Compounds and compositions for treating MC4r related conditions

Abstract

Disclosed herein are MC4R-selective compounds of Formula (I) suitable for use in the treatment of MC4R-related disorders, diseases and conditions.

Description

[0001] COMPOUNDS AND COMPOSITIONS FOR TREATING MC4R RELATED CONDITIONS

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] The present application claims priority to U. S. Provisional Patent Application No. US 63 / 693,594 which was filed September 11, 2024, and U. S. Provisional Patent Application No. US 63 / 716,568, which was filed November 5, 2024, the contents of which are incorporated herein by reference in their entirety.

[0004] FIELD OF THE INVENTION

[0005] The present invention relates to new pharmaceutical compounds, pharmaceutical compositions containing the compounds for treating MC4R related conditions, disorders and diseases.

[0006] BACKGROUND OF THE INVENTION

[0007] Melanocortin receptors (MC1R to MC5R) are a group of five G-protein coupled receptors that bind melanocortin peptide hormones and neurotransmitters. Melanocortin receptor signaling is involved in various physiological processes including appetite, energy homeostasis immune responses and pigmentation. Pro-opiomelanocortin (POMC) undergoes post translational processing to produce melanocortin agonists including: a-melanocyte-stimulating hormone (a-MSH), B -melanocyte-stimulating hormone (B-MSH), g-melanocyte-stimulating hormone (g-MSH), Adrenocorticotropic hormone (ACTH). Endogenous melanocortin receptor antagonists have also been identified in mammals, agouti-related peptide (AgRP) and agouti signaling protein (ASP). MC1R signaling in vivo is modulated primarily by a-MSH, ACTH and ASP to regulate skin pigmentation and immune function. MC2R is primarily modulated by ACTH to regulate cortisol production in the adrenal cortex. MC3R is primarily modulated by a-MSH, B-MSH, g-MSH and AgRP to regulate feeding behavior, anxiety / stress responses, and immune function. MC5R is primarily modulated by a-MSH, ACTH to regulate muscle fatty acid oxidation, glucose uptake, thermoregulation and immune function. MC4R MC5R is primarily modulated by a-MSH, ACTH and AgRP to regulate energy expenditure, food intake, autonomic control of respiratory and cardiovascular function, and sexual behavior.

[0008] MC4R is a constitutively active receptor and can be modulated by inverse agonism or competitive antagonism. MC4R function is modulated by endogenous ligands includes trafficking between PM and endosomes, internalization and sensitization or de-sensitization, Gs, Gq, Gi mediated second messenger signaling, homo-dimerization and hetero-oligomerization with other proteins present of the neuronal plasma membrane (PM) including potassium channels.

[0009] MC4R is particularly important due to its significant role in regulating appetite and energy expenditure. MC4R is expressed in the hypothalamus, a region of the brain that controls hunger and satiety. Activation of MC4R by a-MSH, leads to a decrease in food intake and an increase in energy expenditure, thereby contributing to weight loss. Conversely, inhibition of MC4R, such as by the endogenous inverse agonist AgRP, results in increased food intake and reduced energy expenditure,leading to weight gain. Furthermore, there is evidence of interactions and feedback mechanisms between MC3R and MC4R signaling in the regulation of feeding behavior and energy expenditure. MC4R signaling, cell biology and physiology are complex, it is not known what the optimal pharmacological profile is for therapeutic use of a MC4R antagonist for metabolic or eating disorders.

[0010] Currently, there are several pharmaceutical compounds known to act as MC4R antagonists. These compounds are primarily of interest for treating eating and metabolic disorders including anorexia and cachexia. Several kinds of small-molecule MC4R antagonists have been reported in the literature and patent applications (e.g., W02010052256; W02010081666; US Patent 8,044,068; CN117736206; CN117736205A; CN118510780; WO2021250541; WO2023105387; Chaki et al., Current Topics in Medicinal Chemistry, 2007, 7, 1145-1151; Foster et al., Current Topics in Medicinal Chemistry, 2007, 7, 1131-1136; Pontillo et al., Bioorganic & Medicinal Chemistry Letters 15 (2005) 2541-46; Vos et al., Bioorganic & Medicinal Chemistry Letters 16(2006) 2302-2305; Tao, Endocrine Reviews, 2010, 31(4):506-543; Saleh et al., Front. Pharmacol., 2018, 9: 560; and Garnsey et al., J. Med. Chem. 2023, 66:5).

[0011] Some MC4R antagonist compounds have also been shown to have pharmacological chaperone or corrector effects on MC4R in cell-based assays (W02006133098A3;

[0012] W02012100342A1; Rene, P., et al. (2010). Pharmacological Chaperones Restore Function to MC4R Mutants Responsible for Severe Early-Onset Obesity. Journal of Pharmacology and Experimental Therapeutics, 335(3), 520-532.; Rene, P., et al (2021). Pharmacological chaperone action in humanized mouse models of MC4R-linked obesity. JCI Insight.) and suggested as potentially useful for treating obesity associated with loss-of-function MC4R mutations. However, strong evidence of efficacy in vivo for inducing weight loss is not available.

[0013] MC4R agonists are approved for use in humans including: setmelanotide a MC4R selective super-agonist approved for treating rare types of monogenic obesity and bremelanotide a MC4R / MC3R agonist for treating low sexual desire in women. Several agonists developed for use in humans failed due for reasons related to lack of efficacy and / or safety problems. MK-0493 (developer Merck and Co) was discontinued in phase 2 and associated with adverse effects including sexual arousal and yawning. LY2112688 (developer Eli Lilly) also discontinued in phase 2 was associated with sexual arousal, yawning and increased blood pressure. NN-0543 (developer Novo Nordisk) was also associated with sexual arousal, yawning and cardiotoxicity. Although setmelanotide, a peptide agonist, was approved for use in humans, sexual arousal and depression was also reported by treated subjects.

[0014] There is a need for safer and more effective compounds for modulating MC4R and treating MC4R-related diseases, conditions and disorders.

[0015] Therefore, there is a need for new pharmaceutical compounds that can overcome these challenges and provide a safer, more effective, and more convenient means of modulating MC4R activity.

[0016] SUMMARY OF THE INVENTION

[0017] In one aspect, the present invention is a compound of Formula I:

[0018]

[0019] or a diastereomer or enantiomer thereof, or a pharmaceutical salt thereof,

[0020] wherein

[0021] R1is -S(O)2(RA) or -C(O)(RA);

[0022] each R2is independently H, C1-6 alkyl, oxo, -CN, C3-6 cycloalkyl, C3-6 heterocyclyl, C1-6 alkyl C3-6 heterocyclyl;

[0023] R3is H, optionally substituted C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 heterocyclyl, optionally substituted C3-6 heteroaryl, -C(O)-C1-6 alkyl -C(O)-C3-6 cycloalkyl, -C(O)-C3-6 heterocyclyl or optionally substituted C1-6 alkyl C3-6 heteroaryl;

[0024] R5is H, halogen, -CN, optionally substituted C1-6 alkyl, optionally substituted alkynyl, C3-10 cycloalkyl, optionally substituted C1-10 heteroaryl, optionally substituted C3-10 heterocyclyl, -C(O)(RA), or -QA-RB;

[0025] R6is C1-6 alkyl, -CH2OH, -CH2-O-(C1-6 alkyl);

[0026] or R5and R6together with the atom to which both are attached, combine to form an optionally substituted C6aryl;

[0027] QAis CH2, CH(RB), N(RN), or O;

[0028]

[0029] RAis –QB–RB,

[0030]

[0031] toptionally substituted C1-6 alkyl, optionally substituted C5-6 aryl, optionally substituted C3-10 cycloalkyl, optionally substituted C6 aryl, optionally substituted C8-12 bicyclic aryl, optionally substituted C5-6 heteroaryl, or optionally substituted C3-10 heterocyclyl;

[0032] QBis CH2, CH(RB), N(RN), or O;

[0033] RBis independently selected from -OH, -O-(C1-6 alkyl), optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C6 aryl, optionally substituted C8-12 bicyclic aryl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkyl C6 aryl, optionally substituted C1-6 alkyl C6 aryl, optionally substituted C3-10 heterocyclyl, or optionally substituted C1-6 heteroaryl, or optionally substituted C6-11 bicyclic heteroaryl;

[0034] RNis H, optionally substituted C1-6 alkyl, or RNand RBtogether with the atom to which both are attached, combine to form an optionally substituted C3-10 heterocyclyl or optionally substituted C6-11 bicyclic heterocyclyl;

[0035] wherein each optionally substituted group is optionally substituted with one, two, three, or four groups independently selected from a group consisting of: halogen, oxo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C5-6 aryl, substituted C5-6 aryl substituted with one, two, or three groups independentlyselected from halogen or C1-6 haloalkyl, C2-10 heteroaryl, C3-6 heterocyclyl, -OH, -O-(C1-6 alkyl), -O-(C3-8 cycloalkyl), -O-(C1-6 heterocycloalkyl), -O-(C1-6 haloalkyl), -C(O)NH2, -C(O)NH(C1-6 alkyl), and -C(O)N(C1-6 alkyl)2;

[0036] wherein each heterocyclyl or heteroaryl comprises of one, two, three, or four heteroatoms independently selected from a group consisting of nitrogen, oxygen, and sulfur.

[0037] In some embodiments, R1is selected from a group consisting of:

[0038]

[0039] wherein

[0040] n is 0, 1, 2, 3, or 4;

[0041] each R1Ais independently, halogen, C1-6 alkyl, C1-6 haloalkyl, -O-(optionally substituted C1-6 alkyl), -O-(optionally substituted C3-8 cycloalkyl), -O-(C1-6 optionally substituted heterocycloalkyl), or -O-(C1-6 haloalkyl);

[0042] R1Bis H, C1-6 alkyl, -OH, -O-(C1-6 alkyl), -O-(C3-8 cycloalkyl), or -O-(C1-6 heterocycloalkyl); and

[0043] each X is independently CH, C(R1A), or N.

[0044] In some embodiments, R1Ais selected from a group consisting of: F, -CH3, -O-CH3,

[0045]

[0046] ',

[0047]

[0048] In some embodiments, R1Bis selected from a group consisting of: H, -CH3, -CH2CH3, -OH,

[0049]

[0050]

[0051]

[0052] In some embodiments, R1is -C(O)(RA), wherein RAis -QB-RBand RBis an optionally substituted C3-8cycloalkyl, optionally substituted C1-6alkyl, optionally substituted C6aryl, optionally substituted C5-6heteroaryl, or optionally substituted C3-10heterocyclyl.

[0053]

[0054] F

[0055]

[0056] In some embodiments, R1is -C(O)(RA), wherein RAis optionally substituted C3-10 heterocyclyl.

[0057]

[0058] In some embodiments, R1is -C(O)(RA), wherein RAis optionally substituted C1-6 alkyl, optionally substituted Ce aryl, or optionally substituted Cs-12 bicyclic aryl.

[0059]

[0060] In some embodiments, R1is -C(O)(RA), wherein RAis -QB-RB.

[0061] In some embodiments, RBis optionally substituted C3-6heteroaryl.

[0062]

[0063] , or I, or a stereoisomer thereof.

[0064] In some embodiments, R1is -S(O)2(RA).

[0065] In some embodiments,

[0066]

[0067] R1is

[0068] In some embodiments, one R2is -CH3.

[0069] In some embodiments, where one R2is -CH3 and R3is -CH3.

[0070] In some embodiments, one R2is -CN.In some embodiments, one R3is -CH3.

[0071] In some embodiments, R3is:, or

[0072]

[0073] In some embodiments, R3is:

[0074]

[0075] In some embodiments, R5is optionally substituted C1-6 heteroaryl.

[0076]

[0077] In some embodiments, R5is C3-8 cycloalkyl.

[0078] In some embodiments, R5is

[0079] I

[0080]

[0081] n some embodiments, R5is -C(O)(RA).

[0082] In some embodiments, RAis amino.In some embodiments,

[0083]

[0084] R5is O or O

[0085] In some embodiments, R5is -QA-RB.

[0086] In some embodiments, R5is

[0087] O

[0088]

[0089] In some embodiments, R5is optionally substituted C3-8 heterocyclyl.

[0090] In some embodiments,

[0091]

[0092] R5is

[0093] In some embodiments, R5is halogen.

[0094] In some embodiments, R5is Br.

[0095] In some embodiments, R5is -CN.

[0096] In some embodiments, R5is an optionally substituted alky nyl.

[0097] In some embodiments,

[0098]

[0099] R5is

[0100] In other embodiments, the compound is of Formula la:

[0101]

[0102] wherein

[0103] R1is -S(O)2(RA) or -C(O)(RA);

[0104] R3is H, optionally substituted C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 heterocyclyl, optionally substituted C3-6 heteroaryl, -C(O)-Ci-e alkyl, -C(O)-C3-6 cycloalkyl, -C(O)-C3-6 heterocyclyl or optionally substituted C1-6 alkyl C3-6 heteroaryl;

[0105] R5is H, halogen, -CN, optionally substituted C1-6 alkyl, optionally substituted alkynyl, C3-10 cycloalkyl, optionally substituted C1-10 heteroaryl, optionally substituted C3-10 heterocyclyl, -C(O)(RA), or -QA-RB;

[0106] R6is C1-6 alkyl, -CH2OH, -CH2-O-(C1-6 alkyl);

[0107] or R5and R6together with the atom to which both are attached, combine to form an optionally substituted C6aryl;

[0108] QAis CH2, CH(RB), N(RN), or O;

[0109]

[0110] A^RB

[0111] , optionally substituted Ci-e alkyl, optionally substituted Cs-e aryl, optionally substituted C3-10 cycloalkyl, optionally substituted Cearyl, optionally substituted Ce-12 bicyclic aryl, optionally substituted C3-6 heteroaryl, or optionally substituted C3-10 heterocyclyl;

[0112] QBis CH2, CH(RB), N(RN), or O;

[0113] RBis independently selected from -OH, -O-(Ci-e alkyl), optionally substituted Ci-e alkyl, optionally substituted C1-6haloalkyl, optionally substituted C6aryl, optionally substituted C8-12bicyclic aryl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkyl Ce aryl, optionally substituted Ci-e alkyl Ce aryl, optionally substituted C3-10 heterocyclyl, or optionally substituted Ci-e heteroaryl, or optionally substituted Ce-n bicyclic heteroaryl;

[0114] RNis H, optionally substituted C1-6 alkyl, or RNand RBtogether with the atom to which both are attached, combine to form an optionally substituted C3-10 heterocyclyl or optionally substituted C6-11 bicyclic heterocyclyl;

[0115] wherein each optionally substituted group is optionally substituted with one, two, three, or four groups independently selected from a group consisting of: halogen, oxo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C5-6 aryl, substituted C5-6 aryl substituted with one, two, or three groups independently selected from halogen or Ci-e haloalkyl, C2-10 heteroaryl, Cs-e heterocyclyl, -OH, -O-(Ci-e alkyl), -O-(Cs-8 cycloalkyl), -O-(Ci-e heterocycloalkyl), -O-(Ci-e haloalkyl), -C(O)NH2, -C(O)NH(Ci-e alkyl), and –C(O)N(C1-6alkyl)2;

[0116] wherein each heterocyclyl or heteroaryl comprises of one, two, three, or four heteroatoms independently selected from a group consisting of nitrogen, oxygen, and sulfur.

[0117] In some embodiments, R3is H.

[0118] In some embodiments, R3is -CH3.

[0119] H

[0120] X-OH X

[0121] In some embodiments, R3is O, or

[0122]

[0123] o

[0124] In some embodiments,

[0125]

[0126] R3is.

[0127] In some embodiments, R3is Cs-e heterocyclyl.

[0128] In some embodiments,

[0129]

[0130] R3isv.

[0131] In some embodiments, R3is Cs-e heteroaryl.In some embodiments, R3is, or

[0132] In some embodiments, R3is Ci-e alkyl Cs-e heteroaryl.

[0133]

[0134] In some embodiments, R3is — '.

