID) or its tautomers, its prodrugs, its N-oxides, its stereoisomers, its pharmaceutically acceptable esters or its pharmaceutically acceptable salts, wherein all variables (including rings A, L, R ⁵ , R ⁶ , R ⁷ , R ^c , R ^d , ^Re , R ^f , R ^g , Y ¹ , Y ² and n) are as defined above for compounds of formula (I) .

另一較佳者係式 (I)、 (IB)或 (ID)化合物，其中L為不存在或CH ₂。 Another preferred compound is a compound of formula (I) , (IA) , (IB) , (IC) or (ID) , wherein ring A is selected from

Another preferred is a compound of formula (I) , (IB) or (ID) , wherein L is absent or _CH2 .

Another preferred compound is a compound of formula (I) , (IB) or (ID) , wherein L is absent.

Another preferred compound is a compound of formula (I) , (IB) or (ID) , wherein L is CH ₂ .

Another preferred compound is a compound of formula (I) , (IA) , (IB) , (IC) or (ID) , wherein R ⁵ is hydrogen or halogen.

Another preferred compound is a compound of formula (I) , (IA) , (IB) , (IC) or (ID) , wherein R ⁵ is hydrogen or fluorine.

Another preferred compound is a compound of formula (I) , (IA) , (IB) , (IC) or (ID) , wherein R ⁶ is hydrogen.

Another preferred compound is a compound of formula (I) , (IA) , (IB) , (IC) or (ID) , wherein Y ¹ is N.

Another preferred compound is formula (IA) , (IB) , (IC) or (ID) , wherein R ⁷ is an alkyl group (such as methyl, ethyl or isopropyl), hydroxyl (-OH), side Oxy (=O), -N(R ^z )R ^z (eg -N(CH ₃ ) ₂ ), cycloalkyl (eg cyclopropyl), acetyl (-C(O)CH ₃ ), halo Alkyl (eg -CF ₃ or -CH ₂ CF ₃ ), sulfonylalkyl (eg -SO ₂ Me), -C(O)cycloalkyl (eg -C(O)cyclopropyl) or -C (=O)OR ^z (eg -C(=O)O-tert-butyl), and n is an integer 1 or 2.

Another preferred compound is a compound of formula (I) , (IA) , (IB) , (IC) or (ID) , wherein n is 1 or 2.

選自

Another preferred compound is formula (I) , (IA) , (IB) , (IC) or (ID) , wherein ring

selected from

Representative compounds of the present invention include those designated hereinafter and pharmaceutically acceptable salts thereof. The present invention should not be construed as being limited to these compounds and pharmaceutically acceptable salts thereof.

tert-butyl 4-(6-((5-fluoro-4-(quinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylate; 5-fluoro-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine; 5-fluoro-N-(5 -(Hexahydropyrazin-1-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine hydrochloride; 4-(6-((5-fluoro-4- (8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; 5-fluoro-4-(8-fluoro Quinoline-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine; 5-fluoro-4-(8-fluoroquinoline-6- Base)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; N-(5-((4-ethylhexahydropyrazine-1 -yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-amine; N-(5-((4-ethylhexahydropyridine Oxazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-amine hydrochloride; N-(5-((4 -ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(quinolin-6-yl)pyrimidin-2-amine; N-(5-((4 -Ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(quinolin-6-yl)pyrimidin-2-amine hydrochloride; 4-(6- ((5-fluoro-4-(8-fluoro-2-methyl-4-(prop-1-en-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)pyridine-3 - Base) tertiary butyl hexahydropyrazine-1-carboxylate; 5-fluoro-4-(8-fluoro-2-methyl-4-(prop-1-en-2-yl) quinoline-6 -yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine; 5-fluoro-4-(8-fluoro-2-methyl-4-( Prop-1-en-2-yl)quinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; 5- Fluoro-N-(5-(4-methylhexahydropyrazin-1-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine; 5-fluoro-N- (5-(4-methylhexahydropyrazin-1-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine hydrochloride; 5-fluoro-4-( 8-fluoroquinolin-6-yl)-N-(5-(4-methylhexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine; 5-fluoro-4-(8 -Fluoroquinolin-6-yl)-N-(5-(4-methylhexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; N-(5-( 4-Ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-amine; N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-amine hydrochloride Salt; N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-2-methylquinoline- 6-yl)pyrimidin-2-amine; N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro -2-methylquinolin-6-yl)pyrimidin-2-amine hydrochloride; 4-(6-((5-fluoro-4-(8-fluoro-2-methylquinolin-6-yl) Pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; 5-fluoro-4-(8-fluoro-2-methylquinolin-6-yl )-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine; 5-fluoro-4-(8-fluoro-2-methylquinolin-6-yl )-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; 4-(6-((5-fluoro-4-(8-fluoro- 4-isopropyl-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; 5-fluoro- 4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidine-2- Amine; 5-fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridine-2- Base) pyrimidin-2-amine hydrochloride; N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(quinolin-6-yl ) pyrimidine-2-amine; N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(quinolin-6-yl)pyrimidine-2 -Amine hydrochloride; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-isopropylhexahydropyrazin-1-yl)pyridin-2-yl) Pyrimidin-2-amine; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-isopropylhexahydropyrazin-1-yl)pyridin-2-yl) Pyrimidin-2-amine hydrochloride; 5-fluoro-N-(5-(4-isopropylhexahydropyrazin-1-yl)pyridin-2-yl)-4-(quinolin-6-yl) Pyrimidin-2-amine; 5-fluoro-N-(5-(4-isopropylhexahydropyrazin-1-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidine-2 -Amine hydrochloride; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-((4-methylhexahydropyrazin-1-yl)methyl)pyridine-2 -yl)pyrimidin-2-amine; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-((4-methylhexahydropyrazin-1-yl)methyl) Pyridin-2-yl)pyrimidin-2-amine hydrochloride; 2-(6-(2-((5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridine -2-yl)amino)-5-fluoropyrimidin-4-yl)-8-fluoro-2-methylquinolin-4-yl)propan-2-ol; 2-(6-(2-(( 5-((4-Ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8-fluoro-2-methylquinoline -4-yl)propan-2-ol hydrochloride; 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)-2-methylquin Lin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; 2-(8-fluoro-6-(5-fluoro-2 -((5-(Hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylquinolin-4-yl)propan-2-ol; 2- (8-fluoro-6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylquinoline -4-yl)propan-2-ol hydrochloride; 2-(6-(2-((5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)amino)- 5-fluoropyrimidin-4-yl)-8-fluoro-2-methylquinolin-4-yl)propan-2-ol; 2-(6-(2-((5-(4-ethylhexahydro Pyrazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8-fluoro-2-methylquinolin-4-yl)propan-2-ol hydrochloride ; 4-(4-(Difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-N-(5-(4-ethylhexahydropyrazin-1-yl)pyridine- 2-yl)-5-fluoropyrimidin-2-amine; 4-(4-(difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-N-(5-(4- Ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine hydrochloride; 4-(6-((4-(4-(difluoromethyl)-8 -Fluoro-2-methylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; 4-( 4-(Difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl) Pyrimidin-2-amine; 4-(4-(difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyrazine-1 -yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; 4-(4-(difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-N-(5 -((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine; 4-(4-(difluoromethyl)-8-fluoro -2-methylquinolin-6-yl)-N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoropyrimidine-2- Amine hydrochloride; N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-(2 -Fluoropropane-2 -yl)-2-methylquinolin-6-yl)pyrimidin-2-amine; N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl) -5-fluoro-4-(8-fluoro-4-(2-fluoroprop-2-yl)-2-methylquinolin-6-yl)pyrimidin-2-amine hydrochloride; 4-(6- ((5-fluoro-4-(8-fluoro-4-(2-fluoroprop-2-yl)-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)pyridine-3- Base) tert-butyl hexahydropyrazine-1-carboxylate; 5-fluoro-4-(8-fluoro-4-(2-fluoroprop-2-yl)-2-methylquinolin-6-yl )-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine; 5-fluoro-4-(8-fluoro-4-(2-fluoropropane-2- Base)-2-methylquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; 5-fluoro-N -(5-((4-methylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine; 5-fluoro-N -(5-((4-methylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine hydrochloride; N- (5-((4-Ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(7-fluoroquinolin-6-yl)pyrimidin-2-amine ; N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(7-fluoroquinolin-6-yl)pyrimidine- 2-amine hydrochloride; 4-(6-((5-fluoro-4-(7-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine - tert-butyl 1-carboxylate; 5-fluoro-4-(7-fluoroquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidine -2-amine; 5-fluoro-4-(7-fluoroquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidine-2-amine salt acid salt; N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(7-fluoroquinolin-6-yl)pyrimidine-2- Amine; N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(7-fluoroquinolin-6-yl)pyrimidin-2-amine Hydrochloride; N-(5-(4-(dimethylamino)hexahydropyridin-1-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6-yl ) pyrimidine-2-amine; N-(5-(4-(dimethylamino)hexahydropyridin-1-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinoline- 6-yl)pyrimidin-2-amine hydrochloride; 4-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridine-3- Base) hexahydropyrazin-2-one; 4-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridine Pyridin-3-yl)hexahydropyrazin-2-one hydrochloride; N-(5-(4-cyclopropylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4 -(8-fluoroquinolin-6-yl)pyrimidin-2-amine; N-(5-(4-cyclopropylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4 -(8-fluoroquinolin-6-yl)pyrimidine-2-amine hydrochloride; 1-(4-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidine- 2-yl)amino)pyridin-3-yl)hexahydropyrazin-1-yl)ethan-1-one; 1-(4-(6-((5-fluoro-4-(8-fluoroquinoline -6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazin-1-yl)ethan-1-one hydrochloride; 5-fluoro-4-(8-fluoroquinoline -6-yl)-N-(5-(4-(2,2,2-trifluoroethyl)hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine; 5-fluoro -4-(8-fluoroquinolin-6-yl)-N-(5-(4-(2,2,2-trifluoroethyl)hexahydropyrazin-1-yl)pyridin-2-yl) Pyrimidin-2-amine hydrochloride; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-(methylsulfonyl)hexahydropyrazin-1-yl )pyridin-2-yl)pyrimidin-2-amine; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-(methylsulfonyl)hexahydropyrazine -1-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; Cyclopropyl (4-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidine- 2-yl)amino)pyridin-3-yl)hexahydropyrazin-1-yl)methanone; cyclopropyl (4-(6-((5-fluoro-4-(8-fluoroquinoline-6 -yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazin-1-yl)methanone hydrochloride; 5-fluoro-4-(8-fluoroquinolin-6-yl) -N-(5-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) Pyridin-2-yl)pyrimidin-2-amine; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(3-(trifluoromethyl)-5,6-di Hydrogen-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; N-(5-( (4-Ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-isopropyl-2-methylquinoline-6- Base) pyrimidin-2-amine; N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4 -isopropyl-2-methylquinolin-6-yl)pyrimidin-2-amine hydrochloride; N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl) -5-fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)pyrimidin-2-amine; N-(5-(4-ethylhexahydropyrazine- 1- Base) pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)pyrimidin-2-amine hydrochloride; 1-(6 -((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)-4-methylhexahydropyridin-4-ol; 1- (6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)-4-methylhexahydropyridin-4-olate (±)-4-(6-((4-(4-(1-((tertiary butoxycarbonyl)amino)ethyl)-8-fluoro-2-methylquinoline-6 -yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; (±)-4-(4-(1-amino Ethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine (±)-4-(4-(1-aminoethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyrazine- 1-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; (±)-4-(6-((4-(4-(1-((tertiary butoxycarbonyl)amino) Ethyl)-8-fluoroquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; (±) -4-(4-(1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl ) pyrimidine-2-amine; (±)-4-(4-(1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyrazine -1-yl)pyridin-2-yl)pyrimidin-2-amine dihydrochloride; (±)-4-(6-((5-fluoro-4-(8-fluoro-4-(1-hydroxyethyl Base) quinolin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) tert-butyl hexahydropyrazine-1-carboxylate; (±)-1-(8-fluoro-6 -(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol; (±)- 1-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinoline-4- base) ethanol trimesylate; (±)-(1-(8-fluoro-6-(5-fluoro-2-((5-(4-methylhexahydropyrazin-1-yl)pyridine-2 -yl) amino) pyrimidin-4-yl) quinoline-4-yl) ethyl) tert-butyl carbamate; (±)-4-(4-(1-aminoethyl)-8 -Fluoroquinolin-6-yl)-5-fluoro-N-(5-(4-methylhexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine; (±)-4 -(4-(1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(4-methylhexahydropyrazin-1-yl) )pyridin-2-yl)pyrimidin-2-amine trihydrochloride; (±)-1-(6-(2-((5-(4-ethylhexahydropyrazin-1-yl)pyridine-2 -yl)amino)-5-fluoropyrimidin-4-yl)-8-fluoroquinolin-4-yl)ethanol; (±)-1-(6-(2-((5-(4-ethyl Hexahydropyrazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8-fluoroquinolin-4-yl)ethanol trihydrochloride; (±)-1 -(8-fluoro-6-(5-fluoro-2-((5-(4-isopropylhexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinone (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(4-isopropylhexahydropyrazin-1-yl)pyridine-2 -yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol trihydrochloride; N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl) -5-fluoro-4-(8-fluoro-2-methylquinolin-6-yl)pyrimidin-2-amine; N-(5-(4-ethylhexahydropyrazin-1-yl)pyridine- 2-yl)-5-fluoro-4-(8-fluoro-2-methylquinolin-6-yl)pyrimidin-2-amine hydrochloride; (±)-4-(6-((5-fluoro -4-(8-fluoro-4-(1-hydroxyethyl)-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1 - tert-butyl formate; (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino ) pyrimidin-4-yl)-2-methylquinolin-4-yl)ethanol; (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyrazine -1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylquinolin-4-yl)ethan-1-ol hydrochloride; (±)-1-(8- Fluoro-6-(5-fluoro-2-((5-(4-methylhexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl ) Ethanol; (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(4-methylhexahydropyrazin-1-yl) pyridin-2-yl) amino) Pyrimidin-4-yl)quinolin-4-yl)ethanol trihydrochloride; 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxyprop-2-yl)quinone Lin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; 2-(8-fluoro-6-(5-fluoro-2 -((5-(Hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)propan-2-ol; 2-(8-fluoro- 6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)propan-2-ol ; (±)-4-(6-((5-fluoro-4-(8-fluoro-4-(1-hydroxyethyl)quinolin-6-yl)pyrimidine-2 -yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; (±)-1-(8-fluoro-6-(5-fluoro-2-((5- (Hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol; (±)-1-(8-fluoro-6-(5- Fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol trihydrochloride; (±)- 4-(6-((5-fluoro-4-(8-fluoro-4-(1-hydroxyethyl)quinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexa tert-butyl hydropyridine-1-carboxylate; (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl ) amino) pyrimidin-4-yl) quinoline-4-yl) ethanol; (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridine-4- yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol trihydrochloride; 4-(6-((5-fluoro-4-(8-fluoro-4- (2-Hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester; 2-(8- Fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)propan-2- Alcohol; 2-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinoline-4 -yl)propan-2-ol trihydrochloride; 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxyprop-2-yl)-2-methylquinoline -6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) tert-butyl hexahydropyridine-1-carboxylate; 2-(8-fluoro-6-(5-fluoro-2-( (5-(hexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylquinolin-4-yl)propan-2-ol; 2-(8- Fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylquinolin-4-yl ) propan-2-ol trihydrochloride; (±)-4-(6-((5-fluoro-4-(8-fluoro-4-(1-hydroxyethyl)-2-methylquinoline- 6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester; (±)-1-(8-fluoro-6-(5-fluoro- 2-((5-(Hexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylquinolin-4-yl)ethanol; (±)-1- (8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylquinoline- 4-yl)ethanol trihydrochloride; 4-(2-((5-fluoro-4-(8-fluoro-4 -(2-Hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)pyrimidin-5-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester; 2-(8 -Fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyrimidin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)propan-2 -alcohol; 2-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyrimidin-2-yl)amino)pyrimidin-4-yl)quinoline- 4-yl)propan-2-ol trihydrochloride; (±)-4-(2-((5-fluoro-4-(8-fluoro-4-(1-hydroxyethyl)quinoline-6- Base) pyrimidin-2-yl) amino) pyrimidin-5-yl) tert-butyl hexahydropyridine-1-carboxylate; (±)-1-(8-fluoro-6-(5-fluoro-2- ((5-(Hexahydropyridin-4-yl)pyrimidin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol; (±)-1-(8-fluoro-6- (5-fluoro-2-((5-(hexahydropyridin-4-yl)pyrimidin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol trihydrochloride; 2- (8-fluoro-6-(5-fluoro-2-((5-(1-methylhexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinoline-4 -yl)propan-2-ol; 2-(8-fluoro-6-(5-fluoro-2-((5-(1-methylhexahydropyridin-4-yl)pyridin-2-yl)amino ) pyrimidin-4-yl) quinolin-4-yl) propan-2-ol trihydrochloride; (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(1 -methylhexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol; (±)-1-(8-fluoro-6-(5 -Fluoro-2-((5-(1-methylhexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol trihydrochloride; (±)-4-(6-((4-(4-(1-((3-butoxycarbonyl)amino)ethyl)-8-fluoroquinolin-6-yl)-5-fluoropyrimidine -2-yl)amino)pyridin-3-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester; (±)-4-(4-(1-aminoethyl)-8-fluoroquinoline -6-yl)-5-fluoro-N-(5-(hexahydropyridin-4-yl)pyridin-2-yl)pyrimidin-2-amine; and (±)-4-(4-(1-amine Ethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyridin-4-yl)pyridin-2-yl)pyrimidin-2-amine trihydrochloride; and pharmaceutically acceptable salts thereof.

1A

1B   

   2

2A

2B

   3

3A

   4

4A

   5

5A

5B

6

6A

   7

7A

   8

8A

   9

9A

   10

10A

10B

   11

11A

11B

   12

12A

   13

13A

   14

14A

   15

15A

   16

16A

   17

17A

17B

   18

18A

   19

19A

20

20A

20B

   21

21A

   22

22A

   23

23A

23B

   24

24A

   25

25A

   26

26A

26B

   27

27A

   28

28A

   29

29A

   30

30A

   31

31A

   32

32A

   33

33A

   34

34A

   35

35A

   36

36A

   37

37A

   38

38A

   39

39A

39B

   40

40A

40B

   41

41A

41B

   42

42A

42B

   43

43A

   44

44A

   45

45A

   46

46A

46B

   47

47A

   48

48A

48B

   49

49A

49B

   50

50A

50B

   51

51A

51B

   52

52A

52B

   53

53A

53B

   54

54A

54B

   55

55A

55B

   56

56A

   57

57A

   58

58A

58B

               4-(4-(1-胺基乙基)-8-氟喹啉-6-基)-5-氟-N-(5-(六氫吡嗪-1-基)吡啶-2-基)吡啶-2-胺； 4-(4-(2-胺基丙-2-基)-8-氟喹啉-6-基)-5-氟-N-(5-(六氫吡嗪-1-基)吡啶-2-基)吡啶-2-胺； 4-(4-(1-胺基乙基)-8-氟喹啉-6-基)-5-氟-N-(5-(4-甲基六氫吡嗪-1-基)吡啶-2-基)吡啶-2-胺； 4-(4-(1-胺基乙基)-8-氟喹啉-6-基)-5-氟-N-(5-(六氫吡啶-4-基)吡啶-2-基)嘧啶-2-胺； 4-(4-(2-胺基丙-2-基)-8-氟喹啉-6-基)-5-氟-N-(5-(六氫吡啶-4-基)吡啶-2-基)嘧啶-2-胺； 4-(4-(1-胺基乙基)-8-氟喹啉-6-基)-5-氟-N-(5-(1-甲基六氫吡啶-4-基)吡啶-2-基)嘧啶-2-胺； 2-(8-氟-6-(5-氟-2-((5-(六氫吡嗪-1-基)吡啶-2-基)胺基)吡啶-4-基)喹啉-4-基)丙-2-醇； 2-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)嘧啶-2-基)胺基)吡啶-4-基)喹啉-4-基)丙-2-醇； 2-(8-氟-6-(5-氟-2-((5-(六氫吡啶-4-基)吡啶-2-基)胺基)吡啶-4-基)喹啉-4-基)丙-2-醇； 2-(8-氟-6-(5-氟-2-((1',2',3',6'-四氫-[3,4'-聯吡啶]-6-基)胺基)嘧啶-4-基)喹啉-4-基)丙-2-醇； 1-(8-氟-6-(5-氟-2-((1',2',3',6'-四氫-[3,4'-聯吡啶]-6-基)胺基)嘧啶-4-基)喹啉-4-基)乙-1-醇； N-(4-(4-(1-胺基乙基)-8-氟喹啉-6-基)-5-氟嘧啶-2-基)-1',2',3',6'-四氫-[3,4'-聯吡啶]-6-胺； 2-(8-氟-6-(5-氟-2-((5-(六氫吡啶-3-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)丙-2-醇； 2-(8-氟-6-(5-氟-2-((5-(六氫吡啶-3-基)吡啶-2-基)胺基)嘧啶-4-基)-2-甲基喹啉-4-基)丙-2-醇； 5-氟-4-(8-氟喹啉-6-基)-N-(5-(六氫吡啶-3-基)吡啶-2-基)嘧啶-2-胺； 2-(8-氟-6-(5-氟-2-((5-(吡咯啶-3-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)丙-2-醇； 1-(8-氟-6-(5-氟-2-((5-(吡咯啶-3-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)乙-1-醇； 4-(4-(1-胺基乙基)-8-氟喹啉-6-基)-5-氟-N-(5-(吡咯啶-3-基)吡啶-2-基)嘧啶-2-胺； 2-(6-(2-((5-(1-乙基六氫吡啶-4-基)吡啶-2-基)胺基)-5-氟嘧啶-4-基)-8-氟喹啉-4-基)丙-2-醇； 2-(8-氟-6-(5-氟-2-((5-(1-異丙基六氫吡啶-4-基)吡啶-2-基)胺基)嘧啶-4-基)喹啉-4-基)丙-2-醇；及 2-(6-(2-((5-(1-環丙基六氫吡啶-4-基)吡啶-2-基)胺基)-5-氟嘧啶-4-基)-8-氟喹啉-4-基)丙-2-醇； 或其醫藥學上可接受之鹽。 Representative structures are shown in Table 1 below. Table -1 example structure example structure example structure 1

1A

1B

2

2A

2B

3

3A

4

4A

5

5A

5B

6

6A

7

7A

8

8A

9

9A

10

10A

10B

11

11A

11B

12

12A

13

13A

14

14A

15

15A

16

16A

17

17A

17B

18

18A

19

19A

20

20A

20B

twenty one

21A

twenty two

22A

twenty three

23A

23B

twenty four

24A

25

25A

26

26A

26B

27

27A

28

28A

29

29A

30

30A

31

31A

32

32A

33

33A

34

34A

35

35A

36

36A

37

37A

38

38A

39

39A

39B

40

40A

40B

41

41A

41B

42

42A

42B

43

43A

44

44A

45

45A

46

46A

46B

47

47A

48

48A

48B

49

49A

49B

50

50A

50B

51

51A

51B

52

52A

52B

53

53A

53B

54

54A

54B

55

55A

55B

56

56A

57

57A

58

58A

58B

4-(4-(1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl) Pyridin-2-amine; 4-(4-(2-aminopropan-2-yl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyrazine-1 -yl)pyridin-2-yl)pyridin-2-amine; 4-(4-(1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-( 4-methylhexahydropyrazin-1-yl)pyridin-2-yl)pyridin-2-amine; 4-(4-(1-aminoethyl)-8-fluoroquinolin-6-yl)- 5-fluoro-N-(5-(hexahydropyridin-4-yl)pyridin-2-yl)pyrimidin-2-amine; 4-(4-(2-aminopropan-2-yl)-8-fluoro Quinolin-6-yl)-5-fluoro-N-(5-(hexahydropyridin-4-yl)pyridin-2-yl)pyrimidin-2-amine; 4-(4-(1-aminoethyl )-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(1-methylhexahydropyridin-4-yl)pyridin-2-yl)pyrimidin-2-amine; 2-( 8-fluoro-6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyridin-4-yl)quinolin-4-yl)propane -2-alcohol; 2-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyrimidin-2-yl)amino)pyridin-4-yl)quinone phen-4-yl)propan-2-ol; 2-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl)amino) Pyridin-4-yl)quinolin-4-yl)propan-2-ol; 2-(8-fluoro-6-(5-fluoro-2-((1',2',3',6'-tetra Hydrogen-[3,4'-bipyridyl]-6-yl)amino)pyrimidin-4-yl)quinolin-4-yl)propan-2-ol; 1-(8-fluoro-6-(5- Fluoro-2-((1',2',3',6'-tetrahydro-[3,4'-bipyridyl]-6-yl)amino)pyrimidin-4-yl)quinolin-4-yl ) ethyl-1-ol; N-(4-(4-(1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoropyrimidin-2-yl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-amine; 2-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridine-3 -yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)propan-2-alcohol; 2-(8-fluoro-6-(5-fluoro-2-((5 -(hexahydropyridin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylquinolin-4-yl)propan-2-ol; 5-fluoro-4-( 8-fluoroquinolin-6-yl)-N-(5-(hexahydropyridin-3-yl)pyridin-2-yl)pyrimidin-2-amine; 2-(8-fluoro-6-(5-fluoro -2-((5-(pyrrolidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)propan-2-ol; 1-(8-fluoro-6-(5-fluoro-2-((5-(pyrrolidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl) Ethan-1-ol; 4-(4-(1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(pyrrolidin-3-yl)pyridine- 2-yl)pyrimidin-2-amine; 2-(6-(2-((5-(1-ethylhexahydropyridin-4-yl)pyridin-2-yl)amino)-5-fluoropyrimidine- 4-yl)-8-fluoroquinolin-4-yl)propan-2-ol; 2-(8-fluoro-6-(5-fluoro-2-((5-(1-isopropylhexahydropyridine -4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)propan-2-ol; and 2-(6-(2-((5-(1-ring Propylhexahydropyridin-4-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8-fluoroquinolin-4-yl)propan-2-ol; or its pharmaceutical acceptable salt.

surface -1a : Predictive instance example structure example structure example structure P-1

P-2

P-3

P-4

P-5

P-6

P-7

P-8

P-9

P-10

P-11

P-12

P-13

P-14

P-15

P-16

P-17

P-18

P-19

P-20

P-21

Another embodiment of the present invention is a method of inhibiting one or more of CDK1, CDK2, CDK4 and CDK6 in a patient by administering to the patient an effective amount of at least one of the formulas (I) , ( IA) , (IB) , (IC) or (ID) defined compounds of the invention to implement. One embodiment is a method of inhibiting CDK2, CDK4, and CDK6 (eg, CDK2 and CDK4/6) in a patient by administering to the patient an effective amount of at least one of the formulas (I) , (IA) , ( IB) , (IC) or (ID) defined compounds of the invention to implement.

Another embodiment of the invention is a method of treating an inflammatory, autoimmune or proliferative disease by administering to a patient in need of such treatment an effective amount of at least one compound of the invention. In one embodiment, a compound of the invention is administered in an effective amount to inhibit one or more of CDK1, CDK2, CDK4, and CDK6.

Another embodiment of the invention is a method of treating an inflammatory, autoimmune or proliferative disease (eg, by inhibiting one or more of CDK1, CDK2, CDK4, and CDK6) by introducing The patient is administered (simultaneously or sequentially) an effective amount of at least one compound of the present invention in combination with at least one other anti-inflammatory, immunomodulatory or anti-cancer agent. In one embodiment, compounds of the invention inhibit one or more of CDK1, CDK2, CDK4, and CDK6. In another embodiment, the compounds of the invention inhibit CDK2 and/or CDK4/6.

More specifically, compounds of formula (I) , (IA) , (IB) , (IC) or (ID) and pharmaceutically acceptable esters or salts thereof may be administered for treatment, prevention and/or amelioration Diseases or conditions associated with a CDK enzyme selected from the group consisting of CDK1, CDK2, CDK4, CDK6, and any combination of any of the foregoing, particularly amelioration of a disease or condition mediated by such a CDK enzyme, including but not limited to inflammation diseases or conditions, autoimmune diseases or conditions and cancer and other proliferative diseases or conditions.

The compounds of the present invention are useful in the treatment of a variety of cancers, including (but not limited to): l Cancer, including bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer (including small cell lung cancer) and esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer and skin cancer (including squamous cell carcinoma); l Hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma tumor, pilocytic lymphoma and Burkett's lymphoma (Burkett's lymphoma); l Hematopoietic tumors of the myeloid lineage, including acute and chronic myelogenous leukemia, myelodysplastic syndrome and promyelocytic leukemia; l Tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; l Tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannoma; and l Other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosa, keratoacanthoma, thyroid follicular carcinoma, and Kaposi's sarcoma.

The compounds of the present invention are useful in the chemoprevention of cancer. Chemoprevention is defined as the inhibition of the development of aggressive cancers by blocking the initial mutagenic event or by blocking the progression of pre-malignant cells that have already suffered damage or inhibiting tumor recurrence. The compounds described herein are also useful for inhibiting tumor angiogenesis and metastasis. One embodiment of the invention is a method of inhibiting tumor angiogenesis or metastasis in a patient in need thereof by administering an effective amount of one or more compounds of the invention.

The compounds of the invention may also be used in combination (administered together or sequentially) with known anticancer treatments such as, but not limited to, radiation therapy, or cytostatic, cytotoxic or anticancer agents such as ( But not limited to) DNA interactors such as cisplatin or doxorubicin; topoisomerase II inhibitors such as etoposide; topoisomerase I inhibitors such as CPT -11 or topotecan; natural or synthetic tubulin interacting agents such as paclitaxel, docetaxel or epothilone (e.g. ixabepilone (ixabepilone)); hormone agents, such as tamoxifen; thymidylate synthase inhibitors, such as 5-fluorouracil; antimetabolites, such as methotrexate; other tyrosine kinase inhibitors, such as axa Iressa and OSI-774; Angiogenesis Inhibitors; EGF Inhibitors; VEGF Inhibitors; HDAC Inhibitors; SRC Inhibitors; c-Kit Inhibitors; Her1/2 Inhibitors; Strain antibodies, such as erbitux (EGF) and herceptin (Her2); and other protein kinase modulators.

The compounds of the invention may also be used in combination (administered together or sequentially) with one or more steroidal anti-inflammatory drugs, non-steroidal anti-inflammatory drugs (NSAIDs) or immunoselective anti-inflammatory derivatives (ImSAIDs).

The present invention further provides pharmaceutical compositions comprising one or more compounds of the present invention (such as compounds of formula (I) , (IA) , (IB) , (IC) or (ID) ) and pharmaceutically acceptable carrier. The pharmaceutical composition may further comprise one or more of the active ingredients identified above, such as other anticancer agents.

In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of one or more compounds of formula (I) , (IA) , (IB) , (IC) or (ID) .

Another embodiment is a method of treating cancer in a patient in need thereof by administering a therapeutically effective amount of a compound of the invention. For example, the compounds of the present invention are effective in the treatment of hematopoietic neoplasms of the lymphoid lineage: leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Chiggin's Lymphoma, Pilocytic Lymphoma, and Burkitt's Lymphoma; Hematopoietic Neoplasms of the Myeloid Lineage: Acute Myeloid Leukemia, Chronic Myelogenous Leukemia, Myelodysplastic Syndrome, and Promyelocytic Leukemia. The compound of the present invention is also effective in the treatment of bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer , skin cancer, squamous cell carcinoma; tumors of mesenchymal origin, fibrosarcoma, rhabdomyosarcoma; tumors of the central and peripheral nervous system, astrocytoma, neuroblastoma, glioma, schwannoma; Primary cell tumor, teratocarcinoma, osteosarcoma, xeroderma pigmentosa, keratoacanthoma, follicular carcinoma of the thyroid, and Kaposi's sarcoma.

Another embodiment is a method of treating leukemia in a patient in need thereof by administering a therapeutically effective amount of a compound of the invention. For example, the compounds of the present invention are effective in the treatment of breast cancer, ovarian cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer or gastric cancer.

As used herein, the following definitions shall apply unless otherwise indicated. Furthermore, many of the groups defined herein may be optionally substituted. The lists of substituents in the definitions are exemplary and should not be construed as limiting the substituents defined elsewhere in this specification.

Unless otherwise specified, the term "CDK4/6" refers to both CDK4 and CDK6. For example, inhibiting "CDK4/6" refers to inhibiting (to the same or different extent) both CDK4 and CDK6.

Unless otherwise specified, the term "alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, free of unsaturation, having from 1 to 8 carbon atoms, and consisting of A single bond to the rest of the molecule, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl ( tertiary butyl). The term "C _1-6 alkyl" refers to an alkyl group as defined above having up to 6 carbon atoms. The term "alkyl" refers to a hydrocarbon chain group as mentioned above which is divalent, where appropriate.

Unless otherwise specified, the term "alkenyl" refers to an aliphatic hydrocarbon group containing one or more carbon-carbon double bonds, and which may be straight or branched chain having from about 2 to about 10 carbon atoms, for example Vinyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl. The term "C2-6 alkenyl" refers to an alkenyl group as defined above having up to 6 carbon atoms. The term "alkenyl" refers to a hydrocarbyl group as mentioned above which is divalent, where appropriate.

Unless otherwise specified, the term "alkynyl" refers to a straight or branched chain hydrocarbon group having at least one carbon-carbon triple bond and having a range of 2 to up to 12 carbon atoms (presently, having a range of 2 to up to 10 carbon atoms are preferred), such as ethynyl, propynyl and butynyl. The term "C2-6 alkynyl" refers to an alkynyl group as defined above having up to 6 carbon atoms. The term "alkynyl" refers to a hydrocarbyl group as mentioned above which is divalent, where appropriate.

Unless otherwise specified, the term "alkoxy" denotes an alkyl, cycloalkyl or cycloalkylalkyl group as defined above attached to the rest of the molecule via an oxygen linkage. The term "substituted alkoxy" refers to an alkoxy group in which the alkyl component is substituted (ie -O-(substituted alkyl)). By way of example, "alkoxy" refers to the group -O-alkyl, including straight chain, branched chain, cyclic configurations and combinations thereof of 1 to 8 carbon atoms attached to the parent structure through an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy and cyclohexyloxy. The term "alkoxy" refers to a radical as mentioned above which is divalent, where appropriate.

The term "hydroxyalkyl or hydroxylalkyl" means an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above. Examples of "hydroxyalkyl" include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, propan-2-ol, and the like.

The term "aminoalkyl" means an alkyl group substituted with one or more amino groups, wherein alkyl is as defined above. Examples of "aminoalkyl" include, but are not limited to, aminomethyl, aminoethyl, 2-aminopropyl, and the like.

Unless otherwise specified, the term "cycloalkyl" denotes a non-aromatic monocyclic or multicyclic ring system having about 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of polycyclic cycloalkyl groups include perhydronaphthyl, adamantyl, and norbornyl, bridged cyclic groups, and spirobicyclic groups, such as spiro(4,4)nonan-2-yl. The term "C _3-6 cycloalkyl" refers to a cycloalkyl group as defined above having up to 6 carbon atoms.

Unless otherwise specified, the term "cycloalkylalkyl" refers to a ring-containing group containing in the range of about 3 to 8 carbon atoms directly attached to an alkyl group followed by Attached to main structures such as cyclopropylmethyl, cyclobutylethyl and cyclopentylethyl.

Unless otherwise specified, the term "cycloalkenyl" refers to a ring-containing group containing in the range of about 3 to 8 carbon atoms and having at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl and ring pentenyl. The term "cycloalkenylalkyl" refers to a cycloalkenyl group attached directly to an alkyl group, which is then attached to the main structure at any carbon from the alkyl group.

Unless otherwise specified, the term "aryl" refers to an aromatic group having carbon atoms ranging from 6 to 20, such as phenyl, naphthyl, tetrahydronaphthyl, indenyl and biphenyl.

Unless otherwise specified, the term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, for example -CH ₂ C ₆ H ₅ and -C ₂ H ₅ C ₆ H ₅ .

Unless otherwise specified, the term "heterocycle" refers to a non-aromatic 3- to 15-membered ring group consisting of carbon atoms and at least one heteroatom selected from nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention, a heterocyclic group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, Carbon, oxygen or sulfur atoms are optionally oxidized into various oxidation states. In addition, nitrogen atoms can optionally be quaternary ammonized. A heterocyclic group can be attached to the main structure at any heteroatom or carbon atom.

Unless otherwise specified, the term "heterocyclyl" refers to a heterocyclic group as defined above. A heterocyclyl ring group can be attached to the main structure at any heteroatom or carbon atom.

Unless otherwise specified, the term "heterocyclylalkyl" refers to a heterocyclic group as defined above directly bonded to an alkyl group. A heterocyclylalkyl group can be attached to the main structure at any carbon atom in the alkyl group. Examples of such heterocycloalkyl groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, Isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxohexahydropyrazinyl, 2-oxohexahydropyridyl, 2 - side oxypyrrolidinyl, oxazolidinyl, hexahydropyridyl, hexahydropyrazinyl, 4-hexahydropyridinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, Tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl (thiomorpholinyl, thiamorpholinyl), 1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl.

Unless otherwise specified, the term "heteroaryl" refers to an optionally substituted 5- to 14-membered aromatic ring having one or more heteroatoms selected from N, O and S as ring atoms. Heteroaryl groups can be monocyclic, bicyclic or tricyclic ring systems. Examples of such "heterocycle" or "heteroaryl" include, but are not limited to, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, benzofuryl , indolyl, benzothiazolyl, benzoxazolyl, carbazolyl, quinolinyl, isoquinolyl, azetidinyl, acridinyl, benzodioxolyl, benzene Dioxanyl, benzofuryl, carbazolyl, cinnolinyl, dioxolyl, indolizinyl, naphthyridinyl, perhydroazinyl, phenazinyl, phenothiazinyl, Phenoxazinyl, phthalazinyl, pteridyl, purinyl, quinazolinyl, quinoxalinyl, tetrazolyl, tetrahydroisoquinolinyl, hexahydropyridyl, hexahydropyrazinyl, 2- Pendant oxyhexahydropyrazinyl, 2- pendant oxyhexahydropyridyl, 2- pendant oxypyrrolidinyl, 2- pendant oxahydropyrrolidinyl, nitrogen sulphate, 4-hexahydropyridonyl, pyrrole Pyridyl, pyrazinyl, oxazolyl, oxazolyl, triazolyl, dihydroindenyl, isoxazolyl, isoxazolyl, morpholinyl, thiazolinyl, thiazolidinyl, iso Thiazolyl, quinuclidinyl, isothiazolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolinyl, benzene Imidazolyl, thiadiazolyl, benzopyranyl, tetrahydrofuranyl, tetrahydropyranyl, thienyl, benzothienyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, Dioxaphospholanyl, oxadiazolyl, chromanyl and isochromanyl. A heteroaryl ring group can be attached to the main structure at any heteroatom or carbon atom. The term "substituted heteroaryl" also includes ring systems substituted with one or more oxide substituents, such as pyridyl N-oxides.

Unless otherwise specified, the term "heteroarylalkyl" refers to a heteroaryl ring group as defined above directly bonded to an alkyl group. Heteroarylalkyl groups can be attached to the main structure at any carbon atom from the alkyl group.

The term "ring" refers to a ring containing 3 to 10 carbon atoms.

Unless otherwise specified, the term "substituted" means substituted with any one or any combination of the following substituents, which may be the same or different and independently selected from hydrogen, hydroxyl, halogen, carboxyl, cyano substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl , substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted hetero Arylalkyl, substituted or unsubstituted heterocycle, substituted heterocyclylalkyl ring, substituted or unsubstituted guanidine, -COOR ^t , -C(O)R ^v , -C(S )R ^v , -C(O)NR ^t R ^u , -C(O)ONR ^t R ^u , -NR ^t R ^u , -NR ^t CONR ^u R ^v , -N(R ^t )SOR ^u , -N( R ^t )SO ₂ R ^u , -(=NN(R ^t )R ^u ), -NR ^t C(O)OR ^u , -NR ^t R ^u , -NR ^t C(O)R ^u -, -NR ^t C(S)R ^u -NR ^t C(S)NR ^t R ^u , -SONR ^t R ^u -, -SO ₂ NR ^t R ^u -, -OR ^t , -OC(O)NR ^u R ^v , -OC (O)OR ^u -, -OC(O)R ^t , -OC(O)NR ^t R ^u , -R ^t NR ^u C(O)R ^v , -R ^t OR ^u , -R ^t C(O) OR ^u , -R ^t C(O)NR ^u R ^v , -R ^t C(O)R ^u , -R ^t OC(O)R ^u , -SR ^t , -SOR ^t , -SO ₂ R ^t and - ONO ₂ , wherein R ^t , ^Ru and R ^v in each of the above groups can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or Unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, Substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted heteroaryl, substituted or unsubstituted A substituted heteroarylalkyl ring, a substituted or unsubstituted heterocycle or a substituted heterocyclylalkyl ring, or any two of R ^t , R ^u and R ^v may be joined to form a substituted or unsubstituted Substituted saturated or unsaturated 3- to 10-membered rings, optionally including heteroatoms, which may be the same or different and selected from O, NR ^t (for example R ^t can be hydrogen or C _1-6 alkyl) or S. Substitutions or combinations of substituents contemplated by the present invention are preferably those substitutions or combinations of substituents which result in the formation of stable or chemically feasible compounds. The term stable as used herein refers to a compound or structure that does not substantially change when subjected to conditions that allow its production, detection and, preferably, its recovery, purification and incorporation into pharmaceutical compositions. A substituent in a "substituted" group mentioned above may be further substituted.

The term "halo", "halide" or alternatively "halogen" means fluorine, chlorine, bromine or iodine. The terms "haloalkyl", "haloalkenyl", "haloalkynyl" and "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy groups substituted with one or more halo groups or combinations thereof structure. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy, respectively, wherein halo is fluorine.

The term "protecting group" or "PG" refers to a substituent used to block or protect a specific functional group. Other functional groups on the compound may remain reactive. For example, an "amino protecting group" is a substituent attached to an amine group that blocks or protects the amine functionality in a compound. Suitable amine protecting groups include, but are not limited to, acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), and 9-fenylmethyleneoxycarbonyl ( Fmoc). Similarly, a "hydroxyl protecting group" refers to a hydroxy substituent that blocks or protects the hydroxy functionality. Suitable hydroxy protecting groups include, but are not limited to, acetyl and silyl. "Carboxy protecting group" refers to a carboxyl substituent that blocks or protects the carboxyl functionality. Suitable carboxyl protecting groups include, but are not limited to, _-CH2CH2SO2Ph , cyanoethyl, _2- (trimethylsilyl)ethyl, _2- (trimethylsilyl)ethoxymethyl 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfinyl)ethyl, 2-(diphenylphosphino)-ethyl and nitroethyl. For a general description of protecting groups and their use, see TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

Certain of the compounds described herein contain one or more asymmetric centers from which enantiomers, diastereoisomers and Other stereoisomeric forms. The present chemical entities, pharmaceutical compositions and methods are intended to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Non-limiting examples of intermediate mixtures include isomeric mixtures in ratios of 10:90, 13:87, 17:83, 20:80, or 22:78. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, it is intended that such compounds include both E and Z geometric isomers.

The term "tautomer" refers to compounds characterized by the relative ease with which isomeric forms are interconvertible under equilibrium conditions. The present invention is intended to cover such isomers. "Tautomers" are structurally different isomers that are interconverted by tautomerization. "Tautomerization" is a form of isomerization and includes prototropic or protonotropic tautomerization, which are considered a subset of acid-base chemistry. "Prototropic tautomerization" or "protonotropic tautomerization" involves the migration of protons with concomitant changes in bond order, usually the interchange of a single bond for an adjacent double bond. In situations where tautomerization is possible (eg, in solution), chemical equilibrium of the tautomers can be achieved. An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.

A "leaving group or atom" is any group or atom which, under the reaction conditions, will cleave from the starting material, thereby facilitating reaction at the designated site. Suitable examples of such groups, unless otherwise specified, are halogen atoms and methanesulfonyloxy, p-nitrobenzenesulfonyloxy and tosyloxy.

The term "prodrug" refers to a compound that is an inactive precursor of a compound that is converted in the body by normal metabolic processes to the active form of the compound. An overview of prodrug design is discussed in Hardma et al. (eds.), Goodman and Gilman, The Pharmacological Basis of Therapeutics, 9th Ed., pp. 11-16 (1996). A thorough discussion is provided in Higuchi et al., Prodrugs as Novel Delivery Systems, Vol. 14, ASCD Symposium Series and Roche (eds.), Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987). For illustration, prodrugs may be converted to pharmacologically active forms by hydrolysis of, for example, ester or amide linkages, thereby introducing or exposing functional groups on the resulting product. Prodrugs can be designed to react with endogenous compounds to form water-soluble conjugates that further enhance the pharmacological properties of the compound, such as increasing circulating half-life. Alternatively, prodrugs can be designed to undergo covalent modification at functional groups with, for example, glucuronic acid, sulfate, glutathione, amino acids, or acetate. The resulting conjugates can be deactivated and excreted in urine, or made more potent than the parent compound. High molecular weight conjugates can also be excreted into bile, undergo enzymatic cleavage, and be released back into circulation, thereby effectively extending the biological half-life of the originally administered compound.

The term "ester" refers to a compound formed by the reaction between an acid and an alcohol with the elimination of water. Esters can be represented by the general formula RCOOR'.

Such prodrugs and esters are intended to be encompassed within the scope of this invention.

In addition, the invention also includes compounds that differ only in the presence of one or more isotopically enriched atoms (eg deuterium or tritium in place of hydrogen, or ¹³ C or ¹⁴ C enriched carbon in place of carbon).

The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms constituting such compounds. For example, compounds may be radiolabeled with radioisotopes such as tritium ( ^3H ), iodine-125 ( ^125I ), or carbon-14 ( ^14C ). All isotopic variations of the compounds of the invention, whether radioactive or not, are encompassed within the scope of the invention.

Pharmaceutically acceptable salts which form part of the present invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn and Mn salts; organic bases such as N,N Salts of '-diacetylethylenediamine, glucosamine, triethylamine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine and thiamine; salts of chiral bases , such as salts of alkylphenylamines, glycinol and phenylglycol; salts of natural amino acids, such as glycine, alanine, valine, leucine, isoleucine, orthowhite Amino acid, tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, ornithine, lysine, arginine and serine salts; quaternary ammonium salts of compounds of the invention with alkyl halides, alkyl sulfates such as MeI and (Me) ₂ SO ₄ ; unnatural amino acids such as D-isomers or substituted amines salts of amino acids); guanidinium salts; and substituted guanidinium salts, wherein the substituents are selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substituted ammonium and aluminum salts. Salts may include acid addition salts, as appropriate, such as sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides (e.g. hydrochlorides), acetates, tartrates, maleates , citrate, fumarate, succinate, pamoate, mesylate, benzoate, salicylate, besylate, ascorbate, glycerophosphate and ketoglutarate Salt.

Where ranges are used herein for a physical property (such as molecular weight) or chemical property (such as a chemical formula), all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a quantity or a numerical range means that the referred quantity or numerical range is an approximation within experimental variability (or within statistical experimental error), and thus the quantity or numerical range may, for example, be within Vary between 1% and 15% of the stated amount or range of values. The term "comprising" (and related terms such as "comprises or comprises" or "has" or "including") includes, for example, such embodiments as: any composition of matter, method or process, or the like Embodiments that "consist of" or "consist essentially of" the recited features.

The term "cell proliferation" refers to the phenomenon in which the number of cells changes due to division. The term also encompasses cell growth in which cell morphology changes (eg, increase in size) consistent with a proliferative signal.