[0135] In other embodiments, the compound is of Formula lb:

[0136]

[0137] r6(lb),

[0138] wherein

[0139] R1is–S(O)2(RA) or–C(O)(RA);

[0140] R5is H, halogen, -CN, optionally substituted Ci-e alkyl, optionally substituted alkynyl, C3-10 cycloalkyl, optionally substituted C1-10 heteroaryl, optionally substituted C3-10 heterocyclyl, -C(O)(RA), or -QA-RB;

[0141] R6is C1-6 alkyl, -CH2OH, -CH2-O-(C1-6 alkyl);

[0142] or R5and R6together with the atom to which both are attached, combine to form an optionally substituted C6aryl;

[0143] QAis CH2, CH(RB), N(RN), or O;

[0144]

[0145] RAis -QB-RB, RN

[0146]

[0147] , optionally substituted C1-6 alkyl, optionally substituted C5-6 aryl, optionally substituted C3-10 cycloalkyl, optionally substituted C6 aryl, optionally substituted C8-12 bicyclic aryl, optionally substituted C5-6 heteroaryl, or optionally substituted C3-10 heterocyclyl;

[0148] QBis CH2, CH(RB), N(RN), or O;

[0149] RBis independently selected from -OH, -O-(Ci-e alkyl), optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalky I, optionally substituted Ce aryl, optionally substituted C8-12bicyclic aryl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkyl Ce aryl, optionally substituted Ci-e alkyl Ce aryl, optionally substituted C3-10 heterocyclyl, or optionally substituted Ci-e heteroaryl, or optionally substituted Ce-n bicyclic heteroaryl;

[0150] RNis H, optionally substituted Ci-e alkyl, or RNand RBtogether with the atom to which both are attached, combine to form an optionally substituted C3-10 heterocyclyl or optionally substituted C6-11 bicyclic heterocyclyl;

[0151] wherein each optionally substituted group is optionally substituted with one, two, three, or four groups independently selected from a group consisting of: halogen, oxo, C1-6 alkyl, C3-6 cycloalkyl, C1-6haloalkyl, Cs-e aryl, substituted Cs-e aryl substituted with one, two, or three groups independently selected from halogen or C1-6 haloalkyl, C2-10 heteroaryl, C3-6 heterocyclyl, -OH, -O-(Ci-e alkyl), -O-(C3-8 cycloalkyl), -O-(Ci-e heterocycloalkyl), -O-(Ci-e haloalkyl), -C(O)NH2, -C(O)NH(C1-6alkyl), and –C(O)N(C1-6alkyl)2;

[0152] wherein each heterocyclyl or heteroaryl comprises of one, two, three, or four heteroatoms independently selected from a group consisting of nitrogen, oxygen, and sulfur.

[0153] In some embodiments, R5is optionally substituted C1-6 heteroaryl.

[0154]

[0155] In some embodiments, R5is C3-8 cycloalkyl.

[0156] In some embodiments, R5is

[0157] In some embodiments, R5is -C(O)(RA).

[0158] H1

[0159]

[0160] In some embodiments, R5is O or O

[0161] In some embodiments, R5is -QA-RB.O

[0162]

[0163] In some embodiments, R5is optionally substituted C2-8 heterocyclyl.

[0164] I N /

[0165] In some embodiments,

[0166]

[0167] R5is

[0168] In some embodiments, R5is halogen.

[0169] In some embodiments, R5is Br.

[0170] In some embodiments, R5is -CN.

[0171] In some embodiments,

[0172]

[0173] R5is

[0174] In other preferred embodiments, the compound is of Formula lb’:

[0175]

[0176] wherein

[0177] R1is–S(O)2(RA), –C(O)(RA); and

[0178] R5is H, halogen, -CN, optionally substituted C1-6 alkyl, optionally substituted alkynyl, C3-10 cycloalkyl, optionally substituted C1-10 heteroaryl, optionally substituted C3-10 heterocyclyl, -C(O)(RA), or -QA-RB.

[0179]

[0180]

[0181]

[0182] In specific embodiments, R5is

[0183]

[0184] / N HN

[0185] In preferred embodiments, the compound i

[0186]

[0187] s, or a pharmaceutically acceptable salt thereof.

[0188] In other preferred embodiments, the compound is:

[0189]

[0190] o— or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has an enantiomeric purity of at least 90% (e.g., at least 90%, at least 95%, or at least 98% enantiomeric purity).

[0191] In other embodiments, the compound is of Formula Ic:

[0192] R1

[0193] N=\

[0194]

[0195] or a pharmaceutically acceptable salt thereof,

[0196] wherein

[0197] R1is -S(O)2(RA) or -C(O)(RA);

[0198] R5is H, halogen, -CN, optionally substituted Ci-e alkyl, optionally substituted alkynyl, C3-10 cycloalkyl, optionally substituted C1-10 heteroaryl, optionally substituted C3-10 heterocyclyl, -C(O)(RA), or -QA-RB;

[0199] R6is C1-6 alkyl, -CH2OH, -CH2-O-(C1-6 alkyl);

[0200] or R5and R6together with the atom to which both are attached, combine to form an optionally substituted C6aryl;

[0201] QAis CH2, CH(RB), N(RN), or O;

[0202]

[0203] RAis -QB-RB, RN

[0204]

[0205] , optionally substituted C1-6 alkyl, optionally substituted Cs-earyl, optionally substituted C3-10cycloalkyl, optionally substituted Cearyl, optionally substituted C8-12bicyclic aryl, optionally substituted C5-6heteroaryl, or optionally substituted C3-10 heterocyclyl;

[0206] QBis CH2, CH(RB), N(RN), or O;

[0207] RBis independently selected from -OH, -O-(Ci-e alkyl), optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalky I, optionally substituted Ce aryl, optionally substituted Cs-12 bicyclic aryl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkyl Ce aryl, optionally substituted C1-6 alkyl Ce aryl, optionally substituted C3-10 heterocyclyl, or optionally substituted Ci-e heteroaryl, or optionally substituted Ce-n bicyclic heteroaryl;

[0208] RNis H, optionally substituted C1-6 alkyl, or RNand RBtogether with the atom to which both are attached, combine to form an optionally substituted C3-10 heterocyclyl or optionally substituted C6-11 bicyclic heterocyclyl;

[0209] wherein each optionally substituted group is optionally substituted with one, two, three, or four groups independently selected from a group consisting of: halogen, oxo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C5-6 aryl, substituted C5-6 aryl substituted with one, two, or three groups independently selected from halogen or Ci-e haloalkyl, C2-10 heteroaryl, Cs-e heterocyclyl, -OH, -O-(Ci-e alkyl), -O-(Cs-8 cycloalkyl), -O-(Ci-e heterocycloalkyl), -O-(Ci-e haloalkyl), -C(O)NH2, -C(O)NH(Ci-e alkyl), and –C(O)N(C1-6alkyl)2;

[0210] wherein each heterocyclyl or heteroaryl comprises of one, two, three, or four heteroatoms independently selected from a group consisting of nitrogen, oxygen, and sulfur.

[0211] In other embodiments, the compound is of Formula Id:

[0212] R2R2R3

[0213] y— N

[0214]

[0215] (RC)n(Id),

[0216] wherein

[0217] n is 0, 1, or 2;

[0218] each Rcis independently -OH or -O-(Ci-e alkyl);

[0219] R1is -S(O)2(RA) or -C(O)(RA);

[0220] each R2is independently H, C1-6 alkyl, oxo, -CN, Cs-e cycloalkyl, Cs-e heterocyclyl, Ci-e alkyl Cs-e heterocyclyl;

[0221] R3is H, optionally substituted Ci-e alkyl, Ci-e haloalkyl, Cs-e cycloalkyl, Cs-e heterocyclyl, optionally substituted C3-6 heteroaryl, -C(O)-Ci-e alkyl, -C(O)-Cs-e cycloalkyl, -C(O)-Cs-e heterocyclyl or optionally substituted Ci-e alkyl Cs-e heteroaryl;

[0222]

[0223] ( PR

[0224]

[0225] B

[0226] , optionally substituted Ci-e alkyl, optionally substituted Cs-e aryl, optionally substituted C3-10 cycloalkyl, optionally substituted Cearyl, optionally substituted Ce-12 bicyclic aryl, optionally substituted C3-6 heteroaryl, or optionally substituted C3-10 heterocyclyl;

[0227] QBis CH2, CH(RB), N(RN), or O;

[0228] RBis independently selected from -OH, -O-(Ci-e alkyl), optionally substituted Ci-e alkyl, optionally substituted C1-6haloalkyl, optionally substituted C6aryl, optionally substituted C8-12bicyclic aryl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkyl Ce aryl, optionally substituted Ci-e alkyl Ce aryl, optionally substituted C3-10 heterocyclyl, or optionally substituted Ci-e heteroaryl, or optionally substituted Ce-n bicyclic heteroaryl;

[0229] RNis H, optionally substituted C1-6 alkyl, or RNand RBtogether with the atom to which both are attached, combine to form an optionally substituted C3-10 heterocyclyl or optionally substituted C6-11 bicyclic heterocyclyl;

[0230] wherein each optionally substituted group is optionally substituted with one, two, three, or four groups independently selected from a group consisting of: halogen, oxo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C5-6 aryl, substituted C5-6 aryl substituted with one, two, or three groups independently selected from halogen or Ci-e haloalkyl, C2-10 heteroaryl, Cs-e heterocyclyl, -OH, -O-(Ci-e alkyl), -O-(Cs-8 cycloalkyl), -O-(Ci-e heterocycloalkyl), -O-(Ci-e haloalkyl), -C(O)NH2, -C(O)NH(Ci-e alkyl), and –C(O)N(C1-6alkyl)2;

[0231] wherein each heterocyclyl or heteroaryl comprises of one, two, three, or four heteroatoms independently selected from a group consisting of nitrogen, oxygen, and sulfur.

[0232] In some embodiments, the compound is of Formula Id’:

[0233] R2R2R3

[0234] N=< VO

[0235]

[0236] \= / (Id').

[0237] In some embodiments, the compound is of Formula le:

[0238]

[0239] wherein

[0240] R1is -S(O)2(RA) or -C(O)(RA);each R2is independently H, Ci-e alkyl, oxo, -CN, C3-6 cycloalkyl, C3-6 heterocyclyl, C1-6 alkyl C3-6 heterocyclyl;

[0241] R3is H, optionally substituted C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 heterocyclyl, optionally substituted C3-6 heteroaryl, -C(O)-Cs-6 alkyl, -C(O)-C3-e cycloalkyl, -C(O)-Cs-6 heterocyclyl or optionally substituted C1-6 alkyl C3-6 heteroaryl;

[0242] R5is H, halogen, -CN, optionally substituted C1-6 alkyl, optionally substituted alkynyl, C3-10 cycloalkyl, optionally substituted C1-10 heteroaryl, optionally substituted C3-10 heterocyclyl, -C(O)(RA), or -QA-RB;

[0243] QAis CH2, CH(RB), N(RN), or O;

[0244]

[0245] < T~RBtoptionally substituted C1-6 alkyl, optionally substituted Cs-earyl, optionally substituted C3-10 cycloalkyl, optionally substituted Cearyl, optionally substituted C8-12bicyclic aryl, optionally substituted C5-6heteroaryl, or optionally substituted C3-10 heterocyclyl;

[0246] QBis CH2, CH(RB), N(RN), or O;

[0247] RBis independently selected from -OH, -O-(Ci-e alkyl), optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted Ce aryl, optionally substituted C8-12bicyclic aryl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkyl Ce aryl, optionally substituted C1-6 alkyl Ce aryl, optionally substituted C3-10 heterocyclyl, or optionally substituted Ci-e heteroaryl, or optionally substituted Ce-n bicyclic heteroaryl;

[0248] RNis H, optionally substituted C1-6 alkyl, or RNand RBtogether with the atom to which both are attached, combine to form an optionally substituted C3-10 heterocyclyl or optionally substituted C6-11 bicyclic heterocyclyl;

[0249] wherein each optionally substituted group is optionally substituted with one, two, three, or four groups independently selected from a group consisting of: halogen, oxo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C5-6 aryl, substituted C5-6 aryl substituted with one, two, or three groups independently selected from halogen or Ci-e haloalkyl, C2-10 heteroaryl, Cs-e heterocyclyl, -OH, -O-(Ci-e alkyl), -O-(Cs-8 cycloalkyl), -O-(Ci-e heterocycloalkyl), -O-(Ci-e haloalkyl), -C(O)NH2, -C(O)NH(Ci-e alkyl), and –C(O)N(C1-6alkyl)2;

[0250] wherein each heterocyclyl or heteroaryl comprises of one, two, three, or four heteroatoms independently selected from a group consisting of nitrogen, oxygen, and sulfur.

[0251]

[0252] stereoisomer thereof.

[0253]

[0254]

[0255] In specific embodiments, R5is

[0256]

[0257] In another aspect, the present invention is a compound of Formula II:

[0258]

[0259] or a diastereomer or enantiomer thereof, or a pharmaceutical salt thereof,

[0260] wherein

[0261] R1is -S(O)2(RA) or -C(O)(RA);

[0262] each R2aand R2bis independently H, C1-6 alkyl, oxo, -CN, C3-6 cycloalkyl, C3-6 heterocyclyl, C1-e alkyl C3-6 heterocyclyl;

[0263] R3is H, optionally substituted C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 heterocyclyl, optionally substituted C3-6 heteroaryl, -C(O)-Ci-e alkyl -C(O)-Cs-6 cycloalkyl, -C(O)-C3-e heterocyclyl or optionally substituted C1-6 alkyl Cs-e heteroaryl;

[0264] R5is H, halogen, -CN, optionally substituted C1-6 alkyl, optionally substituted alkynyl, C3-10 cycloalkyl, optionally substituted C1-10 heteroaryl, optionally substituted C3-10 heterocyclyl, -C(O)(RA), or -QA-RB;

[0265] R6is C1-6 alkyl, -CH2OH, -CH2-O-(C1-6alkyl);

[0266] or R5and R6together with the atom to which both are attached, combine to form an optionally substituted C6aryl;QAis CH2, CH(RB), N(RN), or O;

[0267]

[0268]

[0269] , optionally substituted C1-6alkyl, optionally substituted C5-6aryl, optionally substituted C3-10cycloalkyl, optionally substituted C6aryl, optionally substituted C8-12bicyclic aryl, optionally substituted C5-6heteroaryl, or optionally substituted C3-10 heterocyclyl;

[0270] QBis CH2, CH(RB), N(RN), or O;

[0271] RBis independently selected from -OH, -O-(Ci-e alkyl), optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted Ce aryl, optionally substituted C8-12bicyclic aryl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkyl Ce aryl, optionally substituted C1-6 alkyl C5-6 aryl, optionally substituted C3-10 heterocyclyl, or optionally substituted C1-6 heteroaryl, or optionally substituted C6-11 bicyclic heteroaryl;

[0272] RNis H, optionally substituted C1-6alkyl, or RNand RBtogether with the atom to which both are attached, combine to form an optionally substituted C3-10heterocyclyl or optionally substituted C6-11bicyclic heterocyclyl;

[0273] wherein each optionally substituted group is optionally substituted with one, two, three, or four groups independently selected from a group consisting of: halogen, oxo, C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, C5-6aryl, substituted C5-6aryl substituted with one, two, or three groups independently selected from halogen or C1-6haloalkyl, C2-10heteroaryl, C3-6heterocyclyl, -OH, -O-(C1-6alkyl), -O-(C3-8cycloalkyl), -O-(C1-6heterocycloalkyl), -O-(C1-6haloalkyl), -C(O)NH2, -C(O)NH(C1-6alkyl), and -C(O)N(C1-6alkyl)2;

[0274] wherein each heterocyclyl or heteroaryl comprises of one, two, three, or four heteroatoms independently selected from a group consisting of nitrogen, oxygen, and sulfur.

[0275] In some embodiments, R1is selected from a group consisting of:

[0276]

[0277] wherein

[0278] n is 0, 1, 2, 3, or 4;each R1Ais independently, halogen, C1-6 alkyl, C1-6 haloalkyl, -O-(optionally substituted C1-6 alkyl), -O-(optionally substituted C3-8 cycloalkyl), -O-(C1-6 optionally substituted heterocycloalkyl), or -O-(C1-6 haloalkyl);

[0279] R1Bis H, C1-6alkyl, -OH, -O-(C1-6alkyl), -O-(C3-8cycloalkyl), or -O-(C1-6heterocycloalkyl); and

[0280] each X is independently CH, C(R1A), or N.

[0281] In some embodiments, R1Ais selected from a group consisting of: F, -CH3, -O-CH3,

[0282]

[0283]

[0284] In some embodiments, R1Bis selected from a group consisting of: H, -CH3, -CH2CH3, -OH,

[0285]

[0286]

[0287] In some embodiments, R1is -C(O)(RA), wherein RAis -QB-RBand RBis an optionally substituted C3-8cycloalkyl, optionally substituted C1-6alkyl, optionally substituted C6aryl, optionally substituted C5-6heteroaryl, or optionally substituted C3-10heterocyclyl.

[0288] In some embodiments, RBis selected from a group consisting of:

[0289]

[0290]

[0291]

[0292] p p

[0293]

[0294] In some embodiments, R1is -C(O)(RA), wherein RAis optionally substituted C1-6alkyl, optionally substituted C6aryl, or optionally substituted C8-12bicyclic aryl.

[0295]

[0296] In some embodiments, R1is -C(O)(RA), wherein RAis -QB-RB.

[0297] In some embodiments, RBis optionally substituted C3-6heteroaryl.In some embodiments, R1is -S(O)2(RA).

[0298]

[0299] In some embodiments, R1is In some embodiments, R2ais -CH3.

[0300] In some embodiments, R2ais -CH3and R3is -CH3.

[0301] In some embodiments, one R2is -CN.

[0302]

[0303] In some embodiments, R3is:

[0304] In some embodiments, R5is optionally substituted C1-6 heteroaryl.

[0305] \ ',NN-N A

[0306]

[0307] \ N= /

[0308]

[0309] F N

[0310] In some embodiments,

[0311]

[0312] R5is N

[0313] In some embodiments, R5is C3-8 cycloalkyl.

[0314] In some embodiments, R5is

[0315] I

[0316]

[0317] n some embodiments, R5is -C(O)(RA).

[0318] In some embodiments, RAis amino.

[0319] cH< I

[0320] In some embodiments,

[0321]

[0322] R5is O or O

[0323] In some embodiments, R5is -QA-RB.

[0324] A -> N o-" X / O

[0325]

[0326] M, orxIn some embodiments, R5is optionally substituted C3-8 heterocyclyl.

[0327] I N /

[0328] In some embodiments,

[0329]

[0330] R5is — '

[0331] In some embodiments, R5is halogen.

[0332] In some embodiments, R5is Br.

[0333] In some embodiments, R5is -CN.

[0334] In some embodiments, R5is an optionally substituted alky nyl.

[0335] In some embodiments,

[0336]

[0337] R5is<^.

[0338] In other embodiments, the compound is of Formula Ila:R3

[0339] R5

[0340] JI J

[0341] K- N N R6

[0342] N- H

[0343]

[0344] (Ha),

[0345] wherein

[0346] R1is -S(O)2(RA) or -C(O)(RA);

[0347] R3is H, optionally substituted Ci-e alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 heterocyclyl, optionally substituted C3-6 heteroaryl, -C(O)-Ci-e alkyl, -C(O)-C3-6 cycloalkyl, -C(O)-C3-6 heterocyclyl or optionally substituted C1-6 alkyl C3-6 heteroaryl;

[0348] R5is H, halogen, -CN, optionally substituted C1-6 alkyl, optionally substituted alkynyl, C3-10 cycloalkyl, optionally substituted C1-10 heteroaryl, optionally substituted C3-10 heterocyclyl, -C(O)(RA), or -QA-RB;

[0349] R6is C1-6 alkyl, -CH2OH, -CH2-O-(C1-6 alkyl);

[0350] or R5and R6together with the atom to which both are attached, combine to form an optionally substituted C6aryl;

[0351] QAis CH2, CH(RB), N(RN), or O;

[0352]

[0353] RAis -QB-RB, RN

[0354]

[0355] , optionally substituted C1-6 alkyl, optionally substituted C5-6 aryl, optionally substituted C3-10 cycloalkyl, optionally substituted C6 aryl, optionally substituted C8-12 bicyclic aryl, optionally substituted C5-6 heteroaryl, or optionally substituted C3-10 heterocyclyl;

[0356] QBis CH2, CH(RB), N(RN), or O;

[0357] RBis independently selected from -OH, -O-(Ci-e alkyl), optionally substituted Ci-e alkyl, optionally substituted C1-6 haloalkyl, optionally substituted Ce aryl, optionally substituted C8-12bicyclic aryl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkyl Ce aryl, optionally substituted Ci-e alkyl Ce aryl, optionally substituted C3-10 heterocyclyl, or optionally substituted Ci-e heteroaryl, or optionally substituted Ce-n bicyclic heteroaryl;

[0358] RNis H, optionally substituted C1-6 alkyl, or RNand RBtogether with the atom to which both are attached, combine to form an optionally substituted C3-10 heterocyclyl or optionally substituted C6-11 bicyclic heterocyclyl;

[0359] wherein each optionally substituted group is optionally substituted with one, two, three, or four groups independently selected from a group consisting of: halogen, oxo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C5-6 aryl, substituted C5-6 aryl substituted with one, two, or three groups independently selected from halogen or Ci-e haloalkyl, C2-10 heteroaryl, Cs-e heterocyclyl, -OH, -O-(Ci-e alkyl), -O-(Cs-s cycloalkyl), -O-(Ci-e heterocycloalkyl), -O-(Ci-e haloalkyl), -C(O)NH2, -C(O)NH(Ci-e alkyl), and –C(O)N(C1-6alkyl)2;

[0360] wherein each heterocyclyl or heteroaryl comprises of one, two, three, or four heteroatoms independently selected from a group consisting of nitrogen, oxygen, and sulfur.

[0361] In some embodiments, R3is H.

[0362] In some embodiments, R3is -CH3.

[0363] In some embodiments, R

[0364]

[0365] 3is

[0366]

[0367] In some embodiments, R3is

[0368] In some embodiments, R3is C3-6 heterocyclyl.

[0369] In some embodiments,

[0370]

[0371] R3is

[0372] In some embodiments, R3is C3-6 heteroaryl.

[0373] In some embodiments, R3is C1-6 alkyl C3-6 heteroaryl.

[0374]

[0375] In some embodiments, R3is

[0376] In other embodiments, the compound is of Formula lib:

[0377] N H

[0378] R

[0379]

[0380] 1(Hb),

[0381] wherein

[0382] R1is–S(O)2(RA) or–C(O)(RA);

[0383] R5is H, halogen, -CN, optionally substituted Ci-e alkyl, optionally substituted alkynyl, C3-10 cycloalkyl, optionally substituted C1-10 heteroaryl, optionally substituted C3-10 heterocyclyl, -C(O)(RA), or -QA-RB;

[0384] R6is Ci-e alkyl, -CH2OH, -CH2-O-(C1-6alkyl);

[0385] or R5and R6together with the atom to which both are attached, combine to form an optionally substituted C6aryl;

[0386] QAis CH2, CH(RB), N(RN), or O;

[0387]

[0388] A^RB

[0389] , optionally substituted Ci-e alkyl, optionally substituted Cs-e aryl, optionally substituted C3-10 cycloalkyl, optionally substituted Cearyl, optionally substituted Ce-12 bicyclic aryl, optionally substituted C3-6 heteroaryl, or optionally substituted C3-10 heterocyclyl;

[0390] QBis CH2, CH(RB), N(RN), or O;

[0391] RBis independently selected from -OH, -O-(Ci-e alkyl), optionally substituted Ci-e alkyl, optionally substituted C1-6haloalkyl, optionally substituted C6aryl, optionally substituted C8-12bicyclic aryl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkyl Ce aryl, optionally substituted Ci-e alkyl Ce aryl, optionally substituted C3-10 heterocyclyl, or optionally substituted Ci-e heteroaryl, or optionally substituted Ce-n bicyclic heteroaryl;

[0392] RNis H, optionally substituted C1-6 alkyl, or RNand RBtogether with the atom to which both are attached, combine to form an optionally substituted C3-10 heterocyclyl or optionally substituted C6-11 bicyclic heterocyclyl;

[0393] wherein each optionally substituted group is optionally substituted with one, two, three, or four groups independently selected from a group consisting of: halogen, oxo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C5-6 aryl, substituted C5-6 aryl substituted with one, two, or three groups independently selected from halogen or Ci-e haloalkyl, C2-10 heteroaryl, Cs-e heterocyclyl, -OH, -O-(Ci-e alkyl), -O-(Cs-8 cycloalkyl), -O-(Ci-e heterocycloalkyl), -O-(Ci-e haloalkyl), -C(O)NH2, -C(O)NH(Ci-e alkyl), and –C(O)N(C1-6alkyl)2;

[0394] wherein each heterocyclyl or heteroaryl comprises of one, two, three, or four heteroatoms independently selected from a group consisting of nitrogen, oxygen, and sulfur.

[0395] In some embodiments, R5is optionally substituted Ci-e heteroaryl.

[0396]

[0397] F

[0398] N

[0399]

[0400] In some embodiments, R5is N In some embodiments, R5is C3-8 cycloalkyl.

[0401] In some embodiments, R5is

[0402] In some embodiments, R5is -C(O)(RA).

[0403] H

[0404] I

[0405]

[0406] n some embodiments, R5is OorO

[0407] In some embodiments, R5is -QA-RB.

[0408] H H N N N

[0409] In some embodiments, R5is O

[0410] Ck A N

[0411]

[0412] H A or '^ Ox In some embodiments, R5is optionally substituted C2-8 heterocyclyl.

[0413] In some embodiments,

[0414]

[0415] R5is

[0416] In some embodiments, R5is halogen,

[0417] In some embodiments, R5is Br.

[0418] In some embodiments, R5is -CN.

[0419] In some embodiments,

[0420]

[0421] R5is

[0422] In other preferred embodiments, the compound is of Formula lib’:r

[0423]

[0424] 1(Hb’),

[0425] wherein

[0426] R1is–S(O)2(RA), –C(O)(RA); and

[0427] R5is H, halogen, -CN, optionally substituted C1-6 alkyl, optionally substituted alkynyl, C3-10 cycloalkyl, optionally substituted C1-10 heteroaryl, optionally substituted C3-10 heterocyclyl, -C(O)(RA), or -QA-RB.

[0428]

[0429]

[0430] stereoisomer thereof.

[0431]

[0432] In specific embodiments, R5is

[0433]

[0434] In preferred embodiments, the compound is

[0435]

[0436] pharmaceutically acceptable salt thereof.

[0437] In other preferred embodiments, the compound is

[0438]

[0439] or a pharmaceutically acceptable salt thereof.In other embodiments, the compound is of Formula lie:

[0440] /

[0441] r

[0442]

[0443] 1(He),

[0444] or a pharmaceutically acceptable salt thereof,

[0445] wherein

[0446] R1is -S(O)2(RA) or -C(O)(RA);

[0447] R5is H, halogen, -CN, optionally substituted Ci-e alkyl, optionally substituted alkynyl, C3-10 cycloalkyl, optionally substituted C1-10 heteroaryl, optionally substituted C3-10 heterocyclyl, -C(O)(RA), or -QA-RB;

[0448] R6is Ci-e alkyl, -CH2OH, -CH2-O-(Ci-e alkyl);

[0449] or R5and R6together with the atom to which both are attached, combine to form an optionally substituted C6aryl;

[0450] QAis CH2, CH(RB), N(RN), or O;

[0451] O- / LRB R^RB

[0452]

[0453] RA is -QB-RB,, RN rN, I I, O —,

[0454]

[0455] , optionally substituted C1-6 alkyl, optionally substituted Cs-e aryl, optionally substituted C3-10 cycloalkyl, optionally substituted Cearyl, optionally substituted Ce-12 bicyclic aryl, optionally substituted C3-6 heteroaryl, or optionally substituted C3-10 heterocyclyl;

[0456] QBis CH2, CH(RB), N(RN), or O;

[0457] RBis independently selected from -OH, -O-(Ci-e alkyl), optionally substituted C1-6alkyl, optionally substituted C1-6haloalkyl, optionally substituted C6aryl, optionally substituted C8-12bicyclic aryl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkyl Ce aryl, optionally substituted Ci-e alkyl Ce aryl, optionally substituted C3-10 heterocyclyl, or optionally substituted Ci-e heteroaryl, or optionally substituted Ce-n bicyclic heteroaryl;

[0458] RNis H, optionally substituted C1-6 alkyl, or RNand RBtogether with the atom to which both are attached, combine to form an optionally substituted C3-10 heterocyclyl or optionally substituted C6-11 bicyclic heterocyclyl;

[0459] wherein each optionally substituted group is optionally substituted with one, two, three, or four groups independently selected from a group consisting of: halogen, oxo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C5-6 aryl, substituted C5-6 aryl substituted with one, two, or three groups independently selected from halogen or Ci-e haloalkyl, C2-10 heteroaryl, Cs-e heterocyclyl, -OH, -O-(Ci-e alkyl), -O-(Cs-8 cycloalkyl), -O-(Ci-e heterocycloalkyl), -O-(Ci-e haloalkyl), -C(O)NH2, -C(O)NH(Ci-e alkyl), and –C(O)N(C1-6alkyl)2;wherein each heterocyclyl or heteroaryl comprises of one, two, three, or four heteroatoms independently selected from a group consisting of nitrogen, oxygen, and sulfur.

[0460] In other embodiments, the compound is of Formula lid:

[0461]

[0462] R1(lid),

[0463] wherein

[0464] n is 0, 1, or 2;

[0465] each Rcis independently -OH or -O-(Ci-e alkyl);

[0466] R1is -S(O)2(RA) or -C(O)(RA);

[0467] each R2aand R2bis independently H, C1-6alkyl, oxo, –CN, C3-6cycloalkyl, C3-6heterocyclyl, C1-6alkyl C3-6heterocyclyl;

[0468] R3is H, optionally substituted C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 heterocyclyl, optionally substituted C3-6 heteroaryl, -C(O)-Ci-e alkyl, -C(O)-Cs-e cycloalkyl, -C(O)-Cs-6 heterocyclyl or optionally substituted C1-6 alkyl C3-6 heteroaryl;

[0469]

[0470] RAis –QB–RB,

[0471]

[0472] , optionally substituted C1-6 alkyl, optionally substituted Cs-e aryl, optionally substituted C3-10 cycloalkyl, optionally substituted Cearyl, optionally substituted C8-12bicyclic aryl, optionally substituted C5-6heteroaryl, or optionally substituted C3-10 heterocyclyl;

[0473] QBis CH2, CH(RB), N(RN), or O;

[0474] RBis independently selected from -OH, -O-(Ci-e alkyl), optionally substituted C1-6alkyl, optionally substituted C1-6haloalkyl, optionally substituted C6aryl, optionally substituted C8-12bicyclic aryl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkyl Ce aryl, optionally substituted Ci-e alkyl Ce aryl, optionally substituted C3-10 heterocyclyl, or optionally substituted Ci-e heteroaryl, or optionally substituted Ce-n bicyclic heteroaryl;

[0475] RNis H, optionally substituted C1-6 alkyl, or RNand RBtogether with the atom to which both are attached, combine to form an optionally substituted C3-10 heterocyclyl or optionally substituted C6-11 bicyclic heterocyclyl;

[0476] wherein each optionally substituted group is optionally substituted with one, two, three, or four groups independently selected from a group consisting of: halogen, oxo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C5-6 aryl, substituted C5-6 aryl substituted with one, two, or three groups independently selected from halogen or Ci-e haloalkyl, C2-10 heteroaryl, Cs-e heterocyclyl, -OH, -O-(Ci-e alkyl), -O-(C3-8 cycloalkyl), -O-(Ci-e heterocycloalkyl), -O-(Ci-e haloalkyl), -C(O)NH2, -C(O)NH(Ci-e alkyl), and –C(O)N(C1-6alkyl)2;

[0477] wherein each heterocyclyl or heteroaryl comprises of one, two, three, or four heteroatoms independently selected from a group consisting of nitrogen, oxygen, and sulfur.

[0478] In some embodiments, the compound is of Formula lid’:

[0479]

[0480] R1(lid’).

[0481] In some embodiments, the compound is of Formula lie:

[0482]

[0483] r1(He),

[0484] wherein

[0485] R1is -S(O)2(RA) or -C(O)(RA);

[0486] each R2aand R2bis independently H, Ci-e alkyl, oxo, -CN, Cs-e cycloalkyl, Cs-e heterocyclyl, Ci-e alkyl Cs-e heterocyclyl;

[0487] R3is H, optionally substituted C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 heterocyclyl, optionally substituted C3-6 heteroaryl, -C(O)-Cs-6 alkyl, -C(O)-C3-e cycloalkyl, -C(O)-Cs-6 heterocyclyl or optionally substituted C1-6 alkyl C3-6 heteroaryl;

[0488] R5is H, halogen, -CN, optionally substituted C1-6 alkyl, optionally substituted alkynyl, C3-10 cycloalkyl, optionally substituted C1-10 heteroaryl, optionally substituted C3-10 heterocyclyl, -C(O)(RA), or -QA-RB;

[0489] QAis CH2, CH(RB), N(RN), or O;

[0490] / CRB

[0491]

[0492] toptionally substituted C1-6 alkyl, optionally substituted Cs-e aryl, optionally substituted C3-10 cycloalkyl, optionally substituted Cearyl, optionally substituted C8-12bicyclic aryl, optionally substituted C3-6 heteroaryl, or optionally substituted C3-10 heterocyclyl;

[0493] QBis CH2, CH(RB), N(RN), or O;

[0494] RBis independently selected from -OH, -O-(Ci-e alkyl), optionally substituted C-i-e alkyl, optionally substituted Ci-e haloalkyl, optionally substituted Ce aryl, optionally substituted C8-12bicyclic aryl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkyl Ce aryl, optionallysubstituted C1-6 alkyl C5-6 aryl, optionally substituted C3-10 heterocyclyl, or optionally substituted C1-6 heteroaryl, or optionally substituted C6-11 bicyclic heteroaryl;

[0495] RNis H, optionally substituted C1-6 alkyl, or RNand RBtogether with the atom to which both are attached, combine to form an optionally substituted C3-10 heterocyclyl or optionally substituted Ce-11 bicyclic heterocyclyl;

[0496] wherein each optionally substituted group is optionally substituted with one, two, three, or four groups independently selected from a group consisting of: halogen, oxo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, Cs-e aryl, substituted Cs-e aryl substituted with one, two, or three groups independently selected from halogen or C1-6 haloalkyl, C2-10 heteroaryl, C3-6 heterocyclyl, -OH, -O-(Ci-e alkyl), -O-(C3-8 cycloalkyl), -O-(Ci-e heterocycloalkyl), -O-(Ci-e haloalkyl), -C(O)NH2, -C(O)NH(C1-6alkyl), and –C(O)N(C1-6alkyl)2;

[0497] wherein each heterocyclyl or heteroaryl comprises of one, two, three, or four heteroatoms independently selected from a group consisting of nitrogen, oxygen, and sulfur.