As used herein, the terms "co-administration", "combination administration" and their grammatical equivalents encompass the administration of two or more agents to an animal such that both agents and/or their metabolites are present in the animal simultaneously middle. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein sufficient to demonstrate the intended use including, but not limited to, the treatment of disease as defined below. A therapeutically effective amount may vary depending on the intended use (in vitro or in vivo) or on the subject and the disease condition being treated, such as the weight and age of the subject, severity of the disease condition, mode of administration, and the like, which can be determined by skilled Easily determined by those skilled in the art. The term also applies to doses that will induce a particular response in target cells, such as reduced platelet adhesion and/or cell migration. The specific dosage will vary depending on the compound selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the time of administration, the tissue to which it is administered, and the physical delivery system carrying it. In one embodiment, the compound is administered in an amount of about 0.1 mg to 5 g, about 1 mg to 2.0 g, about 100 mg to 1.5 g, about 200 mg to 1.5 g, about 400 mg to 1.5 g, and about 400 mg to 1.0 g range.

As used herein, "treatment, treating" or "improvement" are used interchangeably. These terms refer to means of obtaining beneficial or desired results including, but not limited to, therapeutic benefit and/or prophylactic benefit. Therapeutic benefit means eradication or amelioration of the underlying condition being treated. Likewise, therapeutic benefit is achieved by eradicating or ameliorating one or more physiological symptoms associated with the underlying condition, such that improvement is observed in a patient, but the patient may still be afflicted by the underlying condition. For prophylactic benefit, compositions may be administered to patients at risk of developing a particular disease or to patients reporting one or more physiological symptoms of a disease, even though a diagnosis of the disease may not have been made.

"Therapeutic effect" as the term is used herein encompasses therapeutic and/or prophylactic benefits as set out above. A preventive effect includes delaying or eliminating the onset of a disease or disorder, delaying or eliminating the onset of symptoms of a disease or disorder, slowing, stopping or reversing the progression of a disease or disorder, or any combination thereof.

The term "individual" or "patient" refers to an animal, such as a mammal, eg a human. The methods described herein can be used in both human therapy and veterinary applications such as dogs, cats, cattle, sheep, pigs, horses, goats, chickens, turkeys, ducks and geese.

. In some embodiments, the patient is a mammal, and in some embodiments, the patient is a human.

"Radiation therapy" means exposing a patient to radiation emitters, such as alpha-emitting radionuclides (e.g., actinium and thorium radionuclides), low linear energy transfer (LET) radiation emitters, using conventional methods and compositions known to the practitioner. Emitters (ie, beta emitters), converted electron emitters (such as strontium-89 and samarium-153-EDTMP), or high-energy radiation including, but not limited to, x-rays, gamma rays, and neutrons.

The term "pharmaceutically acceptable excipient" includes, but is not limited to, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, one or more suitable diluents, Agents, fillers, salts, disintegrants, binders, lubricants, glidants, wetting agents, controlled release matrices, colorants/flavors, carriers, buffers, stabilizers, solubilizers, and combinations thereof . Unless any conventional media or agents are incompatible with the active ingredients, they are contemplated for use in the therapeutic compositions of the present invention. Supplementary active ingredients can also be incorporated into the compositions.

The methods of the invention can be applied to cell populations in vivo or ex vivo. "In vivo" means within a living subject, such as an animal or human being or subject. In this context, the methods of the invention can be used therapeutically or prophylactically in an individual. "Ex vivo" or "in vitro" means outside the body of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including, but not limited to, fluid or tissue samples obtained from an individual. Such samples can be obtained by methods known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samples include tumors and biopsies thereof. In this context, the present invention can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the invention can be used ex vivo or in vitro to determine the optimal schedule and/or dose of CDK inhibitor administration for a given indication, cell type, individual, and other parameters. Information collected from this use may be used for experimental or diagnostic purposes, or in a clinic to plan in vivo therapy. Other ex vivo applications to which the present invention may be applicable are described below, or will become apparent to those skilled in the art. pharmaceutical composition

The invention provides pharmaceutical compositions comprising one or more compounds of the invention. Pharmaceutical compositions may include one or more additional active ingredients as set forth herein. Pharmaceutical compositions can be administered for any of the conditions described herein.

A subject pharmaceutical composition is generally formulated to provide a therapeutically effective amount of a compound of the invention as an active ingredient. If desired, pharmaceutical compositions contain a compound of the present invention as the active ingredient together with one or more pharmaceutically acceptable carriers or excipients, such as inert solid diluents and fillers, diluents (including sterile aqueous solutions and various organic solvents) ), penetration enhancers, solubilizers and adjuvants.

Pharmaceutical compositions can be administered alone or in combination with one or more other agents, which are also typically administered in the form of pharmaceutical compositions. If desired, the subject compound and other agents may be mixed into a formulation, or the two components may be formulated into separate formulations for separate or simultaneous combined use.

The method involves administering a compound of the invention by itself or in combination as described herein, and in each case optionally including one or more suitable diluents, fillers, salts, disintegrants, binders, lubricants, auxiliary agents, etc. Fluids, wetting agents, controlled release matrices, colorants/flavors, carriers, excipients, buffers, stabilizers, solubilizers, and combinations thereof.

The preparation of various pharmaceutical compositions is known in the art, for example Anderson, Philip O.; Knoben, James E.; Troutman, William G, ed., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Edited by Pratt and Taylor, Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Edited by Katzung, Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2003; Edited by Goodman and Gilman, The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Edition, Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999), all of which All are incorporated herein by reference in their entirety.

The compounds or pharmaceutical compositions of the present invention may be administered by any route that enables delivery of the compound to the site of action, such as oral, intraduodenal, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal, or infusion), local administration (eg, transdermal application), rectal administration, local delivery via a catheter or stent, or via inhalation. Compounds can also be administered intralipidally or intrathecally.

Compositions may be administered in solid, semi-solid, liquid or gaseous form, or may be in dry powder form, such as lyophilized form. Pharmaceutical compositions can be packaged in a form convenient for delivery including, for example, solid dosage forms such as capsules, sachets, cachets, gelatin, papers, lozenges, capsules, suppositories, granules, pellets, dragees, and lozenges. agent. The type of packaging will generally depend on the desired route of administration. Implantable sustained release formulations as well as transdermal formulations are also contemplated. treatment method

The invention also provides methods of using the compounds or pharmaceutical compositions of the invention to treat disease conditions including, but not limited to, those associated with overexpression of one or more of CDK1, CDK2, CDK4, and CDK6 and /or diseases caused by excess of one or more of CDK1, CDK2, CDK4 and CDK6.

The methods of treatment provided herein comprise administering to a subject a therapeutically effective amount of a compound of the invention. In one embodiment, the present invention provides methods of treating inflammatory disorders, including autoimmune diseases in mammals. The method comprises administering to the mammal a therapeutically effective amount of a compound of the invention.

It will be appreciated that the methods of treatment of the present invention have application in the fields of human medicine as well as veterinary medicine. Thus, the individual to be treated may be a mammal, preferably a human, or another animal. For veterinary purposes, subjects include, but are not limited to, farm animals, including cattle, sheep, pigs, horses, and goats; companion animals, such as dogs and cats; exotic and/or zoo animals; laboratory animals, including mice, rats, rabbits, guinea pigs and hamsters; and poultry such as chickens, turkeys, ducks and geese.

The invention also provides methods of using the compounds or pharmaceutical compositions of the invention to treat disease conditions including, but not limited to, those associated with overexpression of one or more of CDK1, CDK2, CDK4, and CDK6 and /or diseases caused by excess of one or more of CDK1, CDK2, CDK4 and CDK6.

The methods of treatment provided herein comprise administering to a subject a therapeutically effective amount of a compound of the invention. In one embodiment, the present invention provides methods of treating inflammatory disorders, including autoimmune diseases in mammals. The method comprises administering to the mammal a therapeutically effective amount of a compound of the invention.

It will be appreciated that the methods of treatment of the present invention have application in the fields of human medicine as well as veterinary medicine. Thus, the individual to be treated may be a mammal, preferably a human, or another animal. For veterinary purposes, subjects include, but are not limited to, farm animals, including cattle, sheep, pigs, horses, and goats; companion animals, such as dogs and cats; exotic and/or zoo animals; laboratory animals, including mice, rats, rabbits, guinea pigs and hamsters; and poultry such as chickens, turkeys, ducks and geese.

The present invention also relates to a method for treating a hyperproliferative disorder in a mammal, which comprises administering to the mammal a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, Hydrates or derivatives. In some embodiments, the method relates to the treatment of a broad spectrum of tumors, including all solid tumors and hematological malignancies collectively referred to as cancer. Examples of such tumors include, but are not limited to, benign or malignant tumors of the brain, lung (especially small cell and non-small cell lung cancer), squamous cell, bladder, stomach, pancreas, breast, head and neck, Kidney (renal, kidney), ureter, ovary, prostate, colorectum, esophagus, testis, gynecologic tumors (eg, uterine sarcoma, fallopian tube, endometrial, cervix, vagina, or vulva), thyroid, pancreas , bone, skin, melanoma, uterus, ovary, rectum, anus, colon, testis, Hodgkin's disease, esophagus, small intestine, endocrine system (such as thyroid, parathyroid, or adrenal), soft tissue sarcomas, urethra, penis, leukemia , lymphoma, central nervous system neoplasm, sarcoma, myeloma, gallbladder, liver, neurofibromatosis, acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS) and Kaposi's sarcoma.

The invention also relates to methods of treating proliferative diseases such as melanoma, lung cancer (including non-small cell lung cancer (NSCLC)), colorectal cancer (CRC), breast cancer, kidney cancer (such as renal cell carcinoma ( RCC), liver cancer, endometrial cancer, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), thyroid cancer (specifically papillary thyroid cancer), pancreatic cancer, neurofibromatosis, or hepatocellular carcinoma cancer.

The present invention also relates to methods of treating proliferative diseases, such as solid tumors, including melanoma, breast cancer, ovarian cancer, colorectal cancer and generally gastrointestinal cancer, cervical cancer, lung cancer (including small cell lung cancer) and non-small cell lung cancer), head and neck cancer, bladder cancer, prostate cancer, or Kaposi's sarcoma.

In some embodiments, the method is used to treat a disease selected from the group consisting of cancers mediated by one or more of CDK1, CDK2, CDK4, and CDK6, including, for example, solid tumors (e.g., breast cancer (e.g., ER+ breast cancer) and prostate cancer), leukemia (such as acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia and myeloid leukemia), lymphoma (such as Burkitt's lymphoma , cutaneous T-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Hodgkin's lymphoma, mantle cell lymphoma, and non-Hodgkin's lymphoma (NHL) ), adrenocortical carcinoma, AIDS-related cancers, anal cancer, astrocytoma, basal cell carcinoma, skin cancer (non-melanoma), bile duct cancer, bladder cancer, bone cancer (such as fibrosarcoma/osteosarcoma/malignant fibrous tissue cell tumors), brain tumors (such as cerebral astrocytomas, ependymomas, gliomas, medulloblastomas, and supratentorial primitive neuroectodermal tumors (PNETs)), brainstem gliomas, bronchial adenomas/types Carcinoma, carcinoid tumor, central nervous system neoplasm, cervical cancer, biliary tract cancer, chronic myeloproliferative disorder, colon cancer, endometrial cancer, esophageal cancer, melanoma (eg, cutaneous or intraocular), gallbladder cancer , gastrointestinal cancer (such as colorectal cancer, duodenal cancer and gastric cancer (gastric cancer, stomach cancer)), germ cell tumor, head and neck cancer, hepatocellular carcinoma (liver cancer), hypopharyngeal cancer, islet cell carcinoma, Kaposi's sarcoma, Kidney cancer (renal cell carcinoma), laryngeal cancer, lip cancer and mouth cancer, lung cancer (small cell lung cancer and non-small cell lung cancer), Merkel cell carcinoma (Merkel cell carcinoma), mesothelioma, endocrine cancer (such as multiple endocrine neoplastic syndrome), multiple myeloma/plasma cell neoplasm mycosis fungoides, myelodysplastic syndrome, myeloproliferative disorders, nasal cavity and paranasal sinus cancers, nasopharyngeal cancer, neuroblastoma, oropharyngeal cancer, Ovarian cancer, pancreatic cancer, parathyroid cancer, penile cancer, pituitary cancer, pleuropulmonary blastoma, rectal cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Ewing sarcoma, soft tissue sarcoma, plug Sezary syndrome, squamous cell carcinoma, squamous neck carcinoma, synovial sarcoma, testicular carcinoma, thymoma, thymus carcinoma, thyroid carcinoma, transitional cell carcinoma, trophoblastic tumor, urethral carcinoma, uterine carcinoma, fallopian tube carcinoma , vaginal cancer, visual pathway and hypothalamic glioma, vulvar cancer, Waldenstrom's macroglobulinemia and Wilms' tumor.

The present invention further provides a method for inhibiting a CDK enzyme selected from CDK1, CDK2, CDK4, CDK6, and any combination of any of the above. Invention compounds are practiced in contact.

In some embodiments, the present invention provides a method for inhibiting CDK enzyme activity, wherein the CDK enzyme is selected from CDK1, CDK2, CDK4, CDK6 and any combination of any of the above, the method is by making the CDK enzyme and enough This is done by contacting with a compound of the invention in an amount that inhibits the enzymatic activity of the CDK.

In some embodiments, the present invention provides a method for inhibiting CDK enzyme activity, wherein the CDK enzyme is selected from CDK1, CDK2, CDK4, CDK6 and any combination of any of the above. This inhibition can occur in solution, in a cell expressing one or more CDK enzymes selected from CDK1, CDK2, CDK4, and CDK6, in a tissue comprising cells expressing a CDK enzyme, or in an organism expressing a CDK enzyme. In some embodiments, the present invention provides methods of inhibiting CDK enzymatic activity in an animal (including mammals, such as humans) by administering to the animal an amount of the present invention sufficient to inhibit CDK enzymatic activity in the animal. compound contact.

步驟 -2 ：

步驟 -1 ： The following general methods set forth herein provide means and procedures for making and using the compounds of the invention, and are illustrative rather than limiting. Further modifications to the presented methods and additional new methods can also be devised to achieve and serve the objectives of the present invention. Accordingly, there may be other embodiments that fall within the spirit and scope of the invention as defined by this specification. General Process for the Preparation of Compounds of the Invention Scheme -1 : Step -1 :

Step -2 :

Step -1 :

A compound of formula (a) wherein X is a leaving group such as halogen is coupled with a compound of formula (b) to form a compound of formula (c). A protecting group is added to a compound of formula (c) to form a compound of formula (d). Compounds of formula (d) are converted to compounds of formula (e).

Alternatively, a compound of formula (a) wherein X is a leaving group such as halogen is N-arylated with a compound of formula (j) to form a compound of formula (k). Compounds of formula (k) are converted to compounds of formula (l) by reduction.

Compounds of formula (a) wherein X is a leaving group, such as halogen, form compounds of formula (m) upon diborylation with bispinacol. Compounds of formula (m) can be coupled with compounds of formula (n) under Heck coupling conditions to form compounds of formula (o). Compounds of formula (o) form compounds of formula (p) by reductive transformation. Step -2 :

圖解說明 -2

圖解說明 -3 ：

圖解說明 -4 ：

圖解說明 -5 ：

方案 -2 步驟 -1 ：

步驟 -2 ：

步驟 -1 ： Compounds of formula (f) can be converted to compounds of formula (g) by using bis(pinacol diboron) and potassium acetate. Compounds of formula (g) can be coupled with compounds of formula (h) under Suzuki reaction conditions, for example in the presence of a suitable base and a palladium catalyst (such as Pd(dppf) ₂ Cl ₂ .CH ₂ Cl ₂ ) to form Compounds of formula (i). The compound of formula (i) can be coupled with the compound of formula (e) or formula (p) under Buchwald (Buchwald) coupling reaction conditions, for example, in a suitable base and a palladium catalyst (such as ginseng (dibenzylidene acetone) di palladium(0)) to form compounds of formula (1a) or formula (1). Compounds of formula (1a) are deprotected to form compounds of formula (I). Illustration -1

Illustration -2

Illustration -3 :

Illustration -4 :

Illustration- 5 :

Scenario -2 Step -1 :

Step -2 :

Step -1 :

Compounds of formula (a1) wherein X is a leaving group such as halogen can be coupled with compounds of formula (b1) wherein LG is a leaving group to form compounds of formula (c1). Compounds of formula (c1) are converted into compounds of formula (e1). Step -2 :

實驗數據 Compounds of formula (f) can be converted to compounds of formula (g) by using bis(pinacol diboron) and potassium acetate. Compounds of formula (g) can be coupled with compounds of formula (h) under Suzuki reaction conditions, for example in the presence of a suitable base and a palladium catalyst (such as Pd(dppf) ₂ Cl ₂ .CH ₂ Cl ₂ ) to form formula (i ) compounds. Compounds of formula (i) can be coupled with compounds of formula (e1) under Buchwald coupling reaction conditions, for example in the presence of a suitable base and a palladium catalyst (such as ginseng (dibenzylideneacetone) dipalladium (0)) , forming a compound of formula (I). Illustration- 6 :

Experimental data

General: Unless mentioned otherwise, work-up means partitioning the reaction mixture into the aqueous and organic phases mentioned in brackets, separating the organic layer, drying over anhydrous sodium sulfate, filtering and evaporating the organic layer to obtain the crude product .

General Procedure -1 : Preparation of Arylboronic Acid Pinacol Ester: To a solution of aryl bromide (1 eq.) in DMSO was added bis(pinacol diboron) (1.5 eq) and potassium acetate (3.0 eq. ). The mixture was degassed with nitrogen for 15 min. Palladium acetate (0.11 eq) and tricyclohexylphosphine (0.17 eq) were added, and the mixture was degassed for another 15 min and stirred at 80 °C until the starting material disappeared as monitored by TLC. After the reaction was complete, the reaction mixture was filtered on celite and the bed was washed with ethyl acetate. The combined filtrate and washings were washed successively with brine and water, and the organic layer was dried over anhydrous sodium sulfate and distilled under vacuum to obtain crude product, which was purified by column chromatography.

General Procedure -2 : Suzuki Coupling Reaction: To a solution of 2,4-dichloro-4-fluoropyrimidine (1 eq.) in dioxane and water (5:1) is added arylboronic acid or arylboronic acid Nacohol ester (1.3 eq), tetrakis(triphenylphosphine)palladium(0) (0.08 eq) and potassium carbonate (3.3 eq). The mixture was degassed with nitrogen for 30 min and allowed to reflux. After completion of the reaction as indicated by TLC, work-up ( _H2O /AcOEt) and purification afforded the desired product.

General Procedure -3 : Buchwald Coupling Reaction: Suspend chlorine compound (1 eq), aniline (1 eq), Xantphos (0.2 eq) and sodium tert-butoxide (1.6 eq) in dioxane (15 Vol) Neutralize and degas for 15 min. Gins(dibenzylideneacetone)dipalladium(0) (0.17 eq) was added and degassed for another 15 min. The reaction mixture was stirred at 90 °C for 1.5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, filtration through celite, washing the celite pad with DCM-MeOH (9:1 ) followed by work-up (H ₂ O/DCM-MeOH 9:1 ) and purification afforded the desired product.

General Procedure -4 : Boc deprotection reaction: Boc protected amine (1 eq) was dissolved in DCM (20 Vol) and cooled to 0 °C. To this mixture was added trifluoroacetic acid (5 eq) and stirred at 25 °C for 2 h. After completion of the reaction as indicated by TLC, the reaction mixture was basified to pH ~8 with saturated aqueous NaHCO ₃ to obtain a solid. The solid was filtered and dried to afford the title compound. If no solid was formed during basification, workup ( _H2O /AcOEt) afforded the title compound.

Intermediate 1 : 6-(4,4,5,5 -Tetramethyl -1,3,2-dioxaborolan - 2- yl ) quinoline: Following General Procedure-1, from 6- Bromoquinoline (3.0 g, 14.42 mmol) to synthesize the title compound. After work-up, the crude product was purified by column chromatography on 60-120 mesh silica gel using EtOAc and petroleum ether (5:95) as eluents to obtain the title compound (3.2 g) as a brown liquid. Yield: 87%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 8.92-8.96 (m, 1H), 8.35 (s, 1H), 8.19 (dd, J = 8.0, 1.2, 1H), 8.08 (br.s, 2H), 7.41 (dd, J = 8.0, 4.0, 1H), 1.34 (s, 12H).

Intermediate 2 : 6-(2- Chloro -5- fluoropyrimidin - 4 -yl ) quinoline: Following general procedure-2, from Intermediate 1 (3.0 g, 11.75 mmol) and 2,4-dichloro-4- Fluoropyrimidine (1.96 g, 11.75 mmol) was used to synthesize the title compound. After work-up, the crude product was purified by combi-flash using EtOAc and petroleum ether (21:79) as eluents to obtain the title compound (1.7 g) as a light yellow solid. Yield: 55%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 8.90-9.05 (m, 2H), 8.74 (s, 1H), 8.62 (d, J = 8.4, 1H), 8.35 (d, J = 8.8, 1H), 8.20 (d, J = 9.2, 1H), 7.65 (dd, J = 8.4, 4.4, 1H).

Intermediate 3 : 1-(6 -nitropyridin- 3 -yl ) hexahydropyrazine: make 5-bromo-2-nitropyridine (13 g, 64 mmol), hexahydropyrazine (7.17 g, 83 mmol ), tetrabutylammonium iodide (1.18 g, 3.2 mmol) and potassium carbonate (13 g, 94 mmol) were suspended in DMSO (158 ml). This mixture was stirred at 90 °C for 16 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with DCM. The DCM layer was distilled under vacuum to afford the title compound as a tan solid. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 8.23 (d, J = 3.2, 1H), 8.13 (d, J = 9.2, 1H), 7.44 (dd, J = 9.2, 3.2, 1H ), 3.42 (t, J = 5.2, 4H), 2.85 (t, J = 5.2, 4H).

Intermediate 4 : tert-butyl 4-(6 -nitropyridin- 3 -yl ) hexahydropyrazine- 1 -carboxylate: Intermediate 3 (11.6 g, 55.7 mmol) was dissolved in THF (135 ml) And water (13.5 ml) and sodium bicarbonate (2.81 g, 33.4 mmol) were added. This mixture was stirred for 5 min and Boc anhydride (6.08 g, 27.9 mmol) was added slowly. The reaction mixture was stirred at room temperature for 1 h. After 1 h, the reaction mixture was quenched with water and extracted with DCM (2*250 ml). The combined DCM layers were washed with brine (250 ml). The DCM layer was dried _over anhydrous _Na2SO4 and evaporated in vacuo to give a yellow solid which was stirred with diethyl ether (50 ml) for 15 min and filtered to give the title compound (11.2 g) as a yellow solid. Yield: 65%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 8.18 (d, J = 9.2, 1H), 8.13 (d, J = 2.8, 1H), 7.21 (dd, J = 9.2, 2.8, 1H), 3.64 (t, J = 5.2, 4H), 3.45 (t, J = 5.2, 4H), 1.49 (s, 9H).

Intermediate 5 : tert-butyl 4-(6 -aminopyridin- 3 -yl ) hexahydropyrazine- 1 -carboxylate: Intermediate 4 (11 g, 35.7 mmol) was placed in an autoclave and dissolved in A mixture of methanol (110 ml) and ethanol (110 ml) was added and 5% palladium on carbon (2.42 g) was added. This mixture was stirred at room temperature under 5 kg hydrogen pressure for 5 h. After the reaction was complete, the reaction mixture was filtered through a bed of celite, and the bed was washed with a 1:1 mixture of methanol and ethanol (200 ml). The filtrate and washings were combined and the solvent was evaporated. Water was added to the residue and extracted with EtOAc (2*250 ml). The combined organic layers were washed successively with water (150 ml) and brine (150 ml), dried _over anhydrous _Na2SO4 and distilled to give the title compound (7 g) as a brown solid. Yield: 70%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 7.60 (d, J = 2.8, 1H), 7.16 (dd, J = 8.8, 2.8, 1H), 6.38 (d, J = 8.8, 1H ), 5.44 (br. s, 2H), 3.41 (t, J = 4.8, 4H), 2.84 (t, J = 4.8, 4H), 1.40 (s, 9H).

Intermediate 6 : 8- Fluoro -6-(4,4,5,5 -tetramethyl- 1,3,2-dioxaborolan - 2- yl ) quinoline: following general procedure-1 , the title compound was synthesized from 6-bromo-8-fluoroquinoline (3.0 g, 13.27 mmol). After work-up, the crude product was purified by column chromatography on 60-120 mesh silica gel using EtOAc and petroleum ether (20:80) as eluents to obtain the title compound (1.6 g) as a brown liquid. Yield: 44%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 9.00 (dd, J = 4.0, 1.6, 1H), 8.22 (br. d, J = 8.4, 1H), 8.13 (s, 1H), 7.76 ( d, J = 9.8, 1H), 7.48 (dd, J = 8.4, 4.4, 1H).

Intermediate 7 : 6-(2- Chloro -5- fluoropyrimidin - 4 -yl )-8- fluoroquinoline: following general procedure-2, from intermediate 6 (1.5 g, 5.49 mmol) and 2,4-di Chloro-4-fluoropyrimidine (917 mg, 5.49 mmol) was used to synthesize the title compound. After work-up, the crude product was purified by combi-flash using EtOAc and petroleum ether (20:80) as eluents. The pure fractions from the combi-flash were combined and distilled to give the title compound (1.1 g) as a tan solid. Yield: 80%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 9.06-9.12 (m, 1H), 8.62 (d, J = 2.8, 1H), 8.53 (s, 1H), 8.35 (d, J = 8.4, 1H), 8.24 (d, J = 11.6, 1H), 7.59 (dd, J = 8.4, 4.0, 1H).

Intermediate 8 : 1-((6- bromopyridin - 3 -yl ) methyl )-4 -ethylhexahydropyrazine: 6-bromonicotinic aldehyde (5 g, 26.9 mmol) and 1-ethylhexahydropyrazine Hydropyrazine (3.38 g, 29.6 mmol) was dissolved in DCM (50 ml) and stirred at room temperature for 5 min. Sodium triacetyloxyborohydride (6.15 g, 29.03 mmol) was added and stirring was continued for 18 h. Workup (2 N aq. NaOH/DCM) gave a crude product which was co-distilled with EtOAc to afford the title compound (7.2 g) as a brown liquid. Yield: 95%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 8.28 (d, J = 2.4, 1H), 7.54 (dd, J = 8.0, 2.4, 1H), 7.42 (d, J = 8.0, 1H), 3.46 (s, 2H), 2.49 (br. s, 8H), 2.42 (q, J = 7.2, 2H), 1.08 (t, J = 7.2, 3H).

Intermediate 9 : 5-((4- Ethylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- amine: Intermediate 8 (21.0 g, 73.6 mmol), (dicyclohexylphosphino) Benzene (2.6 g, 7.3 mmol) and para(dibenzylideneacetone)dipalladium (3.3 g, 3.6 mmol) were suspended in THF (210 ml) and degassed with nitrogen for 30 min. After 30 min, the mixture was heated to 50 °C and a solution of 1 M LiHMDS in THF (184.6 ml, 184.6 mmol) was added dropwise. After the addition was complete, the mixture was heated at 65 °C overnight. The mixture was cooled to room temperature, water (200 ml) was added and THF was evaporated. To the residual aqueous layer was added 36% aqueous hydrochloric acid (200 ml) and washed with DCM (3*250 ml). The aqueous layer was separated, basified with 10% aqueous NaOH (900 ml) and extracted into DCM (6*500 ml). The combined organic layers were dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was washed with diethyl ether to obtain the title compound (8.6 g) as a light yellow solid. Yield: 52.8%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 7.60 (d, J = 2.0, 1H), 7.42 (dd, J 8.4, 2.0, 1H), 6.48 (d, J 8.4, 1H), 4.37 ( br. s, 2H), 3.38 (s, 2H), 2.30-2.70 (m, 10H), 1.07 (t, J = 7.2, 3H).

Intermediate 10 : 1 -methyl- 4-(6 -nitropyridin- 3 -yl ) hexahydropyrazine: make 5-bromo-2-nitropyridine (6 g, 29.56 mmol), 1-methylhexahydro Hydropyrazine (4.44 g, 44.3 mmol), tetrabutylammonium iodide (546 mg, 1.48 mmol) and potassium carbonate (6.12 g, 44.3 mmol) were suspended in DMSO (60 ml), and stirred at 80°C for 16 h. The reaction mixture was diluted with water (400 ml), extracted with DCM (3*250 ml) and the combined organic layers were distilled under vacuum to obtain crude product. Purification by combi-flash using methanol and DCM (3.5:96.5) as eluents gave the title compound (4 g) as a yellow solid. Yield: 61%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 8.17 (d, J = 9.2, 1H), 8.14 (d, J = 3.2, 1H), 7.20 (dd, J = 9.2, 3.2, 1H), 3.48 (t, J = 4.8, 4H), 2.59 (t, J = 4.8, 4H), 2.37 (s, 3H).

Intermediate 11 : 5-(4 -Methylhexahydropyrazin- 1 -yl ) pyridin -2- amine: Intermediate 10 (4 g, 18.0 mmol) was placed in an autoclave and dissolved in methanol (20 ml) In a mixture with ethanol (20 ml), and 5% palladium on carbon (957 mg) was added. This mixture was stirred at room temperature under 4.5 kg hydrogen pressure for 5 h. After completion of the reaction, the reaction mixture was filtered through a bed of celite, and the bed was washed with a mixture of methanol and ethanol (1:1, 50 ml). The combined filtrate and washings were evaporated. Water was added to the residue and extracted with EtOAc (2*50 ml). The combined organic layers were washed with water (50 ml) and brine (50 ml), dried _over anhydrous _Na2SO4 and distilled to obtain crude product. Purification by combi-flash chromatography using 3.5% MeOH in DCM as eluent afforded the title compound (2.5 g) as a maroon solid. Yield: 72%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 7.57 (d, J = 2.8, 1H), 7.14 (dd, J = 8.8, 2.8, 1H), 6.37 (d, J = 8.8, 1H), 5.36 (br. s, 2H), 2.90 (t, J = 4.8, 4H), 2.41 (t, J = 4.8, 4H), 2.19 (s, 3H).

Intermediate 12 : 5- Bromo -7- fluoroindoline- 2,3- dione: 7-fluoroindoline-2,3-dione (50 g, 303 mmol) was dissolved in acetic acid (330 ml) and cooled to 0°C. Bromine (48.4 g, 303 mmol) was added dropwise to the stirred solution and stirring was continued at 0°C to 5°C for 1 h. After 1 h, the mixture was poured into ice-cold water (500 ml). The precipitated solid was filtered, washed with water (100 ml) and dried in an oven to afford the title compound (65 g) as a brick red solid. Yield: 88%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 11.66 (s, 1H), 7.87 (dd, J = 9.6, 1.6, 1H), 7.56 (s, 1H).

Intermediate 13 : 6- bromo -8- fluoro -2 -methylquinoline- 4 - carboxylic acid: Intermediate 12 (65 g, 0.27 mol) was suspended in potassium hydroxide (103.4 g, 1.84 mol) in water (2.3 L) and acetone (260 ml) was added. This mixture was stirred at 50 °C for 4 h. A further batch of acetone (260 ml) was added to the reaction mixture and stirred at 50 °C for 16 h. The reaction mixture was cooled to room temperature, and when a solid precipitated, the pH was adjusted to about 3 using 6 N HCl. The solid was filtered, washed with hot water (650 ml) and dried in an oven at 70 °C for 15 h to afford the title compound as an off-white solid. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 14.14 (br. s, 1H), 8.72 (s, 1H), 8.00 (s, 1H), 7.90-7.96 (m, 1H), 2.72 (s , 3H).

Intermediate 14 : 6- Bromo -8- fluoro -N- methoxy- N,2 -dimethylquinoline- 4 -carboxamide: Intermediate 13 (800 mg, 2.82 mmol) was dissolved in DCM (16 mL) and cooled to 0 °C. To this mixture was added one drop of DMF followed by the dropwise addition of oxalyl chloride (429 mg, 3.38 mmol). After the oxalyl chloride addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 2 h. Dichloromethane and oxalyl chloride were distilled from the mixture and co-distilled with DCM (10 mL) to obtain the oxalyl chloride residue. Separately, N,O-dimethylhydroxylamine hydrochloride (275 mg, 2.82 mmol) was dissolved in DCM, cooled to 0 °C, added triethylamine (627 mg, 6.2 mmol) and stirred at 0 °C for 30 min. To this mixture was slowly added a solution of the above acid chloride in DCM (16 ml) at 0 °C. After the addition was complete, the reaction mixture was warmed to 25 °C and stirred for 16 h. The reaction mixture was diluted with water and the layers were separated. The aqueous layer was extracted with DCM (2*30 ml). The combined organic layers were washed sequentially with saturated aqueous NaHCO ₃ (30 ml) and brine (30 ml). The organic layer was dried over sodium sulfate and the solvent was distilled off to obtain a crude product. Purification by column chromatography on 60-120 mesh silica gel using EtOAc and petroleum ether (2:8) as eluents gave the title compound (500 mg) as a yellow solid. Yield: 54%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 7.75 (br. s, 1H), 7.54 (dd, J = 9.6, 1.6, 1H), 7.35 (s, 1H), 3.48 (br. s, 3H), 3.41 (br. s, 3H), 2.79 (s, 3H).

Intermediate 15 : 1-(6- Bromo -8- fluoro -2 -methylquinolin- 4 -yl ) ethan - 1 -one: Intermediate 14 (45 g, 137.4 mmol) was dissolved in THF (450 ml) and cooled to 0 °C, and slowly added methylmagnesium chloride (3 M in THF, 69 ml, 207 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with aqueous _NH4Cl . and extracted with EtOAc. The organic layer was washed successively with water and brine solution, dried _over anhydrous _Na2SO4 and distilled to obtain crude product. Purification by combi-flash using EtOAc and petroleum ether (12:88) as eluents afforded the title compound (27.4 g) as a brown solid. Yield: 71%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 8.46 (br. s, 1H), 7.61 (s, 1H), 7.57 (dd, J = 10.0, 2.0, 1H), 2.84 (s, 3H) , 2.75 (s, 3H).

Intermediate 16 : 6- Bromo -8- fluoro -2- methyl- 4-( prop- 1 -en -2- yl ) quinoline: Dissolve methyltriphenylphosphonium bromide (50.65 g, 0.142 mol) In THF (50 ml), potassium tert-butoxide (15.91 g, 0.142 mol) was added and stirred at room temperature for 5 min. To this mixture was added a solution of intermediate 15 (20 g, 71 mol) in THF (100 ml) dropwise over a period of 30 min and stirred at room temperature for 8 h. The reaction was quenched with saturated aqueous NaHCO ₃ and extracted with EtOAc (2*500 ml). The organic layer was washed successively with brine (2*250 ml) and water (250 ml), dried over anhydrous Na ₂ SO ₄ and distilled to obtain crude product. Purification by column chromatography on 60-120 mesh silica gel using EtOAc and petroleum ether (0.5:99.5) as eluents gave the title compound (5.7 g) as an off-white solid. Yield: 29%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 7.93 (s, 1H), 7.50 (dd, J = 8.0, 1.6, 1H), 7.18 (s, 1H), 5.50 (s, 1H), 5.12 (s, 1H), 2.76 (s, 3H), 3.19 (s, 3H).

Intermediate 17 : 8- fluoro -2- methyl- 4-( prop- 1 -en -2- yl )-6-(4,4,5,5 -tetramethyl -1,3,2- dioxo Borolan -2- yl ) quinoline: The title compound was synthesized from Intermediate 16 (1.0 g, 3.57 mmol) following General Procedure-1. After work-up, the crude product was purified by combi-flash using EtOAc and petroleum ether (7:93) as eluents to obtain the title compound (500 mg) as an off-white solid. Yield: 43%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 8.22 (s, 1H), 7.72 (d, J = 10.8, 1H), 7.16 (s, 1H), 5.50 (s, 1H), 5.14 (s , 1H), 2.78 (s, 1H), 2.22 (s, 3H), 1.37 (s, 12H).

Intermediate 18 : 6-(2- Chloro -5- fluoropyrimidin - 4 -yl )-8- fluoro -2- methyl- 4-( prop- 1 -en -2- yl ) quinoline: by general procedure -2, the title compound was synthesized from intermediate 17 (2.5 g, 7.64 mmol) and 2,4-dichloro-4-fluoropyrimidine (1.53 g, 9.17 mmol) with the following modifications: Potassium fluoride (1.33 g, 22.9 mmol) instead of potassium carbonate as base. After work-up (EtOAc/brine), the crude product was purified by combi-flash using petroleum ether and EtOAc (99:1) as eluents to obtain the title compound (1.4 g) as an off-white solid. Yield: 55%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 8.65 (s, 1H), 8.57 (d, J = 2.8, 1H), 8.19 (dd, J = 11.6, 1.6, 1H), 7.27 (s, 1H), 5.57 (s, 1H), 5.19 (s, 1H), 2.82 (s, 3H), 2.25 (s, 3H).

Intermediate 19 : 1- ethyl- 4-(6 -nitropyridin- 3 -yl ) hexahydropyrazine: make 5-bromo-2-nitropyridine (4 g, 19.7 mmol), 1-ethylhexahydropyridine Hydropyrazine (3.38 g, 29.56 mmol), tetrabutylammonium iodide (364 mg, 0.99 mmol) and potassium carbonate (4.09 g, 29.6 mmol) were suspended in DMSO (37.5 ml), and stirred at 80°C for 15 h. The reaction mixture was diluted with water (400 ml), extracted with DCM (3*250 ml), and the combined organic layer was washed with brine (100 ml) and water (100 ml), dried over anhydrous sodium sulfate and distilled under vacuum, A crude product is obtained. Purification by combi-flash using methanol and DCM (4:96) as eluents afforded the title compound (3 g) as a yellow solid. Yield: 64%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 8.17 (d, J = 9.2, 1H), 8.14 (d, J = 3.2, 1H), 7.20 (dd, J = 9.2, 3.2, 1H), 3.48 (t, J = 5.2, 4H), 2.61 (t, J = 5.2, 4H), 2.49 (q, J = 7.2, 3H), 1.14 (t, J = 7.2, 3H).

Intermediate 20 : 5-(4- Ethylhexahydropyrazin- 1 -yl ) pyridin -2- amine: Intermediate 19 (5 g, 18. mmol) was placed in an autoclave and dissolved in methanol (25 ml ) and ethanol (25 ml), and 5% palladium on carbon (1.13 g) was added. This mixture was stirred at room temperature under 4.5 kg hydrogen pressure for 5 h. After completion of the reaction, the reaction mixture was filtered through a bed of celite, and the bed was washed with a mixture of methanol and ethanol (1:1, 50 ml). The combined filtrate and washings were evaporated. Water was added to the residue and extracted with EtOAc (2*50 ml). The combined organic layers were washed with water (50 ml) and brine (50 ml), dried _over anhydrous _Na2SO4 and distilled to obtain crude product. Purification by combi-flash chromatography using 3.2% MeOH in DCM as eluent afforded the title compound (4.0 g) as a gray solid. Yield: 92%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 7.57 (d, J = 2.8, 1H), 7.14 (dd, J = 8.8, 2.8, 1H), 6.38 (d, J = 8.8, 1H ), 5.36 (s, 2H), 2.93-2.85(m, 4H), 2.48-2.42(m, 4H), 2.33 (q, J = 7.2, 2H), 1.00 (t, J = 7.2, 3H).

Intermediate 21 : 6- Bromo -8- fluoro -2 -methylquinoline: Crotonaldehyde (612 mg, 8.74 mmol) was added to 4-bromo-2-fluoroaniline (2.00 g, 10.5 mmol) with 6 N hydrochloric acid aqueous solution (42.1 ml) and stirred at room temperature for 1 h. Toluene (11 ml) was added and the mixture was heated at 110 °C for 17 h, cooled to room temperature and the layers were separated. The organic layer was extracted with 6 N aqueous HCl (50 ml). The combined aqueous layers were basified to pH 10-11 with 10% aqueous sodium hydroxide and extracted into DCM (3*100 ml). The combined organic layers were washed sequentially with brine solution (100 ml) and water (100 ml), dried over sodium sulfate and concentrated. The residue was purified by combi-flash chromatography system using petroleum ether-EtOAc (95:5) as eluent to give the title compound (1.2 g) as light yellow solid. Yield: 47%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 7.80 (dd, J = 8.4, 1.2, 1H), 7.74 (s, 1H), 7.51 (dd, J = 9.6, 1.6, 1H), 7.37 ( d, J = 8.4, 1H), 2.78 (s, 3H).

Intermediate 22 : 8- fluoro -2- methyl -6-(4,4,5,5 -tetramethyl- 1,3,2-dioxaborolan - 2- yl ) quinoline: The title compound was synthesized from Intermediate 21 (1.0 g, 3.57 mmol) following General Procedure-1. After work-up, the crude product was purified by combi-flash using EtOAc and petroleum ether (8:92) as eluents to obtain the title compound (3.5 g) as a light yellow solid. Yield: 60%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 8.03-8.12 (m, 2H), 7.72 (d, J = 11.2, 1H), 7.35 (d, J = 8.4, 1H), 2.80 (s, 3H), 1.37 (s, 12H).

Intermediate 23 : 6-(2- Chloro -5- fluoropyrimidin - 4 -yl )-8- fluoro -2 -methylquinoline: Following general procedure-2, from Intermediate 22 (3.5 g, 12.19 mmol) and 2,4-Dichloro-4-fluoropyrimidine (2.24 g, 13.41 mmol) was used to synthesize the title compound. After work-up, the crude product was purified by combi-flash using EtOAc and petroleum ether (20:80) as eluents to obtain the title compound (2.5 g) as an off-white solid. Yield: 70%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.04 (d, J = 3.2, 1H), 8.45-8.60 (m, 2H), 8.07 (d, J = 12.0, 1H), 7.63 ( d, J = 8.4, 1H), 2.73 (s, 3H).

Intermediate 24 : 1- isopropyl- 4-(6 -nitropyridin- 3 -yl ) hexahydropyrazine : make 5-bromo-2-nitropyridine (5 g, 25.6 mmol), 1-isopropyl Hexahydropyrazine (4.11 g, 32.0 mmol), tetrabutylammonium iodide (455 mg, 1.23 mmol) and potassium carbonate (5.11 g, 36.9 mmol) were suspended in DMSO (253 ml), and at 90°C Stir for 16 h. The reaction mixture was diluted with water (400 ml), extracted with DCM (3*250 ml), and the combined organic layer was washed with brine (100 ml) and water (100 ml), dried over anhydrous sodium sulfate and distilled under vacuum, A crude product is obtained. Purification by combi-flash using methanol and DCM (2:98) as eluents afforded the title compound (3.4 g) as a yellow solid. Yield: 55%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 8.16 (d, J 8, 1H), 8.13 (d, J 3.2, 1H), 7.19 (d, J 8, 3.2, 1H), 3.46 (t, J 5.2, 4H), 2.76 (septet, J 6.4, 1H), 2.69 (t, J 5.2, 4H), 1.09 (d, J 6.4, 6H).

Intermediate 25 : 5-(4- Isopropylhexahydropyrazin- 1 -yl ) pyridin -2- amine: Intermediate 24 (3.4 g, 14 mmol) was placed in an autoclave and dissolved in methanol (35 ml ) and ethanol (35 ml), and 5% palladium on carbon (1.13 g) was added. This mixture was stirred at room temperature under 4.5 kg hydrogen pressure for 5 h. After completion of the reaction, the reaction mixture was filtered through a bed of celite, and the bed was washed with a mixture of methanol and ethanol (1:1, 50 ml). The combined filtrate and washings were evaporated. Water was added to the residue and extracted with EtOAc (2*50 ml). The combined organic layers were washed with water (50 ml) and brine (50 ml), dried _over anhydrous _Na2SO4 and distilled to obtain crude product. The crude product was triturated with diethyl ether to give the title compound (2.3 g) as a gray solid. Yield: 76%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 7.57 (d, J 3.2, 1H), 7.13 (dd, J 8.8, 3.2, 1H), 6.37 (d, J 8.8, 1H), 5.35 (s, 2H), 2.88 (t, J 4.4, 4H), 2.63 (septet, J 6.8, 1H), 0.98 (d, J 6.8, 6H).

Intermediate 26 : 1-((6- bromopyridin - 3 -yl ) methyl )-4 -methylhexahydropyrazine: 6-bromonicotinic aldehyde (5 g, 27 mmol) and 1-methylhexahydro Hydropyrazine (2.96 g, 29.5 mmol) was dissolved in DCM (50 ml) and stirred at room temperature for 5 min. Sodium triacetyloxyborohydride (9.25 g, 43.6 mmol) was added and stirring was continued for 24 h. Workup (2 N aq. NaOH/DCM) gave a crude product which was co-distilled with EtOAc to afford the title compound (7.2 g) as a brown liquid. Yield: 99%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 8.30 (d, J 2, 1H), 7.56 (dd, J = 8, 2, 1H), 7.43 (d, J 8, 1H), 3.46 ( s, 2H), 2.60-2.38 (m, 8H), 2.28 (s, 3H).

Intermediate 27 : 5-((4 -Methylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- amine: Intermediate 25 (7 g, 25.9 mmol), (dicyclohexylphosphino) Benzene (908 mg, 2.6 mmol) and ginseng(dibenzylideneacetone)dipalladium (1.19 g, 1.3 mmol) were suspended in THF (70 ml) and degassed with nitrogen for 30 min. After 30 min, the mixture was heated to 50 °C and a solution of 1 M LiHMDS in THF (64.8 ml, 64.8 mmol) was added dropwise. After the addition was complete, the mixture was heated at 65 °C overnight. The mixture was cooled to room temperature, water (200 ml) was added and THF was evaporated. To the residual aqueous layer was added 36% aqueous hydrochloric acid (200 ml) and washed with DCM (3*250 ml). The aqueous layer was separated, basified with 10% aqueous NaOH (900 ml) and extracted into DCM (6*500 ml). The combined organic layers were dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was washed with diethyl ether to obtain the title compound (3.2 g) as a light yellow solid. Yield: 60%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 7.96 (d, J = 2.5, 1H), 7.42 (dd, J = 8.4, 2.5, 1H), 6.48 (d, J = 8.4, 1H), 4.37 (bs, 2H), 3.37 (s, 2H), 2.70-2.30 (m, 8H), 2.27 (s, 3H).

Intermediate 28 : Methyl 6- bromo -8- fluoro -2 -methylquinoline- 4 -carboxylate: Add sulfuric acid (12 mL, 0.22 mmol) to 6-bromo-8-fluoro-2-methylquinoline Oline-4-carboxylic acid (Intermediate 13, 36 g, 130 mmol) was in a solution in methanol (360 mL), and the mixture was refluxed for 48 h. Methanol was removed by distillation, and water (200 mL) was added to the residue and basified with saturated aqueous NaHCO ₃ . The solid was filtered and dissolved in methanol-dichloromethane (1:9, 400 mL). The solution was washed with saturated aqueous NaHCO ₃ (3*100 mL), the organic layer was dried over sodium sulfate and evaporated to give the title compound (31.5 g) as a yellow solid. Yield: 83%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 8.61 (d, J = 2.0, 1H), 8.0 (s, 1H), 7.96 (dd, J = 10.0, 2.0, 1H), 3.98 ( s, 3H), 2.73 (s, 3H).

Intermediate 29 : 2-(6- Bromo -8- fluoro -2 -methylquinolin- 4 -yl ) propan -2- ol: 1 M methylmagnesium bromide in THF at 0°C ( 290 mL, 290 mmol) was slowly added to a solution of methyl 6-bromo-8-fluoro-2-methylquinoline-4-carboxylate (Intermediate 28, 17 g, 57 mmol) in THF (250 mL) and stirred at the same temperature for 2 h. Saturated aqueous ammonium chloride (50 mL) was added to the mixture and extracted into ethyl acetate (2*50 mL). The organic layer was washed successively with water (50 mL) and brine (50 mL), dried over sodium sulfate and evaporated to give a residue, which was purified by silica gel column chromatography on a combi-flash system using ethyl acetate-hexane (15: 85) The residue was purified by elution to give the title compound (11 g) as an off-white solid. Yield: 65%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 8.89 (br. s, 1H), 7.78 (dd, J = 10.0, 2.0, 1H), 7.50 (s, 1H), 2.65 (s, 3H), 1.64 (s, 6H).

Intermediate 30 : (8- Fluoro - 4-(2 -hydroxypropan- 2- yl )-2 -methylquinolin -6- yl ) boronic acid: Triisopropyl borate was added at -78 °C under nitrogen atmosphere (8.1 mL, 35.0 mmol) was added dropwise to 2-(6-bromo-8-fluoro-2-methylquinolin-4-yl)propan-2-ol (Intermediate 29, 5.1 g, 17 mmol) in Solution in anhydrous THF (20 mL). A solution of 2.5 M n -Buli in THF (8.1 mL, 35 mmol) was added dropwise to the above mixture and stirred at the same temperature for 2 hours. The mixture was allowed to warm to room temperature and acidified with 2 N HCl, stirred for 30 min, neutralized by addition of 10% aqueous NaOH, stirred for 20 min, and extracted into ethyl acetate (2*100 mL). The combined organic layers were washed successively with water (100 mL) and brine (100 mL), dried over sodium sulfate and concentrated. The residue was stirred with petroleum ether (10 mL) for 20 min, and the solid formed was filtered and dried. Off-white solid (3.0 g). Yield: 68%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 8.85 (s, 1H), 8.30 (s, 2H), 7.74 (dd, J = 11.6, 1H), 7.32 (s, 1H), 2.65 (s, 3H), 1.69 (s, 6H).

Intermediate 31 : 2-(6-(2- Chloro -5- fluoropyrimidin - 4 -yl )-8- fluoro -2 -methylquinolin- 4 -yl ) propan -2- ol: following general procedure-2 , from (8-fluoro-4-(2-hydroxypropan-2-yl)-2-methylquinolin-6-yl)boronic acid (3.0 g, 11.4 mmol) and 2,4-dichloro-4-fluoro Pyrimidine (2.09 g, 12.5 mmol) to synthesize the title compound. After work-up, the crude product was purified by combi-flash using MeOH and DCM (1:99) as eluents to obtain the title compound (2.5 g) as a light yellow solid. Yield: 63%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.49 (s, 1H), 9.02 (d, J = 3.2, 1H), 8.02 (d, J = 11.6, 1H), 7.60 (s, 1H), 2.94 (s, 3H), 1.70 (s, 6H).

Intermediate 32 : (6- bromo -8- fluoro -2 -methylquinolin- 4 -yl ) methanol: methyl 6-bromo-8-fluoro-2-methylquinoline-4-carboxylate (intermediate 28, 100 g, 335 mmol) in ethanol (1.0 L) was cooled to 10 °C, and sodium borohydride (50.8, 1.34 mol) was added in portions over 45 min, and the mixture was stirred at 60 °C for 90 min. The mixture was cooled to 25 °C, diluted with water (1.5 L) and stirred for 1 h. The solid formed was filtered, washed with water and dried under vacuum for 5 h and then in a hot air oven at 70 °C for 17 h to give the title compound (74 g) as an off-white solid. Yield: 82%.

Intermediate 33 : 6- Bromo -8- fluoro -2 -methylquinoline- 4 - carbaldehyde: Add dimethylsulfoxide (45.4 mL, 640 mmol) to oxalyl chloride dropwise at -78 °C over 30 min (36.55, 418 mmol) in dichloromethane (300 mL) and stirred for another 20 min. (6-Bromo-8-fluoro-2-methylquinolin-4-yl)methanol (Intermediate 32, 60 g, 222.1 mmol) was dissolved in dichloromethane (300 mL) at -78 °C for 45 min The solution was added to the above mixture and stirred for another 30 min. Triethylamine (111 mL, 800 mmol) was slowly added to the reaction mixture and stirred for 30 min. After adding water (500 mL), the mixture was allowed to warm to room temperature and extracted into dichloromethane (2*500 mL). The combined organic layers were washed successively with water (500 mL) and brine (500 mL), dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography on a combi-flash system using petroleum ether-EtOAc (90:10) as eluent to afford the product (40 g) as an off-white solid. Yield: 67%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 10.37 (s, 1H), 9.00 (s, 1H), 7.76 (s, 1H), 7.63 (dd, J = 9.6, 2.0, 1H), 2.90 (s, 3H).

Intermediate 34 : 6- bromo - 4-( difluoromethyl )-8- fluoro -2 -methylquinoline: (diethylamino)sulfur trifluoride (20.97 g, 130.1 mmol ) was added to a solution of 6-bromo-8-fluoro-2-methylquinoline-4-carbaldehyde (Intermediate 33, 10.0 g, 37.3 mmol) in dichloromethane (108 mL), and the mixture was stirred for 16 h. After adjusting the pH between 7.0 and 8.0 by adding saturated aqueous sodium bicarbonate at 0°C, the mixture was extracted into dichloromethane (2*500 mL). The combined organic layers were washed with water (250 mL) and brine (250 mL), dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography on a combi-flash system using petroleum ether-EtOAc (92:8) as eluent to afford the product (8.0 g) as an off-white solid. Yield: 74%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 7.99 (s, 1H), 7.60 (dd, J = 9.6, 2.0, 1H), 7.55 (s, 1H), 7.03 (t, J = 54.0, 1H), 2.83 (s, 3H).

Intermediate 35 : (4-( Difluoromethyl )-8- fluoro -2 -methylquinolin -6- yl ) boronic acid: Triisopropyl borate (9.93 mL, 43.0 mmol) was added dropwise to 6-bromo-4-(difluoromethyl)-8-fluoro-2-methylquinoline (Intermediate 34, 6.0 g, 20.7 mmol) in anhydrous THF (215 mL) in solution. A solution of 2.5 M n -Buli in THF (16.1 mL, 40.3 mmol) was added dropwise to the above mixture and stirred at the same temperature for 2 hours. The mixture was allowed to warm to room temperature and acidified with 2 N HCl, stirred for 30 min, neutralized by addition of 10% aqueous NaOH, stirred for 20 min, and extracted into ethyl acetate (2*100 mL). The combined organic layers were washed successively with water (100 mL) and brine (100 mL), dried over sodium sulfate and concentrated. The residue was stirred with diethyl ether (30 mL) for 30 min, and the solid formed was filtered and dried. Yellow solid (4.1 g). Yield: 78%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 8.48 (br. s, 2H), 8.37 (s, 1H), 7.89 (d, J =11.6, 1H), 7.73 (s, 1H) , 7.62 (t, J = 53.6, 1H), 2.75 (s, 3H).

Intermediate 36 : 6-(2- Chloro -5- fluoropyrimidin - 4 -yl )-4-( difluoromethyl )-8- fluoro -2 -methylquinoline: following general procedure-2, from (4 -(difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)boronic acid (intermediate 35, 4.0 g, 15.7 mmol) and 2,4-dichloro-4-fluoropyrimidine (2.88 g , 17.3 mmol) to synthesize the title compound. After work-up, the crude product was purified by combi-flash using petroleum ether-EtOAc (8:2) as eluent to obtain the title compound (2.5 g) as an off-white solid. Yield: 46.6%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 8.70 (br. s, 1H), 8.65 (d, J = 3.2, 1H), 8.30 (d, J = 11.2, 1H), 7.66 (s, 1H), 7.20 (t, J = 54.0, 1H), 2.93 (s, 3H).

Intermediate 37 : 6- Bromo -8- fluoro - 4-(2- fluoropropan- 2- yl )-2 -methylquinoline: (diethylamino) trifluorination at 10°C-15°C Sulfur (5.41 g, 33.5 mmol) was added to 2-(6-bromo-8-fluoro-2-methylquinolin-4-yl)propan-2-ol (intermediate 29, 5.0 g, 16.8 mmol) in di chloride (50 mL), and the mixture was stirred overnight. The mixture was diluted with dichloromethane (100 mL) and washed sequentially with saturated aqueous sodium bicarbonate (2*50 mL), water (100 mL) and brine (100 mL), dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography on a combi-flash system using petroleum ether-EtOAc (90:10) as eluent to afford the product (2.30 g) as an off-white solid. Yield: 50%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 8.23 (s, 1H), 7.52 (dd, J = 11.2, 1.2, 1H), 8.30 (d, J = 11.2, 1H), 7.37 (s, 3H), 2.72 (s, 1H), 1.92 (d, J = 22.4, 3H).

Intermediate 38 : (8- Fluoro - 4-(2- fluoropropan- 2- yl )-2 -methylquinolin -6- yl ) boronic acid: triisopropyl borate at -78 °C under nitrogen atmosphere (0.792 mL, 3.43 mmol) was added dropwise to 6-bromo-4-(difluoromethyl)-8-fluoro-2-methylquinoline (intermediate 37, 500 mg, 1.67 mmol) in anhydrous THF (20 mL) in solution. A solution of 2.5 M n -Buli in hexane (2.0 mL, 5.0 mmol) was added dropwise to the above mixture and stirred at the same temperature for 2 hours. The mixture was allowed to warm to room temperature and acidified with 2 N HCl, stirred for 30 min, neutralized by addition of 10% aqueous NaOH, stirred for 20 min, and extracted into ethyl acetate (2*100 mL). The combined organic layers were washed successively with water (100 mL) and brine (100 mL), dried over sodium sulfate and concentrated. The residue was stirred with petroleum ether (20 mL) for 20 min, and the solid formed was filtered and dried. Off-white solid (170 mg). Yield: 38.5%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 8.49 (s, 1H), 8.42 (s, 2H), 7.79 (d, J = 11.2, 1H), 7.52 (s, 1H), 2.69 (s, 3H), 1.92 (d, J = 23.2, 6H).

Intermediate 39 : 6-(2- Chloro -5- fluoropyrimidin - 4 -yl )-8- fluoro - 4-(2- fluoropropan- 2- yl )-2 -methylquinoline: following general procedure-2 , from (8-fluoro-4-(2-fluoroprop-2-yl)-2-methylquinolin-6-yl)boronic acid (intermediate 38, 1.80 g, 6.79 mmol) and 2,4-dichloro -4-fluoropyrimidine (1.25 g, 7.47 mmol) to synthesize the title compound. After work-up, the crude product was purified by combi-flash using methanol-dichloromethane (9:1) as eluent. After removal of solvent from the pooled fractions, the residue was stirred with petroleum ether (20 mL), the solid was filtered and dried to afford the title compound (1.3 g) as a yellow solid. Yield: 54.4%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.03 (d, J = 3.2, 1H), 8.90 (s, 1H), 8.06 (d, J = 11.6, 1H), 7.65 (s, 1H), 2.74 (s, 1H), 1.93 (d, J =22.4, 6H).

Intermediate 40 : 7- fluoro -6-(4,4,5,5 -tetramethyl- 1,3,2-dioxaborolan - 2- yl ) quinoline: as Fei et al., The preparation of 6-bromo-7-fluoroquinoline is described in bioorganic & medicinal Chemistry 2016 , 24(18), 4281-4290. The title compound was synthesized from 6-bromo-7-fluoroquinoline (500 mg, 2.21 mmol) following General Procedure-1. After work-up, the crude product was purified by combi-flash using EtOAc and petroleum ether (3:97) as eluents to obtain the title compound (200 mg) as a yellow liquid. Yield: 33%. Yield: 33%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 8.93 (dd, J = 4.4, 1.6, 1H), 8.31 (d, J = 6.4, 1H), 8.19 (br. d, J = 8.4, 1H ), 7.71 (br. d, J = 10.8, 1H), 7.37 (dd, J = 8.4, 4.4, 1H), 1.42 (s, 12H). MS (m/z): 274.24 (M+H); Calcd. for [ _{C15H17BFNO2 +} H]: _274.14 .

Intermediate 41 : 7- Fluoro -6-(4,4,5,5 -tetramethyl- 1,3,2-dioxaborolan - 2- yl ) quinoline: following general procedure-2 , from 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (intermediate 40, 5.0 g, 18.3 mmol) and 2,4-dichloro-5-fluoropyrimidine (3.67 g, 22.0 mmol) to synthesize the title compound. After work-up, the crude product was purified by combi-flash using petroleum ether-EtOAc (8:2) as eluent to obtain the title compound (3.1 g) as an off-white solid. Yield: 61%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 9.02 (dd, J = 4.4, 1.6, 1H), 8.63 (d, J = 1.6, 1H), 8.28 (d, J = 8.4, 1H), 8.26 (d, J = 7.6, 1H), 7.91 (d, J = 9.6, 1H), 7.49 (dd, J = 8.0, 4.0, 1H).

Intermediate 42 : N,N -Dimethyl- 1-(6 -nitropyridin- 3 -yl ) hexahydropyridin- 4 -amine 5-bromo-2-nitropyridine (5 g, 24.6 mmol), N,N-Dimethylhexahydropyridin-4-amine (4.11 g, 32.0 mmol) and potassium carbonate (5.11 g, 36.9 mmol) were suspended in DMSO (50 ml), and stirred at 90°C for 16 h. The reaction mixture was diluted with water (500 ml), extracted with DCM (2*200 ml), and the combined organic layer was washed with brine (100 ml) and water (100 ml), dried over anhydrous sodium sulfate and distilled under vacuum, A crude product is obtained. Purification by combi-flash using methanol and DCM (2:98) as eluents afforded the title compound (3.6 g) as a yellow solid. Yield: 58%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 8.15 (d, J 9.2, 1H), 8.13 (d, J 3.2, 1H), 7.19 (dd, J 9.2, 3.2, 1H), 4.00-3.93 (m, 2H), 3.10-3.02 (m, 2H), 2.46-2.36 (m, 1H), 2.31 (s, 6H), 2.00 (d, J 12.4, 2H), 1.70-1.56 (m, 2H).

Intermediate 43 : 5-(4-( Dimethylamino ) hexahydropyridin- 1 -yl ) pyridin -2- amine Intermediate 42 (2.7 g, 11 mmol) was placed in an autoclave and dissolved in methanol ( 25 ml) and ethanol (25 ml), and 5% palladium on carbon (1.08 g) was added. This mixture was stirred at room temperature under 4.5 kg hydrogen pressure for 4 h. After completion of the reaction, the reaction mixture was filtered through a bed of celite, and the bed was washed with a mixture of MeOH and DCM (1:9, 100 ml). The combined filtrate and washings were evaporated to give a solid. The solid was triturated with petroleum ether to give the title compound (2.1 g) as a gray solid. Yield: 88%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 7.58 (d, J 3.0, 1H), 7.14 (dd, J 8.8, 3.0, 1H), 6.36 (d, J 8.8, 1H), 5.35 (s, 2H), 3.40-3.32 (m, 2H), 2.55-2.45 (m, 2H), 2.17 (s, 6H), 2.15-2.06 (m, 1H), 1.78 (d, J 12.4, 2H), 1.52-1.40 (m, 2H).

Intermediate 44 : 4-(6 -nitropyridin- 3 -yl ) hexahydropyrazin -2- one: 5-bromo-2-nitropyridine (4.04 g, 19.9 mmol), hexahydropyrazin-2 - Ketone (2.39 g, 23.9 mmol) and DIPEA (9.26 g, 71.6 mmol) were suspended in DMSO (50 ml) and stirred at 120 °C for 16 h in a sealed tube. DIPEA was distilled off to obtain a residue. EtOAc (30 ml) was added to the residue and stirred for 30 min to obtain a solid. The solid was filtered and dried under vacuum for 3 h to obtain the title compound (2.5 g) as a yellow solid. Yield: 57%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz):8.27 (bs, 1H), 8.22-8.15 (m, 2H), 7.44 (dd, J 9.2, 3, 1H), 4.04 (s, 2H ), 3.72-3.65 (m, 2H), 3.41-3.32 (m, 2H).

Intermediate 45 : 4-(6 -Aminopyridin- 3 -yl ) hexahydropyrazin -2- one: Intermediate 44 (1.9 g, 8.55 mmol) was placed in an autoclave and dissolved in methanol (15 ml) In a mixture with ethanol (15 ml), and 5% palladium on carbon (760 mg) was added. This mixture was stirred at room temperature under 4.5 kg hydrogen pressure for 4 h. After completion of the reaction, the reaction mixture was filtered through a bed of celite, and the bed was washed with a mixture of MeOH and DCM (1:9, 100 ml). The combined filtrate and washings were evaporated to give a solid. The solid was triturated with petroleum ether to give the title compound (800 mg) as a tan solid. Yield: 49%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 7.58 (d, J 3.2, 1H), 7.27 (dd, J 8.8, 3.2, 1H), 6.46 (d, J 8.8, 1H), 5.89 (bs, 2H), 3.48 (s, 2H), 3.27-3.22 (m, 2H), 3.48 (s, 2H), 3.18-3.13 (m, 2H).

Intermediate 46 : 1 -cyclopropyl- 4-(6 -nitropyridin- 3 -yl ) hexahydropyrazine: make 5-bromo-2-nitropyridine (5 g, 24.6 mmol), (hexahydropyridine Azin-1-yl)cyclopropane (3.73 g, 29.6 mmol) and potassium carbonate (5.11 g, 36.9 mmol) were suspended in DMSO (63.25 ml) and stirred at 90°C for 16 h. The reaction mixture was diluted with water (500 ml), extracted with DCM (2*200 ml), and the combined organic layer was washed with brine (100 ml) and water (100 ml), dried over anhydrous sodium sulfate and distilled under vacuum, A crude product is obtained. Purification by combi-flash using methanol and DCM (2:98) as eluents afforded the title compound (4 g) as a yellow solid. Yield: 65%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 8.16 (d, J 9.2, 1H), 8.13 (d, J 3.0, 1H), 7.20 (dd, J 9.2, 3.0 (1H), 3.42 (t , J 5.2, 4H), 2.78 (t, J 5.2, 4H), 1.72-1.65 (m, 1H), 0.55-0.49 (m, 2H), 0.48-0.42 (m, 2H).

Intermediate 47 : 5-(4- Cyclopropylhexahydropyrazin- 1 -yl ) pyridin -2- amine: Intermediate 46 (2.7 g, 11 mmol) was placed in an autoclave and dissolved in methanol (25 ml ) and ethanol (25 ml), and 5% palladium on carbon (1.08 g) was added. This mixture was stirred at room temperature under 4.5 kg hydrogen pressure for 4 h. After completion of the reaction, the reaction mixture was filtered through a bed of celite, and the bed was washed with a mixture of MeOH and DCM (1:9, 100 ml). The combined filtrate and washings were evaporated to give a solid. The solid was triturated with petroleum ether to give the title compound (2.1 g) as a gray solid. Yield: 88%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 7.56 (d, J 3, 1H), 7.13 (dd, J 9.2, 3, 1H), 6.37 (d, J 9.2, 1H), 5.36 (s, 2H), 2.85 (t, J 4.8, 4H), 2.62 (t, J 4.8, 4H), 1.62 (quintet, J 3.2, 1H), 0.45-0.38 (m, 2H), 0.32-0.26 (m , 2H).

Intermediate 48 : 1-(4-(6 -nitropyridin- 3 -yl ) hexahydropyrazin- 1 -yl ) ethan - 1 -one Intermediate 3 (1.50 g, 7.20 mmol) and triethylamine ( 729 mg, 7.20 mmol) was dissolved in DCM (30 ml) and stirred at 0 °C for 30 min. Acetyl chloride (679 mg, 8.64 mmol) was added to the above mixture and stirred at room temperature for 30 min. The reaction mixture was quenched with water (100 ml) and the organic and aqueous layers were separated. The aqueous layer was extracted with DCM (3*80 ml). The combined organic layers were distilled to obtain a solid. The solid was triturated with diethyl ether and filtered. The filtered solid was dried under vacuum to obtain the title compound (1.5 g) as a yellow solid. Yield: 83%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 8.25 (s, 1H), 8.18 (d, J 9.2, 1H), 7.48 (d, J 9.2, 1H), 3.60 (bs, 6H) , 3.52 (bs, 2H), 2.05 (s, 3H).

Intermediate 49 : 1-(4-(6 -Aminopyridin- 3 -yl ) hexahydropyrazin- 1 -yl ) ethan - 1 -one: Intermediate 48 (1.50 g, 5.99 mmol) was placed in autoclave and dissolved in a mixture of methanol (13 ml) and ethanol (13 ml), and 5% palladium on carbon (600 mg) was added. This mixture was stirred at room temperature under 4.5 kg hydrogen pressure for 24 h. After the reaction was complete, the reaction mixture was filtered through a bed of celite, and the bed was washed with a mixture of MeOH and DCM (1:9, 170 ml). The combined filtrate and washings were evaporated to give a solid. The solid was triturated with diethyl ether to give the title compound (1 g) as a gray solid. Yield: 80%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 7.60 (d, J 3.0, 1H), 7.17 (dd, J 8.8, 3.0, 1H), 6.39 (d, J 8.8, 1H), 5.44 (s, 2H), 3.53 (q, J 5, 4H), 2.89 (t, J 5, 2H), 2.82 (, J 5, 2H), 2.00 (s, 3H).

Intermediate 50 : 1-(6 -nitropyridin- 3 -yl )-4-(2,2,2- trifluoroethyl ) hexahydropyrazine: make 5-bromo-2-nitropyridine (1.5 g , 7.4 mmol), 1-(2,2,2-trifluoroethyl) hexahydropyrazine (1.5 g, 8.9 mmol) and potassium carbonate (1.5 g, 11 mmol) were suspended in DMSO (20 ml), and Stir at 90 °C for 16 h. The reaction mixture was diluted with water (200 ml), extracted with DCM (2*200 ml), and the combined organic layer was washed with brine (100 ml) and water (100 ml), dried over anhydrous sodium sulfate and distilled under vacuum, A crude product is obtained. Purification by combi-flash using methanol and DCM (2.5:97.5) as eluents gave the title compound (1.1 g) as a yellow solid. Yield: 51%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 8.17 (d, J 9.2, 1H), 8.14 (d, J 3.0, 1H), 7.22 (d, J 9.2, 3.2, 1H), 3.48 (t , J 5, 4H), 3.08 (q, J 9.6, 2H), 2.87 (t, J 5, 4H).

Intermediate 51 : 5-(4-(2,2,2- trifluoroethyl ) hexahydropyrazin- 1 -yl ) pyridin -2- amine: Intermediate 50 (1.1 g, 3.8 mmol) was placed under high pressure in a kettle and dissolved in a mixture of methanol (10 ml) and ethanol (10 ml) and 5% palladium on carbon (440 mg) was added. This mixture was stirred at room temperature under 4.5 kg hydrogen pressure for 4 h. After completion of the reaction, the reaction mixture was filtered through a bed of celite, and the bed was washed with a mixture of MeOH and DCM (1:9, 100 ml). The combined filtrate and washings were evaporated to give the title compound (800 mg) as a tan solid. Yield: 81%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 7.60 (d, J 2.5, 1H), 7.16 (dd, J 8.8, 3.0, 1H), 6.40 (d, J 8.8, 1H), 5.39 (s, 2H), 3.23 (q, J 10, 2H), 2.92 (t, J 5, 4H), 2.74 (t, J 5, 4H).

Intermediate 52 : 1-( Methylsulfonyl )-4-(6 -nitropyridin- 3 -yl ) hexahydropyrazine: Intermediate 3 (1.50 g, 7.20 mmol) and triethylamine (729 mg , 7.20 mmol) was dissolved in DCM (30 ml) and stirred at 0 °C for 30 min. Methanesulfonyl chloride (990 mg, 8.64 mmol) was added to the above mixture and stirred at room temperature for 30 min. The reaction mixture was quenched with water (100 ml) and the organic and aqueous layers were separated. The aqueous layer was extracted with MeOH:DCM (1:9) (2*100 ml). The combined organic layers were distilled to obtain a solid. The solid was triturated with diethyl ether and filtered. The filtered solid was dried under vacuum to obtain the title compound (1.8 g) as a yellow solid. Yield: 87%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 8.31 (d, J 2.8, 1H), 8.19 (d, J 9.2, 1H), 7.55 (dd, J 9.2, 2.8, 1H), 3.65 (t, J 5, 4H), 3.26 (t, J 5, 4H), 2.93 (s, 3H).

Intermediate 53 : 5-(4-(Methylsulfonyl ) hexahydropyrazin - 1 -yl ) pyridin -2- amine: Intermediate 53 (1.7 g, 5.94 mmol) was placed in an autoclave and dissolved in In a mixture of methanol (13 ml) and ethanol (13 ml), and 5% palladium on carbon (600 mg) was added. This mixture was stirred at room temperature under 4.5 kg hydrogen pressure for 4 h. After the reaction was complete, the reaction mixture was filtered through a bed of celite, and the bed was washed with a mixture of MeOH and DCM (1:9, 170 ml). The combined filtrate and washings were evaporated to give a solid. The solid was triturated with diethyl ether to afford the title compound (1.3 g) as a tan solid. Yield: 85%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 7.64 (d, J 2.8, 1H), 7.20 (d, J 8.8, 2.8, 1H), 6.41 (d, J 8.8, 1H), 5.47 (s, 2H), 3.22 (t, J 4.8, 4H), 3.00 (t, J 4.8, 4H), 2.91 (s, 3H).

Intermediate 54 : Cyclopropyl (4-(6 -nitropyridin- 3 -yl ) hexahydropyrazin- 1 -yl ) methanone : Step-1: Cyclopropylcarboxylic acid (744 mg, 8.64 mmol) was dissolved in DCM (10 ml) and cooled to 0 °C. Oxalyl chloride (1.37 g, 10.8 mmol) and DMF (0.05 ml) were added to the above solution and stirred at room temperature for 2 h. After 2 h, the reaction mixture was distilled off to obtain cyclopropylcarbonyl chloride, which was used in the next step without further purification. Step-2: Intermediate 3 (1.50 g, 7.20 mmol) and triethylamine (1.09 g, 10.8 mmol) were dissolved in DCM (10 ml) and stirred at 0 °C for 30 min. Cyclopropylcarbonyl chloride was added to the above mixture by dissolving in DCM (10 ml) and stirred at room temperature for 30 min. The reaction mixture was quenched with aqueous NaHCO ₃ pH up to about 7 and the organic and aqueous layers were separated. The aqueous layer was extracted with DCM (2*100 ml). The combined organic layers were distilled to obtain a solid. The solid was triturated with diethyl ether and filtered. The filtered solid was dried under vacuum to obtain the title compound (1.6 g) as a yellow solid. Yield: 80%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 8.25 (d, J 2.8, 1H), 8.17 (d, J 9.2, 1H), 7.47 (dd, J 9.2, 2.8, 1H), 3.91-3.80 (m, 2H), 3.70-3.49 (m, 6H), 2.05-1.95 (m, 1H), 0.80-0.68 (m, 4H).

Intermediate 55 : (4-(6 -aminopyridin- 3 -yl ) hexahydropyrazin- 1 -yl )( cyclopropyl ) methanone : Intermediate 54 (1.5 g, 5.43 mmol) was placed in autoclave and dissolved in a mixture of methanol (12 ml) and ethanol (12 ml), and 5% palladium on carbon (600 mg) was added. This mixture was stirred at room temperature under 4 kg hydrogen pressure for 5 h. After the reaction was complete, the reaction mixture was filtered through a bed of celite, and the bed was washed with a mixture of MeOH and DCM (1:9, 170 ml). The combined filtrate and washings were evaporated to give a solid. The solid was triturated with diethyl ether to afford the title compound (1.1 g) as a pink solid. Yield: 82%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 7.63 (d, J 2.4, 1H), 7.20 (dd, J 8.8, 2.4, 1H), 6.41 (d, J 8.8, 1H), 5.45 (s, 2H), 3.78 (bs, 2H), 3.57 (bs, 2H), 3.00-2.80 (m, 4H), 2.05-2.97 (m, 1H), 0.80-0.65 (m, 4H).

Intermediate 56 : 7-(6 -nitropyridin- 3 -yl )-3-( trifluoromethyl )-5,6,7,8- tetrahydro- [1,2,4] triazolo [4 ,3-a] pyrazine : make 5-fluoro-2-nitropyridine (4.04 g, 19.9 mmol), 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2 ,4] Triazolo[4,3-a]pyrazine (5 g, 26 mmol) and DIPEA (10.1 g, 78.1 mmol) were suspended in DMF (37 ml) and stirred at 120°C for 16 h. The reaction mixture was quenched with water (100 ml). The aqueous layer was extracted with MeOH:DCM (1:9) (3*100 ml). The combined organic layers were distilled off to obtain a crude product. The crude was purified by combi-flash using MeOH and DCM (2.2:97.8) as eluents to obtain the title compound (2.7 g) as a yellow solid. Yield: 33%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 8.43 (d, J 3.0, 1H), 8.21 (d, J 9.2, 1H), 7.70 (dd, J 9.2, 3.0, 1H), 5.04 (s, 2H), 4.33 (t, J 5.2, 2H), 4.09 (t, J 5.2, 2H).

Intermediate 57 : 5-(3-( trifluoromethyl )-5,6 -dihydro- [1,2,4] triazolo [4,3-a] pyrazin -7(8H) -yl ) Pyridin -2- amine : Intermediate 56 (1.1 g, 4.16 mmol) was placed in an autoclave and dissolved in a mixture of methanol (9 ml) and ethanol (9 ml), and 5% palladium on carbon (440 mg ). This mixture was stirred at room temperature under 4 kg hydrogen pressure for 5 h. After the reaction was complete, the reaction mixture was filtered through a bed of celite, and the bed was washed with a mixture of MeOH and DCM (1:9, 170 ml). The combined filtrate and washings were evaporated to give a solid. The solid was triturated with diethyl ether to afford the title compound (840 mg) as a tan solid. Yield: 86%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 7.75 (d, J 2.8, 1H), 7.31 (dd, J 9.2, 2.8, 1H), 6.43 (d, J 9.2, 1H), 5.57 (s, 2H), 4.42 (s, 2H), 4.22 (t, J 5.2, 2H), 3.51 (t, J 5.2, 2H).

Intermediate 58 : 4- methyl- 1-(6 -nitropyridin- 3 -yl ) hexahydropyridin- 4 - ol : 5-bromo-2-nitropyridine (2.18 g, 12.9 mmol), 4- Methylpyrimidin-4-ol (1.48 g, 12.9 mmol) and potassium carbonate (2.23 g, 16.1 mmol) were suspended in DMSO (14 ml) and stirred at 90°C for 16 h. The reaction mixture was diluted with water (200 ml), extracted with DCM (2*200 ml), and the combined organic layer was washed with brine (100 ml) and water (100 ml), dried over anhydrous sodium sulfate and distilled under vacuum, A crude product is obtained. Purification by combi-flash using methanol and DCM (2.5:97.5) as eluents afforded the title compound (1.1 g) as a yellow solid. Yield: 51%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 8.23 (d, J 2.8, 1H), 8.10 (d, J 9.6, 1H), 7.44 (dd, J 9.6, 2.8, 1H), 4.47 (s , 1H), 3.79-3.70 (m, 2H), 3.41-3.31 (m, 2H), 1.59-1.48 (m, 4H), 1.14 (s, 3H). MS (m/z): 238.16 ( _M +H); Calcd. for _{[ C11H15N3O3} +H]: _238.11 .

Intermediate 59 : 1-(6 -Aminopyridin- 3 -yl )-4 - methylhexahydropyridin- 4- ol: Intermediate 58 (900 mg, 3.79 mmol) was placed in autoclave and dissolved in methanol (10 ml) and ethanol (10 ml), and 5% palladium on carbon (440 mg) was added. This mixture was stirred at room temperature under 4 kg hydrogen pressure for 5 h. After completion of the reaction, the reaction mixture was filtered through a bed of celite, and the bed was washed with a mixture of MeOH and DCM (1 :9, 2000 ml). The combined filtrate and washings were evaporated to give a solid. The solid was triturated with diethyl ether to afford the title compound (700 mg) as a tan solid. Yield: 89%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 7.59 (d, J 2.8, 1H), 7.14 (dd, J 9.6, 3.0, 1H), 6.36 (d, J 8.8, 1H), 5.31 (s, 2H), 4.20 (s, 1H), 2.96-2.85 (m, 4H), 1.57-1.50 (m, 4H), 1.12 (s, 3H). MS (m/z): 208.16 (M+H); Calcd. for _{[ C11H17N3O} +H]: _208.28 .

Intermediate 60 : (±)-1-(6- bromo -8- fluoro -2 -methylquinolin- 4 -yl ) ethan - 1 -amine: Intermediate 15 (200 g, 0.708 mol) was suspended in 2 M methanolic ammonia (1.88 lt, 3.75 mol). To this mixture was added titanium(IV) isopropoxide (403 g, 1.42 mol) and stirred at room temperature for 16 h. After 16 h, the reaction mixture was cooled to 0 °C and sodium borohydride (40.23 g, 1.06 mol) was added, warmed to room temperature and stirred at room temperature for 5 h. After 5 h, the reaction mixture was quenched with ammonia (2 lt) and EtOAc (2 lt) to obtain a solid. The solid was filtered and washed with EtOAc (10 lt). The combined filtrates were washed with water (3 lt) and brine (2.5 lt). The aqueous layer was extracted with EtOAc (8 lt). The combined EtOAc layers were distilled off to obtain crude. The crude was co-distilled with (3*100 ml) toluene to obtain a solid. The solid was stirred with diethyl ether (1 lt) and the solid was filtered. The solid was dried under vacuum to obtain the title compound (120.5 g) as a tan solid. Yield: 60%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 8.22 (s, 1H), 7.81 (dd, J 10.4, 4, 1H), 7.73 (s, 1H), 4.70 (t, J 6.8, 1H), 2.66 (s, 3H), 2.09 (bs, 2H), 1.34 (d, J 6.8, 3H). MS (m/z): _283.17 (M+H); Calcd. for [ _{C12H12BrFN2 +} H]: 284.02.

Intermediate 61 : tert-butyl (±)-(1-(6- bromo -8- fluoro -2 -methylquinolin- 4 -yl ) ethyl ) carbamate: Intermediate 60 (16 g , 56.5 mmol) was dissolved in DCM (160 ml) and cooled to 0 °C. To this solution was added triethylamine (8.58 g, 84.76 mmol). Boc anhydride (14.8 g, 67.8 mmol) was added to this mixture and stirred at room temperature for 2 h. After 2 h, the reaction mixture was diluted with water (900 ml) and the organic layer was separated. The aqueous layer was extracted again with a mixture of MeOH and DCM (1:9) (3*500 ml). The combined organic layers were washed with water (2*500 ml) and aqueous sodium bicarbonate (3*500 ml). The organic layer was dried _over anhydrous _Na2SO4 and distilled to obtain the title compound (20.8 g) as an off-white solid. It was used in the next step without further purification. Yield: 96%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 8.22 (s, 1H), 7.86 (dd, J 10.4, 2, 1H), 7.71 (d, J 7.6, 1H), 7.47 (s, 1H), 5.31 (t, J 7.2, 1H), 2.65 (s, 3H), 1.40 (d, J 7.2, 1H), 1.37 (s, 9H). MS (m/z): 383.18 ( _{M +} H); Calcd. for [ _{C17H20BrFN2O2 +} H]: 383.07.

Intermediate 62 : (±)-(1-(8- fluoro -2- methyl -6-(4,4,5,5 -tetramethyl- 1,3,2- dioxaborolane -2- yl ) quinolin- 4 -yl ) ethyl ) carbamate tert-butyl ester: The title compound was synthesized from Intermediate 61 (18 g, 47 mmol) following General Procedure-1. After work-up, the crude product was purified by combi-flash using EtOAc and petroleum ether (20:80) as eluents to obtain the title compound (15.2 g) as a light yellow solid. Yield: 75.2%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 8.22 (s, 1H), 7.74 (d, J 7.6, 1H), 7.58 (d, J 10.8, 1H), 7.50 (s, 1H) , 5.38 (t, J 6.8, 1H), 2.68 (s, 3H), 1.41 (d, J 6.8, 3H), 1.37 (s, 12 H), 1.15 (s, 9H). MS (m/z): 431.30 (M ₊ H); Calcd. for [ _{C23H32BFN2O4 +} H]: _431.33 .

Intermediate 63 : (±)-(1-(6-(2- chloro -5- fluoropyrimidin - 4 -yl )-8- fluoro -2 -methylquinolin- 4 -yl ) ethyl ) carbamate Tert-butyl ester: The title compound was synthesized from Intermediate 62 (15 g, 34.86 mmol) and 2,4-dichloro-5-fluoropyrimidine (6.98 g, 41.83 mmol) following General Procedure-2. After the reaction was complete, the reaction mixture was cooled to room temperature and stirred for 16 h to obtain a solid. The solid was filtered, washed with a mixture of dioxane and water (1:1) (50 ml) and petroleum ether (100 ml). The solid was co-distilled with toluene (2*100 ml) at 65°C on a rotary evaporator. The solid was stirred with a mixture of diethyl ether and petroleum ether (1:1) (100 ml) for 30 min. The solid was filtered and washed with petroleum ether and diethyl ether mixture (1 :1 ) (50 ml). The solid was dried under vacuum to obtain the title compound (10 g) as a white solid. Yield: 67%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.07 (d, J 3.2, 1H), 8.62 (s, 1H), 8.06 (d, J 11.2, 1H), 7.79 (d, J 3.2 , 1H), 7.58 (s, 1H), 5.41 (t, J 6.8, 1H), 2.73 (s, 3H), 1.46 (d, J 6.8, 3H), 1.37 (s, 9H). MS (m/z): _435.24 (M ₊ H); Calcd. for [ _{C21H21ClF2N4O2 +} H]: _435.13 .

Intermediate 64 : 6- Bromo -8- fluoroquinoline- 2,4- dicarboxylic acid: Intermediate 12 (1 g, 4.10 mmol) was suspended in potassium hydroxide (10 g, 40.98 mmol) in water (360 ml) solution in , and sodium pyruvate (6.76 mg, 61.5 mmol) was added. This mixture was stirred at 50 °C for 16 h. The reaction mixture was cooled to 25 °C and the pH was adjusted to about 3 using 6 N HCl to obtain a solid. The solid was filtered and washed with water (200 ml) and dried in an oven at 70 °C for 6 h to obtain the title compound (8.2 g) as a tan solid. Yield: 64%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 14.01 (bs, 2H), 8.89 (s, 1H), 8.57 (s, 1H), 8.11 (dd, J 10, 1.6, 1H). MS (m/z): 314.08 (M+H); Calcd. for [ _{C11H5BrFNO4 +} H]: _313.94 .

Intermediate 65 : 6- Bromo -8- fluoroquinoline- 4 - carboxylic acid: Intermediate 64 (8 g, 25.5 mmol) was suspended in nitrobenzene (80 ml) and heated to 220 °C for 5 h. After 5 h, the reaction mixture was cooled to room temperature and diluted with petroleum ether (320 ml) to obtain a solid. This mixture was stirred for 1 h and the solid was filtered. The solid was washed with petroleum ether (80 ml). The solid was dried under vacuum for 1 h to obtain the title compound (6.1 g) as a light brown solid. Yield: 89%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 14.21 (s, 1H), 9.12 (d, J 4.4, 1H), 8.81 (s, 1H), 8.10 (d, J 4.4, 1H) , 8.00 (dd, J 10, 2, 1H).

Intermediate 66 : 6- Bromo -8- fluoro -N- methoxy- N -methylquinoline- 4 -formamide : Intermediate 65 (3 g, 11.1 mmol), HATU (6.34 g, 16.7 mmol ) and DIPEA (5.74 g, 44.4, mmol) were dissolved in DMF (30 ml). N,O-Dimethylhydroxylamine hydrochloride (2.17 g, 22.2 mmol) was added to the reaction mixture and stirred at room temperature for 16 h. After 16 h, the reaction mixture was diluted with water (150 ml) and extracted with EtOAc (3*70 ml). The combined organic layers were washed with aqueous NaHCO ₃ (3*100 ml) and brine (100 ml). The organic layer was distilled to obtain a crude product. The crude was suspended in a mixture of diethyl ether and petroleum ether (1 :1 ) (40 ml) and stirred for 30 min to obtain a solid. The solid was filtered and washed with diethyl ether and petroleum ether (1:1) (20 ml). The solid was dried under vacuum to obtain the title compound (2.5 g) as a light brown solid. Yield: 72%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.06 (d, J 4, 1H), 8.00 (dd, J 10, 1, 1H), 7.81 (t, J 1.6, 1H), 7.77 (d, J 4, 1H), 3.41 (bs, 6H). MS (m/z): 313.15 (M ₊ H); Calcd. for [ _{C12H10BrFN2O2 +} H]: _312.99 .

Intermediate 67 : 1-(6- Bromo -8- fluoroquinolin- 4 -yl ) ethan - 1 -one: Intermediate 66 (2.5 g, 7.98 mmol) was dissolved in THF (25 ml) and cooled to 0 ℃. Methylmagnesium chloride (3 M in THF, 24.53 ml, 12 mmol) was added slowly. The mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with aqueous NH ₄ Cl and extracted with EtOAc (2*25 ml). The organic layer was washed successively with water (25 ml) and brine solution (25 ml), dried _over anhydrous _Na2SO4 and distilled to obtain crude product. Purification by combi-flash using EtOAc and petroleum ether (14:86) as eluents afforded the title compound (900 mg) as an off-white solid. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.17 (d, J 4.4, 1H), 8.46 (s, 1H), 8.15 (d, J 4.4, 1H), 8.01 (dd, J 10 .1.6, 1H), 2.76 (s, 3H). MS (m/z): 268.15 (M+H); Calcd. for [ _C11H7BrFNO +H]: _267.97 .

Intermediate 68 : (±)-1-(6- bromo -8- fluoroquinolin- 4 -yl ) ethan - 1 -amine : Intermediate 67 (900 mg, 3.4 mmol) was suspended in 2 M methanolic ammonia (8.4 ml, 17mol). To this mixture was added titanium(IV) isopropoxide (1.9 g, 6.7 mol) and stirred at room temperature for 16 h. After 16 h, the reaction mixture was cooled to 0 °C and sodium borohydride (190 mg, 5.03 mol) was added, warmed to room temperature and stirred at room temperature for 5 h. After 5 h, the reaction mixture was quenched with ammonia (9 ml) and EtOAc (25 ml) to obtain a solid. The solid was filtered and washed with EtOAc (25 ml). The combined filtrates were washed with water (100 ml) and brine (100 ml). The aqueous layer was extracted with EtOAc (2*30 ml). The combined EtOAc layers were distilled off to obtain crude. The crude was purified by combi-flash using MeOH and DCM (3:97) as eluents to afford the title compound (500 mg) as an off-white solid. Yield: 55%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 8.94 (d, J 4.4, 1H), 8.30 (s, 1H), 7.88 (dd, J 10, 1.6, 1H), 7.85 (d, J 4.4, 1H), 4.76 (q, J 6.4, 1H), 1.34 (d, J 6.8, 3H). MS (m/z): 269.16 (M+H); Calcd. for [ _{C11H10BrFN2 +} H]: _270.12 .

Intermediate 69 : tert-butyl (±)-(1-(6- bromo -8- fluoroquinolin- 4 -yl ) ethyl ) carbamate: Intermediate 68 (2.1 g, 7.8 mmol) was dissolved in DCM (21 ml) and cooled to 0 °C. To this solution was added triethylamine (1.18 g, 11.7 mmol). Boc anhydride (2.04 g, 9.36 mmol) was added to this mixture and stirred at room temperature for 2 h. After 2 h, the reaction mixture was diluted with water (100 ml) and the organic layer was separated. The aqueous layer was extracted again with DCM (3*70 ml). The combined organic layers were washed with water (100 ml) and aqueous sodium bicarbonate (3*100 ml). The organic layer was dried _over anhydrous _Na2SO4 and distilled to obtain the title compound (2.8 g) as an off-white solid. It was used in the next step without further purification. Yield: 97%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 8.96 (d, J 4.4, 1H), 8.31 (s, 1H), 7.92 (dd, J 10, 1.6, 1H), 7.78 (d, J 7.6, 1H), 7.61 (d, J 4.4, 1H), 5.36 (t, J 6.8, 1H), 1.40 (d, J 6.8, 3H), 1.37 (s, 9H). MS (m/z): 369.12 (M ₊ H); Calcd. for [ _{C16H18BrFN2O2 +} H]: _369.05 .

Intermediate 70 : (±)-(1-(8- fluoro -6-(4,4,5,5 -tetramethyl- 1,3,2-dioxaborolan - 2- yl ) Quinolin- 4 -yl ) ethyl ) carbamate tert-butyl: The title compound was synthesized from Intermediate 69 (2.8 g, 7.58 mmol) following General Procedure-1. After work-up, the crude product was purified by combi-flash using EtOAc and petroleum ether (23:77) as eluents to obtain the title compound (1.7 g) as a pale yellow solid. Yield: 94%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 8.99 (d, J 4.4, 1H), 8.29 (s, 1H), 7.81 (d, J 7.6, 1H), 7.64 (d, J 7.2 , 1H), 7.62 (s, 1H), 5.42-5.33 (m, 1H), 1.43 (d, J 6.8, 3H), 1.37 (s, 12 H), 1.35 (s, 9H). MS (m/z): 417.32 (M ₊ H); Calcd. for [ _{C22H30BFN2O4 +} H]: _417.23 .

Intermediate 71 : (±)-tert-butyl(1-(6-(2- chloro -5- fluoropyrimidin - 4 -yl )-8- fluoroquinolin- 4 -yl ) ethyl ) carbamate : The title compound was synthesized from Intermediate 70 (1.7 g, 4.08 mmol) and 2,4-dichloro-5-fluoropyrimidine (818 mg, 4.9 mmol) following General Procedure-2. After completion of the reaction, water (100 ml) was added to the reaction mixture and extracted with DCM (3*70 ml). The organic layer was washed with water (100 ml) and distilled to obtain a crude material. The crude was purified by combi-flash using EtOAc and petroleum ether (27:63) as eluents to afford the title compound (600 mg) as an off-white solid. Yield: 30%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.09 (d, J 3.2, 1H), 9.07 (d, J 4.4, 1H), 8.68 (s, 1H), 8.11 (d, J 11.2 , 1H), 7.84 (d, J 7.6, 1H), 7.70 (d, J 4.4, 1H), 5.49-5.38 (m, 1H), 1.47 (d, J 7, 3H), 1.36 (s, 9H). MS (m/z): 421.11 (M ₊ H) _; Calcd. for [ _{C20H19ClF2N4O2 +} H]: _421.12 .

Intermediate 72 : (±)-1-(6- bromo -8- fluoroquinolin- 4 -yl ) ethanol: Intermediate 67 (10 g, 37.3 mmol) was dissolved in MeOH (100 ml) and THF (100 ml ) in the mixture. To this mixture was added NaBH4 ₍ 7.05 g, 186.5 mmol), and this mixture was refluxed for 3 h. After 3 h, the reaction mixture was cooled to room temperature and water (500 ml) was added. The aqueous layer was extracted with EtOAc (3*300 ml). The combined organic layers were washed with water (100 ml) and brine (100 ml). The organic layer was distilled under reduced pressure to obtain a solid. The solid was suspended in diethyl ether (50 ml) and stirred for 30 min. After 30 min, the solid was filtered and washed with diethyl ether (20 ml). The solid was dried under vacuum to obtain the title compound (9 g) as a yellow solid. Yield: 89%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 8.96 (d, J 4.4, 1H), 8.28 (s, 1H), 7.89 (d, J 10, 1H), 7.74 (d, J 4.4 , 1H), 5.69 (d, J 4.4, 1H), 5.50-5.43 (m, 1H), 1.45 (d, J 6.4, 3H). MS (m/z): 270.21 (M+H); Calcd. for [ _C11H9BrFNO +H]: _269.99 .