[0498]

[0499]

[0500] In some embodiments, R1is,

[0501]

[0502] In specific embodiments, R5is

[0503]

[0504] In some embodiments, a compound having the strucutre of Formula I has a diastereomeric enrichment of at least 90% (e.g., at least 90% of the composition is a single diastereomer, at least 92% of the composition is a single diastereomer, at least 95% of the composition is a single diastereomer, or at least 98% of the composition is a single diastereomer).

[0505] In some embodiments, a compound having the strucutre of Formula I has a enantiomeric enrichment of at least 90% (e.g., at least 90% of the composition is a single enantiomer, at least 92%of the composition is a single enantiomer, at least 95% of the composition is a single enantiomer, or at least 98% of the composition is a single enantiomer).

[0506] In some embodiments, a compound having the strucutre of Formula II has a diastereomeric enrichment of at least 90% (e.g., at least 90% of the composition is a single diastereomer, at least 92% of the composition is a single diastereomer, at least 95% of the composition is a single diastereomer, or at least 98% of the composition is a single diastereomer).

[0507] In some embodiments, a compound having the structure of Formula II has a enantiomeric enrichment of at least 90% (e.g., at least 90% of the composition is a single enantiomer, at least 92% of the composition is a single enantiomer, at least 95% of the composition is a single enantiomer, or at least 98% of the composition is a single enantiomer).

[0508] In another aspect, the invention is a compound selected from Table 1 or pharmaceutically acceptable salt thereof.

[0509] Table 1. Compounds of the Invention

[0510]

[0511]

[0512]

[0513] co# Structure CO# Structure

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527] The present invention provides a compound selected from those in Table 1 or a pharmaceutically acceptable salt thereof.

[0528] In particular embodiments, the invention provides a compound selected from:

[0529] CO# Structure CO# Structure

[0530]

[0531] F

[0532]

[0533] In another aspect, the invention is a pharmaceutically acceptable salt of any one of the compounds herein, wherein the counterion is selected from a group consisting of: lactate, lysine, tartrate, and arginine.

[0534] In another aspect the invention is a pharmaceutical composition comprising the compound of any one of the compounds herein and a pharmaceutically acceptable excipient.

[0535] The present invention also provides a pharmaceutical composition comprising a therapeutic amount of a compound of Formula I or a pharmaceutically acceptable salt of the compound and a pharmaceutically acceptable carrier.

[0536] The present invention also provides a pharmaceutical composition comprising a therapeutic amount of a compound of Formula la, lb, lb’, Ic, Id, Id’, le, II, Ila, lib, lib’, lie, lid, lie or a pharmaceutically acceptable salt of the compound and a pharmaceutically acceptable carrier.In another embodiment, the present invention provides a pharmaceutical composition including a compound selected from those in Table 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0537] Methods

[0538] The present invention also provides methods of treating a MC4R-related condition, disease or disorder in a subject (e.g., a human patient) in need of such treatment including administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0539] The present invention also provides methods of treating a MC4R-related condition, disease or disorder in a subject (e.g., a human) in need of such treatment including administering to the subject a therapeutically effective amount of a compound of Formula la, lb, lb’, Ic, Id, Id’, le, II, Ila, lib, lib’, lie, lid, lie or a pharmaceutically acceptable salt thereof.

[0540] The present invention also provides methods of treating a MC4R-related condition, disease or disorder in a subject (e.g., a human patient) in need of such treatment including administering to the subject a therapeutically effective amount of a compound selected from those in Table 1 or a pharmaceutically acceptable salt thereof.

[0541] The present invention also provides methods of treating a MC4R-related condition, disease or disorder in a subject (e.g., a human patient) in need of such treatment including administering to the subject a therapeutically effective amount of a compound selected from:

[0542] CO# Structure CO# Structure

[0543]

[0544]

[0545] In some embodiments, the MC4R-related condition, disease or disorder is obesity in a subject having a genotype associated with MC4R-deficiency.

[0546] In some embodiments, the MC4R-related condition, disease or disorder is obesity in a pediatric subject having a genotype associated with MC4R-deficiency.

[0547] In some embodiments, the MC4R-related condition, disease or disorder is severe obesity in a subject having a genotype associated with MC4R-deficiency.

[0548] In some embodiments, the MC4R-related condition, disease or disorder is severe obesity in a pediatric subject having a genotype associated with MC4R-deficiency.

[0549] In some embodiments, the MC4R-related condition, disease or disorder is severe obesity in an adult subject having a genotype associated with MC4R-deficiency.

[0550] In some embodiments, the MC4R-related condition, disease or disorder is severe obesity in an subject having a homozygous MC4R loss of function genotype comprising one or more variants selected from those in Table 2.

[0551] In some embodiments, the MC4R-related condition, disease or disorder is severe obesity in an subject having a heterozygous MC4R loss of function genotype comprising a MC4R variant selected from those in Table 2.

[0552] In some embodiments, the MC4R-related condition, disease or disorder is severe obesity in an subject having a homozygous MC4R loss of function genotype comprising a MC4R loss-of-function variant associated with a reduction in functional cellular MC4R relative to a fully functional wild-type MC4R variant.

[0553] In some embodiments, the MC4R-related condition, disease or disorder is severe obesity in an subject having a heterozygous MC4R loss of function genotype comprising a MC4R loss-of-function variant associated with a reduction in functional cellular MC4R level relative to a fully functional wild-type MC4R variant.

[0554] In some embodiments, the MC4R-related condition, disease or disorder is severe obesity in an adult subject having a genotype associated with MC4R-deficiency who was affected by severe obesity before age 15.

[0555] In some embodiments, the MC4R-related condition, disease or disorder is severe obesity in an adult subject having a genotype associated with MC4R-deficiency who was affected by severe obesity before age 10.

[0556] In some embodiments, the MC4R-related condition, disease or disorder is severe obesity in an adult subject having a genotype associated with MC4R-deficiency who was affected by severe obesity before age 5.

[0557] In some embodiments, the MC4R-related condition, disease or disorder is cachexia, anorexia or anorexia nervosa, geriatric anorexia, anorexia associated with chemotherapy and / or radiotherapy, nausea, emesis, involuntary weight loss with frailty, failure to thrive, geriatric malnutrition, sarcopenia, muscle wasting, or muscle weakness.

[0558] The present invention also provides a compound of Formula I, la, lb, lb’, Ic, Id, Id’, le, II, Ila, lib, lib’, lie, lid, lie or a pharmaceutically acceptable salt of the compound for treating a MC4R-related condition, disease or disorder in a subject (e.g., a human patient).

[0559] The present invention also provides a compound selected from those in Table 1 herein or a pharmaceutically acceptable salt of the compound for treating a MC4R-related condition, disease or disorder in a subject (e.g., a human patient).

[0560] The present invention also provides a use of a compound of Formula I, la, lb, lb’, Ic, Id, Id’, le, II, Ila, lib, lib’, lie, lid, lie for the manufacture of a medicament for use in any one of the methods disclosed herein.

[0561] The present invention also provides a use of a compound selected from those in Table 1 herein for the manufacture of a medicament for use in any one of the methods disclosed herein.

[0562] The present invention also provides a use of a compound of Formula I, la, lb, lb’, Ic, Id, Id’, le, II, Ila, lib, lib’, lie, lid, lie for the manufacture of a medicament for treating a MC4R related condition, disease or disorder.

[0563] The present invention also provides a use of a compound selected from those in Table 1 herein for the manufacture of a medicament for treating a MC4R related condition, disease or disorder.

[0564] In another embodiment, the present disclosure provides a method of modulating MC4R activity in a subject, comprising administering to the subject an effective amount of a compound disclosed herein a compound selected from those in Table 1 provided herein.

[0565] In another embodiment, the present disclosure provides a method of modulating MC4R activity in a cell, comprising exposing said cell to a compound selected from those in Table 1 provided herein.The present invention also provides a method of modulating MC4R comprising contacting MC4R with a compound of Formula I, la, lb, lb’, Ic, Id, Id’, le, II, Ila, lib, lib’, lie, lid, lie or a pharmaceutically acceptable salt thereof.

[0566] The present invention also provides a method of modulating MC4R comprising contacting MC4R with a compound of Formula I, la, lb, lb’, Ic, Id, Id’, le, II, Ila, lib, lib’, lie, lid, lie or a pharmaceutically acceptable salt thereof.

[0567] In another embodiment, the present invention provides a use of a compound of Formula I, la, lb, lb’, Ic, Id, Id’, le, II, Ila, lib, lib’, lie, lid, lie in the manufacture of a medicament for use in any one of the methods disclosed herein.

[0568] In another embodiment, the present invention provides a use of a compound disclosed in Table 1 for the manufacture of a medicament for use in any one of the methods disclosed herein.

[0569] In another aspect, the present disclosure provides a compound of Formula I, la, lb, lb’, Ic, Id, Id’, le, II, Ila, lib, lib’, lie, lid, lie or a pharmaceutically acceptable salt thereof for use in any one of the methods disclosed herein.

[0570] In another aspect, the present disclosure provides a compound selected from those provided in Table 1 herein or a pharmaceutically acceptable salt thereof for use in any one of the methods disclosed herein.

[0571] DETAILED DESCRIPTION OF THE INVENTION

[0572] Other features and advantages of the invention will be apparent from the following Detailed Description, the drawings, and the claims.

[0573] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0574] Abbreviations

[0575] Abbreviations and terms that are commonly used in the fields of organic chemistry, medicinal chemistry, pharmacology, and medicine and are well known to practitioners in these fields are used herein. Representative abbreviations and definitions include:

[0576] Ac is acetyl [CH₃C(O)-], AC2O is acetic anhydride; AcOH is acetic acid; AcOK is potassium acetate; APC is antigen-presenting cell; aq. is aqueous; 9-BBN is 9-borabicyclo[3.3.1]nonane; BINAP is (2,2'-bis(diphenylphosphino)-1, T-binaphthyl); Bn is benzyl; Boc is tert Butyloxycarbonyl; GDI is carbonyldiimidazole; DBU is 1,8-Diazabicyclo[5.4.0]undec-7-ene. DCM is dichloromethane; DIAD is diisopropylazodicarboxylate; DIBAL is diisobutylaluminum hydride; DIEA (or DIPEA) is diisoproplyethyl amine; DMA is dimethylacetamide; DMAP is 4-dimethylaminopyridine; DMF is N, N-dimethylformamide; DMSO is dimethyl sulfoxide; dppf is 1,1'-bis(diphenylphosphino)ferrocene; EDAC (or EDC) is 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide HCI; ESI is electrospray ionization mass spectrometry; Et2O is diethyl ether; Et₃N is triethylamine; Et is ethyl; EtOAc and EA are ethyl acetate; EtOH is ethanol; EPhos is dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1, T-biphenyl]-2-yl)phosphane; 3-F-Ph is 3-fluorophenyl, HATU is (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HCI is hydrochloric acid; HOBt is 1 -hydroxybenzotriazole; HPLC is high performance liquid chromatography; LCMS is HPLC with mass spectral detection; LiHMDS is lithium bis(trimethylsilyl)amide; M is molar; mCPBA is metachloroperbenzoic acid; mmol is millimole; Me is methyl; MeCN and ACN are acetonitrile; MeOH is methanol; Ms is methanesulfonyl; MS is mass spectrometry; N is normal; NaHMDS is sodium hexamethyldisiliazide; NaOAc is sodium acetate; NaOtBu is sodium tert-butoxide; NMO is N-methylmorpholine N-oxide; NMP is N-methyl pyrrolidinone; NMR is nuclear magnetic resonance spectroscopy; Pd₂(dba)₃ is tris(dibenzylideneacetone)dipalladium; PdCl₂(PPh₃)₂ is dichlorobis-(triphenylphosphene) palladium; [P(tBu)3] Pd(crotyl)CI is chloro(crotyl)(tri-tert-butylphosphine)palladium(ll); PG denotes an unspecified protecting group; Ph is phenyl; PhMe is toluene; PPh₃ is triphenylphosphine; PMB is para-methoxybenzyl; rt is room temperature; TBAB is tetrabutyl ammonium bromide; TBAF is tetrabutyl ammonium fluoride; TBS is tert-butyldimethylsilyl; tBu is tert-butyl; Tf is triflate; TFA is trifluoroacetic acid; THF is tetrahydrofuran; THP is tetrahydropyran; TLC is thin layer chromatography; TMAD is tetramethylazodicarboxamide; TMS is trimethylsilyl; Ts is p-toluenesulfonyl.

[0577] Definitions

[0578] To facilitate the understanding of this invention, several terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the invention.

[0579] Terms such as “a”, “an,” and “the” are not intended to refer to only a singular entity but include the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific embodiments of the invention, buttheir usage does not limit the invention, except as outlined in the claims.

[0580] As used herein, any values provided in a range of values include both the upper and lower bounds, and any values contained within the upper and lower bounds.

[0581] As used herein, the term “pharmaceutically acceptable salt” represents those salts of the compounds described that are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, or allergic response. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P. H. Stahl and C. G. Wermuth), Wiley-VCH, 2008. These salts may be acid addition salts involving inorganic or organic acids. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable acid.

[0582] The term “subject,” as used herein, can be a human, non-human primate, or other mammal, such as but not limited to dog, cat, horse, cow, pig, goat, monkey, rat, mouse, and sheep. In preferred embodiments, the subject is a human.

[0583] As used herein, the term “pharmaceutical composition” refers to an active compound, formulated together with one or more pharmaceutically acceptable excipients. In some embodiments, a compound of the invention is present in unit dose amount appropriate for administration in atherapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In certain embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, or capsules; and parenteral administration, for example, by subcutaneous, intramuscular, or intravenous injection.

[0584] The term “pharmaceutically acceptable excipient,” as used herein, refers to any inactive ingredient (for example, a vehicle capable of suspending or dissolving the active compound) that is biocompatible and suitable for administration to a subject. Typical excipients include, for example: anti-adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes, emollients, emulsifiers, diluents, film formers or coatings, flavors, fragrances, glidants, lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, or waters of hydration.

[0585] Excipients include, but are not limited to: butylated optionally substituted hydroxytoluene (e.g., BHT), calcium carbonate, calcium phosphate dibasic, calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxypropyl cellulose, optionally substituted hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch, stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. Those of ordinary skill in the art are familiar with a variety of agents and materials useful as excipients.

[0586] As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” MC4R with a compound of the invention includes the administration of a compound of the present invention to a mammal, such as a human, having the MC4R, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified Procedure containing the MC4R.

[0587] As used herein the term “MC4R” refers to the Melanocortin receptor 4 (MC4R) gene or the protein expressed from the MC4R gene. The human MC4R gene corresponds to NCBI Gene ID: 4160 and the mouse MC4R gene corresponds to NCBI Gene ID: 17202. The human MC4R protein corresponds to Uniprot entry P32245 and mouse MC4R protein corresponds to Uniprot entry P56450.

[0588] As used herein “modulate MC4R” or “modulating MC4R” refers to a functional change in MC4R signaling or abundance in a cell or tissue induced by compound binding to MC4R.

[0589] As used herein “modulate MC4R” or “modulating MC4R” refers to a ligand-induced increase or decrease in MC4R signaling including but not limited to cAMP signaling, mitogen-activated protein kinase / extracellular Signal-regulated kinase (MAPK / ERK) pathway signaling, phospoinositol-triphosphate / protein kinase B (PI3K / Akt) Pathway, potassium channel Kir7.1 activity; or an increase in “MC4R level” in the plasma membrane or endosomal compartments.As used herein “MC4R level’ or “MC4R abundance” means the level or amount of functional MC4R present in a cell, cellular plasma membrane or endosomal membrane wherein MC4R can induce functional MC4R associated signaling cascades including but not limited to cAMP, ERK / MAPK, B-arrestin mediated, and Gs, Gq / 11 or Gi / o coupled signaling.