Intermediate 73 : (±)-1-(8- fluoro -6-(4,4,5,5 -tetramethyl- 1,3,2-dioxaborolan - 2- yl ) quinone Phenyl- 4 -yl ) ethanol : The title compound was synthesized from Intermediate 72 (3.6 g, 13.3 mmol) following General Procedure-1. After work-up, the crude product was purified by combi-flash using EtOAc and petroleum ether (35:65) as eluents to obtain the title compound (900 mg) as an off-white solid. Yield: 21%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 8.98 (d, J 4.8, 1H), 8.34 (s, 1H), 7.73 (d, J 4.8, 1H), 7.61 (d, J 10 , 1H), 5.68 (d, J 4.8, 1H), 5.50-5.42 (m, 1H), 1.49 (d, J 6.4, 3H), 1.35 (s, 12H). MS (m/z): 318.40 ( _M +H); Calcd. for [ _C17H21BFNO3 +H]: _318.16 .

Intermediate 74 : (±)-1-(6-(2- Chloro -5- fluoropyrimidin - 4 -yl )-8- fluoroquinolin- 4 -yl ) ethanol: following General Procedure-2, from Intermediate 73 (900 mg, 2.84 mmol) and 2,4-dichloro-5-fluoropyrimidine (474 mg, 2.84 mmol) to synthesize the title compound. After completion of the reaction, the reaction mixture was stirred at room temperature for 16 h to obtain a solid. The solid was filtered and washed with a mixture of dioxane and water (1 :1 ) (17 ml) and petroleum ether (100 ml). The solid was co-distilled with toluene at 65 °C. The solid was suspended in diethyl ether (20 ml) and stirred for 30 min. After 30 min, the solid was filtered and washed with diethyl ether (20 ml). The solid was dried under vacuum to afford the title compound (600 mg) as an off-white solid. Yield: 66%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.07 (d, J 3.2, 1H), 9.06 (d, J 4.4, 1H), 8.76 (s, 1H), 8.09 (d, J 11.6 , 1H), 7.82 (d, J 4.4, 1H), 5.79 (d, J 4, 1H), 5.53-5.45 (m, 1H), 1.53 (d, J 6.4, 3H). MS (m/z): _322.25 ( _{M +} H) _; Calcd. for [C15H10ClF2N3O+H]: 322.05.

Intermediate 75 : (±)-1-(6- bromo -8- fluoro -2 -methylquinolin- 4 -yl ) ethan - 1 - ol: To Intermediate 15 (2.7 g, 9.57 mmol) in methanol ( 27 ml) in a mixture of THF (27 ml) was added portionwise with sodium borohydride (50.8, 1.34 mol). The reaction mixture was stirred at 80 °C for 3 h. The mixture was cooled to 25 °C, diluted with water (150 ml) and the aqueous layer was extracted with EtOAc (3*80 ml). The combined organic layers were washed with water (100 ml) and brine (100 ml). The organic layer was distilled to obtain a crude product. The crude was stirred with petroleum ether (40 ml) for 30 min to obtain a solid. The solid was filtered and washed with petroleum ether (20 ml). The solid was dried under vacuum to afford the title compound (2.3 g) as an off-white solid. Yield: 85%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 8.20 (s, 1H), 7.83 (dd, J 10.4, 2, 1H), 7.61 (s, 1H), 5.65 (d, J 4.4, 1H), 5.43-5.35 (m, 1H), 2.66 (s, 3H), 1.43 (d, J 6.4, 3H). MS (m/z): 284.20 (M+H); Calcd. for [ _C12H11BrFNO +H]: _285.13 .

Intermediate 76 : (±)-1-(8- fluoro -2- methyl -6-(4,4,5,5 -tetramethyl- 1,3,2 - dioxaborolane- 2- yl ) quinolin- 4 -yl ) ethan - 1 - ol: The title compound was synthesized from Intermediate 75 (2.3 g, 8.10 mmol) following General Procedure-1. After work-up, the crude product was purified by combi-flash using EtOAc and petroleum ether (35:65) as eluents to obtain the title compound (1 g) as an off-white solid. Yield: 37%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 8.27 (s, 1H), 7.60 (s, 1H), 7.56 (d, J 10.8, 1H), 5.64 (bs, 1H), 5.43- 5.41 (m, 1H), 2.69 (s, 3H), 1.47 (d, J 6.4, 3H), 1.34 (s, 12H). MS (m/z): 332.36 ( _M +H); Calcd. for [ _C18H23BFNO3 +H]: _332.19 .

Intermediate 77 : (±)-1-(6-(2- chloro -5- fluoropyrimidin - 4 -yl )-8- fluoro -2 -methylquinolin- 4 -yl ) ethan - 1 - ol: follow General Procedure-2, The title compound was synthesized from Intermediate 76 (950 mg, 2.9 mmol) and 2,4-dichloro-5-fluoropyrimidine (570 mg, 3.4 mmol). After the reaction was complete, the reaction mixture was cooled to room temperature and water was added to obtain a solid. The solid was filtered and washed with a mixture of dioxane and water (1 :1 ) (10 ml). The solid was further washed with petroleum ether (20 ml). The solid was stirred with diethyl ether (20 ml). The solid was filtered and washed with diethyl ether. The solid was stirred with diethyl ether (20 ml) for another 30 min and the solid was filtered. The solid was dried to obtain the title compound (670 mg) as an off-white solid. Yield: 70%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.05 (s, 1H), 8.69 (s, 1H), 8.04 (d, J 10, 1H), 7.69 (s, 1H), 5.76 ( s, 1H), 5.50-5.40- (m, 1H), 2.73 (s, 3H), 1.51 (d, J 6.4, 3H). MS (m/z): 336.27 (M+H); Calcd. for _{[ C16H12ClF2N3O +} H]: _336.74 .

Intermediate 78 : 8- fluoro - 4 - isopropyl- 2- methyl -6-(4,4,5,5 -tetramethyl- 1,3,2-dioxaborolane - 2 -yl ) quinoline: Intermediate 17 (1.8 g, 5.5 mmol ) was dissolved in MeOH (90 ml) and EtOH (90 ml). To this mixture was added 5% Pd/C (720 mg) and stirred in an autoclave reactor under 1 KG hydrogen atmosphere for 2 h. After 2 h, the reaction mixture was filtered on a bed of celite, and the bed was washed with a mixture of MeOH and DCM (1:9) (200 ml). The combined filtrates were distilled to obtain a crude material. The crude was purified by combi-flash using EtOAc and petroleum ether (8:92) as eluents to afford the title compound (1.35 g) as an off-white solid. Yield: 75%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 8.29 (s, 1H), 7.70 (d, J 10.8, 1H), 7.25 (d, J 5.2, 1H), 3.81 (septet, J 6.4, 1H), 2.77 (s, 3H), 1.39 (s, 6H), 1.37 (s, 12H).

Intermediate 79 : 6-(2- Chloro -5- fluoropyrimidin - 4 -yl )-8- fluoro - 4 - isopropyl- 2 -methylquinoline: following general procedure-2, from Intermediate 78 (1.3 g, 3.95 mmol) and 2,4-dichloro-5-fluoropyrimidine (791 mg, 4.74 mmol) to synthesize the title compound. After the reaction was completed, the precipitated product in the reaction mass was filtered. The solid was dried under vacuum for 2 h to obtain the title compound (1.1 g) as an off-white solid. Yield: 83%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 8.70 (s, 1H), 8.59 (d, J 2.8, 1H), 8.16 (d, J 12.4, 1H), 7.33 (s, 1H), 3.76 (Septet, J 6.8, 1H), 2.81 (s, 3H), 1.43 (s, 6H).

Intermediate 80 : methyl 6- bromo -8- fluoroquinoline- 4 -carboxylate Add sulfuric acid (6 mL, 0.1 mmol) to a solution of intermediate 65 (6 g, 22.2 mmol) in methanol (6 ml) , and the mixture was refluxed for 16 h. Methanol was removed by distillation, and the residue was dissolved in water (600 ml). The aqueous layer was extracted with EtOAc (3*300 ml), and the organic layer was washed with saturated aqueous NaHCO ₃ (300 ml), then water (200 ml) and brine (200 ml). The organic layer was distilled to obtain a crude product. The crude product was purified by combi-flash using EtOAc and petroleum ether (5:95) as eluents to obtain the title compound (4.5 g) as a yellow solid. Yield: 71%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.08 (d, J 4.4, 1H), 8.60 (t, J 1.6, 1H), 8.03 (d, J 4.4, 1H), 7.63 (dd , J 9.2, 2, 1H), 4.06 (s, 3H). MS (m/z): 284.15 (M+H); Calcd. for [ _{C11H7BrFNO2 +} H]: _283.96 .

Intermediate 81 : 2-(6- Bromo -8- fluoroquinolin- 4 -yl ) propan -2- ol: 2 M methylmagnesium bromide in THF at 0 °C (46 mL, 93 mmol ) was slowly added to a solution of Intermediate 80 (3.3 g, 12 mmol) in THF (51.2 mL) and stirred at the same temperature for 2 h. Saturated aqueous ammonium chloride (50 mL) was added to the mixture and extracted into ethyl acetate (200 mL). The organic layer was washed successively with water (100 mL) and brine (200 mL), dried over sodium sulfate and evaporated to give a residue, which was purified by silica gel column chromatography on a combi-flash system using ethyl acetate-hexane (15: 85) The residue was purified by elution to give the title compound (1.5 g) as an off-white solid. Yield: 46%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 8.98 (s, 1H), 8.89 (d, J 4.4, 1H), 7.86 (dd, J 10, 2, 1H), 7.61 (d, J 4.4, 1H), 5.72 (s, 1H), 1.65 (s, 6H). MS (m/z): _284.25 (M+H); Calcd. for [ _C12H11BrFNO +H]: 284.00.

Intermediate 82 : (8- Fluoro - 4-(2 -hydroxypropan- 2- yl ) quinolin -6- yl ) boronic acid: Triisopropyl borate (8.1 mL, 35.0 mmol) was added dropwise to 2-(6-bromo-8-fluoro-2-methylquinolin-4-yl)propan-2-ol (Intermediate 81, 5.1 g, 17 mmol) in anhydrous THF (176 mL ) solution. A solution of 2.5 M n -Buli in hexane (8.1 mL, 35 mmol) was added dropwise to the above mixture and stirred at the same temperature for 2 hours. The mixture was allowed to warm to room temperature and acidified with 2 N HCl, stirred for 30 min, neutralized by addition of 10% aqueous NaOH, stirred for 20 min, and extracted into ethyl acetate (2*100 mL). The combined organic layers were washed successively with water (100 mL) and brine (100 mL), dried over sodium sulfate and concentrated. The residue was stirred with petroleum ether (10 mL) for 20 min, and the solid formed was filtered and dried. Off-white solid (3.0 g). Yield: 68%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 8.94 (s, 1H), 8.86 (d, J 4.4, 1H), 8.37 (s, 2H), 7.80 (d, J 11.6, 1H) , 7.67 (d, J 4.4, 1H), 5.54 (s, 1H), 1.70 (s, 6H). MS (m/z): 249.90 ( _M +H); Calcd. for [ _C12H13BFNO3 +H]: _250.10 .

Intermediate 83 : 2-(6-(2- Chloro -5- fluoropyrimidin - 4 -yl )-8- fluoroquinolin- 4 -yl ) propan -2- ol: following General Procedure-2, from Intermediate 82 (400 mg, 1.61 mmol) and 2,4-dichloro-5-fluoropyrimidine (322 mg, 3.85 mmol) to synthesize the title compound. After work-up, the crude product was purified by combi-flash using EtOAc and petroleum ether (1:1) as eluents to obtain the title compound (260 mg) as an off-white solid. Yield: 48%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.55 (s, 1H), 9.04 (d, J 3.2, 1H), 8.99 (d, J 4.4, 1H), 8.06 (d, J 11.6 , 1H), 7.72 (d, J 4.4, 1H), 5.78 (s, 1H), 1.71 (s, 6H). MS (m/z): 336.22 (M+H); Calcd. for _{[ C16H12ClF2N3O +} H]: _336.06 .

Intermediate 84 : tert-butyl 4-((( trifluoromethyl ) sulfonyl ) oxy )-5,6 -dihydropyridine- 1(2H) -carboxylate: diisopropylamine (8.5 ml, 60.23 mmol) and anhydrous THF (300 ml) were placed in RBF. This mixture was cooled to -78°C and n-BuLi (24.03 ml, 60.23 mmol) was added slowly and stirred at -78°C for 40 min. After 40 min, tert-butyl 4-oxyhexahydropyridine-1-carboxylate (10 g, 50.2 mmol) dissolved in THF (60 ml) was added dropwise to the above mixture for 30 min. 1,1,1-Trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (19.72 g, 55.2 mmol) dissolved in THF (57 ml) was added dropwise Added to the above reaction mixture for 30 min. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 2 h. After 2 h, the reaction mixture was quenched with aqueous NaHCO ₃ (260 ml), stirred for 1 h and extracted into EtOAc (2*300 ml). The combined EtOAc layers were washed with brine. The EtOAc layer was distilled under vacuum to obtain crude. The crude was purified by column chromatography on 60-120 mesh silica gel using EtOAc and petroleum ether (8:92) as eluents to obtain the title compound (12 g) as a yellow liquid. Yield: 72.17%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 5.76 (bs, 1H), 4.09-4.01 (m, 2H), 3.68-3.59 (m, 2H), 2.48-2.40 (m, 2H) , 1.47 (s, 9H).

Intermediate 85 : 2- nitro -5-(4,4,5,5 -tetramethyl- 1,3,2-dioxaborolan - 2- yl ) pyridine: following general procedure-1 , the title compound was synthesized from 2-nitro-5-bromopyridine (20.0 g, 99 mmol). After work-up, the crude product was purified by column chromatography on 60-120 mesh silica gel using EtOAc and petroleum ether (3:7) as eluents to obtain the title compound (4.5 g) as a brown solid. Yield: 18%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 8.81 (d, J 1.6, 1H), 8.42 (dd, J 8.0, 1.6, 1H), 8.30 (d, J 8, 1H), 1.34 (s, 12 H). MS (m/z): 251.24 (M ₊ H); Calcd. for [ _{C11H15BN2O4 +} H]: _251.11 .

Intermediate 86 : tert-butyl 6- nitro- 5',6' -dihydro- [3,4' -bipyridine ]-1'(2'H) -carboxylate : following general procedure-2, from The title compound was synthesized from intermediate 85 (1.5 g, 6 mmol) and intermediate 84 (2.38 g, 7.2 mmol). After completion of the reaction, work-up followed by column purification afforded the title compound (1.4 g) as a light brown solid. Yield: 76%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 8.77 (d, J 2, 1H), 8.30 (d, J 8.4, 1H), 8.24 (dd, J 8.8, 2.4, 1H), 6.56 (bs, 1H), 4.11-4.05 (m, 2H), 3.60-3.52 (m, 2H), 2.58-2.52 (m, 2H), 1.43 (s, 9H). MS (m/z): _306.17 ( _M +H); Calcd. for [ _{C15H19N3O4 +} H]: 306.14.

Intermediate 87 : tert-butyl 4-(6 -aminopyridin- 3 -yl ) hexahydropyridine- 1 -carboxylate Intermediate 86 (1.8 g, 5.9 mmol) was dissolved in MeOH (125 ml) and THF ( 125 ml) in the mixture. 5% palladium on carbon (1.8 g) was added to the above solution and stirred at room temperature under _H2 atmosphere for 44 h. After 44 h, the reaction mixture was filtered on a bed of celite and the bed was washed with EtOAc. The combined filtrates were distilled to obtain the title compound (1.6 g) as a yellow viscous liquid. Yield: 98%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 7.76 (d, J 2.4, 1H), 7.25 (dd, J 8.4, 2.4, 1H), 6.38 (d, J 8.4, 1H), 5.65 (s, 2H), 4.10-4.00 (m, 2H), 2.88-2.70 (m, 2H), 2.50-2.43 (m, 1H), 1.80-1.71 (m, 2H), 1.45-1.35 (m, 11H) . MS (m/z): 278.18 (M+H); Calcd. for _{[ C15H23N3O2 +} H]: _278.18 .

Intermediate 88 : 4-(4,4,5,5 -Tetramethyl -1,3,2-dioxaborolan - 2- yl )-5,6 -dihydropyridine- 1(2H ) -tert-butyl formate: The title compound was synthesized from Intermediate 84 (20.0 g, 99 mmol) following General Procedure-1. In this reaction, PdCl ₂ (dppf).CH ₂ Cl ₂ was used as catalyst and 1,4-dioxane was used as solvent. After work-up, the crude product was purified by combi-flash using EtOAc and petroleum ether (5:95) as eluents to obtain the title compound (600 mg) as an off-white solid. Yield: 64%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 6.38 (s, 1H), 3.86 (s, 2H), 3.35-3.30 (m, 2H), 2.10-2.04 (m, 2H), 1.39 (s, 9H), 1.20 (s, 12H). MS (m/z): _210.24 (M _{+ HC5H9O2} ) _{; Calcd} . for [ _{C16H28BNO4 + HC5H9O2} ]: _210.21 .

Intermediate 89 : tert-butyl 4-(2 -aminopyrimidin -5- yl )-5,6 -dihydropyridine- 1(2H) -carboxylate: following general procedure-2, from 2-amino- The title compound was synthesized from 5-bromopyrimidine (270 mg, 1.6 mmol) and intermediate 88 (580 mg, 1.9 mmol). After completion of the reaction, work-up followed by column purification afforded the title compound (190 mg) as a light brown solid. Yield: 44%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 8.32 (s, 2H), 6.65 (s, 2H), 6.02 (s, 1H), 3.98-3.92 (m, 2H), 3.54-3.47 (m, 2H), 2.41-2.34 (m, 2H), 1.41 (s, 9H). MS (m/z): 277.15 (M ₊ H); Calcd. for [ _{C14H20N4O2 +} H]: _277.16 .

Intermediate 90 : tert-butyl 4-(2 -aminopyrimidin -5- yl ) hexahydropyridine- 1 -carboxylate: Intermediate 89 (180 mg, 0.65 mmol) was dissolved in MeOH (6 ml) and THF (6 ml) in the mixture. 5% palladium on carbon (180 mg) was added to the above solution and stirred at room temperature under _H2 atmosphere for 44 h. After 44 h, the reaction mixture was filtered on a bed of celite, and the bed was washed with a mixture of DCM and MeOH (9:1 ) (100 ml). The combined filtrates were distilled to give the title compound (180 mg) as a brown sticky solid. Yield: 99%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 8.12 (s, 2H), 6.39 (s, 2H), 4.10-4.00 (m, 2H), 2.82-2.68 (m, 2H), 1.74 -1.65 (m, 2H), 1.50-1.35 (m, 2H), 1.40 (s, 9H). MS (m/z): _179.25 (M ₊ H _{- C5H9O2} ); _Calcd . for [ _{C14H22N4O2 +} H _{- C5H9O2} ]: _179.17 .

Intermediate 91 : 1 -Methyl -1,2,3,6 -tetrahydropyridin- 4 -yl trifluoromethanesulfonate: Diisopropylamine (15 ml, 106 mmol) and anhydrous THF (300 ml) were dissolved in in RBF. This mixture was cooled to -78°C and n-BuLi (2 M in hexane) (42.42 ml, 106 mmol) was added slowly and stirred at -78°C for 40 min. After 40 min, 1-methylhexahydropyridin-4-one (10 g, 88.4 mmol) dissolved in THF (60 ml) was added dropwise to the above mixture for 30 min. 1,1,1-Trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (34.72 g, 97.2 mmol) dissolved in THF (100 ml) was added dropwise Added to the above reaction mixture for 30 min. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 2.5 h. After 2.5 h, the reaction mixture was quenched with aqueous NaHCO ₃ (260 ml), stirred for 1 h and extracted into EtOAc (2*300 ml). The combined EtOAc layers were washed with brine. The EtOAc layer was distilled under vacuum to obtain crude. The crude was purified by column chromatography on 60-120 mesh silica gel using EtOAc and petroleum ether (1:1) as eluents to obtain the title compound (19 g) as a brown liquid. Yield: 88%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 5.76-5.71 (m, 1H), 3.14-3.09 (m, 2H), 2.74-2.68 (m, 2H), 2.51-2.44 (m, 2H) , 2.41 (s, 3H). MS (m/z): 246.10 ( _M +H); Calcd. for _{[ C7H10F3NO3S} +H]: _246.03 .

Intermediate 92 : 1' -Methyl -6- nitro- 1',2',3',6' -tetrahydro- 3,4' -bipyridine: following general procedure-2, from Intermediate 85 (2 g, 8 mmol) and intermediate 91 (2.35 g, 9.6 mmol) to synthesize the title compound. After the reaction was completed, work-up followed by column purification gave the title compound (580 mg) as a brown solid. Yield: 33%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 8.77 (d, J 2.4, 1H), 8.27 (d, J 8.8, 1H), 8.23 (dd, J 8.8, 2.4, 1H), 6.61 -6.57 (m, 1H), 3.12-3.07 (m, 2H), 2.63-2.59 (m, 2H), 2.57-2.52 (m, 2H), 2.30 (s, 3H). MS (m/z): 220.20 (M+H); Calcd. for _{[ C11H13N3O2 +} H]: _220.10 .

Intermediate 93 : 5-(1 -Methylhexahydropyridin- 4 -yl ) pyridin -2- amine : Intermediate 92 (580 mg, 2.6 mmol) was dissolved in MeOH (30 ml) and THF (30 ml) in the mixture. 5% palladium on carbon (1.16 g) was added to the above solution and stirred at room temperature under _H2 atmosphere for 45 h. After 45 h, the reaction mixture was filtered on a bed of celite and the bed was washed with EtOAc (200 ml). The combined filtrates were distilled to afford the title compound (460 mg) as a brown sticky solid. Yield: 91%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 7.75 (d, J 2.4, 1H), 7.25 (dd, J 8.4, 2.4, 1H), 6.38 (d, J 8.4, 1H), 5.63 (s, 2H), 2.86-2.78 (m, 2H), 2.30-2.21 (m, 1H), 2.16 (s, 3H), 1.95-1.85 (m, 2H), 1.68-1.50 (m, 4H). MS (m/z): 192.22 ( _M +H); Calcd. for [ _C11H17N3 +H]: _192.14 . Example 1 4-(6-((5- fluoro - 4-( quinolin -6- yl ) pyrimidin -2- yl ) amino ) pyridin - 3 -yl ) hexahydropyrazine- 1 -carboxylic acid tert-butyl ester

The title compound was synthesized from Intermediate 2 (500 mg, 1.93 mmol) and Intermediate 5 (590 mg, 2.1 mmol) following General Procedure-3. After work-up (EtOAc/brine, then _H2O ), the crude product was purified by combi-flash using methanol and DCM (2.7:97.3) as eluents to obtain the title compound (120 mg) as a yellow solid. Yield: 12.4%. Melting point: 223°C-225°C. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 9.02-8.99 (m, 1H), 8.62 (br. s, 1H), 8.49-8.44 (m, 2H), 8.36-8.23 (m, 3H) , 8.15 (br. s, 1H), 8.05 (d, J 2.8, 1H), 7.50 (dd, J 8.4, 4.4, 1H), 7.38 (dd, J 9.2, 2.8, 1H), 3.61 (t, J 4.8 , 4H), 3.10 (t, J 4.8, 4H), 1.49 (s, 9H). MS (m/z): _502.33 (M+H); Calcd. for [ _{C27H28FN7O2 +} H]: _502.24 . Example 1A 5- fluoro -N-(5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl )-4-( quinolin -6- yl ) pyrimidin -2- amine

Following general procedure-4, from 4-(6-((5-fluoro-4-(quinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1- tert-Butyl formate (Example 1) (110 mg, 0.22 mmol) The title compound (35 mg) was synthesized as a pale yellow solid. Yield: 40%. ¹ H-NMR (δ ppm, DMSO- d ₆ + CDCl ₃ , 400 MHz): 9.70 (s, 1H), 9.02-8.95 (m, 1H), 8.70-8.65 (m, 2H), 8.53 (d, J 8.4, 1H), 8.40 (d, J 9.2, 1H), 8.17 (d, J 8.8, 1H), 8.09 (d, J 9.2, 1H), 7.97 (br. s, 1H), 7.60 (dd, J 8.4 , 4.4, 1H), 7.38-7.45 (m, 1H), 3.01 (br. s, 4H), 2.85 (br. s, 4H). Example 1B 5- fluoro -N-(5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl )-4-( quinolin -6- yl ) pyrimidin -2- amine hydrochloride

5-fluoro-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine (Example 1A) (27 mg, 0.067 mmol) was dissolved in methanol (2.7 ml) and HCl (25 mg, 0.67 mmol) was added to obtain a clear solution. The solution was stirred at room temperature for 30 min. After 30 min, methanol was distilled off to obtain a residue. The residue was co-distilled with toluene (5 ml) to obtain the title compound as a yellow solid. Melting point: 220°C-222°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.74 (br. s, 1H) 9.50 (br. s, 2H), 9.19 (br. s, 1H), 9.00-8.80 (m, 3H ), 8.51 (br. s, 1H), 8.39 (t, J 8.4, 1H), 8.16 (br. s, 1H), 8.02 (s, 1H), 7.90-7.80 (m, 2H), 3.50-3.40 ( br. s, 4H), 3.30-3.20 (br. s, 4H). MS (m/z): 402.1 ( _M +H) _; Calcd. for [ _C22H20FN7 +H]: 402.1. Example 2 4-(6-((5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidin -2- yl ) amino ) pyridin - 3 -yl ) hexahydropyrazine- 1 - carboxylic acid tributyl ester

The title compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 5 (551 mg, 1.98 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (2.5:97.5) as eluents to obtain the title compound (130 mg) as a yellow solid. Yield: 14%. Melting point: 227°C-229°C. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 9.08-9.04 (m, 1H), 8.49 (d, J = 3.6, 1H), 8.36-8.19 (m, 4H), 8.07 (d, J 2.4 , 1H), 7.57 (dd, J 8.0, 4.0, 1H), 7.40 (dd, J 9.2, 2.8, 1H), 3.61 (t, J = 4.8, 4H), 3.11 (t, J = 4.8, 4H), 1.50 (s, 9H). MS (m/z): _520.32 (M ₊ H); Calcd. for [ _{C27H27F2N7O2 +} H]: _520.23 . Example 2A 5- fluoro - 4-(8- fluoroquinolin- 6- yl )-N-(5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) pyrimidin -2- amine

Following General Procedure-4, from 4-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine - tert-butyl 1-carboxylate (Example 2) (120 mg, 0.23 mmol) The title compound (55 mg) was synthesized as a pale yellow solid. Yield: 57%. 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.82 (s, 1H), 9.06 (br. s, 1H), 8.72 (d, J 3.2, 1H), 8.67 (d, J 8.0, 1H ), 8.56 (s, 1H), 8.21 (d, J = 12.4, 1H), 8.06-7.96 (m, 2H), 7.74 (dd, J 8.4, 4.0, 1H), 7.44 (d, J = 8.8, 1H ), 3.02 (br. s, 4H), 2.84 (br. s, 4H). Example 2B 5- fluoro - 4-(8- fluoroquinolin- 6- yl )-N-(5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) pyrimidin -2- amine hydrochloride

5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine (Example 2A) ( 50 mg, 0.12 mmol) was dissolved in methanol (2.5 ml) and HCl (43 mg, 1.2 mmol) was added to obtain a clear solution. The solution was stirred at room temperature for 30 min. After 30 min, methanol was distilled off to obtain a residue. The residue was co-distilled with toluene (5 ml) to obtain the title compound (45 mg) as a yellow solid. Yield: 83% Melting point: 220°C-222°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): melting point: 262°C-264°C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 11.78 (br. s, 1H), 9.56 (br. s, 2H), 9.08 (br. s, 1H), 8.94 (br. s, 1H) , 8.70 (d, J 8.4, 1H), 8.61 (s, 1H), 8.12-8.23 (m, 2H), 8.01 (s, 1H), 7.84 (d, J 8.8, 1H), 7.77 (dd, J 8.4 , 4.0, 1H), 3.49-3.41(m, 4H), 3.28-3.20 (m, 4H). MS (m/z): 420.39 (M+H-HCl); Calcd. for [ _{C22H19F2N7.HCl +} H _- HCl]: _420.17 . Example 3 N-(5-((4- ethylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidine -2- amine

The title compound was synthesized from Intermediate 7 (500 mg, 1.8 mmol) and Intermediate 9 (400 mg, 1.8 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (11.5:88.5) as eluents to obtain the title compound (280 mg) as a yellow solid. Yield: 34%. Melting point: 246°C-248°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 10.12 (s, 1H), 9.08 (d, J 3.6, 1H), 8.81 (d, J 3.2, 1H), 8.69 (d, J 8.0 , 1H), 8.60 (s, 1H), 8.30-8.20 (m, 3H), 7.80-7.70 (m, 1H), 7.40-7.30 (m, 1H), 3.47 (br. s, 2H) 2.70-2.20 ( m, 10H), 1.00 (br. s, 3H). MS (m/z): _462.29 (M+H); Calcd. for [ _{C25H25F2N7 +} H]: _462.22 . Example 3A N-(5-((4- ethylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidine -2- amine hydrochloride

Make N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidine- 2-Amine (Example 3) (250 mg, 0.54 mmol) was suspended in methanol (6 ml) and 35% aqueous hydrochloric acid (197 mg, 5.4 mmol) was added to obtain a clear solution. This mixture was stirred at room temperature for 30 min. Addition of methyl tert-butyl ether (18 ml) and stirring for 1 hour gave a solid which was filtered, washed with methyl tert-butyl ether (20 ml) and dried to give the title compound as a brown solid (230 mg ). Yield: 85%. Melting point: 289°C-291°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): Melting point: 289°C-291°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.89 (br. s, 1H), 11.40 (br. s, 1H), 9.08-9.13 (br. s, 1H), 8.92-8.97 ( br. s, 1H), 8.72 (d, J = 8.4, 1H), 8.60-8.70 (m, 2H), 8.25-8.40 (m, 2H), 8.12 (d, J = 8.8, 1H), 7.75-8.15 (m, 1H), 4.45 (br. s, 2H), 3.15-3.82 (m, 10H), 1.27 (t, J = 7.2, 3H). MS (m/z): _461.8 (M+H-HCl); Calcd. for [ _{C25H25F2N7.HCl +} H _- HCl]: 462.2. Example 4 N-(5-((4- ethylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl )-5- fluoro - 4-( quinolin -6- yl ) pyrimidine -2- amine

The title compound was synthesized from Intermediate 2 (500 mg, 1.9 mmol) and Intermediate 9 (420 mg, 1.9 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (13:87) as eluents to obtain the title compound (200 mg) as a yellow solid. Yield: 23%. Melting point: 289°C-291°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 10.07 (s, 1H), 9.04 (s, 1H), 8. 80-8. 70 (m, 2H), 8.60 (d, J 8.0 , 1H), 8.45 (d, J 8.0, 1H), 8. 30-8. 20 (m, 3H), 7. 80-7. 60 (m, 1H), 7.55-7.40 (m, 1H), 3.42 (s, 2H), 2. 80-2. 10 (m, 10H), 1.24 (br. s, 3H). MS (m/z): _444.32 (M+H) _; Calcd. for [ _C25H26FN7 +H]: 444.23. Example 4A N-(5-((4- ethylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl )-5- fluoro - 4-( quinolin -6- yl ) pyrimidine -2- Amine hydrochloride

Make N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(quinolin-6-yl)pyrimidin-2-amine (Example 4) (190 mg, 0.43 mmol) was suspended in methanol (5 ml) and 35% aqueous hydrochloric acid (160 mg, 4.4 mmol) was added to obtain a clear solution. The solution was stirred at room temperature for 30 min. Addition of methyl tert-butyl ether (15 ml) and stirring for 1 hour gave a solid which was filtered, washed with methyl tert-butyl ether (20 ml) and dried to give the title compound as a brown solid (60 mg ). Yield: 85%. Melting point: 255°C-257°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.99 (br. s, 1H), 11.32 (br. s, 1H), 9.21 (d, J = 4.4, 1H), 9.05-8.90 ( m, 3H), 8.52-8.51 (m, 2H), 8.42 (d, J 8.8, 1H), 8.30 (d, J 8.8, 1H), 8.14 (d, J 8.8, 1H), 7.90 (dd, J 8.0 , 4.8, 1H), 4.44 (br. s, 2H), 3.80-3.00 (m, 10H), 1.27 (t, J = 7.2, 3H). MS (m/z): 443.8 (M+H-HCl); Calcd. for [ _{C25H26FN7.HCl} +H _- HCl]: _444.2 . Example 5 4-(6-((5- fluoro - 4-(8- fluoro -2- methyl- 4-( prop- 1 -en -2- yl ) quinolin -6- yl ) pyrimidin -2- yl ) amino ) pyridin - 3 -yl ) hexahydropyrazine- 1 -carboxylic acid tert-butyl ester

The title compound was synthesized from Intermediate 18 (500 mg, 1.51 mmol) and Intermediate 5 (420 mg, 1.51 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (1.8:98.2) as eluents to obtain the title compound (180 mg) as a yellow solid. Yield: 21%. Melting point: 150°C-152°C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.66 (s, 1H), 8.45 (d, J 3.6, 1H), 8.30 (d, J 9.2, 1H), 8.16 (d, J 12.0, 1H), 8.10 (s, 1H), 8.05 (d, J 2.8, 1H), 7.37 (dd, J 9.2, 3.2, 1H), 5.56 (s, 1H), 5.20 (s, 1H), 3.66-3.59(m, 4H ), 3.14-3.08(m , 4H), 2.26 (s, 3H), 1.62 (s, 3H), 1.50 (s, 9H). MS (m/z): _574.35 (M ₊ H); Calcd. for [ _{C31H33F2N7O2 +} H]: _574.28 . Example 5A 5- fluoro - 4-(8- fluoro -2- methyl- 4-( prop- 1 -en -2- yl ) quinolin -6- yl ) -N-(5-( hexahydropyrazine- 1- yl ) pyridin -2- yl ) pyrimidin -2- amine

Following general procedure-4, from 4-(6-((5-fluoro-4-(8-fluoro-2-methyl-4-(prop-1-en-2-yl)quinolin-6-yl) The title compound (110 mg) was synthesized as a yellow solid . Yield: 89%. Melting point: 165°C-167°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.82 (s, 1H), 8.67 (d, J 2.4, 1H), 8.61 (s, 1H), 8.14 (d, J 11.6, 1H) , 8.10-7.95 (m, 2H), 7.49 (s, 1H), 7.40 (d, J 8.0, 1H), 5.61 (s, 1H), 5.19 (s, 1H), 3.10-3.00 (m, 4H), 2.90-2.82 (m, 4H), 2.72 (s, 3H), 2.23 (s, 3H). MS (m/z): _474.53 (M+H); Calcd. for [ _{C26H25F2N7 +} H]: _474.2 . Example 5B 5- fluoro - 4-(8- fluoro -2- methyl- 4-( prop- 1 -en -2- yl ) quinolin -6- yl ) -N-(5-( hexahydropyrazine- 1- yl ) pyridin -2- yl ) pyrimidin -2- amine hydrochloride:

Make 5-fluoro-4-(8-fluoro-2-methyl-4-(prop-1-en-2-yl)quinolin-6-yl)-N-(5-(hexahydropyrazine-1 -yl)pyridin-2-yl)pyrimidin-2-amine (Example 5A) (100 mg, 0.21 mmol) was suspended in methanol (2 ml) and 35% aqueous hydrochloric acid (221 mg, 2.1 mmol) was added to obtain a clear solution . This mixture was stirred at room temperature for 30 min. Addition of methyl tert-butyl ether (6 ml) and stirring for 1 hour gave a solid which was filtered, washed with methyl tert-butyl ether (2 ml) and dried to give the title compound as a yellow solid (95 mg ). Yield: 80%. Melting point: 213°C-215°C. Melting point: 213°C-215°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.74 (br. s, 1H), 9.53 (br. s, 2H), 8.88 (s, 1H), 8.58 (s, 1H), 8.20 -8.10 (m, 2H), 7.98 (s, 1H), 7.83 (d, J 9.6, 1H), 7.54 (s, 1H), 5.63 (s, 1H), 5.21 (s, 1H), 3.49-3.41 ( m, 4H), 3.30-3.19 (m, 4H), 2.73 (s, 3H), 2.23 (s, 3H). MS (m/z): _474.5 (M+H); Calcd. for [ _{C26H25F2N7 +} H]: _474.2 . Example 6 5- fluoro -N-(5-(4- methylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-4-( quinolin -6- yl ) pyrimidin -2- amine

The title compound was synthesized from Intermediate 2 (400 mg, 1.54 mmol) and Intermediate 11 (296 mg, 1.54 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (8:92) as eluents to afford the title compound (150 mg) as a yellow solid after washing with diethyl ether (5 mL). Yield: 23%. Melting point: 255°C-258°C. ¹ H-NMR (δ ppm, DMSO- d 6, 400 MHz): 9.69 (s, 1H), 9.00 (dd, J 4.0, 2.8, 1H), 8.70 (s, 1H), 8.67 (d, J 3.6, 1H), 8.55 (d, J 8.8, 1H), 8.43 (d, J 8.8, 1H), 8.19 (d, J 9.2, 1H), 8.12 (d, J 9.2, 1H), 8.01 (d, J 2.8, 1H), 7.62 (dd, J 8.4, 4.0, 1H), 7.45 (dd, J 9.2, 2.8, 1H), 3.30-3.22 (m, 4H), 3.15-3.10(m, 4H), 2.25 (s, 3H ). MS (m/z): 416.44 (M+H) _; Calcd. for [ _C23H22FN7 +H]: _416.20 . Example 6A 5- fluoro -N-(5-(4- methylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-4-( quinolin -6- yl ) pyrimidin -2- amine hydrochloride :

Make 5-fluoro-N-(5-(4-methylhexahydropyrazin-1-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine (example 6) (120 mg, 0.29 mmol) was suspended in methanol (2.5 ml) and 35% aqueous hydrochloric acid (105 mg, 2.9 mmol) was added, briefly obtaining a clear solution before a solid precipitated. This mixture was stirred at room temperature for 30 min. The solid was filtered, washed with methanol (2 ml) and dried to give the title compound (80 mg) as a yellow solid. Yield: 61%. Melting point: 272°C-274°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.76 (br. s, 1H), 11.47 (br. s, 1H), 9.19 (br. s, 1H), 8.98-8.82 (m, 3H), 8.54 (d, J 8.4, 1H), 8.18 (d, J 9.2, 1H), 8.04 (s, 1H), 8.04 (s, 1H), 7.86-7.81 (m, 2H), 3.85 (d, J 11.6, 2H), 3.52 (d, J 10.4, 1H), 3.32-3.10 (m, 4H), 2.80 (s, 3H). MS (m/z): _416.46 (M+H); Calcd. for [ _C23H22FN7 +H]: _416.20 . Example 7 5- fluoro - 4-(8- fluoroquinolin- 6- yl )-N-(5-(4- methylhexahydropyrazin- 1 -yl ) pyridin -2- yl ) pyrimidin -2- amine

The title compound was synthesized from Intermediate 7 (500 mg, 1.8 mmol) and Intermediate 11 (350 mg, 1.8 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (9:91 ) as eluents to afford the title compound (290 mg) as a yellow solid after washing with diethyl ether (5 mL). Yield: 34%. Melting point: 244°C-246°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.83 (s, 1H), 9.06 (d, J 2.8, 1H), 8.72 (d, J 3.6, 1H), 8.67 (d, J 8.4 , 1H), 8.56 (s, 1H), 8.20 (d, J 8.0, 1H), 8.07-8.00 (m, 2H), 7.74 (dd, J 8.4, 4.4, 1H), 7.47 (dd, J 9.2, 2.8 , 1H), 3.18-3.09 (m, 4H), 2.40-2.55 (m, 4H), 2.23 (s, 3H). MS (m/z): _434.43 (M+H); Calcd. for [ _{C23H22F2N7 +} H]: _434.19 . Example 7A 5- fluoro - 4-(8- fluoroquinolin- 6- yl )-N-(5-(4- methylhexahydropyrazin- 1 -yl ) pyridin -2- yl ) pyrimidin -2- amine Hydrochloride:

Make 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-methylhexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine ( Example 7) (280 mg, 0.65 mmol) was suspended in methanol (7.3 ml) and 35% aqueous hydrochloric acid (240 mg, 6.5 mmol) was added, during which time the mixture became a clear solution briefly and a precipitate formed immediately. The heterogeneous mixture was stirred at room temperature for 30 min. The solid was filtered, washed successively with methanol (3 ml) and diethyl ether (15 ml) and dried to give the title compound (240 mg) as a yellow solid. Yield: 79%. Melting point: 286°C-288°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.83 (br. s, 1H), 11.44 (br. s, 1H), 9.09 (d, J 4.0, 1H), 8.95 (d, J 3.2, 1H), 8.71 (d, J 8.0, 1H), 8.61 (s, 1H), 8.24-8.17 (m, 2H), 8.01 (d, J 2.0, 1H), 7.84 (d, J 9.6, 1H) , 7.78 (dd, J 8.4, 4.0, 1H), 3.90-3.82 (m, 2H), 3.54-3.49 (m, 2H), 3.30-3.10 (m, 4H), 2.80 (d, J 4.0, 3H). MS (m/z): _434.42 (M+H-HCl); Calcd. for [ _{C23H21F2N7.HCl +} H-HCl]: _434.19 . Example 8 N-(5-(4- ethylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidin -2- amine

The title compound was synthesized from Intermediate 7 (400 mg, 1.4 mmol) and Intermediate 20 (300 mg, 1.5 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (7:93) as eluents to afford the title compound (350 mg) as a yellow solid after washing with diethyl ether (5 mL). Yield: 54%. Melting point: 254°C-256°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.06 (d, J 2.8, 1H), 8.70 (d, J 3.6, 1H), 8.64 (d, J 8.4, 1H), 8.55 (s , 1H), 8.20 (d, J 11.6, 1H), 8.05 (d, J 9.2, 1H), 8.01 (d, J 2.4, 2H), 7.72 (dd, J 8.4, 4.4, 1H), 7.46 (dd, J 9.2, 3.2, 1H), 4.04 (s, 4H), 3.15-3.08 (m, 4H), 2.38 (q, J 7.2, 2H), 1.03 (t, J 7.2, 2H). MS (m/z): _448.43 (M+H); Calcd. for [ _{C23H21F2N7 +} H]: _448.21 . Example 8A N-(5-(4- ethylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidin -2- amine Hydrochloride:

Make N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-amine ( Example 8) (210 mg, 0.47 mmol) was suspended in methanol (5.3 ml) and 35% aqueous hydrochloric acid (170 mg, 4.7 mmol) was added during which time the mixture became a clear solution. The mixture was stirred at room temperature for 30 min. Methyl tert-butyl ether (24 ml) was added and stirred at room temperature for 1 h. The precipitated solid was filtered, washed with methyl tert-butyl ether (15 ml) and dried to give the title compound (165 mg) as a yellow solid. Yield: 79%. Melting point: 273°C-275°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.87 (s, 1H), 11.40 (br. s, 1H), 9.09 (br. s, 1H), 8.95 (s, 1H), 8.70 (d, J 7.2, 1H), 8.61 (s, 1H), 8.27-8.06 (m, 2H), 8.02 (s, 1H), 7.84 (d, J 9.2, 1H), 7.78 (dd, J 8.4, 4.4 , 1H), 3.90-3.80 (m, 2H), 3.62-3.55 (m, 2H), 3.34-3.22 (m, 2H), 3.20-3.02 (m, 4H), 1.30 (t, J 7.2, 3H). MS (m/z): 448.43 (M+H-HCl); Calcd. for [ _{C24H23F2N7.HCl +} H _- HCl]: _448.21 . Example 9 N-(5-((4- ethylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoro -2 - methylquinoline- 6- yl ) pyrimidin -2- amine

The title compound was synthesized from Intermediate 23 (400 mg, 1.4 mmol) and Intermediate 9 (300 mg, 1.4 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (7.4:92.6) as eluents to obtain the title compound (120 mg) as a yellow solid. Yield: 18%. Melting point: 203°C-205°C. 1H-NMR (δ ppm, DMSO- d 6, 400 MHz): 10.10 (s, 1H), 8.77 (d, J 3.6, 1H), 8.56-8.51 (m, 2H), 8.22-8.16 (m, 3H) , 7.72 (dd, J 8.4, 2.0, 1H), 7.62 (d, J 8.8, 1H), 3.44 (s, 2H), 2.73 (s, 3H), 2.30-2.60 (m, 10H), 0.98 (t, J 7.2, 3H). MS (m/z): _476.22 (M+H); Calcd. for [ _{C26H27F2N7 +} H]: _476.23 . Example 9A N-(5-((4- ethylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoro -2 - methylquinoline- 6- yl ) pyrimidin -2- amine hydrochloride

Make N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-2-methylquinoline-6 -yl)pyrimidin-2-amine (Example 9, 120 mg, 0.25 mmol) was suspended in methanol (3 ml) and 35% aqueous hydrochloric acid (92 mg, 2.5 mmol) was added to obtain a clear solution. This mixture was stirred at room temperature for 30 min. The mixture was concentrated, the residue was dissolved in water (20 ml) and washed with DCM-MeOH 9:1 (3*50 ml). The aqueous layer was evaporated and the residual solid was co-evaporated with water to give the title compound (15 mg) as a yellow solid. Yield: 12%. Melting point: 257°C-259°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 12.02 (br. s, 1H), 11.51 (br. s, 1H), 8.91 (d, J 2.4, 1H), 8.67-8.54 (m , 3H), 8.40-8.30 (m, 1H), 8.20 (d, J 12.0, 1H), 8.40-8.12 (m, 1H), 7.65 (d, J 8.8, 1H), 4.47 (br. s, 2H) , 3.80-3.35 (m, 8H), 3.17 (br. s, 2H), 2.74 (s, 3H), 1.25 (t, J 7.2, 3H). MS (m/z): 475.3 (M+H) _; Calcd. for [ _{C26H27F2N7 +} H]: _476.2 . Example 10 4-(6-((5- fluoro - 4-(8- fluoro -2 -methylquinolin -6- yl ) pyrimidin -2- yl ) amino ) pyridin - 3 -yl ) hexahydropyrazine -3 -Butyl 1-carboxylate

The title compound was synthesized from Intermediate 23 (500 mg, 1.7 mmol) and Intermediate 5 (480 mg, 1.7 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (7.8:92.2) as eluents to obtain the title compound (100 mg) as a yellow solid. Yield: 11%. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 8.46 (d, J 3.6, 1H), 8.41 (br. s, 1H), 8.29 (d, J 8.8, 1H), 8.23-8.20 (m, 1H), 8.10 (s, 1H), 8.18 (d, J 1.6, 1H), 8.12 (br. s., 1H), 8.07-8.04 (m, 1H), 7.44 (d, J 8.4, 1H), 7.40 (dd, J 8.8, 2.8, 1H), 3.61 (t, J 4.8, 4H), 3.12 (t, J 4.8, 4H), 2.85 (s, 3H), 1.50 (s, 9H). Example 10A 5- fluoro - 4-(8- fluoro -2 -methylquinolin -6- yl )-N-(5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) pyrimidine -2- amine

Following general procedure-4, from 4-(6-((5-fluoro-4-(8-fluoro-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl ) tert-butyl hexahydropyrazine-1-carboxylate (Example 10, 90 mg, 0.17 mmol) The title compound (55 mg) was synthesized as a brown solid. Yield: 75%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.78 (s, 1H), 8.70 (d, J 3.6, 1H), 8.55-8.48 (m, 2H), 8.16 (d, J 11.6, 1H), 8.03 (d, J 9.2, 1H), 7.99 (d, J 2.4, 1H), 7.62 (d, J 8.4, 1H), 7.45 (dd, J 8.8, 2.8, 1H), 3.08-3.02(m , 4H), 2.88-2.81 (m, 4H), 2.79 (s, 3H). Example 10B 5- fluoro - 4-(8- fluoro -2 -methylquinolin -6- yl )-N-(5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) pyrimidine -2- Amine hydrochloride:

Make 5-fluoro-4-(8-fluoro-2-methylquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine (Example 10A, 42 mg, 0.097 mmol) was suspended in methanol (2 ml) and 35% aqueous hydrochloric acid (35 mg, 0.97 mmol) was added to obtain a clear solution. This mixture was stirred at room temperature for 30 min. The solvent was removed in vacuo followed by co-evaporation with toluene to give the title compound (25 mg) as a yellow solid. Yield: 85%. Melting point: 220°C-222°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.78 (br. s, 1H), 9.56 (br. s, 2H), 8.91 (s, 1H), 8.61-8.51 (m, 2H) , 8.22-8.12 (m, 2H), 8.00 (s, 1H), 7.83 (d, J 9.6, 1H), 7.65 (d, J 8.4, 1H), 3.50-3.40 (m, 4H), 3.29-3.20 ( m, 4H), 2.74 (s, 3H). MS (m/z): _434.46 (M+H); Calcd. for [ _{C23H21F2N7 +} H]: _434.19 . Example 11 4-(6-((5- fluoro - 4-(8- fluoro - 4 - isopropyl- 2 -methylquinolin -6- yl ) pyrimidin -2- yl ) amino ) pyridine - 3- base ) tert-butyl hexahydropyrazine- 1 -carboxylate

To 4-(6-((5-fluoro-4-(8-fluoro-2-methyl-4-(prop-1-en-2-yl) quinoline-6-yl)pyrimidin-2-yl) To a solution of amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester (Example 5, 160 mg, 0.261 mmol) in a 3:2 mixture of methanol and EtOAc (15 ml) was added 20% palladium hydroxide was supported on carbon, and the mixture was hydrogenated under a hydrogen pressure of 8 kg/ ^cm2 at room temperature for 64 h. The mixture was diluted with DCM-methanol (9:1, 50 ml) and filtered through a bed of Celite, washing the bed with DCM-methanol (9:1, 150 ml). The combined filtrates were evaporated to give crude product. Purification by combi-flash chromatography system using methanol and DCM (1.8:98.2) as eluent gave the title compound (100 mg) as a green solid. Yield: 66%. Melting point: 178°C-180°C. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 8.72 (s, 1H), 8.46 (d, J 3.6, 1H), 8.31 (d, J 9.2, 1H), 8.15 (d, J 12.8, 1H ), 8.08-8.03 (m, 2H), 7.37 (dd, J 9.2, 2.8, 1H), 7.33 (s, 1H), 3.77 (septet, J = 6.8, 1H), 3.67-3.59 (m, 4H) , 3.15-3.08 (m, 4H), 2.82 (s, 3H), 1.50 (s, 9H), 1.46 (d, J 6.8, 6H). MS (m/z): _576.29 (M ₊ H); Calcd. for [ _{C31H35F2N7O2 +} H]: _576.29 . Example 11A 5- fluoro - 4-(8- fluoro - 4 - isopropyl- 2 -methylquinolin -6- yl )-N-(5-( hexahydropyrazin- 1 -yl ) pyridine -2- base ) pyrimidin -2- amine

Following general procedure-4, from 4-(6-((5-fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)pyrimidin-2-yl)amino )pyridin-3-yl)pyrazine-1-carboxylic acid tert-butyl ester (Example 11, 100 mg, 0.174 mmol) The title compound (60 mg) was synthesized as a yellow solid. Yield: 83%. Melting point: 217°C-219°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.84 (s, 1H), 8.72-8.67 (m, 2H), 8.10 (d, J 11.6, 1H), 8.07-7.97 (m, 2H ), 7.53 (s, 1H), 7.40 (dd, J 9.2, 2.4, 1H), 3.75 (septet, J = 6.8, 1H), 3.08-3.00 (m, 4H), 2.89-2.82(m, 4H) , 2.71 (s, 3H), 1.38 (d, J 6.8, 6H). Example 11B 5- fluoro - 4-(8- fluoro - 4 - isopropyl- 2 -methylquinolin -6- yl )-N-(5-( hexahydropyrazin- 1 -yl ) pyridine -2- base ) pyrimidin -2- amine hydrochloride :

Make 5-fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl ) pyrimidin-2-amine (Example 11A) (55 mg, 0.12 mmol) was suspended in methanol (1.1 ml) and 35% aqueous hydrochloric acid (42 mg, 1.2 mmol) was added to obtain a clear solution. This mixture was stirred at room temperature for 30 min. The solvent was removed in vacuo and co-evaporated with toluene to give the title compound (40 mg) as a light green solid. Yield: 67%. Melting point: 245°C-247°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.77 (br. s, 1H), 9.54 (br. s, 2H), 8.91 (d, J 2.4, 1H), 8.70 (s, 1H ), 8.20-8.10 (m, 2H), 7.99 (s, 1H), 7.85 (d, J 9.6, 1H), 7.59 (s, 1H), 3.76 (septet, J 6.8, 1H), 3.25 (br. s, 4H), 3.15 (br. s, 4H), 2.73 (s, 3H), 1.38 (d, J = 6.8, 3H). MS (m/z): _476.3 (M+H); Calcd. for [ _{C26H27F2N7 +} H]: _476.2 . Example 12 N-(5-(4- ethylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-5- fluoro - 4-( quinolin -6- yl ) pyrimidin -2- amine

The title compound was synthesized from Intermediate 2 (500 mg, 1.93 mmol) and Intermediate 20 (397 mg, 1.93 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (5.6:94.4) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min, filtered, washed with diethyl ether (5 mL) and dried to give the title compound (45 mg) as a yellow solid. Yield: 5.4%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.78 (s, 1H), 9.01 (dd, J 4.0, 2.0, 1H), 8.72-8.68 (m, 2H), 8.57 (d, J 8.4, 1H), 8.41 (d, J 8.8, 1H), 8.19 (d, J 9.2, 1H), 8.08 (d, J 9.2, 1H), 8.01 (d, J 2.8, 1H), 7.63 (dd, J 8.4, 4.0, 1H), 7.47 (dd, J 8.8, 3.2, 1H), 3.18-3.10 (m, 4H), 2.60-2.35 (m, 10H), 1.04 (t, J 7.2, 3H). MS (m/z): _430.44 (M+H); Calcd. for [ _C24H24FN7 +H]: _430.22 . Example 12A N-(5-(4- ethylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-5- fluoro - 4-( quinolin -6- yl ) pyrimidin -2- amine hydrochloride

To 5-fluoro-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)-4-(quinolin-3-yl)pyrimidin-2-amine (Example 12, 35 mg, 0.08 mmol) in methanol (2 mL) was added 35% aqueous hydrochloric acid (30 mg, 0.81 mmol), and the mixture was stirred at room temperature for 30 min. The solid formed was filtered, washed with diethyl ether (5 mL) and dried under vacuum to give the title compound (17 mg) as a yellow solid. Yield: 44%. Melting point: 291°C-294°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.65 (bs, 1H), 11.20 (bs, 1H), 9.15 (bs, 1H), 8.93 (d, J 3.2, 1H), 8.83 ( bs, 2H), 8.50 (d, J 9.2, 1H), 8.35 (d, J 9.2, 1H), 8.15 (d, J 8.4, 1H), 8.03 (d, J 2.8, 1H), 7.88-7.78 (m , 2H), 3.85 (d, J 12.4, 2H), 3.59 (d, J 12.0, 2H), 3.32-3.05 (m, 6H), 1.30 (t, J 7.2, 3H). MS (m/z): _430.44 (M+H); Calcd. for [ _C24H24FN7 +H]: _430.22 . Example 13 5- fluoro - 4-(8- fluoroquinolin- 6- yl )-N-(5-(4- isopropylhexahydropyrazin- 1 -yl ) pyridin -2- yl ) pyrimidine -2- amine

The title compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 25 (397 mg, 1.80 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (8:92) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min, filtered and dried to afford the title compound (80 mg) as a yellow solid. Yield: 9.6%. Melting point: 258°C-261°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.83 (s, 1H), 9.05, (dd, J 4, 1.8, 1H), 8.72 (d, J 3.6, 1H), 8.66 (d , J 8.4, 1H), 8.56 (s, 1H), 8.20 (d, J 11.6, 1H), 8.03 (d, J 8.8, 1H), 8.01 (d, J 2.8, 1H), 7.74 (dd, J 8.4 , 4, 1H), 7.46 (dd, J 9.2, 2.8, 1H), 3.15-3.05 (m, 4H), 2.70-2.66 (m, 1H), 2.61-2.54 (m, 4H), 1.00 (d, J 6.4, 6H). MS (m/z): _462.44 (M+H); Calcd. for [ _{C25H25F2N7 +} H]: _462.22 . Example 13A 5- fluoro - 4-(8- fluoroquinolin- 6- yl )-N-(5-(4- isopropylhexahydropyrazin- 1 -yl ) pyridin -2- yl ) pyrimidine -2- Amine hydrochloride

To 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-isopropylhexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine (Example 13, 80 mg, 0.17 mmol) in methanol (2 mL) was added 35% aqueous hydrochloric acid (63 mg, 1.7 mmol). After 10 min of addition, a clear solution was obtained and the mixture was stirred at room temperature for 30 min. A solid formed during stirring. The mixture was diluted with methyl tert-butyl ether (5 mL) and the solid was filtered, washed with methyl tert-butyl ether (10 mL) and dried under vacuum to give the title compound (50 mg) as a yellow solid. Yield: 58%. Melting point: 295°C-297°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.76 (s, 1H), 11.25 (s, 1H), 9.09 (dd, J 4.0, 1.6, 1H), 8.94 (d, J 3.2, 1H), 8.70 (d, J 8.4, 1H), 8.61 (s, 1H), 8.23-8.17 (m, 2H), 8.01 (d, J 2.8, 1H), 7.83 (d, J 11.2, 1H), 7.78 (dd, J 8.4, 4, 1H), 3.85 (d, J 12.4. 2H), 3.58-3.48 (m, 3H), 3.35 (t, J 11.6, 2H), 3.20-3.10 (m, 2H), 1.32 (d, J 6.4, 6H). MS (m/z): _462.2 (M+H); Calcd. for [ _{C25H25F2N7 +} H]: _462.22 . Example 14 5- fluoro -N-(5-(4- isopropylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-4-( quinolin -6- yl ) pyrimidin -2- amine

The title compound was synthesized from Intermediate 2 (500 mg, 1.93 mmol) and Intermediate 25 (424 mg, 1.93 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (10:90) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min, filtered, washed with diethyl ether (5 mL) and dried to give the title compound (200 mg) as a yellow solid. Yield: 23.4%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.72 (s, 1H), 9.04-8.93 (m, 1H), 8.68-8.64 (m, 2H), 8.53 (d, J 8, 1H ), 8.40 (d, J 8.8, 1H), 8.18 (d, J 9.2, 1H), 8.10 (d, J 9.2, 1H), 8.00 (d, J 2.8, 1H), 7.61 (dd, J 8.4, 3.6 , 1H), 3.18-3.05 (m, 4H), 2.71-2.55 (m, 5H), 1.02 (d, J 6.4, 6H). MS (m/z): _444.48 (M+H) _; Calcd. for [ _C25H26FN7 +H]: 444.23. Example 14A 5- fluoro -N-(5-(4- isopropylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-4-( quinolin -6- yl ) pyrimidin -2- amine hydrochloride Salt

To 5-fluoro-N-(5-(4-isopropylhexahydropyrazin-1-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine (Example 14 , 200 mg, 0.45 mmol) in methanol (2 mL) was added 35% aqueous hydrochloric acid (164 mg, 4.5 mmol). The solution became clear over a period of time and then a solid formed during stirring. The mixture was stirred for 30 min and the solid was filtered, washed sequentially with methanol (5 mL) and diethyl ether (10 mL) and dried under vacuum to give the title compound (90 mg) as a yellow solid. Yield: 41%. Melting point: 278°C-280°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.78 (s, 1H), 11.35 (s, 1H), 9.19 (dd, J 4.8, 1.6, 1H), 8.95 (d, J 3.2, 1H), 8.92 (d, J 8.4, 1H), 8.86 (s, 1H), 8.54 (d, J 9.2, 1H), 8.41 (d, J 9.2, 1H), 8.19 (dd, J 9.6, 2.4, 1H ), 8.04 (d, J 2.4, 1H), 7.90-7.82 (m, 2H), 3.85 (d, J 13.2, 2H), 3.57-3.48 (m, 3H), 3.37 (d, J 13.2, 2H), 3.20-3.09 (m, 2H). MS (m/z): _444.47 (M+H) _; Calcd. for [ _C25H26FN7 +H]: 444.23. Example 15 5- fluoro - 4-(8- fluoroquinolin- 6- yl )-N-(5-((4- methylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl ) pyrimidine -2- amine

The title compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 27 (371 mg, 1.80 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (10:90) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min, filtered, washed with diethyl ether (5 mL) and dried to give the title compound (150 mg) as a light green solid. Yield: 17.4%. Melting point: 250°C-252°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 10.17 (s, 1H), 9.06 (d, J 4, 1H), 8.80 (d, J 3.2, 1H), 8.67 (d, J 8.4 , 1H), 8.58 (s, 1H), 8.22 (t, J 10.8, 1H), 7.75 (dd, J 8, 4, 1H), 3.52 (s, 2H), 3.00-2.90 (m, 4H), 2.61 -2.52 (m, 4H). MS (m/z): 448.3 (M+H); Calcd. for [ _{C24H23F2N7 +} H]: _448.21 Example 15A ₅ - Fluoro - 4-(8- fluoroquinolin- 6- yl )- N-(5-((4- methylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl ) pyrimidin -2- amine hydrochloride

To 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-((4-methylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)pyrimidine- To a mixture of 2-amine (Example 15, 500 mg, 0.34 mmol) in methanol (3 mL) was added 35% aqueous hydrochloric acid (122 mg, 3.4 mmol). The solution became clear over a period of time and then a solid formed during stirring. The mixture was stirred for 30 min and the solid was filtered, washed sequentially with methanol (5 mL) and diethyl ether (10 mL) and dried under vacuum to give the title compound (130 mg) as a yellow solid. Yield: 80%. Melting point: 250°C-253°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.98 (s, 1H), 11.69 (s, 1H), 9.08 (dd, J 4, 1.2, 1H), 8.95-8.91 (m, m , 1H), 8.70 (d, J 8.4, 1H), 8.66-8.59 (m, 2H), 8.42-8.31 (m, 1H), 8.24 (d, J 12, 1H), 8.11-8.04 (m, 1H) , 7.77 (dd, J 8.4, 4, 1H), 4.45 (s, 2H), 3.75-3.60 (m, 4H), 3.45-3.30 (m, 4H), 2.80 (s, 3H). MS (m/z): _448.26 (M+H); Calcd. for [ _{C24H23F2N7 +} H]: _448.21 . Example 16 2-(6-(2-((5-((4- ethylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl ) amino )-5- fluoropyrimidin - 4 -yl )-8- fluoro -2 -methylquinolin- 4 -yl ) propan -2- ol

The title compound was synthesized from Intermediate 31 (500 mg, 1.43 mmol) and Intermediate 9 (315 mg, 1.43 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (12:88) as eluents. The pooled fractions were evaporated and the residue was stirred with petroleum ether (10 mL) for 20 min, filtered and dried to afford the title compound (180 mg) as a yellow solid. Yield: 23.6%. Melting point: 253°C-256°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 10.09 (s, 1H), 9.51 (s, 1H), 8.75 (d, J 7.6, 1H), 8.27 (d, J 8.8, 1H) , 8.18 (d, J 2, 1H), 8.10 (d, J 12, 1H), 7.71 (dd, J 8.8, 2, 1H), 7.60 (s, 1H), 3.43 (s, 2H), 2.71 (s , 3H), 2.50-2.20 (m, 10H), 0.96 (t, J 6.8, 3H). MS (m/z): _534.35 (M+H); Calcd. for [ _{C29H33F2N7O +} H]: _534.28 . Example 16A 2-(6-(2-((5-((4- ethylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl ) amino )-5- fluoropyrimidin - 4 -yl )-8- fluoro -2 -methylquinolin- 4 -yl ) propan -2- ol hydrochloride

To 2-(6-(2-((5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl) To a mixture of -8-fluoro-2-methylquinolin-4-yl)propan-2-ol (Example 16, 180 mg, 0.34 mmol) in methanol (3 mL) was added 35% aqueous hydrochloric acid (123 mg, 3.4 mmol). The solution became clear over a period of time and then a solid formed during stirring. The mixture was stirred for 30 min and the solid was filtered, washed with diethyl ether (10 mL) and dried under vacuum to give the title compound (110 mg) as a yellow solid. Yield: 57.2%. Melting point: 275°C-278°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.92 (bs, 1H), 11.44 (bs, 1H), 9.53 (s, 1H), 8.89 (d, J 3.6, 1H), 8.61 ( d, J 1.2, 1H), 8.37-8.32 (m, 1H), 8.20-8.12 (m, 2H), 7.64 (s, 1H), 4.47 (s, 2H), 3.75-3.55 (m, 4H), 3.50 -3.38 (m, 6H), 2.74 (s, 3H), 1.74 (s, 6H), 1.25 9t, J 7.2, 3H). MS (m/z): _534.37 (M+H); Calcd. for [ _{C29H33F2N7O +} H]: _534.28 . Example 17 4-(6-((5- fluoro - 4-(8- fluoro - 4-(2 -hydroxyprop- 2- yl )-2 -methylquinolin -6- yl ) pyrimidin -2- yl ) Amino ) pyridin - 3 -yl ) hexahydropyrazine- 1 -carboxylic acid tert-butyl ester

The title compound was synthesized from Intermediate 31 (500 mg, 1.43 mmol) and Intermediate 5 (398 mg, 1.43 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (3.5:96.5) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 20 min, filtered and dried to afford the title compound (145 mg) as a light yellow solid. Yield: 17.1%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.83 (s, 1H), 9.47 (s, 1H), 8.70 (d, J 3.6, 1H), 8.14 (d, J 8.8, 1H) , 8.08 (d, J 12.4, 1H), 8.04 (d, J 3.6, 1H), 7.60 (s, 1H), 7.48-7.44 (m, 1H), 5.69 (s, 1H), 3.50-3.44 (m, 4H), 3.10-3.05 (m, 4H), 2.71 (s, 3H), 1.72 (s, 6H), 1.41 (s, 9H). MS (m/z): _592.44 ( _M +H); Calcd. for [ _{C31H35F2N7O3 +} H]: _592.29 . Example 17A 2-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl )-2- Methylquinolin- 4 -yl ) propan -2- ol

Following general procedure-4, from 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)-2-methylquinolin-6-yl)pyrimidine -2-yl)amino)pyridin-3-yl)tert-butyl hexahydropyrazine-1-carboxylate (Example 17, 140 mg, 0.28 mmol) The title compound (60 mg) was synthesized as a pale yellow solid. Yield: 54%. Melting point: 258°C-261°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.79 (s, 1H), 9.47 (s, 1H), 8.69 (d, J 3.6, 1H), 8.11 (d, J 9.2, 1H) , 8.07 (d, J 11.6, 1H), 8.00 (d, J 2.8, 1H), 7.60 (s, 1H), 7.42 (dd, J 8.8, 2.8, 1H), 5.69 (s, 1H), 3.05-2.99 (m, 4H), 2.88-2.81 (m, 4H), 2.71 (s, 3H), 1.72 (s, 6H). MS (m/z): _492.49 (M+H); Calcd. for [ _{C26H27F2N7O +} H]: _492.23 . Example 17B 2-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl )-2- Methylquinolin- 4 -yl ) propan -2- ol hydrochloride

To 2-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methyl To a mixture of (quinolin-4-yl)propan-2-ol (Example 17A, 70 mg, 0.14 mmol) in methanol (2 mL) was added 35% aqueous hydrochloric acid (52 mg, 3.4 mmol). The solution became clear over a period of time and then a solid formed during stirring. The mixture was stirred for 30 min, diluted with methyl tert-butyl ether (5 mL) and the solid was filtered, washed with methyl tert-butyl ether (10 mL) and dried under vacuum to give the title compound as a yellow solid ( 37 mg). Yield: 49%. Melting point: 278°C-280°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.74 (s, 1H), 9.55-9.45 (m, 3H), 8.91 (d, J 3.6, 1H), 8.17 (d, J 12.8, 1H), 8.00 (d, J 2.4, 1H), 7.88 (d, J 9.6, 1H), 7.63 (s, 1H), 3.49-3.42 (m, 4H), 3.29-3.20(m, 4H), 2.73 ( s, 3H), 1.72(s, 6H). MS (m/z): 492.49 (M+H-HCl); Calcd. for [ _{C26H27F2N7O.HCl +} H _- HCl]: _492.23 . Example 18 2-(6-(2-((5-(4- ethylhexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino )-5- fluoropyrimidin - 4 -yl )-8- Fluoro -2 -methylquinolin- 4 -yl ) propan -2- ol

The title compound was synthesized from Intermediate 31 (500 mg, 1.43 mmol) and Intermediate 20 (295 mg, 1.43 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (10:90) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min, filtered, washed with diethyl ether (5 mL) and dried to afford the title compound (110 mg) as a light yellow solid. Yield: 14.8%. Melting point: 206°C-208°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.80 (s, 1H), 9.47 (s, 1H), 8.69 (d, J = 3.6, 1H), 8.12 (d, J = 8.8, 1H), 8.08 (d, J = 12.0, 1H), 8.01 (d, J = 2.8, 1H), 7.60 (s, 1H), 7.44 (dd, J = 8.8, 2.8, 1H), 5.70 (s, 1H ), 3.12 (br. s, 4H), 2.72 (s, 3H), 2.42-2.51 (m, 4H, under DMSO signal), 2.37 (q, J = 7.2, 2H), 1.72 (s, 6H), 1.03 (t, J = 7.2, 3H). MS (m/z): _520.52 (M+H); Calcd. for [ _{C28H31F2N7O +} H]: _520.27 . Example 18A 2-(6-(2-((5-(4- ethylhexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino )-5- fluoropyrimidin - 4 -yl )-8- Fluoro -2 -methylquinolin- 4 -yl ) propan -2- ol hydrochloride

To 2-(6-(2-((5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8-fluoro - To a mixture of 2-methylquinolin-4-yl)propan-2-ol (Example 18, 100 mg, 0.19 mmol) in methanol (2.5 mL) was added 35% aqueous hydrochloric acid (70 mg, 1.9 mmol). The resulting clear solution was stirred for 30 min, diluted with diethyl ether (5 mL) and the solid formed was filtered, washed with diethyl ether (10 mL) and dried under vacuum to give the title compound (25 mg) as a yellow solid. Yield: 37%. Melting point: 215°C-220°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.69 (s, 1H), 11.27 (s, 1H), 9.50 (s, 1H), 8.90 (d, J 3.2, 1H), 8.18 ( br. s, 1H), 8.10 (d, J 12.4, 1H), 8.02 (d, J 2.8, 1H), 7.89 (d, J 9.6, 1H), 7.63 (s, 1H), 3.85 (d, J 12.8 , 2H), 3.59 (d, J 11.6, 2H), 3.27 (t, J 12.8, 2H), 3.23-3.05 (m, 4H), 2.73 (s, 1H), 1.73 (s, 6H), 1.30 (t , J 7.2, 3H). MS (m/z): _520.51 (M+H); Calcd. for [ _{C28H31F2N7O +} H]: _520.27 . Example 19 4-(4-( Difluoromethyl )-8- fluoro -2 -methylquinolin -6- yl )-N-(5-(4- ethylhexahydropyrazin- 1 -yl ) pyridine -2- yl )-5- fluoropyrimidin -2- amine

The title compound was synthesized from Intermediate 36 (500 mg, 1.46 mmol) and Intermediate 20 (302 mg, 1.46 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (4.6:95.4) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min, the solid was filtered, washed with diethyl ether (5 mL) and dried to give the title compound (50 mg) as a yellow solid. Yield: 6.7%. Melting point: 237°C-238°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.87 (s, 1H), 8.73 (d, J 3.6, 1H), 8.71 (br. s, 1H), 8.24 (d, J 9.0, 1H), 8.10-8.02 (m, 2H), 7.86 (s, 1H), 7.68 (t, J 53.6, 1H), 7.43 (dd, J 9.2, 3.2, 1H), 3.14 (br. s, 4H), 2.80 (s, 3H), 2.54 (br (s, 4H), 2.45-2.32 (m, 2H), 1.04 (t, J 7.2, 3H). MS (m/z): 512.46 (M+H); [ Calcd for C ₂₆ H ₂₅ F ₄ N ₇ + H]: 512.22. Example 19A 4-(4-( difluoromethyl )-8- fluoro -2 -methylquinolin -6- yl )-N-(5 -(4- Ethylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-5- fluoropyrimidin -2- amine hydrochloride

To 4-(4-(difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-N-(5-(4-ethylhexahydropyrazin-1-yl)pyridine- To a mixture of 2-yl)-5-fluoropyrimidin-2-amine (Example 19, 40 mg, 0.08 mmol) in methanol (1 mL) was added 35% aqueous hydrochloric acid (29 mg, 0.8 mmol). The resulting clear solution was stirred for 30 min, diluted with diethyl ether (4 mL) and the solid formed was filtered, washed with diethyl ether (2 mL) and dried under vacuum to give the title compound (35 mg) as a yellow solid. Yield: 79%. Melting point: 195°C-197°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.36 (s, 1H), 10.95 (s, 1H), 8.91 (d, J 3.2, 1H), 8.68 (s, 1H), 8.25 ( d, J 11.6, 1H), 8.10-7.97 (m, 2H), 7.86-7.92 (m, 2H), 7.69 (t, J 53.2, 1H), 3.84 (d, J 10.8, 2H), 3.59 (d, J 11.6, 2H), 3.30-3.05 (m, 6H), 2.81 (s, 3H), 1.29 (t, J 7.2, 3H). MS (m/z): _512.52 (M+H); Calcd. for [ _{C26H25F4N7 +} H]: _512.22 . Example 20 4-(6-((4-(4-( difluoromethyl )-8- fluoro -2 -methylquinolin -6- yl )-5- fluoropyrimidin -2- yl ) amino ) pyridine -3 -yl ) hexahydropyrazine- 1 -carboxylic acid tert-butyl ester

The title compound was synthesized from Intermediate 36 (500 mg, 1.46 mmol) and Intermediate 5 (407 mg, 1.46 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (3.5:96.5) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min, the solid was filtered and dried to afford the title compound (110 mg) as a yellow solid. Yield: 12.9%. Melting point: 224°C-227°C. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 8.77 (s, 1H), 8.51 (d, J 3.6, 1H), 8.34 (d, J 9.2, 1H), 8.31-8.17 (m, 2H) , 8.08 (s, 1H), 7.64 (s, 1H), 7.42 (dd, J 9.2, 3.2, 1H), 7.19 (t, J 54.4, 1H), 3.68-3.61 (m, 4H), 3.18-3.10 ( m, 4H), 1.52 (s, 9H). MS (m/z): _584.23 (M ₊ H); Calcd. for [ _{C29H29F4N7O2 +} H]: _584.24 . Example 20A 4-(4-( difluoromethyl )-8- fluoro -2 -methylquinolin -6- yl )-5- fluoro -N-(5-( hexahydropyrazin- 1 -yl ) pyridine -2- yl ) pyrimidin -2- amine

Following general procedure-4, from 4-(6-((4-(4-(difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoropyrimidin-2-yl )amino)pyridin-3-yl)tert-butyl hexahydropyrazine-1-carboxylate (Example 20, 100 mg, 0.17 mmol) The title compound (50 mg) was synthesized as a yellow solid. Yield: 60%. Melting point: 262°C-264°C. ¹ H-NMR (δ ppm, CDCl ₃ , 400 MHz): 9.86 (s, 1H), 8.72 (d, J 8.36, 1H), 8.70 (br. s, 1H), 8.23 (d, J 11.6, 1H) , 8.05 (d, J 8.8, 1H), 8.01 (d, J 3.2, 1H), 7.86 (s, 1H), 7.68 (t, J 53.6, 1H), 7.40 (dd, J 9.2, 3.2, 1H), 3.08-3.03 (m, 4H), 2.91-2.85 (m, 4H), 2.79 (s, 3H). MS (m/z): _484.45 (M+H); Calcd. for [ _{C24H21F4N7 +} H]: _484.19 . Example 20B 4-(4-( difluoromethyl )-8- fluoro -2 -methylquinolin -6- yl )-5- fluoro -N-(5-( hexahydropyrazin- 1 -yl ) pyridine -2- yl ) pyrimidin -2- amine hydrochloride

To 4-(4-(difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyrazin-1-yl)pyridine- To a mixture of 2-yl)pyrimidin-2-amine (Example 20A, 40 mg, 0.08 mmol) in methanol (1 mL) was added 35% aqueous hydrochloric acid (30 mg, 0.8 mmol). The resulting clear solution was stirred for 30 min, diluted with diethyl ether (4 mL) and the solid formed was filtered, washed with diethyl ether (2 mL) and dried. The obtained solid was dissolved in methanol-dichloromethane 1:4 (20 mL), filtered and the filtrate was concentrated in vacuo, and the residue was co-distilled with toluene (5.0 mL) to give the title as a yellow solid compound (25 mg). Yield: 67%. Melting point: 263°C-265°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 10.76 (br. s, 1H), 9.06 (br. s, 2H), 8.84 (d, J 3.2, 1H), 8.69 (s, 1H ), 8.25 (d, J 12.0, 1H), 8.03 (d, J 2.8, 1H), 7.97 (d, J 9.2, 1H), 7.89 (s, 1H), 7.80 (br. s, 1H), 7.69 ( t, J 54, 1H), 3.41-3.35 (m, 4H), 3.30-3.22 (m, 4H), 2.80 (s, 3H). MS (m/z): _484.49 (M+H); Calcd. for [ _{C24H21F4N7 +} H]: _484.19 . Example 21 4-(4-( Difluoromethyl )-8- fluoro -2 -methylquinolin -6- yl )-N-(5-((4- ethylhexahydropyrazin- 1 -yl ) Methyl ) pyridin -2- yl )-5- fluoropyrimidin -2- amine

The title compound was synthesized from Intermediate 36 (500 mg, 1.46 mmol) and Intermediate 9 (322 mg, 1.46 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (12:88) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min, the solid was filtered and dried to afford the title compound (140 mg) as a yellow solid. Yield: 18.2%. Melting point: 219°C-222°C. MS (m/z): 526.3 (M+H) _; Calcd. for [ _{C27H27F4N7 +} H]: _526.24 . Example 21A 4-(4-( Difluoromethyl )-8- fluoro -2 -methylquinolin -6- yl )-N-(5-((4- ethylhexahydropyrazin- 1 -yl ) Methyl ) pyridin -2- yl )-5- fluoropyrimidin -2- amine hydrochloride

To 4-(4-(difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-N-(5-((4-ethylhexahydropyrazin-1-yl)methyl yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine (Example 21, 100 mg, 0.19 mmol) in methanol (2.5 mL) was added 35% aqueous hydrochloric acid (69 mg, 1.9 mmol). The resulting clear solution was stirred for 30 min, diluted with diethyl ether (4 mL) and the solid formed was filtered, washed with diethyl ether (2 mL) and dried. The obtained solid was dissolved in methanol-dichloromethane 1:4 (20 mL), filtered and the filtrate was concentrated in vacuo, and the residue was co-distilled with toluene (5.0 mL) to afford the title as a tan solid. Compound (53 mg). Yield: 50%. Melting point: 218°C-220°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.82 (br. s, 1H), 11.19 (br. s, 1H), 8.90 (d, J 3.2, 1H), 8.72 (s, 1H ), 8.58 (s, 1H), 8.30-8.13 (m, 3H), 7.89 (s, 1H), 7.70 (t, J 53.6, 1H), 5.0-4.6 (m, 7H), 3.80-3.10 (m, 9H), 1.25 (t, J = 7.2, 3H). MS (m/z): 526.25 (M+H-HCl); Calcd. for [ _{C27H27F4N7.HCl +} H _- HCl]: _526.24 . Example 22 N-(5-((4- ethylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoro - 4-(2- fluoropropane -2- yl )-2 -methylquinolin -6- yl ) pyrimidin -2- amine

The title compound was synthesized from Intermediate 39 (500 mg, 1.42 mmol) and Intermediate 9 (313 mg, 1.42 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (6.7:93.3) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min, the solid was filtered, washed with diethyl ether (5 mL) and dried to afford the title compound (170 mg) as a light brown solid. Yield: 22.3%. Melting point: 207°C-209°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 10.14 (s, 1H), 8.99 (s, 1H), 8.76 (d, J 3.6, 1H), 8.28 (m, 3H), 7.68 ( dd, J 8.8, 2.4, 1H), 7.64 (s, 1H), 3.45 (s, 2H), 2.75 (s, 3H), 2.60-2.20 (m, 10H), 1.95 (d, J 22.8, 6H), 0.98 (t, J 7.2, 3H). MS (m/z): _536.33 (M+H); Calcd. for _{[ C29H32F3N7} +H]: _536.27 . Example 22A N-(5-((4- ethylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoro - 4-(2- fluoropropane -2- yl )-2 -methylquinolin -6- yl ) pyrimidin -2- amine hydrochloride

To N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-(2-fluoropropane- 2-yl)-2-methylquinolin-6-yl)pyrimidin-2-amine (Example 22, 150 mg, 0.28 mmol) in methanol (3 mL) was added 35% aqueous hydrochloric acid (102 mg, 2.8 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (6 mL) and stirred for 30 min. The solid formed was filtered, washed with methyl tert-butyl ether (5 mL) and dried to give the title compound (60 mg) as a light yellow solid. Yield: 37%. Melting point: 250°C-253°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.56 (br. s, 1H), 10.95 (br. s, 1H), 8.64 (s, 1H), 8.54 (d, J 3.2, 1H ), 8.25 (s, 1H), 7.96 (d, J 8.8, 1H), 7.88-7.80 (m, 2H), 7.32 (s, 3H), 4.10 (br. s, 2H), 3.40-2.70 (m, 10H), 2.41 (s, 3H), 2.20-2.00 (m, 2H), 1.63 (d, J 22.8, 6H), 0.91 (t, J 7.2, 3H). MS (m/z): _536.39 (M+H-HCl); Calcd. for _{[ C29H32F3N7.HCl} +H]: _536.27 . Example 23 4-(6-((5- fluoro - 4-(8- fluoro - 4-(2- fluoroprop- 2- yl )-2 -methylquinolin -6- yl ) pyrimidin -2- yl ) Amino ) pyridin - 3 -yl ) hexahydropyrazine- 1 -carboxylic acid tert-butyl ester

The title compound was synthesized from Intermediate 39 (500 mg, 1.42 mmol) and Intermediate 5 (396 mg, 1.42 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (6.5:93.5) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min, the solid was filtered, washed with diethyl ether (5 mL) and dried to give the title compound (220 mg) as a yellow solid. Yield: 26.1%. Melting point: 224°C-226°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 8.94 (s, 1H), 8.47 (d, J 3.6, 1H), 8.33 (d, J 8.8, 1H), 8.20-8.14 (m, 2H), 8.06 (d, J 2.8, 1H), 7.48 (s, 1H), 7.37 (dd, J 8.8, 2.8, 1H), 3.62 (t, J 4.8, 4H), 3.11 (t, J 4.8, 4H ), 2.85 (s, 3H), 2.00 (d, J 22.4, 6H), 1.50 (s, 9H). MS (m/z): _594.34 (M+H); Calcd. for _{[ C31H34F3N7O2 +} H]: _594.28 . Example 23A 5- fluoro - 4-(8- fluoro - 4-(2- fluoroprop- 2- yl )-2 -methylquinolin -6- yl )-N-(5-( hexahydropyrazine -1 -yl ) pyridin -2- yl ) pyrimidin - 2- amine

Following general procedure-4, from 4-(6-((5-fluoro-4-(8-fluoro-4-(2-fluoroprop-2-yl)-2-methylquinolin-6-yl)pyrimidine -2-yl)amino)pyridin-3-yl)tert-butyl hexahydropyrazine-1-carboxylate (Example 23, 200 mg, 0.34 mmol) The title compound (120 mg) was synthesized as a yellow solid. Yield: 72%. Melting point: 204°C-206°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.88 (s, 1H), 8.94 (s, 1H), 8.71 (d, J 3.6, 1H), 8.14 (d, J 11.6, 1H) , 8.07 (d, J 8.8, 1H), 8.03 (d, J 3.2, 1H), 7.64 (s, 1H), 7.42 (dd, J 9.2, 3.2, 1H), 3.14 (t, J 5.2, 4H), 2.99 (t, J 5.2, 4H), 2.74 (s, 3H), 1.95 (d, J 22.8, 6H). MS (m/z): _494.49 (M+H); Calcd. for [ _{C27H27F4N7 +} H]: _494.23 . Example 23B 5- fluoro - 4-(8- fluoro - 4-(2- fluoroprop- 2- yl )-2 -methylquinolin -6- yl )-N-(5-( hexahydropyrazine -1 -yl ) pyridin -2- yl ) pyrimidin - 2- amine hydrochloride

To 5-fluoro-4-(8-fluoro-4-(2-fluoroprop-2-yl)-2-methylquinolin-6-yl)-N-(5-(hexahydropyrazine-1- yl)pyridin-2-yl)pyrimidin-2-amine (Example 23A, 80 mg, 0.16 mmol) in methanol (2 mL) was added 35% aqueous hydrochloric acid (59 mg, 1.6 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (6 mL) and stirred for 30 min. The solid formed was filtered, washed with methyl tert-butyl ether (5 mL) and dried to give the title compound (60 mg) as a light yellow solid. Yield: 68%. Melting point: 240°C-243°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.77 (br. s, 1H), 9.53 (br. s, 2H), 8.95-8.89 (m, 2H), 8.22-8.12 (m, 2H), 7.97 (d, J 2.8, 1H), 7.86 (d, J 9.2, 1H), 7.67 (s, 1H), 3.46 (br. s, 4H), 3.25 (br. s, 4H), 2.75 ( s, 3H), 1.95 (d, J 22.4, 6H). MS (m/z): 494.47 (M+H-HCl); Calcd. for [ _{C27H27F4N7.HCl +} H _- HCl]: _494.23 . Example 24 5- fluoro -N-(5-((4- methylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl )-4-( quinolin -6- yl ) pyrimidine -2- amine

The title compound was synthesized from Intermediate 2 (500 mg, 1.93 mmol) and Intermediate 27 (397 mg, 1.93 mmol) following general procedure 3. After work-up, the crude product was purified by combi-flash using methanol and DCM (11.5:89.5) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min, the solid was filtered, washed with diethyl ether (5 mL) and dried to afford the title compound (320 mg) as a yellow solid. Yield: 38.7%. Melting point: 196°C-198°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 10.08 (s, 1H), 9.01 (dd, J 4.4, 1.2, 1H), 8.77 (d, J 3.2, 1H), 8.71 (s, 1H), 8.59 (d, J 7.6, 1H), 8.42 (d, J 9.2, 1H), 8.27-8.16 (m, 3H), 7.72 (dd, J 8.4, 2.4, 1H), 7.64 (dd, J 8.0 , 4.0, 1H), 3.42 (s, 2H), 2.56-2.24 (m, 8H,), 2.15 (s, 3H). MS (m/z): _430.29 (M+H); Calcd. for [ _C24H24FN7 +H]: _430.22 . Example 24A 5- fluoro -N-(5-((4- methylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl )-4-( quinolin -6- yl ) pyrimidine -2- Amine hydrochloride

To 5-fluoro-N-(5-((4-methylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine (Example 24, 300 mg, 0.70 mmol) in methanol (7.5 mL) was added 35% aqueous hydrochloric acid (260 mg, 7.1 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (15 mL) and stirred for 1 h. The resulting solid was filtered, washed with methyl tert-butyl ether (15 mL) and dried to give the title compound (60 mg) as a light brown solid. Yield: 68%. Melting point: 235°C-238°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 12.00 (br. s, 1H), 11.47 (br. s, 1H), 9.23 (dd, J 4.8, 1.2, 1H), 9.01 (d , J 8.4, 1H), 8.94 (d, J 2.8, 1H), 8.91 (s, 1H), 8.64-8.57 (m, 2H), 8.44 (d, J 9.2, 1H), 8.33 (d, J 9.2, 1H), 8.10 (d, J 9.2, 1H), 8.10 (d, J 9.2, 1H), 8.10 (d, J 9.2, 1H), 7.92 (dd, J 8.4, 4.8, 1H), 4.44 (br.s , 2H), 3.70-3.55 (m, 4H), 3.50-3.30 (m, 4H), 2.80 (s, 3H). MS (m/z): 430.33 (M+H-HCl); Calcd. for [ _{C24H24FN7.HCl} +H _- HCl]: _430.22 . Example 25 N-(5-((4- ethylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl )-5- fluoro - 4-(7- fluoroquinolin- 6- yl ) pyrimidine -2- amine

The title compound was synthesized from Intermediate 41 (500 mg, 1.80 mmol) and Intermediate 9 (400 mg, 1.80 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (8.7:91.3) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min, the solid was filtered, washed with diethyl ether (5 mL) and dried to afford the title compound (370 mg) as a light yellow solid. Yield: 44.5%. Melting point: 198°C-200°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 10.19 (s, 1H), 9.03 (br. d, J 3.2, 1H), 8.00 (d, J 1.6, 1H), 8.59 (d, J 8.0, 1H), 8.47 (d, J 8.0, 1H), 8.21-8.15 (m, 2H), 7.99 (d, J 11.2, 1H), 7.68-7.60 (m, 2H), 3.39 (s, 2H) , 2.40-2.20 (m, 10H), 0.96 (t, J = 10.8, 3H). MS (m/z): _462.34 (M+H); Calcd. for [ _{C25H25F2N7 +} H]: _462.22 . Example 25A N-(5-((4- ethylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl )-5- fluoro - 4-(7- fluoroquinolin- 6- yl ) pyrimidine -2- amine hydrochloride

To N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(7-fluoroquinolin-6-yl)pyrimidine- To a mixture of 2-amine (Example 25, 330 mg, 0.72 mmol) in methanol (8.25 mL) was added 35% aqueous hydrochloric acid (260 mg, 7.1 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (24.7 mL) and stirred for 1 h. The resulting solid was filtered, washed with methyl tert-butyl ether (20 mL) and dried to give the title compound (290 mg) as a light yellow solid. Yield: 81%. Melting point: 255°C-257°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.94 (br. s, 1H), 11.51 (br. s, 1H), 9.12 (dd, J = 4.4, 1.6, 1H), 8.96 ( d, J = 1.6, 1H), 8.74 (d, J = 7.4, 1H), 8.62-8.56 (m, 2H), 8.28 (d, J = 9.2, 1H), 8.14-8.04 (m, 2H), 7.74 (dd, J = 8.4, 4.8, 1H), 4.43 (br. s, 2H), 3.80-3.10 (m, 10H), 1.24 (t, J = 7.2, 3H). MS (m/z): _462.35 (M+H-HCl); Calcd. for [ _{C25H25F2N7.HCl +} H _- HCl]: 462.22. Example 26 4-(6-((5- fluoro - 4-(7- fluoroquinolin- 6- yl ) pyrimidin -2- yl ) amino ) pyridin - 3 -yl ) hexahydropyrazine- 1 - carboxylic acid tributyl ester

The title compound was synthesized from Intermediate 41 (500 mg, 1.80 mmol) and Intermediate 5 (500 mg, 1.80 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (2.3:97.7) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min, the solid was filtered, washed with diethyl ether (5 mL) and dried to afford the title compound (360 mg) as a yellow solid. Yield: 38.5%. Melting point: 248°C-250°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.93 (s, 1H), 9.03 (dd, J 4.0, 1.6, 1H), 8.74 (d, J 1.6, 1H), 8.58 (d, J 7.6, 1H), 8.06-7.95 (m, 3H), 7.63 (dd, J 8.4, 4.4, 1H), 7.42 (dd, J 9.2, 3.2, 1H), 3.48-3.42 (m, 4H), 3.08- 3.02 (m, 4H), 1.41 (s, 9H). MS (m/z): _520.31 (M ₊ H); Calcd. for [ _{C27H27F2N7O2 +} H]: _520.22 . Example 26A 5- fluoro - 4-(7- fluoroquinolin- 6- yl )-N-(5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) pyrimidin -2- amine

Following General Procedure-4, from 4-(6-((5-fluoro-4-(7-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine - tert-butyl 1-carboxylate (Example 26, 330 mg, 0.64 mmol) The title compound (250 mg) was synthesized as a yellow solid. Yield: 93%. Melting point: 228°C-230°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.89 (s, 1H), 9.05-9.00 (m, 1H), 9.03 (s, 1H), 8.58 (d, J 7.6, 1H), 8.45 (d, J 7.6, 1H), 8.02-7.87 (m, 3H), 7.63 (dd, J 8.4, 4.0, 1H), 7.37 (d, J 8.8, 1H), 3.02-2.94 (m, 4H), 2.84-2.78 (m, 4H). MS (m/z): _420.47 (M+H); Calcd. for [ _{C22H19F2N7 +} H]: _420.17 . Example 26B 5- fluoro - 4-(7- fluoroquinolin- 6- yl )-N-(5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) pyrimidin -2- amine hydrochloride

To 5-fluoro-4-(7-fluoroquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine (example 26A, 230 mg, 0.55 mmol) in methanol (5.75 mL) was added 35% aqueous hydrochloric acid (200 mg, 5.48 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (17.3 mL) and stirred for 1 h. The solid formed was filtered, washed with methyl tert-butyl ether (20 mL) and dried to give the title compound (190 mg) as a tan solid. Yield: 76%. Melting point: 259°C-262°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.87 (br. s, 1H), 9.66 (br. s, 2H), 9.08-9.13 (m, 1H), 8.98 (d, J = 2.0, 1H), 8.72 (d, J = 8.4, 1H), 8.59 (d, J = 7.6, 1H), 8.16 (d, J = 9.2, 1H), 8.10 (d, J = 11.6, 1H), 7.99 (d, J = 2.8, 1H), 7.84 (d, J = 9.6, 1H), 7.72 (dd, J = 8.0, 4.4, 1H), 3.42 (bs, 4H), 3.22 (bs, 4H). MS (m/z): 420.48 (M+H); Calcd. for [ _{C22H19F2N7.HCl +} H _- HCl]: _420.17 . Example 27 N-(5-(4- ethylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-5- fluoro - 4-(7- fluoroquinolin- 6- yl ) pyrimidin -2- amine

The title compound was synthesized from Intermediate 41 (500 mg, 1.80 mmol) and Intermediate 20 (371 mg, 1.80 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (5.8:94.2) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min, the solid was filtered, washed with diethyl ether (5 mL) and dried to give the title compound (200 mg) as a yellow solid. Yield: 24.8%. Melting point: 258°C-260°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.88 (s, 1H), 9.03-9.01 (m, 1H), 8.73 (bs, 1H), 8.58 (d, J 7.6, 1H), 8.45 (d, J 7.6, 1H), 8.02-7.88 (m, 3H), 7.63 (dd, J 8.4, 4.4 1H), 7.42-7.38 (m, 1H), 3.03 (bs, 4H), 2.60-2.40 ( m, 4H), 2.40-2.30 (m, 2H), 1.02 (t, J = 6.8, 3H). MS (m/z): _448.47 . (M+H); Calcd. for [ _{C24H23F2N7 +} H]: _448.20 . Example 27A N-(5-(4- ethylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-5- fluoro - 4-(7- fluoroquinolin- 6- yl ) pyrimidin -2- amine Hydrochloride