[0590] “MC4R-deficient” or “MC4R-D” refers to a reduced cellular, plasma membrane or endosomal MC4R level in a human, mouse or cellular system wherein a loss-of-function MC4R variant is present at a level that is lower than the corresponding level of a wild type MC4R variant in the same subject or system i.e. 95% lower 90% lower, 85% lower, 80% lower, 75% lower, 70% lower, 65% lower, 60% lower, 55% lower, 50% lower, 45% lower, 40% lower, 35% lower, 30% lower, 25% lower, 20% lower, 15% lower, 10% lower or 5% lower.

[0591] As used herein the term “MC4R loss of function” means a decrease in MC4R level in a human, mouse or cellular system caused by a MC4R missense variant, single nucleotide variant or short deletion which has been shown to cause a reduction in MC4R level or MC4R signaling function in a experimental cellular system. “MC4R loss of function” as used herein also refers to a decrease MC4R cellular signaling capacity in a human, mouse or cellular system caused by a MC4R missense variant, single nucleotide variant or short deletion.

[0592] “MC4R loss of function”, including MC4R level or MC4R expression, can be determined in cell-based assays using methods known in the art e.g., (Brouwers et al., (2021). Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation. Cell Reports, 34(12), 108862) and described in the examples disclosed herein e.g., Examples 214, 216 and 217. MC4R loss of function can be due to a reduction in MC4R plasma membrane level or a reduction in MC4R activity or a combination of both types of defects. For example, some MC4R mutations cause a reduction in a fraction of synthesized MC4R which is trafficked from an endoplasmic reticulum (ER) to a plasma membrane and an increase in a fraction of MC4R degraded by a regulated proteolysis system in a cell resulting in reduced expression of functional, cellular MC4R. Other MC4R mutations do not affect the fraction of synthesized MC4R trafficked to the PM but affect the intrinsic activity of MC4R at its functional subcellular location i.e. at the plasma membrane or endosome. Examples of clinically important MC4R mutations are provided in Table 2.

[0593] As used herein MC4R corrector or MC4R pharmacological chaperone effect refers to a compound-induced increase in functional MC4R in a cell or in vivo, wherein the MC4R expressing cells affected express a variant MC4R sequence which is not normally trafficked from the ER to the plasma membrane or endosomal membrane following synthesis in the cell resulting in reduce MC4R cellular level and reduce MC4R function. As shown in Example 216, 217 and 218 herein some compounds of the present invention have MC4R corrector activity.

[0594] Variants, which in some cases can also be referred to as mutations, of the MC4R gene are identified herein by the effect of the variant on the MC4R protein sequence e.g., pArg165Trp. MC4R loss-of-function variants can be identified using methods well known in the art through studies which identify variants associated with human disease e.g. severe obesity in population or clinical cohortstudies in combination with function studies to characterize the nature and severity of the MC4R loss-of-function associated with a particular variant or mutation.

[0595] Many MC4R variants or mutations that are clinically important and have been associated with MC4R-D and MC4R-D obesity in humans, including but not limited to those listed in Table 2. The association of variants with disease is systematically classified based on clinical geneticist submissions in the NIH database ClinVar.

[0596] Table 2. Examples of Clinically Important MC4R Variants

[0597] Protein ClinVar ID ClinVar Associated Phenotypes dbSNP rsID Change

[0598] Ser30Phe 2634239 MC4R-Related Condition, Obesity rs 13447323 Glu42Lys 3669807 none rs776051881 Gln43Lys 1693542 Inherited obesity n / a Phe51Leu 4082014 BMIQ20 not available Leu54Pro 492861 Obesity, autosomal dominant obesity rs376439188 Gly55Asp not available

[0599] Ser58Cys 14321 OBESITY, Body Mass Index rs121913558

[0600] Quantitative Trait Locus 20 (BMIQ20)

[0601] Glu61Lys 435831 Obesity, autosomal dominant obesity rs370479598 Asn62Ser 14334 BMIQ20, early-onset obesity rs121913566 lle69Thr 3353693 MC4R-Related Condition, Obesity not available lle69Arg 211442 Obesity, autosomal dominant rs751160202 His76Arg 2078431 BMIQ20, MC4R-Related Condition rs199558727 Pro78Leu 2663185 Obesity not available Tyr80Cys 435830 BMIQ20, MC4R-Related Condition rs1368643838 Leu86Phe 1339319 BMIQ20 rs2143967182 Asp90Asn 1301992 BMIQ20, autosomal dominant obesity rs2143967167 Met91Lys 3350589 MC4R-Related Condition not available Ser94Asn 381723 Obesity rs772213710 Val95lle 3236583 Inherited obesity rs 13447328 Asn97Asp 14333 BMIQ20, early-onset obesity rs121913565 lle102Thr 2634476 MC4R-related Obesity not available lle102Ser 14322 Obesity, BMIQ20 rs121913559 lle125Lys 14328 Obesity not available Asp126Glu not available

[0602] Ser127Leu 14336 Inherited obesity; autosomal dominant rs13447331

[0603] obesity, BMIQ20

[0604] Ser136Phe 976165 BMIQ20 rs1380965800 lle137Thr 1712021 MC4R-Related Condition, Obesity rs151102515Protein ClinVar ID ClinVar Associated Phenotypes dbSNP rsID Change

[0605] Ser139Arg 4077401 Adipositas not available Thr150lle 435829 Obesity, autosomal dominant obesity rs766665118 Met161Thr not available

[0606] Thr162lle 499550 BMIQ20 rs1555691402 Arg165Trp 1284736 BMIQ20, autosomal dominant obesity rs 13447332 Arg165Gln 327713 Autosomal dominant obesity, severe rs747681609 early-onset obesity, juvenile onset

[0607] obesity

[0608] Val166lle 562224 BMIQ20, obesity rs942758928 lle170Val 14323 BMIQ20 rs121913560 Ala175Thr 14330 Inherited obesity, BMIQ20, Obsisty, rs121913563 MC4R-Related Condition

[0609] Ser180Pro 36483 Early-onset obesity rs 193922685 Gly181Asp 976326 BMIQ20 rs 13447333 Ala219Val 14338 BMIQ20, juvenile-onset obesity rs121913567 Gly231Ser 995181 BMIQ20 rs 1363347811 Leu250Gln 549551 Monogenetic diabetes, obesity, rs772393451 autosomal dominant obesity, BMIQ20

[0610] Gly252Ser 1709503 BMIQ20 rs 13447336 Pro260Gln 976250 BMIQ20 rs1435358988 lle269Asn 36486 obesity, early onset obesity rs79783591 Cys271Tyr 14329 Obesity, autosomal dominant obesity, rs121913562 BMIQ, early-onset obesity

[0611] Cys271Arg 372803 BMIQ20 rs1057517991 Pro272Lys not available

[0612] Gln273Pro not available

[0613] Asn274Ser 14324 Obesity, BMIQ20, morbidly obese rs121913561 Phe280Leu 492863 Obesity rs756232889 Pro299His 36488 Early onset diabetes, BMIQ20 rs52804924 Leu300Pro 2584829 BMIQ20, MC4R-Related Condition rs1326028718 He301Thr 945179 Obesity rs1915335064 Arg305T rp 586138 Obesity autosomal dominant rs549442687 He316Ser 14331 BMIQ20, obesity, early-onset obesity rs121913564

[0614] As used herein, “ M C4 R- related condition, disease or disorder” refers to a medical condition, disease, or disorder present in a subject (e.g., human patient) selected from obesity; obesity associated with MC4R-deficiency (MC4R-deficient obesity); pediatric early-onset obesity; severeobesity; and obesity in combination with any known comorbidity or obesity including but not limited to type 2 diabetes mellitus; hypertension; nonalcoholic fatty liver disease; obstructive sleep apnea; dyslipidemia, or a combination thereof; cachexia anorexia or anorexia nervosa (e.g., geriatric anorexia, anorexia associated with chemotherapy and / or radiotherapy); nausea; emesis; weight loss (e.g., involuntary weight loss); geriatric malnutrition; failure to thrive; sarcopenia; muscle wasting; muscle weakness (e.g., muscle weakness associated with chronic obstructive pulmonary disease); frailty; osteoporosis; bone disorders (e.g., bone loss); pain; neuropathic pain; anxiety (e.g., posttraumatic stress disorder, or PTSD); depression; hypertension; malnutrition; sexual dysfunction; and inflammatory disease (e.g., an inflammatory disease associated with anorexia or cachexia or sarcopenia or muscle wasting).

[0615] As used herein adult “severe obesity” means a person or study subject having a body mass index (BMI) > 35 kg / m2and “moderate obesity” means a person or study subject having a BMI >25.

[0616] As used herein pediatric ‘severe obesity’ is defined by age and sex-matched index BMI cut offs to account for growth e.g., as set by the World Health Organization. Guidelines and tables for defining index BMI cut offs for children are known in the art. For children between 5 and 19, obesity is defined as BMI-for-age greater than 2 standard deviations above the WHO Growth Reference median. For children under 5, obesity is defined as weight-for-height greater than 3 standard deviations above the WHO Child Growth Standards median. Severe obesity in children can be defined as a BMI at or above the 99thpercentile for the child’s age and gender or above the 95thpercentile for the child’s age and gender, or above the 90thpercentile for the child’s age and gender. Early onset obesity is obesity which affects a subject during childhood typically before the age of 12, before the age of 10, before the age of 8, before the age of 7, before the age of 6 or before the age of 5. Early onset obesity can be severe or moderate obesity. As used herein, the phrase, “standardized growth charts” refers to percentile curves showing the distribution of selected body measurements in children. Growth charts are used by pediatricians, nurses, and parents to track the growth of infants, children, and adolescents.

[0617] Obesity associated with MC4R deficiency or MC4R-deficient obesity means obesity that affects a subject with a heterozygous or homozygous, loss of function MC4R genotype comprising a single nucleotide variant or short deletion that has been shown to cause a reduction in MC4R cellular level and / or function in cell-based assay experiments. Examples of such variants include but are not limited to those exemplified in Table 2.

[0618] As used herein the term “MC4R-deficient obesity”, “MC4R-D obesity” or “MC4R-D severe obesity” means obesity that affects a subject with a heterozygous or homozygous MC4R loss of-function genotype comprising a single nucleotide variant or short deletion that has been shown to cause a reduction in MC4R cellular level of function in cell-based assay experiments.

[0619] As used herein, the term anorexia refers reduced appetite and food intake in a subject resulting in a BMI less than 20, between 16 and 17, between 15 and 16 or less than 15.

[0620] As used herein, the term geriatric malnutrition refers deficiency or imbalance of energy, protein or other critical nutrients in a patient 65 years of age or older which adversely affects bodycomposition, physical function and clinical treatment outcomes. Geriatric malnutrition in patients affected by cancer or heart failure can significantly affect disease prognosis and treatment outcomes in these patients. Clinical signs of geriatric anorexia include weight loss, sarcopenia (muscle wasting), impaired immunity, delayed wound healing, frailty, falls and increased mortality and morbidity.

[0621] As used herein, the term “cachexia” refers to cachexia associated with a chronic illness, such as cachexia associated with cancer, cachexia associated with acquired immunodeficiency syndrome (AIDS), cachexia associated with heart failure for example cachexia associated with congestive heart failure (CHF), cachexia associated with chronic kidney disease (CKD); cachexia associated with treatment of a chronic illness, such as, cachexia associated with treatment of cancer or cachexia associated with treatment of heart failure (e.g., CHF).

[0622] As used herein, “MC4R- related condition, disease or disorder” refers to a medical condition, disease, or disorder present in a mammal (e.g., Human) selected from obesity; obesity associated with MC4R-deficiency (MC4R-deficient obesity); pediatric early-onset obesity; severe obesity; and obesity in combination with any known comorbidity or obesity including but not limited to type 2 diabetes mellitus; hypertension; nonalcoholic fatty liver disease; obstructive sleep apnea; dyslipidemia, or a combination thereof; cachexia anorexia or anorexia nervosa (e.g., geriatric anorexia, anorexia associated with chemotherapy and / or radiotherapy); nausea; emesis; weight loss (e.g., involuntary weight loss); failure to thrive; sarcopenia; muscle wasting; muscle weakness (e.g., muscle weakness associated with chronic obstructive pulmonary disease); frailty; osteoporosis; bone disorders (e.g., bone loss); pain; neuropathic pain; anxiety (e.g., posttraumatic stress disorder, or PTSD); depression; hypertension; malnutrition; sexual dysfunction; and inflammatory disease (e.g., an inflammatory disease associated with anorexia or cachexia or sarcopenia or muscle wasting).

[0623] As used herein, the term “effective amount” or “therapeutically effective amount” refers to an amount sufficient to effect beneficial or desired results, such as clinical results, and, as such, a “therapeutically effective amount” depends upon the context in which it is being applied.

[0624] As used herein, and as well understood in the art, “to treat” a condition or “treatment” of various diseases and disorders is an approach for obtaining beneficial or desired results, such as clinical results. Beneficial or desired results can include, but are not limited to, alleviation of one or more symptoms or conditions; diminishment of extent of disease, disorder, or condition; stabilizing (i.e., not worsening) state of disease, disorder, or condition; delay or slowing the progress of the disease, disorder, or condition; amelioration or palliation of the disease, disorder, or condition; and remission (whether partial or total), whether detectable or undetectable. “Preventing” or “Palliating” a disease, disorder, or condition means that the extent and / or undesirable clinical manifestations of the disease, disorder, or condition are lessened and / or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment.

[0625] At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual sub-combination of the members of such groups and ranges. For example, the term “C1-4 alkyl” is specifically intended to include Ci alkyl (methyl), C2 alkyl (ethyl), C3 alkyl, and C4 alkyl. Foranother example, the term “4- to 7-membered heterocycloalkyl” is specifically intended to include any 4-, 5-, 6-, or 7-membered heterocycloalkyl group.

[0626] As used herein, a compound of Formula I, la, lb, lb’, Ic, Id, Id’, le II, Ila, lib, lib’, lie, lid, lid’, or lie includes optional substitutions and variables. It is understood that the normal valency of each of the designated (optionally substituted) atom or moiety is not exceeded, and that any of the optional substitution results in a stable compound. It is also understood that combinations of optional substituents and / or variables are permissible only if such combinations result in a stable compound. As used herein, unless otherwise specified, the point of attachment of a substituent can be from any suitable position of the substituent.

[0627] As used herein, the term “n-membered”, where n is an integer, typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, pyridinyl is an example of a 6-membered heteroaryl ring and pyrazolyl is an example of a 5-membered heteroaryl group.

[0628] The term “acyl,” as used herein, represents a group –C(=O)–R, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, or heterocyclyl.

[0629] The term “alkyl,” as used herein, refers to a branched or straight-chain monovalent saturated aliphatic radical containing only C and H when unsubstituted. The monovalency of an alkyl group does not include the optional substituents on the alkyl group. For example, if an alkyl group is attached to a compound, monovalency of the alkyl group refers to its attachment to the compound and does not include any additional substituents that may be present on the alkyl group. In some embodiments, the alkyl group may contain, e.g., 1-8, 1-6, 1-4, or 1-2 carbon atoms (e.g., C1-8, C1-6, C1-4, or C1-2). Examples include, but are not limited to, methyl, ethyl, isobutyl, sec-butyl, tert-butyl, 2-methylpropyl, and 2,2-dimethylpropyl.

[0630] The term “alkylene,” as used herein, refers to a divalent alkyl group. The divalency of an alkylene group does not include the optional substituents on the alkylene group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, and n-propylene.

[0631] The term “alkynyl,” as used herein, represents monovalent straight or branched chain hydrocarbon groups of from two to six carbon atoms containing at least one carbon-carbon triple bond and is exemplified by ethynyl, 1-propynyl, and the like.

[0632] The term “amino,” as used herein, refers to a radical of structure -NH2. An amino group, when substituted, can be a radical of structure NHR or NR2, in which each R is alkyl, cycloalkyl, or aryl, each of which can be substituted as described herein.

[0633] The term “aryl,” as used herein, represents a mono-, bicyclic, or multicyclic carbocyclic ring system having one or two aromatic rings. Aryl group may include from 6 to 10 carbon atoms (e.g., six carbons (Ce aryl), ten carbons (C10 aryl), or fourteen carbons (C14 aryl)). All atoms within an unsubstituted carbocyclic aryl group are carbon atoms. Non-limiting examples of carbocyclic aryl groups include phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl, 2,3-dihydro-1H-indene, etc.The term “arylene,” as used herein, refers to a divalent radical obtained by removing a hydrogen atom from a carbon atom of an aryl group. The divalency of an arylene group does not include the optional substituents on the arylene group. An example of the arylene group is a phenylene group.

[0634] The term “cyano,” as used herein, refers to a radical of structure -CN.

[0635] The term “cycloalkyl,” as used herein, refers to a cyclic alkyl group having from three to ten carbons (e.g., a C3-C10 cycloalkyl), unless otherwise specified. Cycloalkyl groups may be monocyclic or bicyclic. Bicyclic cycloalkyl groups may be of bicyclo[p.q.0]alkyl type, in which each of p and q is, independently, 1, 2, 3, 4, 5, 6, or 7, provided that the sum of p and q is 2, 3, 4, 5, 6, 7, or 8.

[0636] Alternatively, bicyclic cycloalkyl groups may include bridged cycloalkyl structures, e.g., bicyclo[p.q.r]alkyl, in which r is 1, 2, or 3, each of p and q is, independently, 1, 2, 3, 4, 5, or 6, provided that the sum of p, q, and r is 3, 4, 5, 6, 7, or 8. The cycloalkyl group may be a spirocyclic group, e.g., spiro[p.q]alkyl, in which each of p and q is, independently, 2, 3, 4, 5, 6, or 7, provided that the sum of p and q is 4, 5, 6, 7, 8, or 9. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1 -bicyclo[2.2.1. ]heptyl, 2-bicyclo[2.2.1.]heptyl, 5-bicyclo[2.2.1. ]heptyl, 7-bicyclo[2.2.1.]heptyl, and decalinyl.

[0637] The term “cycloalkyl alkyl,” as used herein, represents an alkyl group substituted with a cycloalkyl group, each as defined herein. The cycloalkyl and alkyl portions may be optionally substituted as the individual groups described herein.

[0638] The term “halo,” as used herein, refers to a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.

[0639] The term “alkyl” as used herein, refers to any acyclic combination of carbon atoms ranging from 1-10 carbons interconnected by single bonds, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, 3, 3-dimethyl-1 -propyl, various forms of hexyl, heptyl, octyl, etc. and these groups may bear up to 5 distinct subsitutents, including but not limited to fluorine, chlorine, bromine, hydroxyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, trifluoroethyloxy, t-butoxy, O-linked acetoxy, C-linked-acetoxy amino, methylamino, dimethylamino, trimethylammonium, ethylamino, diethylamino, methylethylamino, azetidinyl, pyrrolidinyl, morpholino, piperidinyl, piperazinyl, methyl, ethyl, cyclopropyl, cyclobutyl, N-linked acetamido, N-linked N-methyl acetamido, C-linked acetamido, C-linked-N-methyl acetamido, C-linked-N, N-dimethyl acetamido, thiol, methylthioether, etc.

[0640] For alkyl and cycloalkyl groups, the prefix Ci-j indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive. For example, the term “C1-4 alkyl” is specifically intended to include Ci alkyl (methyl), C2 alkyl (ethyl), C3 alkyl, and C4 alkyl.

[0641] The term “ haloalky I, ” as used herein, represents a group containing at least one “halo” as defined herein and at least one “alkyl” portion as defined herein. The alkyl portion of haloalkyl can be optionally substituted as defined for alkyl. For example, the term “C1-4 haloalkyl” refers to a C1-4 alkyl group having one or more halogen substituents (upto perhaloalkyl, i.e., every hydrogen atom of the alkyl group has been replaced by a halogen atom); and the term “C1-2 haloalkyl” refers to a C1-2 alkylgroup (i.e., methyl or ethyl) having one or more halogen substituents (upto perhaloalkyl, i.e., every hydrogen atom of the alkyl group has been replaced by a halogen atom). Examples of haloalkyl groups include —CF3, —CHF2, —CH2F, —CH2CF3, —C2F5, —CH2Cl and the like.

[0642] The term “heteroalkyl,” as used herein refers to an alkyl, alkenyl, or alkynyl group interrupted once by one or two heteroatoms; twice, each time, independently, by one or two heteroatoms; three times, each time, independently, by one or two heteroatoms; or four times, each time, independently, by one or two heteroatoms. In some embodiments, each heteroatom is, independently, O, N, or S.

[0643] The term “heteroaryl,” as used herein, refers to an aromatic monocyclic or fused ring bicyclic or multicyclic system having at least one heteroatom as a ring atom. For example, a heteroaryl ring may have five to ten ring atoms (e.g., five, six, seven, eight, nine, or ten), in which one or more (e.g., one, two, three, four, or five) ring atoms are heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, but are not limited to pyrrole, pyrazole, isoxazole, imidazole, thiazole, thiophene, furan, diazole, triazole, tetrazole, oxazole, 1,3,4-oxadiazole, 1, 3,4-thiadiazole, 1,2,3,4-oxatriazole, 1,2,3,4-thiatriazole, pyridine, pyrimidine, pyrazine, pyridazine, and triazine.

[0644] The term “heteroaryl alkyl,” as used herein, represents an alkyl group substituted with a heteroaryl group, each as defined herein. For example, a C1-6 alkyl C3-6 heteroaryl as used herein refers to an alkyl group of one to six carbon atoms substituted at any position with a heteroaryl group comprising of three to five carbon atoms. The heteroaryl and alkyl portions may be optionally substituted as the individual groups described herein.

[0645] The term “heteroarylene,” as used herein, refers to a divalent radical obtained by removing a hydrogen atom from a ring atom of a heteroaryl group. The divalency of a heteroarylene group does not include the optional substituents on the heteroarylene group.

[0646] The term “heterocyclyl” and “heterocycloalkyl” as used interchangeably herein, represents a monocyclic, bicyclic, or tricyclic ring system having fused, bridging, and / or spiro 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered rings, unless otherwise specified, containing one, two, three, four, or five heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.

[0647] Heterocyclyl can be aromatic or non-aromatic. Non-aromatic 5-membered heterocyclyl has zero or one double bonds, non-aromatic 6- and 7-membered heterocyclyl groups have zero to two double bonds, and non-aromatic 8-membered heterocyclyl groups have zero to two double bonds and / or zero or one carbon-carbon triple bond. Examples of heterocycle groups include, but are not limited to pyrrolidine, thiolane, tetrahydrofuran, morpholine, piperidine, and piperazine, 2H-pyran, 4H-pyran, and tetrahydropyran. The term “heterocyclyl” also represents a heterocyclic compound having a bridged multicyclic structure in which one or more carbons and / or heteroatoms bridges two non-adjacent members of a monocyclic ring. Examples of bicyclic ring systems include C6-11 bicycloheterocyclyl ring systems, e.g., trihydro-2, 6-naphthyridine.

[0648] The term “heterocyclylene,” as used herein, refers to a divalent radical obtained by removing a hydrogen atom from a ring atom of a heterocycle group. The divalency of a heterocycle group does not include the optional substituents on the heterocycle group.The term “heterocyclyl alkyl,” as used herein, represents an alkyl group substituted with a heterocyclyl group, each as defined herein. For example, a C1-6 alkyl C3-6 heterocyclyl as used herein refers to an alkyl group of one to six carbon atoms substituted at any position with a heterocyclyl group comprising of three to six carbon atoms. The heterocyclyl and alkyl portions may be optionally substituted as the individual groups described herein.

[0649] The terms “hydroxyl” and “hydroxy,” as used interchangeably herein, represent an -OH group. The term “oxo,” as used herein, refers to a divalent oxygen atom represented by the structure =0.

[0650] The phrase “optionally substituted X,” as used herein, is intended to be equivalent to “X, wherein X is optionally substituted” (e.g., “alkyl, wherein said alkyl is optionally substituted”). It is not intended to mean that the feature “X” (e.g., alkyl) perse is optional. The term “optionally substituted,” as used herein, refers to having 0, 1, or more substituents (e.g., 0-25, 0-20, 0-10, or 0-5 substituents), valency permitting. Any functional group herein may be optionally substituted, valency permitting, with another optionally substituted group as specified herein. For example, a Ci alkyl group, i.e., methyl, may be substituted with oxo to form a formyl group and further substituted with -OH or amino to form a carboxyl group or an amido group.

[0651] The term “protecting group,” as used herein, represents a group intended to protect a hydroxy, an amino, or a carbonyl from participating in one or more undesirable reactions during chemical synthesis. The term “O-protecting group,” as used herein, represents a group intended to protect a hydroxy or carbonyl group from participating in one or more undesirable reactions during chemical synthesis. The term “N-protecting group,” as used herein, represents a group intended to protect a nitrogen containing (e.g., an amino, amido, heterocyclic N-H, or hydrazine) group from participating in one or more undesirable reactions during chemical synthesis. Commonly used O- and N-protecting groups are disclosed in Greene, “Protective Groups in Organic Synthesis,” 3rd Edition (John Wiley & Sons, New York, 1999), which is incorporated herein by reference. Exemplary O- and N-protecting groups include alkanoyl, aryloyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, 0-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, t-butyldimethylsilyl, tri-iso-propylsilyloxymethyl, 4,4'-dimethoxytrity I, isobutyryl, phenoxyacetyl, 4-isopropylphenoxyacetyl, dimethylformamidino, and 4-nitrobenzoyl.

[0652] As used herein, the term “selectivity” or “selective” refers to a greater effect of a compound in a first assay, compared to the effect of the same compound in a second assay. For example, for “gut-selective” compounds, the first assay is for the half-life of the compound in the intestine and the second assay is for the half-life of the compound in the liver. In another example for “MC4R selective” compounds the first assay is for determining efficacy in a MC4R signaling and the second assay is for determining efficacy in a MC1R, MC2R, MC3R or MC5R signaling. In another example for “MC4R selective” compounds the first assay is for determining a binding affinity in a MC4R binding assay and the second assay is for determining binding affinity in a MC1 R, MC2R, MC3R or MC5R binding assay.Compounds

[0653] The present disclosure provides compounds that are useful in the treatment of a MC4R related condition, disease or disorder. The compounds are generally described by Formulas I, la, lb, lb’, Ic, Id, Id’, and le:

[0654] R2R2R3

[0655]

[0656] R2R2R3

[0657]

[0658] In some embodiments, R1is -S(O)2(RA) or-C(O)(RA).

[0659] In some embodiments, R1is selected from a group consisting of:

[0660]

[0661] R1B

[0662]

[0663] n

[0664] R1B

[0665] , wherein n is 0, 1, 2, 3, or 4; each R1Ais independently, halogen, C1-6 alkyl, C1-6 haloalkyl, -O-(optionally substituted C1-6 alkyl), -O-(optionally substituted C3-8 cycloalkyl), -O-(C1-6 optionally substituted heterocycloalkyl), or -O-(C1-6 haloalkyl); R1Bis H, C1-6 alkyl, -OH, -O-(C1-6 alkyl), -O-(C3-8 cycloalkyl), or -O-(C1-6 heterocycloalkyl); and each X is independently CH, C(R1A), or N. In specific embodiments, R1Ais selected from a group consisting of: F, -CH3, -O-CH3,

[0666]

[0667]

[0668] o

[0669] In particularly preferred embodiments, R1is

[0670]

[0671] In other embodiments, R1is -C(O)(RA), wherein RAis -QB-RBand RBis an optionally substituted C3-8 cycloalkyl, optionally substituted C1-6 alkyl, optionally substituted Ce aryl, optionally substituted C3-6 heteroaryl, or optionally substituted C3-10 heterocyclyl. In specific embodiments, RBis

[0672]

[0673]

[0674] In some embodiments, R1is -C(O)(RA), wherein RAis optionally substituted C3-10 heterocyclyl.In particular embodiments, R1is a optionally substituted C3-10 heterocyclyl selected from a

[0675] group consisting of:

[0676]

[0677] In other embodiments, R1is -C(O)(RA), wherein RAis optionally substituted C1-6 alkyl, optionally substituted Ce aryl, or optionally substituted Cs-12 bicyclic aryl.

[0678] In particular embodiments, R1is -C(O)(RA), wherein RAis optionally substituted C1-6 alkyl, optionally substituted Ce aryl, or optionally substituted Cs-12 bicyclic aryl selected from a group

[0679]

[0680] In some embodiments, R1is -C(O)(RA), wherein RAis -QB-RB. In particular embodiments, RBis optionally substituted C3-6 heteroaryl. In particular embodiments, the optionally substituted C3-6

[0681] heteroaryl is selected from:

[0682]

[0683]

[0684] In other embodiments, R1is -S(O)2(RA). In particular embodiments, R1is

[0685]

[0686] In some embodiments, each R2is independently H, C-i-e alkyl, oxo, -CN, C3-6 cycloalkyl, C3-6 heterocyclyl, C1-6 alkyl C3-6 heterocyclyl.In particular embodiments, each R2is H (e.g., formulas la, lb, lb’, and Ic).

[0687] In particular embodiments, each R2is D (e.g., formulas I and la-e).

[0688] In particular embodiments, one R2is -CH3 and one R2is H.

[0689] In particular embodiments, one R2is -CH3 and R3is CHs.

[0690] In particular embodiments, one R2is -CN.

[0691] In some embodiments, R3is H, optionally substituted C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, Cs-e heterocyclyl, optionally substituted C3-6 heteroaryl, -C(O)-Cs-e alkyl, -C(O)-Cs-e cycloalkyl, -C(O)- Cs-e heterocyclyl or optionally substituted C1-6 alkyl Cs-e heteroaryl.

[0692] In particular embodiments, R3is -CH3(e.g., formulas lb and lb’).

[0693] In particular embodiments, R3is -CDs (e.g., formulas I and la-e).

[0694] In some embodiments, R3is optionally substituted C3-6 heteroaryl or optionally substituted C1-6

[0695] alkyl Cs-e heteroaryl selected from:

[0696]

[0697] H

[0698] In some embodiments, R3is optionally substituted C1-6 alkyl, C1-6 haloalkyl, or Cs-e cycloalkyl

[0699] OH

[0700] selected from:

[0701]

[0702] In some embodiments, R3is optionally substituted Ci-e alkyl selected from:

[0703]

[0704]

[0705] In some embodiments, R5is H, halogen, -CN, optionally substituted Ci-e alkyl, optionally substituted alkynyl, C3-10 cycloalkyl, optionally substituted C1-10 heteroaryl, optionally substituted C3-10 heterocyclyl, — C(O)(RA), or -QA-RB.

[0706] In particular embodiments, R5is optionally substituted Ci-e heteroaryl.

[0707] In particular embodiments, R5is optionally substituted C1-6 heteroaryl selected from:

[0708]

[0709] F

[0710] In preferred embodiments, R5is

[0711]

[0712] In some embodiments, R5is C3-8 cycloalkyl.

[0713]

[0714] In some embodiments, R5is -C(O)(RA).

[0715] In particular embodiments, R5is -C(O)(RA), wherein RAis amino.

[0716] JH

[0717]

[0718] nN

[0719] In particular embodiments, R5is O or O

[0720] In some embodiments, R5is -QA-RB.

[0721] In specific embodiments, QAis NH or O.

[0722]

[0723] In some embodiments, R5is optionally substituted C3-8 heterocyclyl.

[0724] L N. /

[0725] In specific embodiments, R5is the C3-8 heterocyclyl:

[0726]

[0727] .

[0728] In some embodiments, R5is halogen. In particular embodiments, R5is bromo (Br).

[0729] In some embodiments, R5is a cyano (-CN).

[0730] In some embodiments, R5is an optionally substituted alky nyl.

[0731] In particular embodiments, R5is the optionally substituted alky nyl:

[0732]

[0733] .

[0734] In some embodiments, R6is C1-6 alkyl, -CH2OH, -CH2-O-(Ci-e alkyl).

[0735] In specific preferred embodiments, R6is -CHs (e.g., formula lb’).

[0736] In specific embodiments, R6is -CH2OH.

[0737] In specific embodiments, R6is -CH2-O-CH3.

[0738] In some embodiments, R5and R6together with the atom to which both are attached, combine n optionally substituted Cearyl (e.g., formulas Id and Id’).

[0739] In specific embodiments, the Cearyl is substituted with one -O-CHsgroup (e.g., formula Id’). In some embodiments, QAis CH2, CH(RB), N(RN), or O.

[0740] In specific embodiments, QAis CH2.In specific embodiments, QAis CH(Ci-e alkyl).

[0741] In specific embodiments, QAis C-CHs.

[0742] In specific embodiments, QAis CH(-O-Ci-e alkyl).

[0743] In specific embodiments, QAis NH.

[0744] In specific embodiments, QAis N(Ci-e alkyl).

[0745] In specific embodiments, QAis N-CHs.

[0746] In specific embodiments, QAis O.

[0747] In some embodiments, QBis CH2, CH(RB), N(RN), or O.

[0748] In specific embodiments, QBis CH2.

[0749] In specific embodiments, QBis CH(Ci-e alkyl).

[0750] In specific embodiments, QBis C-CHs.

[0751] In specific embodiments, QBis CH(-O-Ci-e alkyl).

[0752] In specific embodiments, QBis NH.

[0753] In specific embodiments, QBis N(Ci-e alkyl).

[0754] In specific embodiments, QBis N-CHs.

[0755] In specific embodiments, QBis O.

[0756]

[0757] , optionally substituted C1-6 alkyl, optionally substituted Cs-e aryl, optionally substituted C3-10 cycloalkyl, optionally substituted Cearyl, optionally substituted C8-12bicyclic aryl, optionally substituted C5-6heteroaryl, or optionally substituted C3-10 heterocyclyl.