To N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(7-fluoroquinolin-6-yl)pyrimidin-2-amine ( To a mixture of Example 27, 180 mg, 0.40 mmol) in methanol (4.5 mL) was added 35% aqueous hydrochloric acid (147 mg, 4.02 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (13.5 mL) and stirred for 1 h. The resulting solid was filtered, washed with methyl tert-butyl ether (20 mL) and dried to give the title compound (160 mg) as a yellow solid. Yield: 82.5%. Melting point: 240°C-242°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.91 (bs, 1H), 11.42 (bs, 1H), 9.11 (dd, J 4.4, 1.2, 1H), 8.99(d, J 1.6, 1H), 8.72 (d, J 8.4, 1H), 8.59 (d, J 8.0, 1H), 8.20 (dd, J 9.6, 2.4, 1H), 8.10 (d, J 11.6, 1H), 8.00 (d, J 2.4, 1H), 7.82 (d, J 9.6, 1H), 7.73 (d, J 8.0, 4.4, 1H), 3.84 (d, J 12.8, 2H), 3.57 (d, J 11.6, 2H), 3.27 (d , J 12.0, 2H), 3.04-3.00 (m, 4H), 1.29 (t, J 7.2, 3H). MS (m/z): 448.46. (M+H); Calcd. for [ _{C24H23F2N7.HCl +} H _- HCl]: _448.20 . Example 28 N-(5-(4-( dimethylamino ) hexahydropyridin- 1 -yl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidine -2- amine

The title compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 43 (400 mg, 1.80 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (16:84) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (20 mL) for 30 min, the solid was filtered, washed with diethyl ether (20 mL) and dried to give the title compound (270 mg) as a yellow solid. Yield: 32%. Melting point: 238°C-240°C. Melting point: 238°C-240°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.48 (s, 1H), 9.06 (d, J 2.8, 1H), 8.73 (d, J 4, 1H), 8.66 (d, J 8.4 , 1H), 8.56 (s, 1H), 8.20 (d, J 12, 1H), 8.07-8.01 (m, 2H), 7.74 (dd, J 8.4, 4, 1H), 7.50 (dd, J 9.2, 2.8 , 1H), 3.76 (d, J 12, 2H), 2.72-2.64 (m, 2H), 2.61-2.50 (m, 7H), 1.99 (d, J 12, 2H), 1.72-1.60 (m, 2H) . MS (m/z): _462.40 . (M+H); Calcd. for [ _{C25H25F2N7 +} H]: _462.21 . Example 28A N-(5-(4-( dimethylamino ) hexahydropyridin- 1 -yl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidine -2- amine hydrochloride

To N-(5-(4-(dimethylamino)hexahydropyridin-1-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidine- To a mixture of 2-amine (Example 28, 250 mg, 0.54 mmol) in methanol (6.25 mL) was added 35% aqueous hydrochloric acid (20 mg, 5.4 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (18.75 mL) and stirred for 1 h. The resulting solid was filtered, washed with methyl tert-butyl ether (20 mL) and dried to give the title compound (230 mg) as a tan solid. Yield: 85%. Melting point: 292°C-294°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.87 (bs, 1H), 11.14 (bs, 1H), 9.08 (dd, J 4, 1.6, 1H), 8.95 (d, J 4, 1H), 8.70 (dd, J 8.8, 1.6, 1H), 8.61 (s, 1H), 8.25 (d, J 9.6, 1H), 8.21 (dd, J 12, 1.2, 1H), 7.97 (d, J 2.4 , 1H), 7.82-7.76 (m, 2H), 3.86 (d, J 12, 2H), 3.38-3.28 (m, 1H), 2.81 (t, J 12, 2H), 2.71 (s, 3H), 2.70 (s, 3H), 2.17 (d, J 12, 2H), 1.85-1.72 (m, 2H). MS (m/z): 462.40. (M+H); Calcd. for [ _{C25H25F2N7.HCl +} H _- HCl]: _462.21 . Example 29 4-(6-((5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidin -2- yl ) amino ) pyridin - 3 -yl ) hexahydropyrazin -2- one

The title compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 45 (350 mg, 1.80 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (5.7:94.3) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (20 mL) for 30 min, the solid was filtered, washed with diethyl ether (20 mL) and dried to give the title compound (180 mg) as a yellow solid. Yield: 23%. Melting point: 205°C-207°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.87 (s, 1H), 9.06 (dd, J 4, 1.6, 1H), 8.73 (d, J 3.2, 1H), 8.66 (d, J 8.8, 1H), 8.56 (s, 1H), 8.20 (d, J 12, 1H), 8.06 (d, J 9.2, 2H), 8.03 (d, J 2.8, 1H), 7.74 (dd, J 8.8, 4.4, 1H), 3.71 (s, 2H), 3.42-3.37 (m, 2H), 3.40-3.30 (m, 2H). MS (m/z): _434.42 . (M+H); Calcd. for [ _{C22H17F2N7O +} H]: _434.15 . Example 29A 4-(6-((5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidin -2- yl ) amino ) pyridin - 3 -yl ) hexahydropyrazin -2- one salt salt

To 4-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazin-2-one (example 29, 150 mg, 0.35 mmol) in methanol (3.75 mL) was added 35% aqueous hydrochloric acid (13 mg, 3.5 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (11.25 mL) and stirred for 1 h. The resulting solid was filtered, washed with methyl tert-butyl ether (20 mL) and dried to give the title compound (125 mg) as a tan solid. Yield: 77%. Melting point: 236°C-238°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.91 (s, 1H), 9.08 (d, J 4, 1H), 8.94 (d, J 2.4, 1H), 8.70 (d, J 8 , 1H), 8.59 (s, 1H), 8.25-8.17 (m, 3H), 7.89 (d, J 2.8, 1H), 7.77 (dd, J 8, 3.6, 2H), 3.81 (s, 2H), 3.50 -3.45 (m, 2H), 3.38-3.32 (m, 2H). MS (m/z): 434.38. (M+H); Calculated for [C ₂₂ H ₁₇ F ₂ N ₇ O.HCl + H-HCl]: 434.15 Example 30 N-(5-(4 -cyclopropylhexa Hydropyrazin - 1 -yl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidin -2- amine

The title compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 47 (390 mg, 1.80 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (6.8:93.2) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min to obtain a solid which was filtered, washed with diethyl ether (5 mL) and dried to afford the title compound (180 mg ). Yield: 27%. Melting point: 246°C-248°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.83 (s, 1H), 9.06 (dd, J 4, 1.6, 1H), 8.72 (d, J 4, 1H), 8.67 (d, J 8.4, 1H), 8.56 (s, 1H), 8.21 (d, J 12.8, 1H), 8.03 (d, J 9.2, 1H), 8.00 (d, J 3.2, 1H), 7.75 (dd, J 8.4, 4, 1H), 7.47 (dd, J 8.8, 2.8, 1H), 3.11-3.05 (m, 4H), 2.71-2.65 (m, 4H), 1.65 (quintet, J 3.6, 1H), 0.46-0.41 (m , 2H), 0.36-0.31 (m, 2H). MS (m/z): _460.40 . (M+H); Calcd. for [ _{C25H23F2N7 +} H]: _460.20 . Example 30A N-(5-(4 -cyclopropylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidine -2- Amine hydrochloride

To N-(5-(4-cyclopropylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-amine (Example 30, 200 mg, 0.435 mmol) in methanol (4 mL) was added 35% aqueous hydrochloric acid (159 mg, 4.35 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (12 mL) and stirred for 1 h. The resulting solid was filtered, washed with methyl tert-butyl ether (15 mL) and dried to give the title compound (200 mg) as a tan solid. Yield: 91%. Melting point: 296°C-298°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.64 (s, 1H), 9.09 (dd, J 4, 1.6, 1H), 8.98-8.92 (m, 1H), 8.20 (d, J 8.4, 1H), 8.61 (s, 1H), 8.20 (dd, J 12, 1.6, 1H), 8.18-8.12 (m, 1H), 8.00 (d, J 2.8, 1H), 7.84-7.75 (m, 2H ), 3.84 (d, J 12, 2H), 3.59 (d, J 10, 2H), 3.39-3.22 (m, 4H), 2.95-2.87 (m, 1H), 1.22-1.14 9m, 2H), 0.85- 0.78 (m, 2H). MS (m/z): 460.40. (M+H); Calcd. for [ _{C25H23F2N7.HCl +} H _- HCl]: _459.50 . Example 31 1-(4-(6-((5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidin -2- yl ) amino ) pyridin - 3 -yl ) hexahydropyrazine -1 -yl ) ethan - 1 -one

The title compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 49 (400 mg, 1.80 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (4.8:95.2) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (20 mL) for 30 min to obtain a solid which was filtered, washed with diethyl ether (20 mL) and dried to afford the title compound (300 mg ). Yield: 40%. Melting point: 240°C-242°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.87 (s, 1H), 9.06 (dd, J 4, 1.6, 1H), 8.73 (d, J 4, 1H), 8.67 (d, J 8.8, 1H), 8.56 (s, 1H), 8.21 (d, J 13.2, 1H), 8.06 (d, J 9.2, 1H), 8.04 (d, J 3.2, 1H), 7.75 (dd, J 8.8, 4, 1H), 7.51 (dd, J 9.2, 3.2, 1H), 3.62-3.56 (m, 4H), 3.18-3.12 (m, 2H), 3.10-3.05 (m, 2H), 2.03 (s, 3H) . MS (m/z): 462.49. (M+H); Calcd. for [ _{C24H21F2N7O +} H]: _462.18 Example 31A 1-(4-(6-((5- _fluoro - 4- (8- fluoroquinolin- 6- yl ) pyrimidin -2- yl ) amino ) pyridin - 3 -yl ) hexahydropyrazin- 1 -yl ) ethan - 1 -one hydrochloride

To 1-(4-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1- To a mixture of ethyl)ethan-1-one (Example 31, 260 mg, 0.56 mmol) in methanol (6.5 mL) was added 35% aqueous hydrochloric acid (210 mg, 5.6 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (20 mL) and stirred for 1 h. The resulting solid was filtered, washed with methyl tert-butyl ether (20 mL) and dried to give the title compound (200 mg) as a tan solid. Yield: 96%. Melting point: 228°C-230°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.97 (s, 1H), 9.09 (dd, J 4, 1.2, 1H), 8.95 (d, J 3.2, 1H), 8.71 (d, J 8, 1H), 8.61 (s, 1H), 8.27 (dd, J 9.2, 3.5, 1H), 8.19 (d, J 11.6, 1H), 7.92 (d, J 3.5, 1H), 7.80-7.74 (m , 2H), 3.62 (t, J 4.8, 4H), 3.24 (t, J 4.8, 2H), 3.17 (t, J 4.8, 2H), 2.05 (s, 3H). MS (m/z): 462.49. (M+H); Calculated for [C ₂₄ H ₂₁ F ₂ N ₇ O.HCl + H-HCl]: 462.18 Example 32 5- Fluoro - 4-(8- fluoroquinoline -6- yl )-N-(5-(4-(2,2,2- trifluoroethyl ) hexahydropyrazin- 1 -yl ) pyridin -2- yl ) pyrimidin -2- amine

The title compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 51 (469 mg, 1.80 mmol) following General Procedure-3. After working up, the crude product was suspended in MeOH (50 ml) and DCM (50 ml) and stirred for 30 min to obtain a solid. The solid was filtered and dried under vacuum to obtain the title compound (280 mg) as a yellow solid. Yield: 31%. Melting point: 260°C-262°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.86 (s, 1H), 9.05 (dd, J 4, 2.8, 1H), 8.72 (d, J 3.2, 1H), 8.66 (d, J 8.4, 1H), 8.55 (s, 1H), 8.11 (d, J 12, 1H), 8.04 (d, J 9.2, 1H), 8.02 (d, J 2.8, 1H), 7.74 (dd, J 8.4, 4, 1H), 7.48 (dd, J 8.4, 2.8, 1H), 3.25 (q, J 10.4, 2H), 3.17-3.11 (m, 4H), 2.80-2.73 (m, 4H). MS (m/z): 502.52 (M+H); Calcd. for [ _C24H20F5N7 +H]: _502.17 Example 32A ₅ - Fluoro - 4-(8- _{fluoroquinolin} - 6- yl )- N-(5-(4-(2,2,2- trifluoroethyl ) hexahydropyrazin- 1 -yl ) pyridin -2- yl ) pyrimidin -2- amine hydrochloride

To 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-(2,2,2-trifluoroethyl)hexahydropyrazin-1-yl)pyridine- To a mixture of 2-yl)pyrimidin-2-amine (Example 32, 250 mg, 0.50 mmol) in methanol (5 mL) was added 35% aqueous hydrochloric acid (182 mg, 5.0 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (15 mL) and stirred for 1 h. The resulting solid was filtered, washed with methyl tert-butyl ether (10 mL) and dried to give the title compound (200 mg) as a tan solid. Yield: 75%. Melting point: 238°C-240°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.89 (s, 1H), 9.09 (dd, J 4, 1.2, 1H), 8.95 (d, J 3.2, 1H), 8.70 (d, J 8.4, 1H), 8.61 (s, 1H), 8.24-8.18 (m, 2H), 7.90 (bs, 1H), 7.78 (dd, J 8.4, 4.0, 1H), 7.22 (d, J 9.6, 1H) , 3.45-3.31 (m, 2H), 3.29-3.23 (m, 4H), 2.90-2.82 (m, 4H). MS (m/z): _502.50 ( _M +H); Calcd. for [ _{C24H20F5N7.HCl} +H-HCl]: _502.17 . Example 33 5- fluoro - 4-(8- fluoroquinolin- 6- yl )-N-(5-(4-( methylsulfonyl ) hexahydropyrazin- 1 -yl ) pyridin -2- yl ) Pyrimidin -2- amine

The title compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 53 (469 mg, 1.80 mmol) following General Procedure-3. After working up, the crude product was suspended in MeOH (1 ml) and DCM (9 ml) and stirred for 30 min to obtain a solid. The solid was filtered, washed with diethyl ether (20 ml) and dried under vacuum to obtain the title compound (220 mg) as a yellow solid. Yield: 25%. Melting point: 295°C-297°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.90 (s, 1H), 9.06 (d, J 2.8, 1H), 8.74 (d, J 2.8, 1H), 8.67 (d, J 8.4 , 1H), 8.57 (s, 1H), 8.21 (d, J 12.4, 2H), 8.10-8.05 (m, 1H), 7.75 (d, J 8.4, 1H), 7.53 (d, J 12.4, 1H), 3.28-3.20 (m, 4H), 2.93 (s, 3H), 2.60-2.50 (m, 4H). Example 33A 5- fluoro - 4-(8- fluoroquinolin- 6- yl )-N-(5-(4-( methylsulfonyl ) hexahydropyrazin- 1 -yl ) pyridin -2- yl ) Pyrimidin -2- amine hydrochloride

To 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-(methylsulfonyl)hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidine - To a mixture of 2-amine (Example 33, 200 mg, 0.40 mmol) in methanol (5 mL) was added 35% aqueous hydrochloric acid (150 mg, 4.0 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (15 mL) and stirred for 1 h. The resulting solid was filtered, washed with methyl tert-butyl ether (20 mL) and dried to give the title compound (210 mg) as a yellow solid. Yield: 98%. Melting point: 258°C-260°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 12.01 (s, 1H), 9.08 (dd, J 4, 1.2, 1H), 8.94 (t, J 3.2, 1H), 8.70 (d, J 8.4, 1H), 8.59 (s, 1H), 8.27 (d, J 9.6, 1H), 8.00 (d, J 11.6, 1H), 7.95 (d, J 2.4, 1H), 7.84-7.74 (m, 2H ), 3.34-3.25 (m, 8H), 2.95 (s, 3H). MS (m/z): 497.80. (M ₊ H); Calcd. for [ _{C23H21F2N7O2S.HCl +} H _- HCl]: _498.14 . Example 34 cyclopropyl (4-(6-((5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidin -2- yl ) amino ) pyridin - 3 - yl ) hexahydropyrazine- 1- yl ) methanone

The title compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 55 (440 mg, 1.80 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (4.7:95.3) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (20 mL) for 30 min, the solid was filtered, washed with diethyl ether (20 mL) and dried to give the title compound (300 mg) as a yellow solid. Yield: 34%. Melting point: 236°C-238°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.89 (s, 1H), 9.06 (d, J 3, 1H), 8.73 (d, J 3, 1H), 8.67 (d, J 7.6 , 1H), 8.56 (s, 1H), 8.21 (d, J 12.8, 1H), 8.10-8.03 (m, 2H), 7.74 (dd, J 8.4, 4.4, 1H), 7.53 (dd, J 8.4, 2.4 , 1H), 3.88-3.80 (m, 2H), 3.67-3.58 (m, 2H), 3.20-3.03 (m, 4H), 2.07-1.98 (m, 1H), 0.78-0.65 (m, 4H). MS (m/z): _488.47 . (M+H); Calcd. for [ _{C26H23F2N7O +} H]: _488.19 . Example 34A Cyclopropyl (4-(6-((5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidin -2- yl ) amino ) pyridin - 3 - yl ) hexahydropyrazine- 1- yl ) methanone hydrochloride

Cyclopropyl(4-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1 To a mixture of -yl)methanone (Example 34, 260 mg, 0.53 mmol) in methanol (5 mL) was added 35% aqueous hydrochloric acid (150 mg, 4.0 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (20 mL) and stirred for 1 h. The resulting solid was filtered, washed with methyl tert-butyl ether (20 mL) and dried to give the title compound (280 mg) as a yellow solid. Yield: 100%. Melting point: 228°C-230°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.98 (s, 1H), 9.08 (dd, J 4, 1.2, 1H), 8.95-8.92 (m, 1H), 8.70 (d, J 8.4, 1H), 8.60 (s, 1H), 8.27 (dd, J 9.6, 2.8, 1H), 8.20 (d, J 12, 1H), 7.93 (d, J 2.8, 1H), 7.82-7.74 (m, 2H), 3.87 (bs, 2H), 3.65 (bs, 2H), 3.27 (bs, 2H), 3.19 (bs, 2H), 2.09-2.01 (m, 1H), 0.79-0.70 (m, 4H). MS (m/z): 488.0. (M+H); Calcd. for [ _{C26H23F2N7O.HCl +} H _- HCl]: _488.19 . Example 35 5- fluoro - 4-(8- fluoroquinolin- 6- yl )-N-(5-(3-( trifluoromethyl )-5,6 -dihydro- [1,2,4] tri Azolo [4,3-a] pyrazin -7(8H) -yl ) pyridin -2- yl ) pyrimidin -2- amine

The title compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 57 (510 mg, 1.80 mmol) following General Procedure-3. After working up, the crude product was suspended in a mixture of MeOH (2 ml) and DCM (18 ml) and stirred for 30 min to obtain a solid. The solid was filtered, washed with diethyl ether (20 ml) and dried under vacuum to obtain the title compound (90 mg) as a light yellow solid. Yield: 10%. Melting point: 288°C-290°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.97 (s, 1H), 9.07 (d, J 4.4, 1H), 8.75 (d, J 3.6, 1H), 8.67 (d, J 7.6 , 1H), 8.57 (s, 1H), 8.25-8.19 (m, 2H), 8.13 (d, J 9.2, 1H), 7.75 (dd, J 8.4, 4, 1H), 7.68 (d, J 9.2, 1H ), 4.68 (s, 2H), 4.29 (d, J 5.6, 2H), 3.77 (t, J 5.6, 2H). MS (m/z): _526.48 . (M+H); _Calcd . for [ _C24H16F5N9 +H]: _526.14 . Example 35A 5- fluoro - 4-(8- fluoroquinolin- 6- yl )-N-(5-(3-( trifluoromethyl )-5,6 -dihydro- [1,2,4] tri Azolo [4,3-a] pyrazin -7(8H) -yl ) pyridin -2- yl ) pyrimidin -2- amine hydrochloride

To 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazole To a mixture of [4,3-a]pyrazin-7(8H)-yl)pyridin-2-yl)pyrimidin-2-amine (Example 35, 70 mg, 0.1 mmol) in methanol (1.75 mL) was added 35% aqueous hydrochloric acid (50 mg, 1 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (5.25 mL) and stirred for 1 h. The solid formed was filtered, washed with methyl tert-butyl ether (10 mL) and dried to give the title compound (60 mg) as a yellow solid. Yield: 80%. Melting point: 270°C-272°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.80 (s, 1H), 9.08 (dd, J 4, 1.2, 1H), 8.94 (d, J 3.2, 1H), 8.70 (d, J 8.4, 1H), 8.60 (s, 1H), 8.32 (dd, J 9.6, 2.8, 1H), 8.10 (d, J 11.6, 1H), 8.11 (d, J 2.8, 1H), 7.87 (d, J 9.6, 1H), 7.77 (dd, J 8.4, 4, 1H), 4.80 (s, 2H), 4.32 (t, J 5.2, 2H), 3.87 (t, J 5.2, 2H). MS (m/z): _524.54 . (MH); Calcd. for [ _{C24H16F5N9 -} H]: _524.45 . Example 36 N-(5-((4- ethylhexahydropyrazin- 1 -yl ) methyl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoro - 4 - isopropyl- 2 -Methylquinolin - 6- yl ) pyrimidin -2- amine

The title compound was synthesized from Intermediate 79 (400 mg, 1.20 mmol) and Intermediate 9 (264 mg, 1.20 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (7.5:92.5) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min to obtain a solid which was filtered, washed with diethyl ether (5 mL) and dried to afford the title compound (300 mg ). Yield: 24%. Melting point: 182°C-184°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 10.14 (s, 1H), 8.75 (d, J 3.6, 1H), 8.74 (s, 1H), 8.20 (d, J 4.4, 1H) , 8.18 (s, 1H), 8.11 (d, J 12, 1H), 7.68 (dd, J 8.4, 1.6, 1H), 7.52 (s, 1H), 3.76 (septet, J 6.8, 1H), 3.43 ( s, 2H), 3.45-3.35 (m, 2H), 2.70 (s, 3H), 2.45-2.25 (m, 8H), 1.39 (d, J 6.8, 6H), 0.96 (t, J 7.2, 3H). MS (m/z): 518.39. (M+H); Calcd. for [ _{C29H33F2N7 +} H]: _518.28 Example 36A N-(5-((4- _{ethylhexahydropyrazine} - 1 -yl ) methyl ) pyridin -2- yl ) -5- fluoro - 4-(8- fluoro - 4 - isopropyl- 2 -methylquinolin -6- yl ) pyrimidin -2- amine hydrochloride

To N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-isopropyl-2- To a mixture of methylquinolin-6-yl)pyrimidin-2-amine (Example 36, 140 mg, 0.27 mmol) in methanol (1.75 mL) was added 35% aqueous hydrochloric acid (98.6 mg, 2.70 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (12 mL) and stirred for 1 h. The resulting solid was filtered, washed with methyl tert-butyl ether (15 mL) and dried to give the title compound (100 mg) as a light yellow solid. Yield: 66%. Melting point: 208°C-210°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 12.05 (bs, 1H), 11.56 (bs, 1H), 8.90 (d, J 3.2, 1H), 8.74 (s, 1H), 8.65- 8.59 (m, 1H), 8.40-8.30 (m, 1H), 8.17 (d, J 11.6, 1H), 8.11 (d, J 8.8, 1H), 7.61 (s, 1H), 4.48 (bs, 2H), 3.78 (Septet, J 6.8, 1H), 3.70-3.60 (m, 4H), 3.50-3.38 (m, 4H), 3.72-3.10 (m, 2H), 2.74 (s, 3H), 1.40 (d, J 6.8, 6H), 1.25 (t, J 7.2, 3H). MS (m/z): 518.35. (M+H); Calcd. for [ _{C29H33F2N7.HCl +} H _- HCl]: _518.28 . Example 37 N-(5-(4- ethylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoro - 4 - isopropyl- 2 -methylquine Lin -6- yl ) pyrimidin - 2- amine

The title compound was synthesized from Intermediate 79 (400 mg, 1.20 mmol) and Intermediate 20 (247 mg, 1.20 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using methanol and DCM (7.8:92.2) as eluents. The pooled fractions were evaporated and the residue was stirred with diethyl ether (10 mL) for 30 min to obtain a solid which was filtered, washed with diethyl ether (5 mL) and dried to afford the title compound (150 mg). Yield: 24%. Melting point: 211°C-213°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.84 (s, 1H), 8.71 (s, 1H), 8.69 (d, J 3.6, 1H), 8.10 (d, J 11.6, 1H) , 8.03 (d, J 8.8, 1H), 8.02 (s, 1H), 7.52 (s, 1H), 7.42 (dd, J 9.2, 3.2, 1H), 3.74 (septet, J 6.8, 1H), 3.15- 3.09 (m, 4H), 2.70 (s, 3H), 2.55-2.45 (m, 4H), 2.37 (q, J 6.8, 2H), 1.38 (d, J 6.8, 6H), 1.02 (t, J 6.8, 3H). MS (m/z): _504.55 . (M+H); Calcd. for [ _{C28H31F2N7 +} H]: _504.26 . Example 37A N-(5-(4- ethylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoro - 4 - isopropyl- 2 -methylquine ( Pyrimin -6- yl ) pyrimidin -2- amine hydrochloride

To N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-isopropyl-2-methylquinoline To a mixture of -6-yl)pyrimidin-2-amine (Example 37, 140 mg, 0.278 mmol) in methanol (2.8 mL) was added 35% aqueous hydrochloric acid (101 mg, 2.78 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (8.4 mL) and stirred for 1 h. The resulting solid was filtered, washed with methyl tert-butyl ether (15 mL) and dried to give the title compound (110 mg) as a light yellow solid. Yield: 71%. Melting point: 228°C-230°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.84 (s, 1H), 11.42 (bs, 1H), 8.92 (d, J 3.2, 1H), 8.70 (s, 1H), 8.22 ( d, J 9.6, 2.8, 1H), 8.13 (d, J 11.6, 1H), 8.00 (d, J 2.8, 1H), 7.85 (d, J 9.6, 1H), 7.60 (s, 1H), 3.85 (d , J 12.8, 2H), 3.76 (septet, J 7.0, 1H), 3.59 (d, J 11.6, 2H), 3.29 (t, J 11.6, 2H), 3.20-3.05 (m, 4H), 2.73 (s , 3H), 1.38 (d, J 7, 6H), 1.30 (t, J 7.2, 3H). MS (m/z): 504.61. (M+H); Calcd. for [ _{C28H31F2N7.HCl +} H _- HCl]: _504.26 . Example 38 1-(6-((5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidin -2- yl ) amino ) pyridin - 3 -yl )-4 -methylhexahydropyridine- 4- ol

The title compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 59 (373 mg, 1.80 mmol) following General Procedure-3. After working up, the crude product was stirred with a mixture of DCM (50 ml) and MeOH (50 ml) for 45 min to obtain a solid. The solid was filtered and washed with DCM (20 ml). The solid was triturated with diethyl ether (10 ml) and the solid was filtered. The solid was washed with diethyl ether (5 ml) and dried to obtain the title compound (210 mg) as a yellow solid. Yield: 26%. Melting point: 198°C-200°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.79 (s, 1H), 9.05 (d, J 4, 1H), 8.71 (d, J 3.2, 1H), 8.66 (d, J 8.4 , 1H), 8.55 (s, 1H), 8.20 (d, J 12, 1H), 8.02 (s, 1H), 8.01 (d, J 5.2, 1H), 7.74 (dd, J 8.4, 3.2, 1H), 7.46 (dd, J 9.2, 2.8, 1H), 4.29 (s, 1H), 3.29-3.21 (m, 2H), 3.13-3.06 (m, 2H), 1.60-1.55 (m, 4H), 1.14 (s, 3H). MS (m/z): 449.44 (M+H); Calcd. for _{[ C24H22F2N6O +} H]: _449.18 . Example 38A 1-(6-((5- fluoro - 4-(8- fluoroquinolin- 6- yl ) pyrimidin -2- yl ) amino ) pyridin - 3 -yl )-4 -methylhexahydropyridine- 4- alcohol hydrochloride

To 1-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)-4-methylhexahydropyridine-4 - To a mixture of alcohol (Example 38, 200 mg, 0.446 mmol) in methanol (4 mL) was added 35% aqueous hydrochloric acid (163 mg, 4.46 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (12 mL) and stirred for 1 h. The resulting solid was filtered, washed with methyl tert-butyl ether (15 mL) and dried to give the title compound (195 mg) as a red solid. Yield: 71%. Melting point: 249°C-251°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.67 (s, 1H), 9.08 (dd, J 4.4, 1.6, 1H), 8.92 (d, J 2.8, 1H), 8.70 (d, J 8.4, 1H), 8.60 (s, 1H), 8.29 (dd, J 9.2, 2.4, 1H), 8.21 (d, J 11.6, 1H), 7.90 (bs, 1H), 7.77 (dd, J 8.4, 4 , 1H), 5.33 (bs, -OH), 3.43-3.36 (m, 2H), 3.35-3.25 (m, 2H), 1.81-1.70 (m, 2H), 1.69-1.60 (m, 2H), 1.18 ( s, 3H). MS (m/z): _449.46 (M+H); Calcd. for _{[ C24H22F2N6O +} H]: 449.48. Example 39 (±)-4-(6-((4-(4-(1-(( tertiary butoxycarbonyl ) amino ) ethyl )-8- fluoro -2 -methylquinoline -6- Base )-5- fluoropyrimidin -2- yl ) amino ) pyridin - 3 -yl ) hexahydropyrazine- 1 -carboxylic acid tert-butyl ester

The title compound was synthesized from Intermediate 63 (500 mg, 1.15 mmol) and Intermediate 5 (320 mg, 1.15 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using MeOH and DCM (2:98) as eluents. Distillation of the combined clean fractions from the column afforded a solid. The solid was triturated with diethyl ether (10 ml). The solid was filtered and washed with diethyl ether (5 ml) to obtain the title compound (210 mg) as a yellow solid. Yield: 32.1%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.93 (s, 1H), 8.73 (s, 1H), 8.72 (s, 1H), 8.18-8.10 (m, 2H), 8.06 (d , J 3.6, 1H), 7.86 (d, J 7.6, 1H), 7.56 (s, 1H), 7.50 (d, J 6, 1H), 5.50-5.43 (m, 1H), 3.51-3.45 (m, 4H ), 3.11-3.05 (m, 4H), 2.27 (s, 3H), 1.45 (d, J 7.2, 3H), 1.42 (s, 9H), 1.38 (s, 9H). MS (m/z): _677.44 (M ₊ H); Calcd. for [ _{C35H42F2N8O4 +} H]: _677.33 . Example 39A (±)-4-(4-(1 -aminoethyl )-8- fluoro -2 -methylquinolin -6- yl )-5- fluoro -N-(5-( hexahydropyrazine -1 -yl ) pyridin -2- yl ) pyrimidin -2- amine

Following general procedure-4, from 4-(6-((4-(4-(1-((tert-butoxycarbonyl)amino)ethyl)-8-fluoro-2-methylquinoline-6 -yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester (Example 39, 250 mg, 0.37 mmol) was synthesized as an off-white solid Title compound (80 mg). Yield: 45%. Melting point: 241°C-243°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.86 (s, 1H), 8.77 (s, 1H), 8.71 (d, J 4, 1H), 8.11 (d, J 12.4, 1H) , 8.07 (d, J 8.8, 1H), 8.01 (d, J 2.8, 1H), 7.81 (s, 1H), 7.43 (dd, J 9.2, 2.8, 1H), 4.86-4.79 (m, 1H), 3.07 -3.01 (m, 4H), 2.88-2.82 (m, 4H), 2.72 (s, 3H), 1.43 (d, J 6.8, 3H). MS (m/z): _477.54 (M+H); Calcd. for [ _{C25H26F2N8 +} H]: _477.22 . Example 39B (±)-4-(4-(1 -aminoethyl )-8- fluoro -2 -methylquinolin -6- yl )-5- fluoro -N-(5-( hexahydropyrazine -1 -yl ) pyridin -2- yl ) pyrimidin -2- amine hydrochloride

To 4-(4-(1-aminoethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyrazin-1-yl) To a mixture of pyridin-2-yl)pyrimidin-2-amine (Example 39A, 60 mg, 0.13 mmol) in methanol (1.2 mL) was added 35% aqueous hydrochloric acid (46 mg, 1.3 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (3.6 mL) and stirred for 1 h. The reaction mixture was distilled under vacuum to give a solid. Diethyl ether (12 ml) was added to the solid. The solid was filtered and washed with diethyl ether (5 mL) and dried to give the title compound (35 mg) as a yellow solid. Yield: 54%. Melting point: 253°C-256°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.77 (bs, 1H), 9.60-9.45 (m, 2H), 9.17 (bs, 3H), 8.96 (s, 1H), 8.69 (s , 1H), 8.23-8.15 (m, 2H), 8.06 (s, 1H), 7.99 (s, 1H), 7.88 (d, J 8.8, 1H), 5.35-5.25 (m, 1H), 3.55-3.45 ( m, 4H), 3.30-3.20 (m, 4H), 2.76 (s, 3H), 1.69 (d, J 6.8, 3H). MS (m/z): _477.53 (M+H); Calcd. for [ _{C25H26F2N8 +} H-HCl]: _477.22 . Example 40 (±)-4-(6-((4-(4-(1-(( tertiary butoxycarbonyl ) amino ) ethyl )-8- fluoroquinolin- 6- yl )-5- Fluoropyrimidin -2- yl ) amino ) pyridin - 3 -yl ) hexahydropyrazine- 1 -carboxylic acid tert-butyl ester

The title compound was synthesized from Intermediate 71 (500 mg, 1.15 mmol) and Intermediate 5 (320 mg, 1.15 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using MeOH and DCM (2:98) as eluents. Distillation of the combined clean fractions from the column afforded a solid. The solid was triturated with diethyl ether (10 ml). The solid was filtered and washed with diethyl ether (5 ml) to obtain the title compound (210 mg) as a yellow solid. Yield: 32.1%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.93 (s, 1H), 9.04 (d, J 4.4, 1H), 8.78 (s, 1H), 8.74 (d, J 3.6, 1H) , 8.17 (d, J 12, 1H), 8.11 (d, J 8.8, 1H), 8.07 (d, J 3.2, 1H), 7.92 (d, J 7.2, 1H), 7.69 (d, J 4.4, 1H) , 7.48 (dd, J 9.2, 2.8, 1H), 5.55-5.45 (m, 1H), 3.52-3.45 (m, 4H), 3.11-3.05 (m, 4H), 1.46 (d, J 6.8, 3H), 1.43 (s, 9H), 1.38 (s, 9H). MS (m/z): _663.51 (M ₊ H); Calcd. for [ _{C34H40F2N8O4 +} H]: _663.31 . Example 40A (±)-4-(4-(1 -aminoethyl )-8- fluoroquinolin- 6- yl )-5- fluoro -N-(5-( hexahydropyrazin- 1 -yl ) Pyridin -2- yl ) pyrimidin -2- amine

Following general procedure-4, from 4-(6-((4-(4-(1-((tert-butoxycarbonyl)amino)ethyl)-8-fluoroquinolin-6-yl)-5 -Fluoropyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester (Example 40, 850 mg, 1.28 mmol) synthesized the title compound as an off-white solid (325 mg ). Yield: 55%. Melting point: >270°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.84 (s, 1H), 9.02 (d, J 4.4, 1H), 8.84 (s, 1H), 8.72 (d, J 3.6, 1H) , 8.15 (d, J 11.6, 1H), 8.07 (d, J 9.2, 1H), 8.01 (d, J 2.8, 1H), 7.92 (d, J 4.4, 1H), 7.43 (dd, J 9.2, 2.8, 1H), 4.90-4.82 (m, 1H), 3.07-3.01 (m, 4H), 2.88-2.82 (m, 4H), 2.20 (bs, 3H), 1.44 (d, J 6.4, 3H). MS (m/z): 463.55 ( _M +H); Calcd. for [ _{C24H24F2N8 +} H]: _463.21 Example 40B (±)-4-(4-(1 -aminoethyl )- 8- fluoroquinolin- 6- yl )-5- fluoro -N-(5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) pyrimidin -2- amine dihydrochloride

To 4-(4-(1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl ) pyrimidin-2-amine (Example 40A, 60 mg, 0.13 mmol) in methanol (1.2 mL) was added 35% aqueous hydrochloric acid (46 mg, 1.3 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (3.6 mL) and stirred for 1 h. The reaction mixture was distilled under vacuum to give a solid. Diethyl ether (12 ml) was added to the solid. The solid was filtered and washed with diethyl ether (5 mL) and dried to give the title compound (35 mg) as a yellow solid. Yield: 54%. Melting point: 253°C-256°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.37 (bs, 1H), 9.55-9.50 (m, 2H), 9.27 (bs, 3H), 9.17 (d, J 4.4, 1H), 8.92 (s, 1H), 8.75 (s, 1H), 8.21 (d, J 11.2, 1H), 8.10-8.00 (m, 3H), 7.96 (d, J 7.2, 1H), 5.40-5.30 (m, 1H ), 3.51-3.45 (m, 4H), 3.29-3.20 (m, 4H), 1.71 (d, J 6.8, 3H). MS (m/z): 463.47 ( _M +H-2HCl); Calcd. for [ _{C24H24F2N8.2HCl +} H-2HCl]: _463.21 . Example 41 (±)-4-(6-((5- fluoro - 4-(8- fluoro - 4-(1- hydroxyethyl ) quinolin -6- yl ) pyrimidin -2- yl ) amino ) pyridine -3 -yl ) hexahydropyrazine- 1 -carboxylic acid tert-butyl ester

The title compound was synthesized from Intermediate 74 (500 mg, 1.6 mmol) and Intermediate 5 (430 mg, 1.6 mmol) following General Procedure-3. After workup, the crude product was purified by combi-flash using MeOH and DCM (4:96) as eluents. Distillation of the combined clean fractions from the column afforded a solid. The solid was triturated with diethyl ether (20 ml). The solid was filtered and washed with diethyl ether (20 ml) to obtain the title compound (70 mg) as a yellow solid. Yield: 8%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.90 (s, 1H), 9.03 (d, J 4.4, 1H), 8.81 (s, 1H), 8.73 (d, J 3.6, 1H) , 8.16 (d, J 11.6, 1H), 8.10 (d, J 8.8, 1H), 8.06 (d, J 2.8, 1H), 7.81 (d, J 4.4, 1H), 7.47 (d, J 9.2, 3.2, 1H), 5.78 (d, J 4, 1H), 5.58-5.50 (m, 1H), 3.52-3.44 (m, 4H), 3.12-3.05 (m, 4H), 1.54 (d, J 6.8, 3H), 1.42 (s, 9H). MS (m/z): _564.49 [ _M +H]; Calcd. for [ _{C29H31F2N7O3 +} H]: _564.25 . Example 41A (±)-1-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl ) quinolin- 4 -yl ) ethanol

Following general procedure-4, from 4-(6-((5-fluoro-4-(8-fluoro-4-(1-hydroxyethyl)quinolin-6-yl)pyrimidin-2-yl)amino) Pyridin-3-yl)tert-butyl hexahydropyrazine-1-carboxylate (Example 41, 310 mg, 0.55 mmol) The title compound (120 mg) was synthesized as a yellow solid. Yield: 47%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.86 (s, 1H), 9.03 (d, J 4.4, 1H), 8.81 (s, 1H), 8.72 (d, J 3.2, 1H) , 8.15 (d, J 12, 1H), 8.08 (d, J 8.8, 1H), 8.02 (d, J 2.8, 1H), 7.81 (d, J 4.4, 1H), 7.43 (d, J 8.8, 2.8, 1H), 5.85-5.80 (m, 1H), 5.60-5.50 (m, 1H), 3.08-3.00 (m, 4H), 2.90-2.80 (m, 4H), 1.54 (d, J 6.4, 3H). MS (m/z): _464.59 [ _{M +} H]; Calcd. for [ _C24H23F2N7O +H]: 464.19. Example 41B (±)-1-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl ) quinoline- 4 -yl ) ethanol trimesylate

To 1-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinoline-4 To a mixture of -yl)ethanol (Example 41A, 50 mg, 0.108 mmol) in methanol ( ₁ mL) was added _CH3SO3H (15.6 mg, 0.162 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (5 mL) and stirred for 1 h. The reaction mixture was distilled under vacuum to give a solid. Diethyl ether (10 ml) was added to the solid. The solid was filtered and washed with diethyl ether (10 mL) and dried to give the title compound (35 mg) as a yellow solid. Yield: 58%. Melting point: Hygroscopic ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.56 (s, 1H), 9.07 (d, J 3.6, 1H), 8.94 (d, J 2.4, 1H), 8.89 (bs, 2H), 8.80 (s, 1H), 8.17 (d, J 11.6, 1H), 8.12 (d, J 9.6, 1H), 8.00 (s, 1H), 7.83 (d, J 4.4, 1H), 7.80 (d, J 9.6, 1H), 5.57-5.50 (m, 1H), 3.48-3.40 (m, 4H), 3.35-3.25 (m, 4H), 2.35 (s, 9H), 1.55 (d, J 6.4 , 3H). MS (m/z): _{464.10 [ M +} H _{- 3CH3SO3H} ]; Calcd for [ _C24H23F2N7O .( _3CH3SO3H )+H _{- 3CH3SO3H} ]: 464.19. Example 42 (±)-(1-(8- fluoro -6-(5- fluoro -2-((5-(4- methylhexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino ) Pyrimidin - 4 -yl ) quinolin- 4 -yl ) ethyl ) carbamate tert-butyl ester

The title compound was synthesized from Intermediate 71 (1 g, 2.38 mmol) and Intermediate 11 (457 mg, 2.38 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using MeOH and DCM (9:91 ) as eluents. Distillation of the combined clean fractions from the column afforded a solid. The solid was triturated with diethyl ether (10 ml). The solid was filtered and washed with diethyl ether (5 ml) to obtain the title compound (310 mg) as a yellow solid. Yield: 23%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.88 (s, 1H), 9.04 (d, J 4.4, 1H), 8.78 (s, 1H), 8.74 (d, J 3.6, 1H) , 8.17 (d, J 11.6, 1H), 8.10 (d, J 9.2, 1H), 8.04 (d, J 2.8, 1H), 7.91 (d, J 7.2, 1H), 7.69 (d, J 4.8, 1H) , 7.48 (dd, J 9.2, 2.8, 1H), 5.55-5.45 (m, 1H), 3.18-3.10 (m, 4H), 2.50-2.44 (m, 4H), 2.24 (s, 3H), 1.47 (d , J 7.6, 3H), 1.37 (s, 9H). MS (m/z): _577.48 (M ₊ H); Calcd. for [ _{C30H34F2N8O2 +} H]: _577.28 . Example 42A (±)-4-(4-(1 -aminoethyl )-8- fluoroquinolin- 6- yl )-5- fluoro -N-(5-(4 - methylhexahydropyrazine- 1- yl ) pyridin -2- yl ) pyrimidin -2- amine

Following general procedure-4, from (±)-(1-(8-fluoro-6-(5-fluoro-2-((5-(4-methylhexahydropyrazin-1-yl)pyridine-2- Base) amino) pyrimidin-4-yl) quinolin-4-yl) ethyl) tert-butyl carbamate (Example 42, 300 mg, 0.52 mmol) The title compound (190 mg) was synthesized as a yellow solid . Yield: 77%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.86 (s, 1H), 9.02 (d, J 4.4, 1H), 8.83 (s, 1H), 8.72 (d, J 3.6, 1H) , 8.15 (d, J 11.6, 1H), 8.07 (d, J 9.2, 1H), 8.03 (d, J 4.8, 1H), 7.92 (d, J 3.6, 1H), 7.45 (dd, J 9.2, 3, 1H), 4.90-4.82 (m, 1H), 3.20-3.09 (m, 4H), 2.52-2.45 (m, 4H), 2.25 (bs, 2H), 2.23 (s, 3H), 1.44 (d, J 6.4 , 3H). MS (m/z): _476.61 (M+H); Calcd. for [ _{C25H26F2N8 +} H]: _477.22 . Example 42B (±)-4-(4-(1 -aminoethyl )-8- fluoroquinolin- 6- yl )-5- fluoro -N-(5-(4 - methylhexahydropyrazine- 1- yl ) pyridin -2- yl ) pyrimidin -2- amine trihydrochloride

4-(4-(1-Aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(4-methyl 35% aqueous hydrochloric acid (138 mg, 3.78 mmol). The resulting clear solution was stirred for 30 min, diluted with methyl tert-butyl ether (10.8 mL) and stirred for 1 h. The solid was filtered and dried under vacuum to obtain the title compound (170 mg) as a yellow solid. Yield: 87%. Melting point: 260°C-262°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.41 (bs, 1H), 11.10 (bs, 1H), 9.19 (d, J 4.4, 1H), 9.17-9.10 (m, 3H), 8.95 (d, J 3.2, 1H), 8.74 (s, 1H), 8.21 (d, J 11.2, 1H), 8.12-8.04 (m, 2H), 8.01 (d, J 4.8, 1H), 7.92 (d, J 10, 1H), 5.41-5.32 (m, 1H), 3.90-3.80 (m, 3H), 3.55-3.49 (m, 3H), 3.22-3.15 (m, 2H), 2.82 (d, J 4.4, 3H ), 1.70 (d, J 6.4, 3H). MS (m/z): 477.4 (M+H-3HCl); Calcd. for [ _{C25H26F2N8.3HCl +} H- _3HCl ]: _477.22 . Example 43 (±)-1-(6-(2-((5-(4- ethylhexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino )-5- fluoropyrimidin - 4 -yl )-8- fluoroquinolin- 4 -yl ) ethanol

The title compound was synthesized from Intermediate 74 (500 mg, 1.55 mmol) and Intermediate 20 (321 mg, 1.55 mmol) following General Procedure-3. After work-up, the crude product was triturated with a mixture of DCM and MeOH (9:1 ) (10 ml) to obtain a solid. The solid was filtered and washed with DCM (5 ml). The solid was dried under vacuum on a rotary evaporator at 55°C to obtain the title compound (100 mg) as a yellow solid. Yield: 13%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.86 (s, 1H), 9.03 (d, J 4.4, 1H), 8.81 (s, 1H), 8.73 (d, J 3.6, 1H) , 8.15 (d, J 12, 1H), 8.08 (d, J 8.8, 1H), 8.03 (d, J 2.8, 1H), 7.80 (d, J 4.4, 1H), 7.45 (dd, J 9.2, 3.2, 1H), 5.81 (d, J 4.4, 1H), 5.57-5.50 (m, 1H), 3.18-3.10 (m, 4H), 2.55-2.48 (m, 4H), 2.38 (q, J 7.2, 2H), 1.54 (d, J 6.4, 3H), 1.03 (t, J 7.2, 3H). MS (m/z): _492.54 (M+H); Calcd. for [ _{C26H27F2N7O +} H]: _492.22 . Example 43A (±)-1-(6-(2-((5-(4- ethylhexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino )-5- fluoropyrimidin - 4 -yl )-8- fluoroquinolin- 4 -yl ) ethanol trihydrochloride

4-(4-(1-Aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(4-methyl 35% aqueous hydrochloric acid (138 mg, 3.78 mmol). The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (5.7 mL) and stir for 1 h to obtain a solid. The solid was filtered and dried under vacuum to obtain the title compound (80 mg) as a yellow solid. Yield: 76%. Melting point: 249°C-251°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.75 (s, 1H), 11.51 (s, 1H), 9.06 (d, J 4.4, 1H), 8.93 (d, J 3.2, 1H) , 8.82 (s, 1H), 8.25-8.14 (m, 2H), 8.04 (d, J 2.8, 1H), 7.93 (d, J 9.6, 1H), 7.83 (d, J 4.4, 1H), 5.58-5.50 (m, 1H), 3.90-3.83 (m, 2H), 3.63-3.56 (m, 2H), 3.39-3.28 (m, 2H), 3.20-3.08 (m, 4H), 1.54 (d, J 6.8, 3H ), 1.31 (t, J 7.2, 3H). MS (m/z): 492.58 (M+H-3HCl); Calcd. for [ _{C26H27F2N7O.3HCl +} H _- 3HCl]: _492.22 . Example 44 (±)-1-(8- fluoro -6-(5- fluoro -2-((5-(4- isopropylhexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino ) Pyrimidin - 4 -yl ) quinolin- 4 -yl ) ethanol