[0758] In some embodiments, RBis independently selected from -OH, -O-(Ci-e alkyl), optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted Ce aryl, optionally substituted Cs-12 bicyclic aryl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkyl Ce aryl, optionally substituted C1-6 alkyl Ce aryl, optionally substituted C3-10 heterocyclyl, or optionally substituted Ci-e heteroaryl, or optionally substituted Ce-n bicyclic heteroaryl.

[0759] In some embodiments, each Rcis independently -OH or -O-(Ci-e alkyl) (e.g., formula Id). In specific embodiments, one Rcis -O-(Ci-e alkyl).

[0760] In particular embodiments, one Rcis -O-CHs (e.g., formula Id’).

[0761] In some embodiments, RNis H, optionally substituted C1-6 alkyl, or RNand RBtogether with the atom to which both are attached, combine to form an optionally substituted C3-10 heterocyclyl or optionally substituted Ce-n bicyclic heterocyclyl;

[0762] In some embodiments, (Rc)n is n = 0, 1, or 2 (e.g., formula Id).

[0763] In preferred embodiments, (Rc)n is n = 1 (e.g., formula Id’).

[0764] Representative examples of specific embodiments are in Table 1.Where the compounds of the present invention possess two or more stereogenic centers and the absolute or relative stereochemistry is given in the name, the designations R and S refer respectively to each stereogenic center in ascending numerical order (1, 2, 3, etc.) according to the conventional ILJPAC number schemes for each molecule. Where the compounds of the present invention possess one or more stereogenic centers and no stereochemistry is given in the name or structure, it is understood that the name or structure is intended to encompass all forms of the compound, including the racemic form. When absolute stereochemistry is indicated for a compound (e.g., a stereogenic center is labeled R or S), the compound can have at least 90% enantiomeric purity (e.g., at least 90% of the material contains a single enantiomer). When relative stereochemistry is indicated for a compound, the compound can have a distereomeric purity of at least 90% (e.g., at least 90% of the material contains a single diastereomer).

[0765] It is also possible that the intermediates and compounds of the present invention may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. The term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations.

[0766] Included within the scope of the claimed compounds present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of Formula I, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.

[0767] The compounds of the present invention may be isolated and used per se, or when possible, in the form of its pharmaceutically acceptable salt. The term “salts” refers to inorganic and organic salts of a compound of the present invention. These salts can be prepared in situ during the final isolation and purification of a compound, or by separately treating the compound with a suitable organic or inorganic acid and isolating the salt thus formed. See e.g., Berge, et al. J. Pharm. Sci. 66, 1-19 (1977); Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).

[0768] The compounds of the invention include compounds of Formula I, Formula II, or Table 1 or their pharmaceutically acceptable salts as herein defined.

[0769] Pharmaceutical Compositions

[0770] A pharmaceutical composition of the invention contains one or more of the compounds disclosed herein (e.g., one or more of the compounds having the structure of Formula I, Formula II, and Table 1) as the therapeutic compound. In addition to a therapeutically effective amount of the compound, the pharmaceutical compositions also contain a pharmaceutically acceptable excipient, which can be formulated by methods known to those skilled in the art. In some embodiments, the pharmaceutical compositions for treating cancer contain one or more of the compounds disclosed herein (e.g., one or more of the compounds having the structure of Formula I, la, lb, lb’, Ic, Id, Id’, le,II, Ila, lib, lib’, lie, lid, lie, or the compounds of Table t) may be formulated and / or administered with or without other therapeutics for a particular condition. Examples of such therapeutics (second therapeutic agents) are described herein.

[0771] The compounds disclosed herein (e.g., the compounds having a structure according to Formula I, la, lb, lb’, Ic, Id, Id’, le, II, Ila, lib, lib’, lie, lid, or lie or compounds specifically disclosed herein such as those in Table 1 ) may be used in the form of free base, or in the form of salts. All forms are within the scope of the disclosure.

[0772] Exemplary routes of administration of the pharmaceutical compositions (or the compounds of the composition) include oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intra-arterial, intracranial, subcutaneous, intraorbital, intraventricular, intraspinal, intraperitoneal, intranasal, inhalation, and topical administration.

[0773] Formulations for Oral Administration

[0774] The pharmaceutical compositions of the invention include those formulated for oral administration (“oral dosage forms”). Oral dosage forms can be, for example, in the form of tablets, capsules, a liquid solution or suspension, a powder, or liquid or solid crystals, which contain the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.

[0775] Pharmaceutical compositions for oral administration may also be presented as chewable tablets, as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules where the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.

[0776] The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils, e.g., cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.The pharmaceutical compositions of the invention can be administered in a pharmaceutically acceptable parenteral (e.g., intravenous, intramuscular, subcutaneous or the like) formulation as described herein. The pharmaceutical composition may also be administered parenterally in dosage forms or formulations containing conventional, non-toxic pharmaceutically acceptable carriers and adjuvants. In particular, formulations suitable for parenteral administration include aqueous and nonaqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and nonaqueous sterile suspensions which may include suspending agents and thickening agents. For example, to prepare such a composition, the compounds of the invention may be dissolved or suspended in a parenterally acceptable liquid vehicle. Among acceptable vehicles and solvents that may be employed are water; water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide, or a suitable buffer; 1,3-butanediol; Ringer’s solution; and isotonic sodium chloride solution. The aqueous formulation may also contain one or more preservatives, for example, methyl, ethyl, or n-propyl p-hydroxybenzoate. Additional information regarding parenteral formulations can be found, for example, in the United States Pharmacopeia-National Formulary (USP-NF), herein incorporated by reference in its entirety.

[0777] The parenteral formulation can be any of the five general types of preparations identified by the USP-NF as suitable for parenteral administration: “Drug Injection:” a liquid preparation that is a drug substance (e.g., a compound of the invention), or a solution thereof; “Drug for Injection:” the drug substance (e.g., a compound of the invention) as a dry solid that will be combined with the appropriate sterile vehicle for parenteral administration as a drug injection; “Drug Injectable Emulsion:” a liquid preparation of the drug substance (e.g., a compound of the invention) that is dissolved or dispersed in a suitable emulsion medium; “Drug Injectable Suspension:” a liquid preparation of the drug substance (e.g., a compound of the invention) suspended in a suitable liquid medium; and “Drug for Injectable Suspension:” the drug substance (e.g., a compound of the invention) as a dry solid that will be combined with the appropriate sterile vehicle for parenteral administration as a drug injectable suspension.

[0778] Exemplary formulations for parenteral administration include solutions of the compound prepared in water suitably mixed with a surfactant, e.g., hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 23rdEd., Adejare, Ed., Academic Press (2020) and in The United States Pharmacopeia and National Formulary (USP-NF 2021 Issues 1-3), published in 2021.

[0779] Formulations for parenteral administration may, for example, contain sterile water, saline, polyalkylene glycols (e.g., polyethylene glycol), oils of vegetable origin, or hydrogenated naphthalenes. Biocompatible, biodegradable lactide polymer, lactide / glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds.Other potentially useful parenteral delivery systems for compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.

[0780] Methods of Use

[0781] The compounds of the present invention are useful for treating or preventing MC4R-related conditions diseases and disorders including cachexia (e.g., obesity; obesity associated with MC4R-deficiency (MC4R-deficient obesity); pediatric early-onset obesity; severe obesity; and obesity in combination with any known comorbidity or obesity including but not limited to type 2 diabetes mellitus; hypertension; nonalcoholic fatty liver disease; obstructive sleep apnea; dyslipidemia, or a combination thereof; cachexia associated with a chronic illness, such as cachexia associated with cancer, cachexia associated with acquired immunodeficiency syndrome (AIDS), cachexia associated with heart failure for example cachexia associated with congestive heart failure (CHF), cachexia associated with chronic kidney disease (CKD); cachexia associated with treatment of a chronic illness, such as, cachexia associated with treatment of cancer or cachexia associated with treatment of heart failure (e.g., CHF)); anorexia or anorexia nervosa (e.g., geriatric anorexia, anorexia associated with chemotherapy and / or radiotherapy); nausea; emesis; weight loss (e.g., involuntary weight loss); failure to thrive; sarcopenia; muscle wasting; muscle weakness; frailty; osteoporosis; bone disorders (e.g., bone loss); pain; neuropathic pain; anxiety (e.g., posttraumatic stress disorder, or PTSD); depression; hypertension; malnutrition; sarcopenia; sexual dysfunction; and inflammatory disease (e.g., an inflammatory disease associated with anorexia or cachexia or sarcopenia or muscle wasting).

[0782] Without wishing to be bound by theory, the compounds disclosed herein (e.g., the compounds of Formulas I, la, lb, lb’, Ic, Id, Id’, le, II, Ila, lib, lib’, lie, lid, lie and provided in Table 1) may in addition to acting as antagonists may sensitize MC4R responses through a corrector effect on MC4R resulting in increased functional MC4R in a cell.

[0783] The dosage of the compound of the disclosure depends on factors including the route of administration, the disease to be treated, and physical characteristics, e.g., age, weight, and general health, of the subject. Typically, the amount of a compound disclosed herein (e.g., a compound of formula I, la, lb, lb’, Ic, Id, Id’, le, II, Ila, lib, lib’, lie, lid, lie and provided in Table 1) contained within a single dose may be an amount that effectively treats the disease without inducing significant toxicity. Pharmaceutical compositions of the disclosure that contain one or more of the compounds disclosed herein (e.g., a compound of formula I, la, lb, lb’, Ic, Id, Id’, le, II, Ila, lib, lib’, lie, lid, lie and provided in Table 1) may be administered to a subject in need thereof one or more times daily, or as medically necessary.

[0784] The present invention further comprises use of a compound of Formula I or its pharmaceutically acceptable salt for use as a medicament (such as a unit dosage tablet or unit dosage capsule). In another embodiment, the present invention comprises the use of a compound ofFormula I or its pharmaceutically acceptable salt for the manufacture of a medicament (such as a unit dosage tablet or unit dosage capsule) to treat one or more of the conditions previously identified in the above sections discussing methods of treatment. A pharmaceutical composition of the invention may be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses. As used herein, a "unit dose" is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage. These agents and compounds of the invention can be combined with pharmaceutically acceptable vehicles such as saline, Ringer’s solution, dextrose solution, and the like. The particular dosage regimen, i.e., dose, timing and repetition, will depend on the particular individual and that individual’s medical history including body mass index for the individual.

[0785] The treatment methods of the invention include oral routes, parenteral, intraduodenal routes, buccal, intranasal, etc. Generally, the compounds of this invention are administered orally, but parenteral administration (e.g., intravenous, intramuscular, subcutaneous or intramedullary) may be utilized, for example, where oral administration is inappropriate for the target or where the patient is unable to ingest the drug. For administration to human patients, an oral daily dose of the compounds herein may be, for example, in the range 10 mg to 1000 mg depending on the mode of and frequency of administration, the disease state, and the age and condition of the patient, etc.

[0786] An oral daily dose may be in the range of 10 mg to 750 mg may be used and administered either once daily i.e., quaque die (QD) or twice daily i.e., bis in die (BID). A further oral daily dose is in the range of 50 mg to 1000 mg. For convenience, the compounds of the present invention can be administered in a unit dosage form. If desired, multiple doses per day of the unit dosage form can be used to increase the total daily dose. The unit dosage form, for example, may be a tablet or capsule containing about 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 250, 300, 500, or 1000 mg of the compound of the present invention. The total daily dose may be administered in single or divided doses and may, at the physician’s discretion, fall outside of the typical ranges given herein. The dosage of the compound of the disclosure depends on factors including the route of administration, the disease to be treated, and physical characteristics, e.g., age, weight, and general health, of the subject. Typically, the amount of a compound disclosed herein (e.g., a compound of Formula (I), (la) or (lb) or in Table 1) contained within a single dose may be an amount that effectively treats the disease without inducing significant toxicity. Pharmaceutical compositions of the disclosure that contain one or more of the compounds disclosed herein (e.g., a compound having the structure of Formula (I), (la) or (lb), or in Table 1) may be administered to a subject in need thereof one or more times daily, or as medically necessary.

[0787] MC4R genotypes associated with severe obesity or pediatric-onset severe obesity in humans include biallelic loss of function genotypes, heterozygous loss of function genotypes and homozygous genotypes. These genotypes are associated with MC4R haploinsufficiency and in many cases MC4R loss of function including reduced cellular functional MC4R level. In many cases the loss of functionMC4R variant is a missense mutation which causes a nonsynonymous change in the MC4R amino acid sequence and structure. A biallelic loss of function genotype means that the individual carries 2 different MC4R loss of function variants, one on each MC4R gene allele, including but not limited to the variants provided in T able 2 herein. A homozygous loss of function genotype means that the individual carries the same MC4R loss of function variants on each of 2 alleles, including but not limited to the variants provided in Table 2 herein. A heterozygous loss of function genotype means that the individual carries a single MC4R loss of function variants one allele, including but not limited to the variants provided in Table 2 herein, and a fully functional WT variant on a second allele.

[0788] Despite evidence indicating that modulating MC4R can promote weight gain in anorexia or cachexia or promote weight loss in obesity, there are several potential challenges associated with compounds that modulate MC4R activity. One major concern is the potential for off-target effects including through modulation of other closely related melanocortin receptors i.e., MC1R, MC2R MC34 or MC5R.

[0789] The melanocortin 1 receptor (MC1R) regulates pigment balance and UV response.

[0790] Therapeutic modulation risks hyperpigmentation, melanocyte proliferation, or pheomelanin-driven oxidative stress and melanoma. Beyond pigmentation, MC1R may affect immunity, vascular tone, and metabolism, so systemic targeting may impair immune defense or cause vascular / metabolic issues. Reduced MC1R function is associated with risk of melanoma and increased function with hyperpigmentation (Mun, Y., et al. (2023). Melanocortin 1 Receptor (MC1R): Pharmacological and Therapeutic Aspects. International Journal of Molecular Sciences, 24(15), 12152; Garcfa-Borron JC, et al. MC1R, the cAMP pathway, and the response to solar UV: extending the horizon beyond pigmentation. Pigment Cell Melanoma Res. 2014 Sep;27(5):699-720).

[0791] Melanocortin 2 receptor (MC2R) is the only known receptor for adrenocorticotrophin hormone (ACTH) and functions to regulate adrenal cortisol production. Modulating MC2R would be expected to disrupt hypothalamic-pituitary-adrenal axis (HPA) function. Therapeutic modulation risks adrenal insufficiency or Cushing-like states if under- or overstimulated (Webb, T. R., & Clark, A. J. L. (2010). Minireview: The melanocortin 2 receptor accessory proteins. Molecular Endocrinology (Baltimore, Md.), 24(3), 475-484). Because cortisol impacts immunity, metabolism, and cardiovascular tone, MC2R targeting may disrupt stress responses, immune regulation, and glucose balance (Chan LF, Metherell LA, Clark AJ. Effects of melanocortins on adrenal gland physiology. Eur. J. Pharmacol. 2011;660:171-180).

[0792] The melanocortin 3 receptor (MC3R) regulates energy balance and circadian rhythm and also influences immune function, puberty and reproduction (Lam, B. Y. H., et. al. (2021). MC3R links nutritional state to childhood growth and the timing of puberty. Nature, 599(7885), 436-441). MC3R is expressed on macrophages and other immune cells and MC3R activation reduces cytokine release and has anti-inflammatory effects (Meng, X., et al. (2025). Biased agonism of G protein-coupled receptors as a novel strategy for osteoarthritis therapy. Bone Research, 13(1), 52; Gravina, A. G., et al. (2023). The Melanocortin System in Inflammatory Bowel Diseases: Insights into Its Mechanisms and Therapeutic Potentials. Cells, 12(14), 1889). Inhibition of MC3R has the potential to causeadverse inflammation, increase autoimmunity, worsen chronic inflammatory disease and interfere with normal onset of puberty.

[0793] The melanocortin 5 receptor (MC5R) is widely expressed in exocrine glands, skeletal muscle, immune cells, adipose tissue and brain. Inhibition of MC5R has the potential to reduce sebum secretion leading to dermatitis or eczema, reduce tear lipid secretion leading to ocular surface irritation and higher risk of keratitis or dry eye disease, increase inflammatory responses leading to autoimmunity risk or slower resolution of inflammation (Xu, Y., et al. (2020). Melanocortin 5 receptor signaling pathway in health and disease. Cellular and Molecular Life Sciences, 77(19), 3831-3840). MC5R has also been implicated in maintenance of podocyte integrity and function suggesting that chronic inhibition could cause adverse effects related to kidney function (Sun, H. (2025). From MC1R to MC5R, a new horizon for the podocyte-protective effect of melanocortin. Kidney International, 107(5), 779-781).