The title compound was synthesized from Intermediate 74 (500 mg, 1.55 mmol) and Intermediate 25 (342 mg, 1.55 mmol) following General Procedure-3. After work-up, the crude product was triturated with diethyl ether (10 ml) to obtain a solid. The solid was filtered and dried under vacuum on a rotary evaporator at 55 °C to obtain the title compound (320 mg) as a yellow solid. Yield: 41%. Melting point: 238°C-240°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.84 (s, 1H), 9.03 (d, J 4.4, 1H), 8.81 (s, 1H), 8.72 (d, J 3.6, 1H) , 8.15 (d, J 12, 1H), 8.07 (d, J 9.2, 1H), 8.03 (d, J 2.8, 1H), 7.80 (d, J 4.4,1H), 7.44 (dd, J 9.2, 3.2, 1H), 5.78 (d, J 4.4,1H), 5.58-5.50 (m, 1H), 3.17-3.09 (m, 4H), 2.72-2.63 (m, 1H), 2.62-2.55 (m, 4H), 1.54 (d, J 6.4, 3H), 1.01 (d, J 6.4, 6H). MS (m/z): _506.64 (M+H); Calcd. for [ _{C27H29F2N7O +} H]: _506.24 . Example 44A (±)-1-(8- fluoro -6-(5- fluoro -2-((5-(4- isopropylhexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino ) Pyrimidin - 4 -yl ) quinolin- 4 -yl ) ethanol trihydrochloride

To (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(4-isopropylhexahydropyrazin-1-yl) )pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol (Example 44, 300 mg, 0.593 mmol) in methanol (5 mL) was added 35% aqueous hydrochloric acid ( 216 mg, 5.93 mmol) The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (18 mL) and stir for 1 h to obtain a solid. The solid was filtered and dried under vacuum on a rotary evaporator at 55 °C to obtain the title compound (290 mg) as a yellow solid. Melting point: 245°C-247°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.74 (s, 1H), 11.32 (s, 1H), 9.06 (d, J 4.4, 1H), 8.94 (d, J 3.2, 1H) , 8.81 (s, 1H), 8.22-8.15 (m, 2H), 8.03 (d, J 2.8, 1H), 7.89 (d, J 9.6, 1H), 7.83 (, J 4.8, 1H), 5.58-5.50 ( m, 1H), 3.91-3.83 (m, 2H), 3.60-3.50 (m, 3H), 3.41-3.32 (m, 2H), 3.22-3.10 (m, 2H), 1.54 (d, J 6.8, 3H) , 1.34 (d, J 6.8, 6H). MS (m/z): 506.65 (M+H-3HCl); Calcd. for [ _{C27H29F2N7O +} H _- 3HCl]: _506.24 . Example 45 N-(5-(4- ethylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoro -2 -methylquinolin -6- yl ) Pyrimidin -2- amine

The title compound was synthesized from Intermediate 23 (500 mg, 1.55 mmol) and Intermediate 20 (342 mg, 1.55 mmol) following General Procedure-3. After workup, the crude product was purified by combi-flash using MeOH and DCM (6:94) as eluents. The pure compound from column chromatography was suspended in diethyl ether (20 ml) and stirred for 30 min to obtain a solid. The solid was filtered and washed with diethyl ether. The solid was dried under vacuum to afford the title compound (200 mg) as a yellow solid. Yield: %. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.81 (s, 1H), 8.70 (d, J 3.6, 1H), 8.52 (d, J 8.8, 1H), 8.49 (s, 1H) , 8.15 (d, J 12. 1H), 8.03 (d, J 9.2, 1H), 8.01 (d, J 2.4, 1H), 7.61 (d, J 8.8, 1H), 7.47 (dd, J 8.8, 2.4, 1H), 3.18-3.10 (m, 4H), 2.72 (s, 3H), 2.60-2.50 (m, 4H), 2.42-2.36 (m, 2H), 1.03 (t, J 6.8, 3H). MS (m/z): _462.45 (M+H); Calcd. for [ _{C25H25F2N7 +} H]: _462.21 . Example 45A N- (5-(4- ethylhexahydropyrazin- 1 -yl ) pyridin -2- yl )-5- fluoro - 4-(8- fluoro -2 -methylquinolin -6- yl ) Pyrimidin -2- amine hydrochloride

To N- (5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-2-methylquinolin-6-yl)pyrimidine - To a mixture of 2-amine (Example 45, 180 mg, 0.39 mmol) in methanol (4.5 mL) was added 35% aqueous hydrochloric acid (216 mg, 5.93 mmol). The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (13.5 mL) and stir for 1 h to obtain a solid. The solid was filtered and dried under vacuum on a rotary evaporator at 55 °C to obtain the title compound (150 mg) as a yellow solid. Melting point: 265°C-267°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.82 (bs, 1H), 11.33 (bs, 1H), 8.93 (d, J 3.2, 1H), 8.57 (d, J 9.2, 1H) , 8.55 (s, 1H), 8.23 (dd, J 9.2, 2.4, 1H), 8.17 (d, J 11.6, 1H), 8.01 (d, J 2.4, 1H), 7.82 (d, J 9.2, 1H), 7.65 (d, J 8.4, 1H), 3.90-3.80 (m, 2H), 3.63-3.55 (m, 2H), 3.33-3.24 (m, 2H), 3.20-3.05 (m, 4H), 2.74 (s, 3H), 1.29 (t, J 7.2, 3H). MS (m/z): 462.49 (M+H-HCl); Calcd. for [ _{C25H25F2N7.HCl +} H _- HCl]: _462.21 . Example 46 (±)-4-(6-((5- fluoro - 4-(8- fluoro - 4-(1- hydroxyethyl )-2 -methylquinolin -6- yl ) pyrimidin -2- yl ) amino ) pyridin - 3 -yl ) hexahydropyrazine- 1 -carboxylic acid tert-butyl ester

The title compound was synthesized from Intermediate 77 (500 mg, 1.55 mmol) and Intermediate 5 (342 mg, 1.55 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using MeOH and DCM (3:97) as eluents. The pure compound from column chromatography was suspended in diethyl ether (20 ml) and stirred for 30 min to obtain a solid. The solid was filtered and washed with diethyl ether (20 ml). The solid was dried under vacuum to afford the title compound (200 mg) as a yellow solid. Yield: 12%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.89 (s, 1H), 8.75 (s, 1H), 8.72 (d, J 3.5, 1H), 8.15-8.03 (m, 3H), 7.68 (s, 1H), 7.46 (dd, J 9.0, 2.4, 1H), 5.75 (d, J 4.0, 1H), 5.50-5.42 (m, 1H), 3.52-3.44 (m, 4H), 3.11-3.05 (m, 4H), 2.73 (s, 3H), 1.53 (d, J 6.5, 3H), 1.42 (s, 9H). MS (m/z): _578.38 ( _M +H); Calcd. for [ _{C30H33F2N7O3 +} H]: _578.26 . Example 46A (±)-1-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl )-2 -methylquinolin- 4 -yl ) ethanol

Following general procedure-4, from (±)-4-(6-((5-fluoro-4-(8-fluoro-4-(1-hydroxyethyl)-2-methylquinolin-6-yl) Pyrimidin-2-yl)amino)pyridin-3-yl)tert-butyl hexahydropyrazine-1-carboxylate (Example 46, 190 mg, 0.33 mmol) The title compound (90 mg) was synthesized as a yellow solid. Yield: 60%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.82 (s, 1H), 8.80-8.69 (m, 2H), 8.20-8.00 (m, 3H), 7.68 (s, 1H), 7.43 (d, J 8.6, 1H), 5.80-5.70 (m, 1H), 5.51-5.44 (m, 1H), 3.45-3.35 (m, 4H), 3.10-3.00 (m, 2H), 2.90-2.82 (m , 2H), 2.73 (s, 3H), 1.53 (d, J 6.3, 3H). MS (m/z): _478.50 (M+H); Calcd. for [ _{C25H25F2N7O +} H]: _478.21 . Example 46B (±)-1-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl )-2 -methylquinolin- 4 -yl ) ethan - 1 - ol hydrochloride

1-(8-Fluoro-6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino) by dissolving in MeOH (0.1 ml) )pyrimidin-4-yl)-2-methylquinolin-4-yl)ethan-1-ol (Example 46A, 90 mg, 0.2 mmol) in methanol (4.5 mL) was added 35% aqueous hydrochloric acid ( 30 mg, 0.8 mmol). The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (5.4 mL) and stir for 1 h to obtain a solid. The solid was filtered and washed with methyl tert-butyl ether (20 mL). The solid was dried under vacuum on a rotary evaporator at 55°C to obtain the title compound (75 mg) as a yellow solid. Melting point: 238°C-240°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.92 (s, 1H), 9.60 (bs, 2H), 8.95-8.90 (m, 1H), 8.79-8.72 (m, 1H), 8.25 -8.18 (m, 1H), 8.14 (dd, J 11.2, 4, 1H), 8.00 (s, 1H), 7.88 (dd, J 9.2, 4.8, 1H), 7.73 (d, J 4.8, 1H), 5.51 -5.40 (m, 1H), 3.50-3.42 (m, 4H), 3.30-3.20 (m, 4H), 2.75 (d, J 4.4, 3H), 1.11 (d, J 4.8, 3H). MS (m/z): 478.50 (M+H-HCl); Calcd. for [ _{C25H25F2N7O +} H _- HCl]: _478.21 . Example 47 (±)-1-(8- fluoro -6-(5- fluoro -2-((5-(4- methylhexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino ) pyrimidine -4 -yl ) quinolin- 4 -yl ) ethanol

The title compound was synthesized from Intermediate 74 (500 mg, 1.55 mmol) and Intermediate 11 (299 mg, 1.55 mmol) following General Procedure-3. After workup, the crude product was purified by combi-flash using MeOH and DCM (13:87) as eluents. The pure fraction from the column was distilled to obtain a residue. The residue was triturated with diethyl ether (20 ml) to obtain a solid. The solid was filtered and washed with diethyl ether (10 ml). The solid was dried under vacuum on a rotary evaporator at 55°C to obtain the title compound (330 mg) as a yellow solid. Yield: 45%. Melting point: 235°C-237°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.84 (s, 1H), 9.03 (d, J 4.8, 1H), 8.81 (s, 1H), 8.72 (d, J 3.6, 1H) , 8.14 (d, J 12, 1H), 8.08 (d, J 9.2, 1H), 8.03 (d, J 2.8, 1H), 7.80 (d, J 4.8, 1H), 7.45 (dd, J 9.2, 3.2, 1H), 5.78 (d, J 4.4, 1H), 5.56-5.48 (m, 1H), 3.18-3.10- (m, 4H), 2.50-2.42 (m, 4H), 2.23 (s, 3H), 1.54 ( d, J 6.4, 3H). MS (m/z): _478.50 (M+H); Calcd. for [ _{C25H25F2N7O +} H]: _478.21 . Example 47A (±)-1-(8- fluoro -6-(5- fluoro -2-((5-(4- methylhexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino ) pyrimidine -4 -yl ) quinolin- 4 -yl ) ethanol trihydrochloride

To (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(4-methylhexahydropyrazin-1-yl) To a mixture of pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol (Example 47, 300 mg, 0.63 mmol) in methanol (5 mL) was added 35% aqueous hydrochloric acid (229 mg, 6.3 mmol). The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (18 mL) and stir for 1 h to obtain a solid. The solid was filtered and dried under vacuum on a rotary evaporator at 55 °C to obtain the title compound (270 mg) as a yellow solid. Melting point: 268°C-270°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.66 (s, 1H), 11.33 (s, 1H), 9.06 (d, J 4.4, 1H), 8.93 (d, J 2.8, 1H) , 8.81 (s, 1H), 8.20-8.13 (m, 2H), 8.02 (d, J 2.8, 1H), 7.89 (d, J 9.2, 1H), 7.83 (d, J 4.8, 1H), 5.58-5.50 (m, 1H), 3.90-3.82 (m, 2H), 3.59-3.50 (m, 2H), 3.30-3.12 (m, 4H), 2.83 (s, 3H), 1.55 (d, J 6.8, 3H). MS (m/z): 478.50 (M+H-3HCl); Calcd. for [ _{C25H25F2N7O +} H _- 3HCl]: _478.21 . Example 48 4-(6-((5- fluoro - 4-(8- fluoro - 4-(2 -hydroxyprop- 2- yl ) quinolin -6- yl ) pyrimidin -2 - yl ) amino ) pyridine- 3- yl ) Hexahydropyrazine- 1 -carboxylic acid tert-butyl ester

The title compound was synthesized from Intermediate 83 (810 mg, 2.5 mmol) and Intermediate 5 (700 mg, 2.5 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using MeOH and DCM (3:97) as eluents. The pure compound from column chromatography was suspended in diethyl ether (50 ml) and stirred for 30 min to obtain a solid. The solid was filtered and washed with diethyl ether (50 ml). The solid was dried under vacuum to afford the title compound (760 mg) as a light green solid. Yield: 54%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.86 (bs, 1H), 9.53 (s, 1H), 8.97 (d, J 4.4, 1H), 8.67 (bs, 1H), 8.13 ( d, J 12.4, 1H), 8.12-8.05 (m, 1H), 8.03 (d, J 2.8, 1H), 7.73 (d, J 4.4, 1H), 7.45 (dd, J 9.2, 2.8, 1H), 5.88 (bs, 1H), 3.51-3.44 (m, 4H), 3.11-3.04 (m, 4H), 1.74 (s, 6H), 1.42 (s, 9H). MS (m/z): _578.63 ( _M +H); Calcd. for [ _{C30H33F2N7O3 +} H]: _578.26 . Example 48A 2-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 - yl ) quinoline- 4- yl ) propan -2- ol

Following general procedure-4, from 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl) Amino)pyridin-3-yl)pyrazine-1-carboxylic acid tert-butyl ester (Example 48, 490 mg, 0.87 mmol) The title compound (370 mg) was synthesized as a yellow solid. Yield: 77%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.81 (s, 1H), 9.55 (s, 1H), 8.98 (d, J 4.8, 1H), 8.72 (d, J 3.6, 1H) , 8.17-8.10 (m, 2H), 8.01 (d, J 3.2, 1H), 7.81 (d, J 4.4, 1H), 7.43 (dd, J 9.2, 3.2, 1H), 5.83 (bs, 1H), 5.59 -5.50 (m, 1H), 3.08-3.01 (m, 4H), 2.88-2.81 (m, 4H), 1.75 (s, 6H). MS (m/z): _478.67 (M+H); Calcd. for [ _{C25H25F2N7O +} H]: _478.21 . Example 48B 2-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 - yl ) quinoline- 4- yl ) propan -2- ol

1-(8-Fluoro-6-(5-fluoro-2-((5-(4-methylhexahydropyrazin-1-yl)pyridine-2-yl)pyridine-2- yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol (Example 48A, 300 mg, 0.63 mmol) in methanol (5 mL) was added 35% aqueous hydrochloric acid (229 mg, 6.3 mmol ). The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (18 mL) and stir for 1 h to obtain a solid. The solid was filtered and dried under vacuum on a rotary evaporator at 55 °C to obtain the title compound (270 mg) as a yellow solid. Melting point: 268°C-270°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.81 (s, 1H), 9.60 (bs, 1H), 9.57 (s, 1H), 9.01 (d, J 4.8, 1H), 8.94 ( d, J 3.2, 1H), 8.21 (d, J 9.6, 1H), 8.16 (d, J 12.4, 1H), 8.02 (d, J 2.8, 1H), 7.91 (d, J 9.6, 1H), 7.75 ( d, J 4.8, 1H), 3.52-3.44 (m, 4H), 3.30-3.21 (m, 4H), 1.75 (s, 6H). MS (m/z): 478.65 (M+H-3HCl); Calcd. for [ _{C25H25F2N7O.3HCl +} H _- 3HCl]: _478.21 . Example 49 (±)-4-(6-((5- fluoro - 4-(8- fluoro - 4-(1- hydroxyethyl ) quinolin -6- yl ) pyrimidin -2- yl ) amino ) pyridine -3 -yl ) hexahydropyrazine- 1 -carboxylic acid tert-butyl ester

The title compound was synthesized from Intermediate 74 (1.8 g, 5.6 mmol) and Intermediate 5 (1.56 g, 5.6 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using MeOH and DCM (3:97) as eluents. The pure compound from column chromatography was suspended in diethyl ether (50 ml) and stirred for 30 min to obtain a solid. The solid was filtered and washed with diethyl ether (50 ml). The solid was dried under vacuum to afford the title compound (1.8 g) as a pale green solid. Yield: 57%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.90 (s, 1H), 9.03 (d, J 4.4, 1H), 8.81 (s, 1H), 8.73 (d, J 3.6, 1H) , 8.16 (d, J 11.6, 1H), 8.10 (d, J 8.8, 1H), 8.06 (d, J 2.8, 1H), 7.81 (d, J 4.4, 1H), 7.47 (dd, J 9.2, 3.2, 1H), 5.78 (d, J 4, 1H), 5.57-5.50 (m, 1H), 3.52-3.44 (m, 4H), 3.12-3.05 (m, 4H), 1.54 (d, J 6.8, 3H), 1.43 (s, 9H). MS (m/z): _564.49 ( _M +H); Calcd. for [ _{C29H31F2N7O3 +} H]: _564.25 . Example 49A (±)-1-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl ) quinoline- 4 -yl ) ethanol

Following general procedure-4, from (±)-4-(6-((5-fluoro-4-(8-fluoro-4-(1-hydroxyethyl)quinolin-6-yl)pyrimidin-2-yl )amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester (Example 49, 1.0 g, 1.77 mmol) The title compound (650 mg) was synthesized as a yellow solid. Yield: 79%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.86 (s, 1H), 9.03 (d, J 4.4, 1H), 8.82 (s, 1H), 8.73 (d, J 3.6, 1H) , 8.15 (d, J 12, 1H), 8.08 (d, J 9.2, 1H), 8.02 (d, J 2.8, 1H), 7.80 (d, J 4.4, 1H), 7.43 (dd, J 9.2, 2.8, 1H), 5.79 (d, J 4, 1H), 5.57-5.49 (m, 1H), 3.09-3.01 (m, 4H), 2.90-2.83 (m, 4H), 1.54 (d, J 6.4, 3H). MS (m/z): _464.54 (M+H); Calcd. for [ _{C24H23F2N7O +} H]: _464.19 . Example 49B (±)-1-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyrazin- 1 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl ) quinolin- 4 -yl ) ethanol trihydrochloride

(±) -1-(8-Fluoro-6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridine-2- yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol (Example 49A, 300 mg, 0.65 mmol) in methanol (6 mL) was added 35% aqueous hydrochloric acid (229 mg, 6.3 mmol ). The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (18 mL) and stir for 1 h to obtain a solid. The solid was filtered and dried under vacuum on a rotary evaporator at 55 °C to obtain the title compound (320 mg) as a yellow solid. Yield: 93%. Melting point: 236°C-238°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.88 (s, 1H), 9.63 (bs, 2H), 9.07 (d, J 4.4, 1H), 8.95 (d, J 3.2, 1H) , 8.81 (s, 1H), 8.22 (d, J 9.6, 1H), 8.18 (d, J 11.6, 1H), 8.01 (d, J 2.8, 1H), 7.888 (d, J 9.6, 1H), 7.84 ( d, J 4.4, 1H), 5.56-5.49 (m, 1H), 3.52-3.44 (m, 4H), 3.30-3.20 (m, 4H), 1.54 (d, J 6.8, 3H). MS (m/z): 464.63 (M+H-3HCl); Calcd. for [ _{C24H23F2N7O +} H _- 3HCl]: _464.19 . Example 50 (±)-4-(6-((5- fluoro - 4-(8- fluoro - 4-(1- hydroxyethyl ) quinolin -6- yl ) pyrimidin -2- yl ) amino ) pyridine -3 -yl ) tert-butyl hexahydropyridine- 1 -carboxylate

The title compound was synthesized from Intermediate 74 (810 mg, 2.5 mmol) and Intermediate 87 (700 mg, 2.5 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using MeOH and DCM (3:97) as eluents. The pure compound from column chromatography was suspended in diethyl ether (50 ml) and stirred for 30 min to obtain a solid. The solid was filtered and washed with diethyl ether (50 ml). The solid was dried under vacuum to afford the title compound (760 mg) as a light green solid. Yield: 54%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 10.09 (s, 1H), 9.04 (d, J 4.4, 1H), 8.83 (s, 1H), 8.78 (d, J 3.6, 1H) , 8.22 (d, J 2.4, 1H), 8.21-8.14 (m, 2H), 7.81 (d, J 4.4, 1H), 7.70 (dd, J 8.8, 2.4, 1H), 5.79 (d, J 4.4, 1H ), 5.58-5.50 (m, 1H), 4.12-4.05 (m, 2H), 2.90-2.75 (m, 2H), 2.74-2.65 (m, 1H), 1.81-1.74 (m, 2H), 1.60-1.50 (m, 5H), 1.42 (s, 9H). MS (m/z): 563.45 ( _M +H); Calcd. for _{[ C30H32F2N6O3 +} H]: _563.25 . Example 50A (±)-1-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyridin- 4 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl ) Quinolin- 4 -yl ) ethanol

Following general procedure-4, from (±)-4-(6-((5-fluoro-4-(8-fluoro-4-(1-hydroxyethyl)quinolin-6-yl)pyrimidin-2-yl )amino)pyridin-3-yl)tert-butyl hexahydropyridine-1-carboxylate (Example 50, 490 mg, 0.87 mmol) The title compound (310 mg) was synthesized as a yellow solid. Yield: 77%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 10.07 (s, 1H), 9.04 (d, J 4.4, 1H), 8.83 (s, 1H), 8.77 (d, J 3.2, 1H) , 8.22-8.12 (m, 3H), 7.81 (d, J 4.4, 1H), 7.66 (dd, J 8.8, 2.5, 1H), 5.83 (bs, 1H), 5.58-5.50 (m, 1H), 3.08- 2.99 (m, 2H), 2.62-.2.54 (m, 3H), 1.72-1.64 (m, 2H), 1.55 (d, J 6.4, 3H), 1.55-1.45 (m, 2H). MS (m/z): 463.19 (M+H); Calcd. for _{[ C25H24F2N6O +} H]: _463.67 . Example 50B (±)-1-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyridin- 4 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl ) Quinolin- 4 -yl ) ethanol trihydrochloride

(±) -1-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl) )amino)pyrimidin-4-yl)quinolin-4-yl)ethanol (Example 50A, 190 mg, 0.41 mmol) in methanol (2.8 mL) was added 35% aqueous hydrochloric acid (150 mg, 4.1 mmol) . The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (19 mL) and stir for 1 h to obtain a solid. The solid was filtered and dried under vacuum on a rotary evaporator at 55 °C to obtain the title compound (190 mg) as a yellow solid. Yield: 59%. Melting point: 250°C-252°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.98 (s, 1H), 9.31-9.22 (m, 2H), 9.06 (d, J 4.4, 1H), 8.96 (d, J 2.8, 1H), 8.83 (s, 1H), 8.31 (d, J 2.5, 1H), 8.19 (d, J 11.2, 1H), 7.97 (d, J 8.8, 1H), 7.84 (d, J 4.8, 1H), 5.58-5.50 (m, 1H), 3.41-3.35 (m, 2H), 3.08-2.95 (m, 3H), 2.05-1.90 (m, 4H), 1.55 (d, J 6.4, 3H). MS (m/z): 463.58 (M+H-3HCl); Calcd. for _{[ C25H24F2N6O.3HCl +} H-3HCl]: _463.67 . Example 51 4-(6-((5- fluoro - 4-(8- fluoro - 4-(2 -hydroxyprop- 2- yl ) quinolin -6- yl ) pyrimidin -2 - yl ) amino ) pyridine- 3- yl ) tert-butyl hexahydropyridine- 1 -carboxylate

The title compound was synthesized from Intermediate 83 (540 mg, 1.6 mmol) and Intermediate 87 (450 mg, 1.6 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using MeOH and DCM (2.5:97.5) as eluents. The pure compound from column chromatography was suspended in diethyl ether (30 ml) and stirred for 30 min to obtain a solid. The solid was filtered and washed with diethyl ether (30 ml). The solid was dried under vacuum to afford the title compound (400 mg) as a pale green solid. Yield: 43%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 10.04 (s, 1H), 9.57 (s, 1H), 8.98 (d, J 4.4, 1H), 8.77 (d, J 3.6, 1H) , 8.25 (d, J 8.8, 1H), 8.21 (d, J 2.4, 1H), 8.15 (d, J 12, 1H), 7.73 (d, J 4.4, 1H), 7.70 (dd, J 8.8, 2.4, 1H), 5.76 (s, 1H), 4.12-4.03 (m, 2H), 2.90-2.78 (m, 2H), 2.75-2.65 (m, 1H), 1.82-1.73 (m, 8H), 1.60-1.50 ( m, 2H), 1.42 (s, 9H). MS (m/z): 577.48 ( _M +H); Calcd. for _{[ C31H34F2N6O3 +} H]: _577.27 . Example 51A 2-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyridin- 4 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl ) quinoline- 4 -yl ) propan - 2- ol

Following general procedure-4, from 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl) Amino)pyridin-3-yl)tert-butylhexahydropyridine-1-carboxylate (Example 51, 370 mg, 0.64 mmol) The title compound (290 mg) was synthesized as a yellow solid. Yield: 95%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 10.02 (s, 1H), 9.57 (s, 1H), 8.99 (d, J 4.8, 1H), 8.77 (d, J 3.6, 1H) , 8.24 (d, J 8.8, 1H), 8.19 (d, J 2.5, 1H), 8.16 (d, J 12.4, 1H), 7.73 (d, J 4.8, 1H), 7.67 (d, J 8.4, 2.5, 1H), 5.78 (s, 1H), 3.05-2.98 (m, 2H), 2.62-2.52 (m, 3H), 2.00 (bs, NH), 1.79 (s, 6H), 1.72-1.65 (m, 2H) , 1.57-1.48 (m, 2H). MS (m/z): 477.60 (M+H); Calcd. for _{[ C26H26F2N6O +} H]: _477.21 . Example 51B 2-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyridin- 4 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl ) quinoline- 4 -yl ) propan - 2- ol trihydrochloride

2-(8-Fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl)amino) To a mixture of pyrimidin-4-yl)quinolin-4-yl)propan-2-ol (Example 51A, 240 mg, 0.5 mmol) in methanol (2.8 mL) was added 35% aqueous hydrochloric acid (180 mg, 5 mmol) . The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (14.4 mL) and stir for 1 h to obtain a solid. The solid was filtered and dried under vacuum on a rotary evaporator at 55°C to afford the title compound (250 mg) as an off-white solid. Yield: 78%. Melting point: 223°C-225°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 12.30-12.10 (m, 1H), 9.59 (s, 1H), 9.40-9.28 (m, 2H), 9.02 (d, J 4.8, 1H ), 8.98 (d, J 3.2, 1H), 8.32 (bs, 1H), 8.30-8.22 (m, 1H), 8.19 (d, J 11.6, 1H), 7.97 (d, J 8.8, 1H), 7.76 ( d, J 4.8, 1H), 5.94 (bs, 1H), 3.42-3.33 (m, 2H), 3.09-2.92 (m, 3H), 2.05-1.90 (m, 4H), 1.76 (s, 6H). MS (m/z): 477.56 (M+H-3HCl); Calcd. for _{[ C26H26F2N6O.3HCl +} H-3HCl]: _477.21 . Example 52 4-(6-((5- fluoro - 4-(8- fluoro - 4-(2 -hydroxypropan- 2- yl )-2 -methylquinolin -6- yl ) pyrimidin -2- yl ) Amino ) pyridin - 3 -yl ) hexahydropyridine- 1 -carboxylic acid tert-butyl ester

The title compound was synthesized from Intermediate 31 (530 mg, 1.5 mmol) and Intermediate 87 (420 mg, 1.5 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using MeOH and DCM (2.5:97.5) as eluents. The pure compound from column chromatography was suspended in diethyl ether (30 ml) and stirred for 30 min to obtain a solid. The solid was filtered and washed with diethyl ether (30 ml). The solid was dried under vacuum to afford the title compound (380 mg) as a pale green solid. Yield: 42%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 10.01 (s, 1H), 9.50 (s, 1H), 8.75 (d, J 3.6, 1H), 8.25 (d, J 8.4, 1H) , 8.21 (d, J 2.4, 1H), 8.10 (d, J 11.6, 1H), 7.70 (dd, J 8.8, 2.4, 1H), 7.61 (s, 1H), 5.70 (s, 1H), 4.12-4.06 (m, 2H), 2.90-2.75 (m, 2H), 2.74-2.65 (m, 4H), 1.81-1.70 (m, 8H), 1.60-1.45 (m, 2H), 1.42 (s, 9H). MS (m/z): 591.52 ( _M +H); Calcd. for _{[ C32H36F2N6O3 +} H]: _591.28 . Example 52A 2-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyridin- 4 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl )-2- methyl ylquinolin- 4 -yl ) propan -2- ol

Following general procedure-4, from 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)-2-methylquinolin-6-yl)pyrimidine -2-yl)amino)pyridin-3-yl)tert-butyl hexahydropyridine-1-carboxylate (Example 52, 360 mg, 0.61 mmol) The title compound (260 mg) was synthesized as an off-white solid. Yield: 87%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 9.99 (s, 1H), 9.50 (s, 1H), 8.75 (d, J 3.6, 1H), 8.25 (d, J 8.8, 1H) , 8.19 (d, J 2.4, 1H), 8.11 (d, J 12, 1H), 7.67 (dd, J 8.4, 2.4, 1H), 7.62 (s, 1H), 5.71 (s, 1H), 3.08-3.00 (m, 2H), 2.73 (s, 3H), 2.62-2.52 (m, 3H), 2.00 (bs, 1H, NH), 1.78-1.68 (m, 8H), 1.60-1.48 (m, 2H). MS (m/z): 491.62 (M+H); Calcd. for _{[ C27H28F2N6O +} H]: _491.23 . Example 52B 2-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyridin- 4 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl )-2- methyl Quinolin- 4 -yl ) propan -2- ol trihydrochloride

2-(8-Fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl)amino) To a mixture of pyrimidin-4-yl)-2-methylquinolin-4-yl)propan-2-ol (Example 52A, 230 mg, 0.47 mmol) in methanol (3.6 mL) was added 35% aqueous hydrochloric acid (170 mg, 4.7 mmol). The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (13.8 mL) and stir for 1 h to obtain a solid. The solid was filtered and dried under vacuum on a rotary evaporator at 55°C to afford the title compound (250 mg) as an off-white solid. Yield: 78%. Melting point: 221°C-223°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 12.17 (s, 1H), 9.53 (s, 1H), 9.27 (bs, 2H), 8.96 (d, J 3.2, 1H), 8.32 ( s, 1H), 8.26 (d, J 8.8, 1H), 8.15 (d, J 11.6, 1H), 7.96 (d, J 8.8, 1H), 7.65 (s, 1H), 5.23 (bs, 1H), 3.43 -3.34 (m, 2H), 3.10-2.95 (m, 3H), 2.75 (s, 3H), 2.05-1.88 (m, 4H), 1.74 (s, 6H). MS (m/z): 491.61 (M+H-3HCl); Calcd. for _{[ C27H28F2N6O.3HCl +} H-3HCl]: _491.61 . Example 53 (±)-4-(6-((5- fluoro - 4-(8- fluoro - 4-(1- hydroxyethyl )-2 -methylquinolin -6- yl ) pyrimidin -2- yl ) amino ) pyridin - 3 -yl ) hexahydropyridine- 1 -carboxylic acid tert-butyl ester

The title compound was synthesized from Intermediate 77 (540 mg, 1.6 mmol) and Intermediate 87 (450 mg, 1.6 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using MeOH and DCM (2.5:97.5) as eluents. The pure compound from column chromatography was suspended in diethyl ether (20 ml) and stirred for 30 min to obtain a solid. The solid was filtered and washed with diethyl ether (20 ml). The solid was dried under vacuum to obtain the title compound (300 mg) as a yellow solid. Yield: 32%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 10.05 (s, 1H), 8.77 (s, 1H), 8.76 (d, J 3.6, 1H), 8.22 (d, J 2.4, 1H) , 8.20 (d, J 8.8, 1H), 8.12 (d, J 12, 1H), 7.71-7.66 (m, 2H), 5.75 (d, J 4, 1H), 5.52-5.44 (m, 1H), 4.12 -4.05 (m, 2H), 2.90-2.76 (m, 2H), 2.73 (s, 3H), 2.75-2.65 (m, 1H), 1.81-1.72 (m, 2H), 1.60-1.45 (m, 2H) , 1.54 (d, J 6.4, 3H), 1.42 (s, 9H). MS (m/z): 577.43 ( _M +H); Calcd. for _{[ C31H34F2N6O3 +} H]: _577.27 . Example 53A (±)-1-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyridin- 4 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl ) -2 -methylquinolin- 4 -yl ) ethanol

Following general procedure-4, from 4-(6-((5-fluoro-4-(8-fluoro-4-(1-hydroxyethyl)-2-methylquinolin-6-yl)pyrimidine-2- yl)amino)pyridin-3-yl)tert-butyl hexahydropyridine-1-carboxylate (Example 53, 280 mg, 0.49 mmol) The title compound (180 mg) was synthesized as an off-white solid. Yield: 78%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 10.03 (s, 1H), 8.77 (s, 1H), 8.75 (d, J 3.6, 1H), 8.20 (d, J 2.0, 1H) , 8.19 (d, J 3.6, 1H), 8.12 (d, J 12, 1H), 7.68 (s, 1H), 7.66 (d, J 8.8, 2, 1H), 5.75 (s, 1H), 5.53-5.45 (m, 1H), 3.08-3.00 (m, 2H), 2.73 (s, 3H), 2.63-2.56 (m, 3H), 1.74-1.68 (m, 2H), 1.60-1.45 (m, 2H), 1.54 (d, J 6.8, 3H). MS (m/z): 477.62 (M+H); Calcd. for _{[ C26H26F2N6O +} H]: _477.21 . Example 53B (±)-1-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyridin- 4 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl ) -2 -Methylquinolin- 4 -yl ) ethanol trihydrochloride

1-(8-Fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl)amino) To a mixture of pyrimidin-4-yl)-2-methylquinolin-4-yl)ethanol (Example 53A, 160 mg, 0.34 mmol) in methanol (2.2 mL) was added 35% aqueous hydrochloric acid (120 mg, 3.4 mmol ). The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (16 mL) and stir for 1 h to obtain a solid. The solid was filtered and dried under vacuum on a rotary evaporator at 55°C to afford the title compound (180 mg) as an off-white solid. Yield: 56%. Melting point: 220°C-222°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 12.17 (s, 1H), 9.26 (bs, 2H), 8.96 (d, J 3.2, 1H), 8.78 (s, 1H), 8.31 ( s, 1H), 8.24 (d, J 8.8, 1H), 8.15 (d, J 12, 1H), 7.93 (d, J 8.8, 1H), 7.73 (s, 1H), 5.52-5.45 (m, 1H) , 3.42-3.33 (m, 2H), 3.10-2.92 (m, 3H), 2.76 (s, 3H), 2.05-1.89 (m, 4H), 1.54 (d, J 6.4, 3H). MS (m/z): 477.56 (M+H-3HCl); Calcd. for _{[ C26H26F2N6O.3HCl +} H-3HCl]: _477.21 . Example 54 4-(2-((5- fluoro - 4-(8- fluoro - 4-(2 -hydroxyprop- 2- yl ) quinolin -6- yl ) pyrimidin -2 - yl ) amino ) pyrimidine- 5- yl ) tert-butyl hexahydropyridine- 1 -carboxylate

The title compound was synthesized from Intermediate 83 (217 mg, 0.65 mmol) and Intermediate 90 (180 mg, 0.65 mmol) following General Procedure-3. After workup, the crude product was purified by combi-flash using MeOH and DCM (4:96) as eluents. The pure compound from column chromatography was suspended in diethyl ether (20 ml) and stirred for 30 min to obtain a solid. The solid was filtered and washed with diethyl ether (5 ml). The solid was dried under vacuum to afford the title compound (65 mg) as an off-white solid. Yield: 17%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 10.47 (s, 1H), 9.53 (s, 1H), 8.97 (d, J 4.4, 1H), 8.79 (d, J 3.6, 1H) , 8.56 (s, 2H), 8.21 (d, J 12, 1H), 7.74 (d, J 4.8, 1H), 5.71 (s, 1H), 4.14-4.05 (m, 2H), 2.90-2.62 (m, 3H), 1.84-1.77 (m, 2H), 1.74 (s, 6H), 1.62-1.51 (m, 2H), 1.42 (s, 9H). MS (m/z): _578.48 ( _M +H); Calcd. for [ _{C30H33F2N7O3 +} H]: _578.26 . Example 54A 2-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyridin- 4 -yl ) pyrimidin -2- yl ) amino ) pyrimidin - 4 -yl ) quinoline- 4 -yl ) propan - 2- ol

Following general procedure-4, from 4-(2-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl) Amino)pyrimidin-5-yl)tert-butylhexahydropyridine-1-carboxylate (Example 54, 300 mg, 0.52 mmol) The title compound (215 mg) was synthesized as an off-white solid. Yield: 87%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 10.45 (bs, 1H), 9.52 (s, 1H), 8.98 (d, J 3.2, 1H), 8.79 (d, J 3.6, 1H) , 8.52 (s, 2H), 8.21 (d, J 12, 1H), 7.75 (d, J 4.8, 1H), 5.73 (s, 1H), 3.08-2.99 (m, 2H), 2.70-2.52 (m, 4H), 2.10 (bs, 1H, NH), 1.74 (s, 8H), 1.61-1.49 (m, 2H). MS (m/z): _478.50 (M+H); Calcd. for [ _{C25H25F2N7O +} H]: _478.21 . Example 54B 2-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyridin- 4 -yl ) pyrimidin -2- yl ) amino ) pyrimidin - 4 -yl ) quinoline- 4 -yl ) propan - 2- ol trihydrochloride

2-(8-Fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyrimidin-2-yl)amino) To a mixture of pyrimidin-4-yl)quinolin-4-yl)propan-2-ol (Example 54A, 200 mg, 0.42 mmol) in methanol (3 mL) was added 35% aqueous hydrochloric acid (153 mg, 4.2 mmol) . The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (20 mL) and stir for 1 h to obtain a solid. The solid was filtered and dried under vacuum on a rotary evaporator at 55°C to afford the title compound (180 mg) as an off-white solid. Yield: 56%. Melting point: 257°C-259°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.08 (bs, 1H), 9.55 (s, 1H), 9.23 (bs, 1H), 9.08 (bs, 1H), 9.00 (d, J 4.4, 1H), 8.63 (d, J 3.2, 1H), 8.22 (d, J 12, 1H), 7.77 (d, J 4.8, 1H), 3.41-3.34 (m, 2H), 3.07-2.90 (m, 3H), 2.07-1.90 (m, 4H), 1.75 (s, 6H). MS (m/z): 478.48 (M+H-3HCl); Calcd. for [ _{C25H25F2N7O.3HCl +} H _- 3HCl]: _478.51 . Example 55 (±)-4-(2-((5- fluoro - 4-(8- fluoro - 4-(1- hydroxyethyl ) quinolin -6- yl ) pyrimidin -2- yl ) amino ) pyrimidine -5- yl ) tert-butyl hexahydropyridine- 1 -carboxylate

The title compound was synthesized from Intermediate 77 (500 mg, 1.55 mmol) and Intermediate 90 (433 mg, 1.55 mmol) following General Procedure-3. After workup, the crude product was purified by combi-flash using MeOH and DCM (4:96) as eluents. The pure compound from column chromatography was suspended in diethyl ether (20 ml) and stirred for 30 min to obtain a solid. The solid was filtered and washed with diethyl ether (15 ml). The solid was dried under vacuum to afford the title compound (270 mg) as a light brown solid. Yield: 31%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 10.50 (s, 1H), 9.03 (d, J 4.4, 1H), 8.84 (s, 1H), 8.80 (d, J 3.6, 1H) , 8.56 (s, 2H), 8.21 (d, J 12, 1H), 7.81 (d, J 4.4, 1H), 5.76 (d, J 4.4, 1H), 5.57-5.49 (m, 1H), 4.14-4.06 (m, 2H), 2.90-2.78 (m, 2H), 2.77-2.65 (m, 1H), 1.85-1.78 (m, 2H), 1.64-1.55 (m, 2H), 1.53 (d, J 6.4, 3H ), 1.42 (s, 9H). MS (m/z): _564.37 ( _M +H); Calcd. for [ _{C29H31F2N7O3 +} H]: _564.25 . Example 55A (±)-1-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyridin- 4 -yl ) pyrimidin -2- yl ) amino ) pyrimidin - 4 -yl ) Quinolin- 4 -yl ) ethanol

Following general procedure-4, from 4-(2-((5-fluoro-4-(8-fluoro-4-(1-hydroxyethyl)quinolin-6-yl)pyrimidin-2-yl)amino) Pyrimidin-5-yl) tert-butyl hexahydropyridine-1-carboxylate (Example 55, 250 mg, 0.44 mmol) The title compound (200 mg) was synthesized as an off-white solid. Yield: 97%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 10.50 (s, 1H), 9.03 (d, J 4.4, 1H), 8.85 (s, 1H), 8.80 (d, J 3.6, 1H) , 8.53 (s, 2H), 8.21 (d, J 12, 1H), 7.81 (d, J 4.4, 1H), 5.77 (s, 1H), 5.58-5.49 (m, 1H), 3.08-3.00 (m, 2H), 2.68-2.53 (m, 3H), 1.78-1.70 (m, 2H), 1.62-1.53 (m, 2H), 1.53 (d, J 6.8, 3H). MS (m/z): _464.46 (M+H); Calcd. for [ _{C24H23F2N7O +} H]: _464.19 . Example 55B (±)-1-(8- fluoro -6-(5- fluoro -2-((5-( hexahydropyridin- 4 -yl ) pyrimidin -2- yl ) amino ) pyrimidin - 4 -yl ) Quinolin- 4 -yl ) ethanol trihydrochloride

1-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyrimidin-2-yl)amino) To a mixture of pyrimidin-4-yl)quinolin-4-yl)ethanol (Example 55A, 200 mg, 0.43 mmol) in methanol (3 mL) was added 35% aqueous hydrochloric acid (157 mg, 4.3 mmol). The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (20 mL) and stir for 1 h to obtain a solid. The solid was filtered and dried under vacuum on a rotary evaporator at 55 °C to afford the title compound (200 mg) as an off-white solid. Yield: 59%. Melting point: 220°C-222°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.08 (s, 1H), 9.28-9.20 (m, 1H), 9.15-9.08 (m, 1H), 9.05 (d, J 4.4, 1H ), 8.87 (d, J 3.2, 2H), 8.63 (s, 2H), 8.23 (d, J 12, 1H), 7.84 (d, J 4.4, 1H), 5.58-5.51 (m, 1H), 3.42- 3.34 (m, 2H), 3.06-2.92 (m, 3H), 2.07-1.90 (m, 4H), 1.55 (d, J 6.4, 3H). MS (m/z): 464.43 (M+H); Calcd. for [ _{C24H23F2N7O.3HCl +} H _- 3HCl]: _464.19 . Example 56 2-(8- fluoro -6-(5- fluoro -2-((5-(1 -methylhexahydropyridin- 4 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl ) Quinolin- 4 -yl ) propan -2- ol

The title compound was synthesized from Intermediate 83 (700 mg, 2.1 mmol) and Intermediate 93 (400 mg, 2.1 mmol) following General Procedure-3. After work-up, the crude product was suspended in a mixture of _Et2O and EtOAc (1 :1 ) (20 ml) and stirred for 30 min to obtain a solid. The solid was filtered and washed with a mixture of _Et2O and EtOAc (1:1) (10 ml). The solid was dried under vacuum to obtain the title compound (200 mg) as an off-white solid. Yield: 20%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 10.03 (s, 1H), 9.57 (s, 1H), 8.98 (d, J 4.4, 1H), 8.77 (d, J 3.6, 1H) , 8.25 (d, J 8.4, 1H), 8.21 (d, J 2, 1H), 8.15 (d, J 12, 1H), 7.73 (d, J 4.4, 1H), 7.69 (d, J 8.4, 2, 1H), 5.77 (s, 1H), 2.95-2.86 (m, 2H), 2.55-2.49 (m, 1H), 2.24 (s, 3H), 2.09-1.99 (m, 2H), 1.80-1.65 (m, 4H), 1.75 (s, 6H). MS (m/z): 491.57 (M+H); Calcd. for _{[ C27H28F2N6O +} H]: _491.23 . Example 56A 2-(8- fluoro -6-(5- fluoro -2-((5-(1 -methylhexahydropyridin- 4 -yl ) pyridin -2- yl ) amino ) pyrimidin - 4 -yl ) Quinolin- 4 -yl ) propan -2- ol trihydrochloride

2-(8-fluoro-6-(5-fluoro-2-((5-(1-methylhexahydropyridin-4-yl)pyridin-2-yl) )amino)pyrimidin-4-yl)quinolin-4-yl)propan-2-ol (Example 56, 200 mg, 0.41 mmol) in methanol (3 mL) was added 35% aqueous hydrochloric acid (150 mg , 4.1 mmol). The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (12 mL) and stir for 1 h to obtain a solid. The solid was filtered and dried under vacuum on a rotary evaporator at 55 °C to afford the title compound (200 mg) as an off-white solid. Yield: 59%. Melting point: 238°C-240°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 12.11 (s, 1H), 11.12 (s, 1H), 9.59 (s, 1H), 9.02 (d, J 4.8, 1H), 8.97 ( d, J 3.2, 1H), 8.33 (d, J 2.5, 1H), 8.25 (dd, J 9.2, 2.5, 1H), 8.18 (d, J 12, 1H), 7.97 (d, J 9.2, 1H), 7.75 (d, J 4.8, 1H), 3.55-3.47 (m, 2H), 3.12-3.03 (m, 2H), 3.02-2.94 (m, 1H), 2.76 (d, J 4.8, 3H), 2.13-2.04 (m, 4H), 1.76 (s, 6H). MS (m/z): 491.52 (M+H-3HCl); Calcd. for _{[ C27H28F2N6O.3HCl +} H-3HCl]: _491.23 . Example 57 (±)-1-(8- fluoro -6-(5- fluoro -2-((5-(1 -methylhexahydropyridin- 4 -yl ) pyridin -2 - yl ) amino ) pyrimidine- 4- yl ) quinolin- 4 -yl ) ethanol

The title compound was synthesized from Intermediate 77 (780 mg, 2.4 mmol) and Intermediate 93 (460 mg, 2.4 mmol) following General Procedure-3. After work-up, the crude product was suspended in a mixture of _Et2O and MeOH (1 :1 ) (20 ml) and stirred for 30 min to obtain a solid. The solid was filtered and washed with a mixture of _Et2O and MeOH (1:1) (10 ml). The solid was suspended in Et2O and stirred for 30 min. The solid was filtered and dried under vacuum to obtain the title compound (230 mg) as a yellow solid. Yield: 20%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 10.08 (s, 1H), 9.04 (d, J 4.4, 1H), 8.83 (s, 1H), 8.77 (d, J 3.6, 1H) , 8.23-8.12 (m, 3H), 7.81 (d, J 4.4, 1H), 7.69 (dd, J 8.8, 2.5, 1H), 5.80 (d, J 4.4, 1H), 5.58-5.49 (m, 1H) , 2.91-2.84 (m, 2H), 2.50-2.43 (m, 1H), 2.21 (s, 3H), 2.03-1.94 (m, 2H), 1.79-1.62 (m, 4H), 1.55 (d, J 6.4 , 3H). MS (m/z): 477.57 (M+H); Calcd. for _{[ C26H26F2N6O +} H]: _477.21 . Example 57A (±)-1-(8- fluoro -6-(5- fluoro -2-((5-(1 -methylhexahydropyridin- 4 -yl ) pyridin -2 - yl ) amino ) pyrimidine- 4- yl ) quinolin- 4 -yl ) ethanol trihydrochloride

1-(8-fluoro-6-(5-fluoro-2-((5-(1-methylhexahydropyridin-4-yl)pyridin-2-yl) )amino)pyrimidin-4-yl)quinolin-4-yl)ethanol (Example 57, 200 mg, 0.42 mmol) in methanol (3 mL) was added 35% aqueous hydrochloric acid (150 mg, 4.2 mmol) . The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (20 mL) and stir for 1 h to obtain a solid. The solid was filtered and dried under vacuum on a rotary evaporator at 55 °C to afford the title compound (200 mg) as an off-white solid. Yield: 44%. Melting point: 238°C-240°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 12.22 (bs, 1H), 11.13 (s, 1H), 9.07 (d, J 4.4, 1H), 8.99 (d, J 3.2, 1H) , 8.83 (s, 1H), 8.33 (d, J 2.4, 1H), 8.27 (dd, J 8.8, 2.4, 1H), 8.19 (d, J 12, 1H), 7.93 (d, J 9.2, 1H), 7.84 (d, J 4.4, 1H), 5.58-5.50 (m, 1H), 3.55-3.46 (m, 2H), 3.12-3.03 (m, 2H), 3.02-2.93 (m, 1H), 2.76 (d, J 4.8, 3H), 2.18-2.05 (m, 4H), 1.56 (d, J 6.8, 3H). MS (m/z): 477.57 (M+H-3HCl); Calcd. for _{[ C26H26F2N6O.3HCl +} H-3HCl]: _477.53 . Example 58 (±)-4-(6-((4-(4-(1-(( tertiary butoxycarbonyl ) amino ) ethyl )-8- fluoroquinolin- 6- yl )-5- Fluoropyrimidin -2- yl ) amino ) pyridin - 3 -yl ) tert-butyl hexahydropyridine- 1 -carboxylate

The title compound was synthesized from Intermediate 71 (600 mg, 1.43 mmol) and Intermediate 87 (395 mg, 1.43 mmol) following General Procedure-3. After work-up, the crude product was purified by combi-flash using MeOH and DCM (3:97) as eluents. The pure compound from column chromatography was suspended in diethyl ether (20 ml) and stirred for 30 min to obtain a solid. The solid was filtered and washed with diethyl ether (10 ml). The solid was dried under vacuum to obtain the title compound (370 mg) as a light yellow solid. Yield: 39%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 10.11 (s, 1H), 9.05 (d, J 4.4, 1H), 8.81 (s, 1H), 8.79 (d, J 3.2, 1H) , 8.25-8.15 (m, 3H), 7.98-7.89 (m, 1H), 7.74-7.65 (m, 2H), 5.57-5.49 (m, 1H), 4.14-4.05 (m, 2H), 2.88-2.78 ( m, 2H), 2.72-2.65 (m, 1H), 1.81-1.74 (m, 2H), 1.59-1.47 (m, 2H), 1.46 (d, J 6.8, 3H), 1.42 (s, 9H), 1.38 (s, 9H). MS (m/z): _662.36 (M ₊ H); Calcd. for [ _{C35H41F2N7O4 +} H]: _662.32 . Example 58A (±)-4-(4-(1 -aminoethyl )-8- fluoroquinolin- 6- yl )-5- fluoro -N-(5-( hexahydropyridin- 4 -yl ) pyridine -2- yl ) pyrimidin -2- amine

Following general procedure-4, from (±)-4-(6-((4-(4-(1-((tert-butoxycarbonyl)amino)ethyl)-8-fluoroquinoline-6- The title compound was synthesized as a yellow solid (37 mg). Yield: 97%. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 10.08 (s, 1H), 9.03 (d, J 4.4, 1H), 8.85 (s, 1H), 8.77 (d, J 3.6, 1H) , 8.21-8.14 (m, 3H), 7.92 (d, J 4.4, 1H), 7.67 (d, J 8.8, 2.4, 1H), 4.91-4.83 (m, 1H), 3.10-3.00 (m, 2H), 2.69-2.55 (m, 3H), 1.76-1.68 (m, 2H), 1.62-1.49 (m, 2H), 1.45 (d, J 6.4, 3H). MS (m/z): _462.49 (M+H); Calcd. for [ _{C25H25F2N7 +} H]: _462.21 . Example 58B (±)-4-(4-(1 -aminoethyl )-8- fluoroquinolin- 6- yl )-5- fluoro -N-(5-( hexahydropyridin- 4 -yl ) pyridine -2- yl ) pyrimidin -2- amine trihydrochloride

To (±)-4-(4-(1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5- To a mixture of (hexahydropyridin-4-yl)pyridin-2-yl)pyrimidin-2-amine (Example 58A, 80 mg, 0.17 mmol) in methanol (2 mL) was added 35% aqueous hydrochloric acid (63 mg, 1.7 mmol). The resulting clear solution was stirred for 30 min. After 30 min, dilute with methyl tert-butyl ether (10 mL) and stir for 1 h to obtain a solid. The solid was filtered and dried under vacuum on a rotary evaporator at 55°C to afford the title compound (70 mg) as an off-white solid. Yield: 87%. Melting point: 246°C-248°C. ¹ H-NMR (δ ppm, DMSO- d ₆ , 400 MHz): 11.59 (s, 1H), 9.35-9.20 (m, 4H), 9.18 (d, J 4.4, 1H), 8.76 (s, 1H), 8.32 (d, J 2, 1H), 8.24 (d, J 12, 1H), 8.11 (d, J 8.4, 1H), 8.07 (d, J 4.4, 1H), 8.03 (d, J 8.8, 1H), 5.41-5.32 (m, 1H), 3.40-3.32 (m 2H), 3.08-2.94 (m, 3H), 2.05-1.90 (m, 4H), 1.72 (d, J 6.8, 3H). MS (m/z): 462.48 (M+H-3HCl); Calcd. for [ _{C25H25F2N7.3HCl +} H _- 3HCl]: _462.21 . biological analysis

The pharmacological properties of the compounds of the invention can be confirmed by several pharmacological assays. Examples of pharmacological assays that can be performed on the compounds of the present invention and/or their pharmaceutically acceptable salts are shown below. EXAMPLE -A CDK1 Enzyme Assay Protocol Target for Screening Compounds of Formula (I ) or Determining the _IC50 of Compounds of Formula (I)

Using the ADP-Glo kinase assay, the compounds of the invention were screened for % inhibition of the CDK1 enzyme or the _IC50 of the activity of the compounds of the invention against the CDK1 enzyme was determined. set

CDK1 enzyme assays were performed using the ADP-glow kinase kit. ADP-Glo Kinase Assay Protocol

The kinase assay has 3 steps: a) enzymatic reaction, b) ATP depletion, c) kinase detection. The protocol below is designed for a 384-well plate, using a 1:1:2 ratio for each of the 3 steps. a) Enzymatic reaction : l The total volume of the kinase-catalyzed reaction is 5 µL. 1 μL DMSO/drug (diluted in Kinase Buffer as 5X) and the final concentration in the wells is 1X. 2 µL of enzyme (prepared at 1 ng/µL in kinase buffer). Add 2 μL of ATP/substrate (histone) mix (2.5x, prepared in kinase buffer) so that the final concentration of ATP/well is 50 μM and histone is 125 ng per well. l Add 1 µL of test compound at 5X concentration to each well. For control wells (blank and enzyme blank), add 1 µL of DMSO prepared in 1X buffer. The final DMSO concentration in all wells was maintained at 0.5%. l Add 2 µL (1 ng/µl) of CDK1/Cyclin A2 enzyme to enzyme blank and drug-treated wells. Add 2 µL of 1X Kinase Reaction Buffer to control (blank) wells. l Centrifuge the plate for 10 seconds and incubate at room temperature for 15 minutes. l Add 2 µL of ATP (2.5X) + substrate (histone) solution to each well (final concentration of ATP/well is 50 µM and histone is 125 ng/well). l Centrifuge the plate for 10 seconds and incubate at room temperature for 60 minutes. b) ATP depletion : l Thaw ADP-glo reagent to room temperature before use. l Add 5 µL of ADP-Glo Reagent to terminate the kinase-catalyzed reaction to deplete unconsumed ATP. l Centrifuge the plate for 10 seconds and incubate at room temperature for 40 minutes. c) Kinase detection : l Thaw the kinase detection buffer to room temperature before use. l Add 10 µL Kinase Detection Reagent to convert ADP to ATP, and introduce luciferase and luciferin to detect ATP. l Incubate the plate at room temperature for 30 minutes. l Use BMG Labtech, FLUOstar Omega to record luminescence.

Screening calculation : 1) Calculate the average value of each well. 2) Subtract the average value of the blank wells from the average value of each enzyme blank well and treated wells. 3) Calculate the average value of blank subtracted wells 4) Calculate the inhibition % based on the following formula 100 - (average value of blank subtracted treated wells * 100) / (average value of blank subtracted enzyme blank wells) 5) For IC ₅₀ calculation, use GraphPad Prism, _IC50 curves were plotted using mean blank subtracted values. Example - B CDK2 Enzyme Assay Protocol Objectives for Screening or Determining the IC ₅₀ of Compounds of Formula (I )

Using the ADP-Glo kinase assay, the compounds of the invention were screened for % inhibition of the CDK2 enzyme or the _IC50 of the activity of the compounds of the invention against the CDK2 enzyme was determined. Set:

CDK2 enzyme assays were performed using the ADP-glow kinase kit. ADP-Glo Kinase Assay Protocol

The kinase assay has 3 steps: a) enzymatic reaction, b) ATP depletion, c) kinase detection. The protocol below is designed for a 384-well plate, using a 1:1:2 ratio for each of the 3 steps. a) Enzymatic reaction : l The total volume of the kinase-catalyzed reaction is 5 µL. 1 μL DMSO/drug (diluted in Kinase Buffer as 5X) and the final concentration in the wells is 1X. 2 µL of enzyme (prepared at 1 ng/µL in kinase buffer). Add 2 μL of ATP/substrate (histone) mix (2.5x, prepared in kinase buffer) so that the final concentration of ATP/well is 50 μM and histone is 125 ng per well. l Add 1 µL of test compound at 5X concentration to each well. For control wells (blank and enzyme blank), add 1 µL of DMSO prepared in 1X buffer. The final DMSO concentration in all wells was maintained at 0.5%. l Add 2 µL (1 ng/µl) of CDK2/Cyclin A2 enzyme to enzyme blank and drug-treated wells. Add 2 µL of 1X Kinase Reaction Buffer to control (blank) wells. l Centrifuge the plate for 10 seconds and incubate at room temperature for 15 minutes. l Add 2 µL of ATP (2.5X) + substrate (histone) solution to each well (final concentration of ATP/well is 50 µM and histone is 125 ng/well). l Centrifuge the plate for 10 seconds and incubate at room temperature for 20 minutes. b ) ATP- depletion : l Thaw ADP-glo reagent to room temperature before use. l Add 5 µL of ADP-Glo Reagent to terminate the kinase-catalyzed reaction to deplete unconsumed ATP. l Centrifuge the plate for 10 seconds and incubate at room temperature for 40 minutes. c) Kinase detection : l Thaw the kinase detection buffer to room temperature before use. l Add 10 µL Kinase Detection Reagent to convert ADP to ATP, and introduce luciferase and luciferin to detect ATP. l Incubate the plate at room temperature for 30 minutes. l Use BMG Labtech, FLUOstar Omega to record luminescence.

Screening calculations : 1) Calculate the mean value for each well 2) Subtract the mean value of the blank wells from the mean values of each enzyme blank well and treated wells. 3) Calculate the average value of blank subtracted wells 4) Calculate the inhibition % based on the following formula 100 - (average value of blank subtracted treated wells * 100) / (average value of blank subtracted enzyme blank wells) 5) For IC ₅₀ calculation, use GraphPad Prism, _IC50 curves were plotted using mean blank subtracted values. Example - C CDK4 Enzyme Assay Protocol Objectives for Screening Compounds of Formula (I ) or Determining the IC ₅₀ of Compounds of Formula (I)

Using the ADP-Glo kinase assay, compounds of the invention are screened for % inhibition of CDK4 enzyme and/or _IC50 of compounds of the invention against CDK4 enzyme are determined. Set:

CDK4 enzyme assays were performed using the ADP-glow kinase kit. ADP-Glo Kinase Assay Protocol

The kinase assay has 3 steps: a) enzymatic reaction, b) ATP depletion, c) kinase detection. The protocol below is designed for a 384-well plate, using a 1:1:2 ratio for each of the 3 steps. a) Enzymatic reaction : l The total volume of the kinase-catalyzed reaction is 5 µL. 1 μL DMSO/drug (diluted in Kinase Buffer as 5X) and the final concentration in the wells is 1X. 2 µL of enzyme (prepared at 20 ng/µL in kinase buffer). 2 μL of ATP (2.5x, prepared in Kinase Buffer)/substrate (Rb protein) for a final concentration of ATP/well of 100 μM and 0.005 μg of Rb protein per well. l Add 1 µL of test compound at 5X concentration to each well. For control wells (blank and enzyme blank), add 1 µL of DMSO prepared in 1X buffer. The final DMSO concentration in all wells was maintained at 0.5%. l Add 2 µL (20 ng/µl) of CDK4/cyclin D3 enzyme to enzyme blank and drug-treated wells. Add 2 µL of 1X Kinase Reaction Buffer to control (blank) wells. Plates were centrifuged for 10 seconds and incubated at room temperature for 15 minutes. l Add 2 µL of ATP (2.5X) + substrate (Rb protein) solution to each well (final concentration of ATP/well is 100 µM and Rb protein is 0.005 µg). l Centrifuge the plate for 10 seconds and incubate at room temperature for 60 minutes. b) ATP depletion : l Thaw ADP-glo reagent to room temperature before use. l Add 5 µL of ADP-Glo Reagent to terminate the kinase-catalyzed reaction to deplete unconsumed ATP. Plates were centrifuged for 10 seconds and incubated at room temperature for 40 minutes. c) Kinase detection : l Thaw the kinase detection buffer to room temperature before use. l Add 10 µL Kinase Detection Reagent to convert ADP to ATP, and introduce luciferase and luciferin to detect ATP. l Incubate the plate at room temperature for 30 minutes. l Use BMG Labtech, FLUOstar Omega to record luminescence.

Screening calculations : 1) Calculate the mean value for each well 2) Subtract the mean value of the blank wells from the mean values of each enzyme blank well and treated wells. 3) Calculate the average value of blank subtracted wells 4) Calculate the % inhibition based on the following formula: 100 - (average value of blank subtracted treated wells * 100) / (average value of blank subtracted enzyme blank wells) 5) For _IC50 calculation, use GraphPad Prism, plotting _IC50 curves using mean blank subtracted values. Example - D CDK6 Enzyme Assay Protocol Objectives for Screening Compounds of Formula (I ) or Determining the IC ₅₀ of Compounds of Formula (I)

Using the ADP-Glo kinase assay, the compounds of the invention are screened for % inhibition of the CDK6 enzyme and/or the _IC50 of the compounds of the invention against the CDK6 enzyme is determined. set

CDK6 enzyme assays were performed using the ADP-glow kinase kit. The kit components include kinase detection reagent, ADP-glo reagent, ATP, substrate (histone) and CDK6 enzyme. All such reagents were prepared and stored according to the manufacturer's instructions. ADP-Glo Kinase Assay Protocol

The kinase assay has 3 steps: a) enzymatic reaction, b) ATP depletion, c) kinase detection. The protocol below is designed for a 384-well plate, using a 1:1:2 ratio for each of the 3 steps. a) Enzymatic reaction: l The total volume of the kinase-catalyzed reaction is 5 µL. 1 μL DMSO/drug (diluted in Kinase Buffer as 5X) and the final concentration in the wells is 1X. 2 µL of enzyme (prepared at 10 ng/µL in kinase buffer). 2 μL ATP (2.5x, prepared in Kinase Buffer)/substrate (histone) so that the final concentration of ATP/well is 250 μM and histone is 0.025 μg l per well Add 1 μL to each well 5X concentration of test compound. For control wells (blank and enzyme blank), add 1 µL of DMSO prepared in 1X buffer. The final DMSO concentration in all wells was maintained at 0.5%. l Add 2 µL (10 ng/µl) of CDK6/cyclin D3 enzyme to enzyme blank and drug-treated wells. Add 2 µL of 1X Kinase Reaction Buffer to control (blank) wells. l Centrifuge the plate for 10 seconds and incubate at room temperature for 15 minutes. l Add 2 µL of ATP (2.5X) + substrate solution to each well (final concentration of ATP/well is 250 µM and histone is 0.025 µg. l Centrifuge the plate for 10 seconds and incubate at room temperature for 60 minutes. b) ATP depletion : l Thaw ADP-glo reagent to room temperature before use. l Add 5 µL of ADP-Glo Reagent to terminate the kinase-catalyzed reaction to deplete unconsumed ATP. l Centrifuge the plate for 10 seconds and incubate at room temperature for 40 minutes. c) Kinase detection : l Thaw the kinase detection buffer to room temperature before use. l Add 10 µL Kinase Detection Reagent to convert ADP to ATP, and introduce luciferase and luciferin to detect ATP. l Incubate the plate at room temperature for 30 minutes. l Use BMG Labtech, FLUOstar Omega to record luminescence.

Screening calculations : 1) Calculate the mean value for each well 2) Subtract the mean value of the blank wells from the mean values of each enzyme blank well and treated wells. 3) Calculate the average value of blank subtracted wells 4) Calculate the % inhibition based on the following formula: 100 - (average value of blank subtracted treated wells * 100) / (average value of blank subtracted enzyme blank wells) 5) For _IC50 calculation, use GraphPad Prism, plotting _IC50 curves using mean blank subtracted values. Results : Inhibition % values are given in Table-2 and Table-3 below, and _IC50 values are given in Table-4 below: Example - E is used to screen breast cancer cells for GI ₅₀ of selected formula (I) compounds Cell Proliferation Assay in Strains Protocol Goals:

Cell proliferation assays were performed in breast cancer cell lines ( _ZR.75.1 , MCF-7 and MDA-MB-231) to determine the GI50 of selected compounds of the invention using the MTT assay. Method : MTT analysis (3--2,5-diphenyltetrazolium bromide)

Procedure : Cells are processed, pelleted and counted. Cells were plated in triplicate at 100 μl/well in complete medium at the desired density in 96-well plates and the plates were incubated at 37°C and 5% CO ₂ . Cells in each well were treated in triplicate with inhibitor dilutions prepared in complete medium, and plates were incubated at 37°C and 5% _CO2 for 144 h. After 144 h, 15 µL of 5 mg/mL (1X final concentration) of MTT was added to the test wells and mixed well. Plates were incubated for 3.5 hours at 37°C and 5% _CO2 . After incubation, the cells were pelleted and sedimented at 4000 rpm for 10 min. Aspirate the medium and add 150 µL DMSO per well. The crystals were dissolved by repeated pipetting. Absorbance was read at A560 nm and A640 nm. GI ₅₀ values were calculated using GraphPad Prism.

Results: GI ₅₀ values for selected compounds of the invention were determined in Table 4 below. Table -2 instance number Inhibition % CDK1 CDK2 CDK4 CDK6 100nM 1000 nM 100nM 1000nM 100nM 1000nM 100nM 1000nM 1B B A B A 2B D. D. D. C A A B A 3A D. D. D. D. A A C B 4A A A C B 5B B A B A 6A B A D. B 7A A A C B 8A D. D. D. C A A B A 9A B A C B 10B B A B A 11B A A A A 12A B A C B 13A B A C B 14A B A C B 15A B A C B 17B D. B B A Table -3 instance number Inhibition % CDK1 CDK2 CDK4 CDK6 30nM 100nM 30nM 100nM 30nM 100nM 30nM 100nM 16A B A D. C 17B C A C B 18A C A C B 19A D. D. D. D. 20B D. B D. C 21A D. C D. D. 22A D. C D. D. 23B D. B D. C 24A D. C D. D. 25A D. D. D. D. 26B D. C D. D. 27A D. C D. D. 28A C B D. C 29A D. B D. D. 30A D. D. D. D. 31A D. D. D. C D. B D. D. 32A D. D. D. D. 33A D. C D. D. 34A D. C D. D. 35A D. C D. D. 36A D. B D. D. 37A C C D. C 38A D. C D. D. D. D. D. D. 39B D. D. D. D. C B D. C 40B D. D. C C B A A A 41B C B B A A A B A 42B D. D. D. D. C A C B 43A D. D. C C B A B A 44A D. C D. C C A C A 45A D. D. D. D. C C D. D. 46B C A B A 47A D. C C B B B B A 48B C A A A B B A A 49B D. C D. B B B B B 50B D. D. C B B B C B 51B C B B A B A B A 52B D. D. D. C B A C B 53B D. C B A C B 54B C B B A D. B 55B D. D. C B D. D. 56A C B A A B A A A 58B D. C C A C C

Inhibition %: A stands for >75% to 100%; B stands for >50% to ≤75%; C stands for >25% to ≤50% and D stands for ≤25%; Table -4 instance number IC50 GI50 (nM) CDK1 CDK2 CDK4 CDK6 MCF-7 ZR-75.1 MDA-MB-231 1B ++++ ++ b 2B +++ +++ b 3A +++++ + d 5B +++++ ++++ a 7A +++++ ++ b 8A +++++ ++ b 9A ++ + e 10B ++++ +++ b 11B ++++ +++ b 16A ++++ ++ 17B +++ +++ ++++ a b b 18A ++++ +++ a 41B +++ +++ +++++ ++++ c c IC50: "++++" stands for 1 nM to ≤25 nM; "++++" stands for >25 nM to ≤50 nM; "+++" stands for >50 nM to ≤100 nM; "++" Represents >100 nM to ≤200 nM, "+" represents >200 nM; GI50: "a" represents 100 nM to ≤200 nM; "b" represents >200 nM to ≤500 nM; "c" represents >500 nM to ≤ 1000nM; "d" stands for >1000 nM to ≤10000 nM, "e" stands for >10000 nM;

Although the present invention has been described herein with reference to the embodiments, it should be understood that these embodiments are merely illustrative of the principles and applications of the invention. It will therefore be understood that various modifications may be made and other configurations may be devised in the illustrative embodiments without departing from the spirit and scope of the invention as set forth above. The accompanying claims are intended to define the scope of the invention and to thereby cover methods and structures within the scope of these claims and their equivalents.

All publications and patents and/or patent applications cited in this application are hereby incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be Incorporated herein generally by way of reference.

Claims (32)

A compound of formula (I) ,

(I) or its tautomer, its prodrug, its N ^- oxide, its stereoisomer, its pharmaceutically acceptable ester or its pharmaceutically acceptable salt, wherein Y is selected from CR ^a or N; Y ² is selected from CR ^b or N; proviso that at least one of Y ¹ and Y ² is N; R ^a , R ^b , R ^c , R ^d , ^Re , R ^f and R ^g are in each The second occurrence is independently selected from hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted Alkoxy, substituted or unsubstituted aminoalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkane group, substituted or unsubstituted heterocyclyl or substituted or unsubstituted heterocyclylalkyl; Y is selected from CR ^h or N; Z is selected from CR ⁱ or N; the proviso is that at least one of Y and Z One is N; R ^h and R ⁱ are independently selected from each occurrence of hydrogen, halogen, substituted or unsubstituted C _(1-3) alkyl or substituted or unsubstituted C ₍ 1-3) ₃₎ Haloalkyl; X ¹ is selected from CR ¹ or N; X ² is selected from CR ² or N; X ³ is selected from CR ³ or N; X ⁴ is selected from CR ⁴ or N; R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from hydrogen, halogen, hydroxyl, substituted or unsubstituted alkyl or substituted or unsubstituted haloalkyl, substituted or unsubstituted Substituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heterocyclic L is absent, NH, O, S-, -SO-, -SO ₂ -, -C(=O)-, or substituted or unsubstituted alkyl; Ring A is substituted or unsubstituted Substituted heterocyclyl ring ^; each occurrence of R is independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted Substituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl , substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, side oxy (=O), -C(=O)OR ^z , -C(=O)R ^z , -C(=S)R ^z , -C(=O)NR ^z R ^z , -C(=O)ONR ^z R ^z , -NR ^z R ^z , -NR ^z C(=O)NR ^z R ^z , -NR ^z S(=O)R ^z , -NR ^z S(=O) ₂ R ^z , -N=N R ^z , -NR ^z C(=O)OR ^z , -NR ^z C(=O)R ^z , -NR ^x C(=S)R ^y -NR ^z C(=S)NR ^z R ^z , -SONR ^z R ^z , -SO ₂ NR ^z R ^z , -OR ^z , -OC(=O)NR ^z R ^z , -OC(=O)OR ^z , -OC(=O)R ^z , -OC(=O )NR ^z R ^z , -CR ^x R ^y -NR ^z C(=O)R ^z , -CR ^x R ^y -OR ^z , -CR ^x R ^y -C(=O)OR ^z , -CR ^x R ^y -C(=O)NR ^z R ^z , -CR ^x R ^y -OC(=O)R ^z , SR ^z , -SOR ^z , -SO ₂ R ^z , -CR ^x R ^y C(=O)R ^z or -CR ^x R ^y C(=S) R ^z ; R ^z is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl , substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted hetero Cyclic, substituted heterocyclylalkyl or substituted or unsubstituted amino, or any two R ^z when bound to a common atom may be linked to form (i) substituted or unsubstituted saturated or An unsaturated 3- to 14-membered ring, which optionally includes one or more heteroatoms, which (the) heteroatoms may be the same or different and are selected from O, NR ^za and S, or (ii) pendant oxy (=O ), thio (=S) or imino (=NR ^za ); wherein R ^za , R ^x and R ^y are each independently selected from hydrogen, halo, hydroxyl, amino, alkoxy, C _1-5 alkyl, C _3-7 cycloalkyl, C _5-7 aryl, C _5-7 heteroaryl or C _3-7 heterocycloalkyl; and n is selected from 0, 1, 2, Integer of 3 and 4. The compound according to claim 1, wherein X ¹ , X ² , X ³ and X ⁴ are independently selected from CH or N. The compound as claimed in item 2, wherein X ¹ and X ² are N. The compound as claimed in item 2, wherein X ¹ is N. The compound according to claim 2, wherein X ² , X ³ and X ⁴ are independently selected from CH. The compound of claim 1, wherein Y and Z are independently selected from CH or N. The compound as claimed in item 6, wherein Y is N. The compound as claimed in item 6, wherein Z is N. As the compound of claim 1, wherein the formula (IA) , (IB) , (IC) or (ID) compound:

(IA) (IB)

(IC) (ID) or its tautomers, its prodrugs, its N-oxides, its stereoisomers, its pharmaceutically acceptable esters or its pharmaceutically acceptable salts, wherein all variables (including rings A, L, R ⁵ , R ⁶ , R ⁷ , R ^c , R ^d , ^Re , R ^f , R ^g , Y ¹ , Y ² and n) are as defined in formula (I) . The compound according to any one of claims 1 to 9, wherein ring A is selected from

. The compound according to any one of claims 1 to 10, wherein L is absent or CH ₂ . The compound as claimed in item 11, wherein L is absent. The compound according to claim 11, wherein L is CH ₂ . The compound according to any one of claims 1 to 13, wherein R ⁵ is hydrogen or halogen. The compound as claimed in claim 14, wherein R ⁵ is hydrogen or fluorine. The compound as claimed in any one of items 1 to 15, wherein R ⁶ is hydrogen. The compound as claimed in any one of items 1 to 16, wherein Y ¹ is N. The compound according to any one of claims 1 to 17, wherein ring

selected from

. A compound selected from the group consisting of: 4-(6-((5-fluoro-4-(quinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1- tert-butyl formate; 5-fluoro-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine; 5 -Fluoro-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine hydrochloride; 4-(6-( (5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; 5-fluoro -4-(8-fluoroquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine; 5-fluoro-4-(8 -Fluoroquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; N-(5-((4-ethyl N-(5-(( 4-Ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-amine hydrochloride; N -(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(quinolin-6-yl)pyrimidin-2-amine; N -(5-((4-Ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(quinolin-6-yl)pyrimidin-2-amine hydrochloride Salt; 4-(6-((5-fluoro-4-(8-fluoro-2-methyl-4-(prop-1-en-2-yl)quinolin-6-yl)pyrimidin-2-yl )amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; 5-fluoro-4-(8-fluoro-2-methyl-4-(prop-1-ene-2 -yl) quinoline-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine; 5-fluoro-4-(8-fluoro-2 -Methyl-4-(prop-1-en-2-yl)quinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidine-2- Amine hydrochloride; 5-fluoro-N-(5-(4-methylhexahydropyrazin-1-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine ; 5-fluoro-N-(5-(4-methylhexahydropyrazin-1-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine hydrochloride; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-methylhexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine; 5 -Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-methylhexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride ; N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinoline-6 -yl)pyrimidin-2-amine; N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinoline-6- Base) pyrimidin-2-amine hydrochloride; N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8- Fluoro-2-methylquinolin-6-yl)pyrimidin-2-amine; N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5 -Fluoro-4-(8-fluoro-2-methylquinolin-6-yl)pyrimidin-2-amine hydrochloride; 4-(6-((5-fluoro-4-(8-fluoro-2- Methylquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; 5-fluoro-4-(8-fluoro-2 -Methylquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine; 5-fluoro-4-(8-fluoro-2 -Methylquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; 4-(6-((5- Fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid Tributyl ester; 5-fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridine -2-yl)pyrimidin-2-amine; 5-fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)-N-(5-(hexahydropyrazine -1-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro- 4-(quinolin-6-yl)pyrimidin-2-amine; N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(quinolin Lin-6-yl)pyrimidin-2-amine hydrochloride; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-isopropylhexahydropyrazine-1 -yl)pyridin-2-yl)pyrimidin-2-amine; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-isopropylhexahydropyrazine-1 -yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; 5-fluoro-N-(5-(4-isopropylhexahydropyrazin-1-yl)pyridin-2-yl)-4 -(quinolin-6-yl)pyrimidin-2-amine; 5-fluoro-N-(5-(4-isopropylhexahydropyrazin-1-yl)pyridin-2-yl)-4-(quinolin Lin-6-yl)pyrimidin-2-amine hydrochloride; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-((4-methylhexahydropyrazine-1 -yl)methyl)pyridin-2-yl)pyrimidin-2-amine; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-((4-methylhexahydropyridine oxazin-1-yl)methyl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; 2-(6-(2-((5-((4-ethylhexahydropyridine oxazin-1-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8-fluoro-2-methylquinolin-4-yl)propan-2-ol; 2-(6-(2-((5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)- 8-fluoro-2-methylquinolin-4-yl)propan-2-ol hydrochloride; 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan- 2-yl)-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; 2-(8- Fluoro-6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylquinoline-4- Base) propan-2-ol; 2-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidine-4 -yl)-2-methylquinolin-4-yl)propan-2-ol hydrochloride; 2-(6-(2-((5-(4-ethylhexahydropyrazin-1-yl) Pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8-fluoro-2-methylquinolin-4-yl)propan-2-ol; 2-(6-(2-( (5-(4-Ethylhexahydropyrazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8-fluoro-2-methylquinoline-4- base) propan-2-ol hydrochloride; 4-(4-(difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-N-(5-(4-ethylhexa Hydropyrazin-1-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine; 4-(4-(difluoromethyl)-8-fluoro-2-methylquinolin-6-yl )-N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine hydrochloride; 4-(6-((4-( 4-(Difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1- tert-butyl formate; 4-(4-(difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyrazine- 1-yl)pyridin-2-yl)pyrimidin-2-amine; 4-(4-(difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoro-N- (5-(Hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; 4-(4-(Difluoromethyl)-8-fluoro-2-methylquinoline -6-yl)-N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine; 4-(4- (Difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridine-2- N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4 -(8- Fluoro-4-(2-fluoroprop-2-yl)-2-methylquinolin-6-yl)pyrimidin-2-amine; N-(5-((4-ethylhexahydropyrazine-1- Base) methyl) pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-(2-fluoroprop-2-yl)-2-methylquinolin-6-yl)pyrimidine-2 -Amine hydrochloride; 4-(6-((5-fluoro-4-(8-fluoro-4-(2-fluoroprop-2-yl)-2-methylquinolin-6-yl)pyrimidine- 2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; 5-fluoro-4-(8-fluoro-4-(2-fluoroprop-2-yl) -2-methylquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine; 5-fluoro-4-(8-fluoro -4-(2-fluoroprop-2-yl)-2-methylquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidine-2 -Amine hydrochloride; 5-fluoro-N-(5-((4-methylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-4-(quinolin-6-yl) Pyrimidin-2-amine; 5-fluoro-N-(5-((4-methylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-4-(quinolin-6-yl) Pyrimidin-2-amine hydrochloride; N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(7-fluoroquine Lin-6-yl)pyrimidin-2-amine; N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(7 -Fluoroquinolin-6-yl)pyrimidin-2-amine hydrochloride; 4-(6-((5-fluoro-4-(7-fluoroquinolin-6-yl)pyrimidin-2-yl)amino )pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; 5-fluoro-4-(7-fluoroquinolin-6-yl)-N-(5-(hexahydropyrazine- 1-yl)pyridin-2-yl)pyrimidin-2-amine; 5-fluoro-4-(7-fluoroquinolin-6-yl)-N-(5-(hexahydropyrazin-1-yl)pyridine -2-yl)pyrimidin-2-amine hydrochloride; N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(7-fluoro Quinolin-6-yl)pyrimidin-2-amine; N-(5-(4-ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(7-fluoroquine Pyrimin-6-yl)pyrimidin-2-amine hydrochloride; N-(5-(4-(dimethylamino)hexahydropyridin-1-yl)pyridin-2-yl)-5-fluoro-4 -(8-fluoroquinolin-6-yl)pyrimidin-2-amine; N-(5-(4-(dimethylamino)hexahydropyridin-1-yl)pyridin-2-yl)-5- Fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-amine hydrochloride; 4-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidine- 2-yl)amino)pyridin-3-yl)hexahydropyrazin-2-one; 4-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl) Pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazin-2-one hydrochloride; N-(5-(4-cyclopropylhexahydropyrazin-1-yl)pyridine-2 -yl)-5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-amine; N-(5-(4-cyclopropylhexahydropyrazin-1-yl)pyridine-2 -yl)-5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-amine hydrochloride; 1-(4-(6-((5-fluoro-4-(8-fluoro Quinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazin-1-yl)ethan-1-one; 1-(4-(6-((5-fluoro -4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazin-1-yl)ethan-1-one hydrochloride; 5-fluoro -4-(8-fluoroquinolin-6-yl)-N-(5-(4-(2,2,2-trifluoroethyl)hexahydropyrazin-1-yl)pyridin-2-yl) Pyrimidin-2-amine; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-(2,2,2-trifluoroethyl)hexahydropyrazine-1 -yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-(methylsulfonyl ) Hexahydropyrazin-1-yl) pyridin-2-yl) pyrimidin-2-amine; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-(methyl Cyclopropyl (4-(6-((5-fluoro-4-(8-fluoro Quinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazin-1-yl)methanone; cyclopropyl (4-(6-((5-fluoro-4 -(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazin-1-yl)methanone hydrochloride; 5-fluoro-4-(8 -Fluoroquinolin-6-yl)-N-(5-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyridine Azin-7(8H)-yl)pyridin-2-yl)pyrimidin-2-amine; 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(3-(trifluoro Methyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyridin-2-yl)pyrimidin-2-amine salt acid salt; N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-isopropyl- 2-methylquinolin-6-yl)pyrimidin-2-amine; N-(5-((4-ethylhexahydropyrazin-1-yl)methyl)pyridin-2-yl)-5-fluoro -4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)pyrimidin-2-amine hydrochloride; N-(5-(4-ethylhexahydropyrazine-1 -yl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)pyrimidin-2-amine; N-(5-( 4-Ethylhexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)pyrimidine- 2-amine hydrochloride; 1-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)-4-methyl ylhexahydropyridin-4-ol; 1-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)-4 -Methylhexahydropyridin-4-ol hydrochloride; (±)-4-(6-((4-(4-(1-((tertiary butoxycarbonyl)amino)ethyl)-8 -Fluoro-2-methylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; (±) -4-(4-(1-aminoethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyrazin-1-yl) Pyridin-2-yl)pyrimidin-2-amine; (±)-4-(4-(1-aminoethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoro- N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride; (±)-4-(6-((4-(4-(1-( (Third butoxycarbonyl)amino)ethyl)-8-fluoroquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1 - tert-butyl formate; (±)-4-(4-(1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyridine Azin-1-yl)pyridin-2-yl)pyrimidin-2-amine; (±)-4-(4-(1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro -N-(5-(hexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine dihydrochloride; (±)-4-(6-((5-fluoro-4-( ( ±)-1-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinoline -4-yl)ethanol; (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino) Pyrimidin-4-yl)quinolin-4-yl)ethanol trimesylate; (±)-(1-(8-fluoro-6-(5-fluoro-2-((5-(4-methylhexa Hydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethyl)tert-butyl carbamate; (±)-4-(4 -(1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(4-methylhexahydropyrazin-1-yl)pyridin-2-yl) Pyrimidin-2-amine; (±)-4-(4-(1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(4 -Methylhexahydropyrazin-1-yl)pyridin-2-yl)pyrimidin-2-amine trihydrochloride; (±)-1-(6-(2-((5-(4-ethylhexa Hydropyrazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8-fluoroquinolin-4-yl)ethanol; (±)-1-(6-( 2-((5-(4-Ethylhexahydropyrazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8-fluoroquinolin-4-yl) Ethanol trihydrochloride; (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(4-isopropylhexahydropyrazin-1-yl)pyridin-2-yl ) amino) pyrimidin-4-yl) quinoline-4-yl) ethanol; (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(4-isopropylhexa Hydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol trihydrochloride; N-(5-(4-ethylhexahydropyrazine -1-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-2-methylquinolin-6-yl)pyrimidin-2-amine; N-(5-(4-ethyl Hexahydropyrazin-1-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-2-methylquinolin-6-yl)pyrimidin-2-amine hydrochloride; (±) -4-(6-((5-fluoro-4-(8-fluoro-4-(1-hydroxyethyl)-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)pyridine -3-yl) tert-butyl hexahydropyrazine-1-carboxylate; (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyrazine-1 -yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylquinolin-4-yl)ethanol; (±)-1-(8-fluoro-6-(5-fluoro- 2-((5-(Hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylquinolin-4-yl)ethan-1-ol hydrochloride Salt; (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(4-methylhexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidine -4-yl)quinolin-4-yl)ethanol; (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(4-methylhexahydropyrazine-1- yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol trihydrochloride; 4-(6-((5-fluoro-4-(8-fluoro-4- (2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; 2-(8 -Fluoro-6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)propane- 2-alcohol; 2-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinoline (±)-4-(6-((5-fluoro-4-(8-fluoro-4-(1-hydroxyethyl) Quinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyrazine-1-carboxylic acid tert-butyl ester; (±)-1-(8-fluoro-6-( 5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol; (±)-1- (8-fluoro-6-(5-fluoro-2-((5-(hexahydropyrazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl) Ethanol trihydrochloride; (±)-4-(6-((5-fluoro-4-(8-fluoro-4-(1-hydroxyethyl)quinolin-6-yl)pyrimidin-2-yl) Amino)pyridin-3-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester; (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridine -4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol; (±)-1-(8-fluoro-6-(5-fluoro-2-( (5-(Hexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol trihydrochloride; 4-(6-((5-fluoro -4-(8-fluoro-4-(2-hydroxyprop-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyridine-1-carboxylic acid Tributyl ester; 2-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinoline phen-4-yl)propan-2-ol; 2-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl)amino) Pyrimidin-4-yl)quinolin-4-yl)propan-2-ol trihydrochloride; 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2 -yl)-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester; 2-(8-fluoro- 6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylquinolin-4-yl)propane -2-alcohol; 2-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)- 2-methylquinolin-4-yl)propan-2-ol trihydrochloride; (±)-4-(6-((5-fluoro-4-(8-fluoro-4-(1-hydroxyethyl Base)-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester; (±)-1-(8 -Fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylquinoline-4- base) ethanol; (±)-1-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidine-4- Base)-2-methylquinolin-4-yl)ethanol trihydrochloride; 4-(2-((5 -Fluoro-4-(8-fluoro-4-(2-hydroxyprop-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)pyrimidin-5-yl)hexahydropyridine-1- tert-butyl formate; 2-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyrimidin-2-yl)amino)pyrimidin-4-yl )quinolin-4-yl)propan-2-ol; 2-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyrimidin-2-yl)amine Base) pyrimidin-4-yl) quinolin-4-yl) propan-2-ol trihydrochloride; (±)-4-(2-((5-fluoro-4-(8-fluoro-4-( 1-hydroxyethyl) quinoline-6-yl) pyrimidin-2-yl) amino) pyrimidin-5-yl) tert-butyl hexahydropyridine-1-carboxylate; (±)-1-(8- Fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyrimidin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol; (± )-1-(8-fluoro-6-(5-fluoro-2-((5-(hexahydropyridin-4-yl)pyrimidin-2-yl)amino)pyrimidin-4-yl)quinoline-4 -yl)ethanol trihydrochloride; 2-(8-fluoro-6-(5-fluoro-2-((5-(1-methylhexahydropyridin-4-yl)pyridin-2-yl)amino ) pyrimidin-4-yl) quinoline-4-yl) propan-2-ol; 2-(8-fluoro-6-(5-fluoro-2-((5-(1-methylhexahydropyridine-4 -yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)propan-2-ol trihydrochloride; (±)-1-(8-fluoro-6-(5 -Fluoro-2-((5-(1-methylhexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol; (±)- 1-(8-fluoro-6-(5-fluoro-2-((5-(1-methylhexahydropyridin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinoline -4-yl)ethanol trihydrochloride; (±)-4-(6-((4-(4-(1-((tertiary butoxycarbonyl)amino)ethyl)-8-fluoroquine (Pyridine-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester; (±)-4-(4-(1- Aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyridin-4-yl)pyridin-2-yl)pyrimidin-2-amine; (±) -4-(4-(1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(hexahydropyridin-4-yl)pyridin-2-yl) pyrimidin-2-amine trihydrochloride; and pharmaceutically acceptable salts thereof. A pharmaceutical composition comprising the compound according to any one of claims 1 to 19 and a pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 20, further comprising one or more additional therapeutic agents. The pharmaceutical composition of claim 21, wherein the one or more additional therapeutic agents are anticancer agents, anti-inflammatory agents, immunosuppressants, steroids, non-steroidal anti-inflammatory agents, antihistamines, analgesics or any of the above any combination. A method for inhibiting the catalytic activity of a CDK enzyme present in a cell selected from CDK1, CDK2, CDK4, CDK6, and any combination of any of the above, which includes making the cell an effective amount of the following claims 1 to 19 any one of the compounds in contact. The method of claim 23, wherein the inhibition occurs in an individual suffering from the following diseases or conditions: cancer, bone disorder, inflammatory disease, immune disease, nervous system disease, metabolic disease, respiratory disease, thrombosis or cardiac disease. A use of a compound according to any one of claims 1 to 19 for the manufacture of a medicament for the treatment of a disease, disorder or condition which would benefit from inhibition of the catalytic activity of a CDK enzyme selected from the group consisting of CDK1, CDK2, CDK4, CDK6, and any combination of any of the above. A method of treating a disease, disorder or disorder associated with CDK1, CDK2, CDK4, CDK6, or any combination of any of the above, comprising administering to an individual in need thereof an effective amount of any of claims 1 to 19 One of the compounds. The method of claim 26, further comprising the step of simultaneously or sequentially administering to the individual at least one other anticancer agent, anti-inflammatory agent, immunosuppressant, steroid, non-steroidal anti-inflammatory agent, antihistamine, analgesic agent or any combination of any of the above. The method of claim 26 or 27, wherein the disease, disorder or disorder is an immune system related disease, a disease or disorder involving inflammation, cancer or other proliferative disease, liver disease or disorder or kidney disease or disorder. The method of claim 26 or 27, wherein the disease, condition or condition is selected from inflammation, glomerulonephritis, uveitis, liver disease or condition, kidney disease or condition, chronic obstructive pulmonary disease, rheumatoid arthritis Inflammatory bowel disease, vasculitis, dermatitis, osteoarthritis, inflammatory myopathy, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenogeneic Transplantation, graft rejection, graft versus host disease, lupus erythematosus, pulmonary fibrosis, dermatomyositis, thyroiditis, myasthenia gravis, autoimmune hemolytic anemia, cystic fibrosis, chronic relapsing hepatitis, primary Biliary cirrhosis, allergic conjunctivitis, hepatitis, atopic dermatitis, asthma, Sjogren's syndrome, organ transplant rejection, multiple sclerosis, Guillain-Barre syndrome, autoimmunity Uveitis, autoimmune hemolytic anemia, pernicious anemia, autoimmune thrombocytopenia, temporal arteritis, antiphospholipid syndrome, vasculitis, Wegener's granulomatosis, Behcet's disease (Behcet's disease), psoriasis, dermatitis herpetiformis, pemphigus vulgaris, leukoplakia, Crohn's disease, colitis, ulcerative colitis, primary biliary cirrhosis, autoimmune hepatitis, type 1 Diabetes or immune-mediated diabetes, Grave's disease, Hashimoto's thyroiditis, autoimmune oophoritis and orchitis, adrenal autoimmune disorders, systemic lupus erythematosus, multiple Myositis, dermatomyositis, adhesive spondylitis, graft rejection, skin graft rejection, arthritis, osteopathy associated with increased bone resorption, ileitis, Barrett's syndrome, adult respiratory Distress syndrome, chronic obstructive airway disease; corneal dystrophy, trachoma, onchocerciasis, sympathetic ophthalmia, endophthalmitis, gingivitis, root periostitis, tuberculosis, leprosy, uremia complications, nephropathy, Sclerosing dermatitis, psoriasis, chronic demyelinating diseases of the nervous system, AIDS-related neurodegeneration, Alzheimer's disease, infectious meningitis, encephalomyelitis, Parkinson's disease , Huntington's disease, amyotrophic lateral sclerosis, viral or autoimmune encephalitis, autoimmune disorders, immune complex vasculitis, systemic lupus and erythematodes, systemic lupus erythematosus lupus erythematosus, SLE), cardiomyopathy, ischemic heart disease, high cholesterol Alcoholemia, atherosclerosis, preeclampsia, chronic liver failure, brain and spinal cord trauma, and cancer. The method of claim 26 or 27, wherein the disease, disease or disease is selected from hematopoietic tumors of the lymphoid lineage: leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, cholangiocarcinoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, pilocytic lymphoma and Burkett's lymphoma; hematopoietic tumors of the myeloid lineage: acute myelogenous leukemia, chronic myelogenous leukemia, Myelodysplastic syndrome, promyelocytic leukemia, bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophagus cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer Carcinoma, prostate cancer, skin cancer, squamous cell carcinoma; tumors of mesenchymal origin: fibrosarcoma, rhabdomyosarcoma; tumors of the central and peripheral nervous system: astrocytoma, neuroblastoma, glioma, schwannoma; Melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosa, keratoacanthoma, follicular carcinoma of the thyroid, brain cancer, and Kaposi's sarcoma. The method according to claim 26 or 27, wherein the disease, disease or condition is selected from breast cancer, ovarian cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, brain cancer or gastric cancer. The method according to claim 26 or 27, wherein the disease, disorder or condition is breast cancer or ovarian cancer.