[0794] Regions of the hypothalamus, where MC4R-mediated signaling occurs critical for regulation of food intake and metabolism, are circumventricular organs (CVO). Unlike most brain regions, which are protected by the blood-brain barrier (BBB), CVO have a highly permeable capillary network, allowing direct interaction with circulating blood and the hormones, ligands and drugs it may contain. It is not known if BBB penetration is required for a drug that acts on hypothalamus MC4R and what level of penetration is associated with optimal efficacy and safety. The fact that peptide drugs like setmelanotide can induce weight loss indicates that their site of action is probably not fully protected by the blood brain barrier e.g. regions of the hypothalamus which are considered circumventricular organ (CVO) or regions that are close to a CVO. Limiting exposure of other brain regions, more fully protected by the BBB which could mediate, adverse neurological or psychiatric effects or adverse CNS regulation of blood pressure, heart rate, sympathetic tone or lipid metabolism could be advantageous. Currently available MC4R antagonists and agonists may lead to unwanted side effects due to the activation or inhibition of MC4Rs in deeper brain regions which are not in or near a CVO.

[0795] Since MC4R is also expressed in other brain regions and tissues, besides the hypothalamus, (e.g. brain stem, hippocampus, Cortex, nucleus accumbens, skin, adrenal glands, and immune cells) activation or inhibition of MC4R in these brain regions may lead to unwanted side effects.

[0796] The new pharmaceutical compounds proposed in this invention are designed to selectively target MC4R in the hypothalamus, thereby minimizing potential for CNS off-target effects. Another challenge is the development of sensitization to MC4R agonists or desensitization with prolonged inverse agonist or antagonist use. Prolonged use may lead to a decrease in effectiveness due to compensatory mechanisms that increase the expression or sensitivity of MC4R to endogenous or exogenous MC4R agonists, which could reduce MC4R antagonist effectiveness or response.

[0797] Similarly, some MC4R agonists can induce desensitization which could weaken potency in vivo over time.

[0798] Currently available MC4R agonists for use in humans outside a clinical trial are peptides which need to be administered subcutaneously. Small molecule MC4R agonists or positive modulators would have advantages in terms of ease of use and patient compliance.MC4R modulating therapeutics which are administered orally, can lead to variable absorption and bioavailability due to factors such as food intake and individual differences in metabolism which may impact in vivo antagonist pharmacokinetic profile limiting the desired pharmacodynamic or therapeutic effects or resulting in adverse effects.

[0799] Therefore, there is a need for new pharmaceutical compounds that can overcome these challenges and provide a safer, more effective, and more convenient means of modulating MC4R activity.

[0800] Synthesis Methods

[0801] Compounds of the invention can be made using methods and processes analogous to those known in the chemical arts and considering the description and Examples provided herein. Examples 1-193 herein provide specific synthetic procedures for compounds of Formula I. The starting materials are generally available from commercial sources or can be readily prepared using methods known to those skilled in the art (e.g., generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York (1967-1999 ed.), or Beilsteins Handbuch der Organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database)).

[0802] In some of the synthesis methods described in Examples 1 to 213 herein some require protection of a remote reactive group e.g., primary amine, secondary amine, or carboxyl in Formula I compound precursors. The need for such protection will vary depending on the nature of said group and conditions of the reaction methods. Certain primary amines or carboxylic acid groups contained in a compound may interfere with reactions at other sites if left unprotected. Suitable protecting groups for amine or carboxylic acid groups include N-tert-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc) and benzyloxycarbonyl (Cbz). Such protecting groups are generally not reactive under compound synthesis reaction steps and can be subsequently removed (deprotection). The need for such protection is readily determined by one skilled in the art and use of protection and deprotection methods is well known in the art e.g., Greene, “Protective Groups in Organic Synthesis,” 3rd Edition (John Wiley & Sons, New York, 1999), which is incorporated herein by reference.

[0803] Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g.,1H NMR or13C NMR), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high-performance liquid chromatography (HPLC) or thin-layer chromatography (TLC).

[0804] The synthetic methods and reaction schemes herein provide a description of a methodology for preparing compounds of Formula I and the compounds of Table 1. Some compounds of the invention exemplified herein contain one or more chiral centers (R or S) and are enantiomer-enriched and others are racemic. It will be apparent to one skilled in that the synthetic reactions described in Examples can be conducted in a similar manner whether the compound is enantiomer-enriched or racemic and method for characterizing compound stereochemistry experimentally is well known in thechemistry literature and practice manuals and can be conducted a selected steps in a synthesis sequence.

[0805] Procedures for the synthesis of compounds of the invention are provided as described in Synthesis Procedures 1 to 24 and in Table 3.

[0806] Synthesis Procedure 1 (P1)

[0807]

[0808] P1 Step 1 Synthesis of 1-(tert-butoxycarbonyl)-3-((6-methyl-3-nitropyridin-2-yl)amino)pyrrolidine-3-carboxylic acid (INT-1a)

[0809] Into a 10 L 4-necked round-bottom flask were added DMF (5 L) and 3-amino-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (250 g, 1.086 mol, 1 equiv.) at room temperature. To the above mixture was added CS2CO3 (531 g, 1.630 mol, 1.50 equiv.) and 2-fluoro-6-methyl-3-nitropyridine (170 g, 1.088 mmol, 1.00 equiv.) in portions. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of water (2 L) at room temperature. The mixture was acidified to pH 5 with HCI (aq.). The aqueous layer was extracted with EtOAc (5 Lx 3). The combined organic layer was concentrated under reduced pressure. The crude product was recrystallized with EtOAc (500 mL). The precipitated solids were collected by filtration and dried to afford 1-(tert-butoxycarbonyl)-3-[(6-methyl-3-nitropyridin-2-yl)amino]pyrrolidine-3-carboxylic acid (217 g, 55%) as a yellow solid.

[0810] LC / MS: mass calcd. for C16H22N4O6: 366.15 m / z, found: 389.05 [M+Na]+.

[0811] P1 Step 2 Synthesis of tert-butyl 6-methyl-2-oxo-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1 '-carboxylate (INT -1 b)

[0812] Into a 10 L 4-necked round-bottom flask were added DMF (4L) and 1-(tert-butoxycarbonyl)-3-[(6-methyl-3-nitropyridin-2-yl)amino]pyrrolidine-3-carboxylic acid (217 g, 592.8 mmol, 1 equiv.). To the above mixture was added (dihydroxyboranyl)boronic acid (160.0 g, 1.778 mol, 3 equiv.). The reaction was cooled to -30°C. To the above mixture was added 4-(pyridin-4-yl)py ridine (4.62 g, 29.6 mmol,0.05 equiv.) in portions over 1 h at -30°C. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water (2 L), extracted with EtOAc (5 L x 3). The combined organic layer was concentrated under reduced pressure. The crude product was recrystallized with EtOAc (500 mL) to afford tert-butyl 6-methyl-2-oxo-1,4-dihydrospiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (175 g, 92.8 %) as a white solid.

[0813] LC / MS: mass calcd. for C16H22N4O3: 318.17 m / z, found: 319.10 [M+H]+.

[0814] P1 Step 3 Synthesis of tert-butyl 7-bromo-6-methyl-2-oxo-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (INT-1c)

[0815] Into a 10L 4-necked round-bottom flask were added THF (4 L) and tert-butyl 6-methyl-2-oxo-1,4-dihydrospiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (175 g, 550.3 mmol, 1 equiv.) at room temperature. The mixture was cooled to -78°C. To the above mixture was added NBS (107.8 g, 605.3 mmol, 1.1 equiv.) in THF (500 mL) dropwise over 2h at -78°C. The resulting mixture was stirred at -78°C for additional 3h. The reaction was quenched with water (2 L), extracted with EtOAc (5 L x 3). The combined organic layer was concentrated under reduced pressure. The crude product was recrystallized with EtOAc (500 mL) to afford tert-butyl 7-bromo-6-methyl-2-oxo-1,4-dihydrospiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (93 g, 42.6%) as a white solid. LC / MS: mass calcd. for C16H21BrN4O3: 396.08 m / z, found: 397.0 [M+H]+.

[0816] P1 Step 4 Synthesis of tert-butyl 7-bromo-6-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (INT-1d)

[0817] To a solution of tert-butyl 7-bromo-6-methyl-2-oxo-1,4-dihydrospiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (80 g, 202.0 mmol, 1 equiv.) in tetrahydrofuran (5 L) was added Boranetetrahydrofuran complex (1.0M in THF) (606 mL, 606.0 mmol, 3 equiv.) at 0°C. The resulting mixture was stirred at 60°C for 2 h under N2 atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of MeOH (0.1 L) at 0°C. The resulting mixture was refluxed for 1 h, then concentrated under reduced pressure. The crude product was slurried in water (500 mL) for 2hr, then filtered and dried to afford tert-butyl 7-bromo-6-methyl-2,4-dihydro-1 H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (77 g, 99%) as a white solid. LC / MS: mass calcd. for C16H23BrN4O2: 382.29 m / z, found: 383.17 [M+H]+.

[0818] P1 Step 5 Synthesis of tert-butyl 6-methyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-r-carboxylate (INT-1e)

[0819] To a solution of tert-butyl-7-bromo-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (420 mg, 1.10 mmol, 1 equiv.) in dioxane (4 mL) was added 2-(tributylstannyl)pyrimidine (809 mg, 2.192 mmol, 2 equiv.) and [P(tBu)3] Pd(crotyl)Cl (87 mg, 0.219 mmol, 0.2 equiv.) under N2. After stirring for 4 h at 100 °C under a nitrogen atmosphere, the reaction was quenched with water (30 mL) and extracted with EA (30 mL x 3). The combined extract was washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluted with MeOH / DCM (0-20%) to afford tert-butyl-6-methyl-7-(pyrimidin-2-yl)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (380 mg, 90.67%) as a yellow solid.LC / MS: mass calcd. for C20H26N6O2, 382.31 m / z, found 383.10 [M+H]+.

[0820] P1 Step 6 Synthesis of 6-methyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine] hydrogen chloride (INT-1f)

[0821] To a solution of tert-butyl-6-methyl-7-(pyrimidin-2-yl)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (380 mg, 0.994 mmol, 1 equiv.) in DCM (2 ml_) / MeOH (1 mL) was added HCI in 1,4-dioxane (4.0 M) (1.2 mL). The reaction was stirred for 4h at rt. The resulting mixture was concentrated under vacuum to afford 6-methyl-7-(pyrimidin-2-yl)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine] (450 mg, crude) as a yellow solid.

[0822] LC / MS: mass calcd. for C15H18N6, 282.16 m / z, found 283.20 [M+H]+.

[0823] P1 Step 7 Synthesis of (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-(6-methyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl)propan-1-one (Compound 1A) To a solution of (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)propanoic acid (310 mg, 1.558 mmol, 1.5 equiv.) and 6-methyl-7-(pyrimidin-2-yl)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine] (450 mg, 1.06 mmol, 1 equiv.) in DMF (5 mL) was added DIEA (1.37 g, 10.6 mmol, 10 equiv.), HATU (605 mg, 1.59 mmol, 1.5 equiv.). The reaction was stirred at rt. for 1 hours, quenched with water (30 mL) and extracted with EA (30 mL x 3). The combined extract was washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 reversed phase column chromatography, eluted with MeCN / H2O (0-50%) to afford (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[6-methyl-7-(pyrimidin-2-yl)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl]propan-1-one (210 mg, 42.6%) as a light yellow solid.1H NMR (500 MHz, Methanol-d4) δ 8.81 (dd, J = 5.0, 2.4 Hz, 2H), 7.99 (dd, J = 17.3, 1.6 Hz, 1H), 7.37-7.27 (m, 2H), 6.76(dd, J = 20.1, 4.9 Hz, 1H), 4.22 (dq, J = 42.8, 6.9 Hz, 1H), 3.89 (d, J = 3.5 Hz, 3H), 3.87-3.73 (m, 1H), 3.65-3.52(m, 2H), 3.37(d, J = 12.3 Hz, 1H), 3.24-3.11 (m, 1H), 3.06-2.97 (m, 1H), 2.50 (d, J = 9.0 Hz, 3H), 2.23-2.03 (m, 2H), 1.44 (t, J = 7.3 Hz, 3H).

[0824] LC / MS: mass calcd. for C24H26FN7O2, 463.21 m / z, found 464.30 [M+H]+.

[0825] P1 Step 8 Synthesis of Synthesis of (2R)-1-[1,6-dimethyl-7-(pyrimidin-2-yl)-2,4-dihydrospiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidin]-1'-yl]-2-(5-fluoro-2-methoxypyridin-4-yl) propan-1 -one (Example 193)

[0826] To a solution of (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[6-methyl-7-(pyrimidin-2-yl)-2,4-dihydro-1 H-spiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidin]-1'-yl] propan-1-one (50 mg, 0.108 mmol, 1 equiv.) in MeOH (5 mL) was added 30% HCHO (0.5 mL). The reaction was stirred at rt for 1 h. Then NaBH3CN (34 mg, 0.540 mmol, 5 equiv.) was added to the reaction. The reaction was stirred at rt for1 h. The reaction was quenched with water (30 mL) and extracted with EA (30 ml_ x 3). The combined extract was washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC using a XBridge Prep C18 OBD Column, 19*250 mm, 5μm Column (eluent: 28% B to 58% (V / V), water and MeCN with10mmol / L NH4HCO3) to afford (2R)-1-[1,6-dimethy l-7-(py rimidin-2-y l)-2,4-dihydrospiro[pyrido[2, 3-b] pyrazine-3, 3'-pyrrolidin]-1 '-yl]-2-(5-fluoro-2-methoxypyridin-4-yl) propan-1-one (2.5 mg, 4.83%) as a green solid.1H NMR (400 MHz, Methanol-d4) δ 8.83 (d, J = 4.9, 2.7 Hz, 2H), 8.03 - 7.90 (m, 1H), 7.44 - 7.30 (m, 2H), 6.80 - 6.65 (m, 1H), 4.36 -4.11 (m, 1H), 4.00 - 3.76 (m, 4H), 3.79 - 3.65 (m, 1H), 3.67 - 3.55 (m, 1H), 3.52 - 3.40 (m, 1H), 3.25 - 3.04 (m, 1H), 2.98 (d, J = 10.2 Hz, 2H), 2.89 (d, J = 23.3 Hz, 1H), 2.71 (s, 1H), 2.53 (t, J = 4.4 Hz, 3H), 2.24 - 1.98 (m, 2H), 1.55 - 1.38 (m, 3H), 1.34 - 1.17 (m, 1H).

[0827] LC / MS: mass calcd. C25H28FN7O2 for: 477.23, found: 478.20 [M+H]+.

[0828] Procedure 1: Alternative Routes

[0829] P1 Alt Step 5 Synthesis of 7-bromo-6-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine] (INT 1g)

[0830] To a solution of tert-butyl 7-bromo-6-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (200 mg, 0.522 mmol, 1 equiv.) in 1,4-dioxane (10 mL) was added HCI (4 M solution of 1,4-dioxane) (1.5 mL). The reaction was stirred at room temperature for 1.5 h. The resulting mixture was concentrated under vacuum to afford 7-bromo-6-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine] (180 mg, crude) as a yellow solid.

[0831] LC / MS: mass calcd. for C11H15BrN4: 282.05, found: 283.10 [M+H]+.

[0832] P1 Alt Step 6 Synthesis of (2R)-1-(7-bromo-6-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1 '-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)propan-1 -one (INT 1 h)

[0833] To a solution of 7-bromo-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine] (180 mg, 0.636 mmol, 1 equiv.) in DMF (10 mL) was added (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)propanoic acid (190 mg, 0.954 mmol, 1.5 equiv.), NMI (156 mg, 1.908 mmol, 3 equiv.) and TCFH (267 mg, 0.954 mmol, 1.5 equiv.). The reaction was stirred for 1h at rt. The reaction was quenched with water (20 mL), extracted with EA (20 mL x 3). The combined extract was washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by C18 reversed phase column chromatography, eluted with MeCN / H2O (10% - 100%) to afford (2R)-1-(7-bromo-6-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)propan-1-one (130 mg, 44.04%) as a yellow solid.

[0834] LC / MS: mass calcd. for C20H23BrFN5O2: 463.10, found: 464.2 [M+H]+.P1 Alt Step 7 Synthesis of (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-(6-methyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-T-yl)propan-1-one (Compound 1A)

[0835] To a solution of (2R)-1-(7-bromo-6-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-T-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)propan-1-one (130 mg, 0.280 mmol, 1 equiv.) in 1,4-dioxane (5 mL) were added 2-(tributylstannyl)pyrimidine (320 mg, 0.842 mmol, 3 equiv.) and [P(tBu)3] Pd(crotyl)CI (II) (22 mg, 0.056 mmol, 0.2 equiv.) under nitrogen atmosphere. The reaction was stirred for 4 h at 100 °C under a nitrogen atmosphere. The reaction was quenched with water (10 mL) and extracted with EA (10 mL x 3). The combined extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by C18 reversed phase column chromatography, eluted with MeCN / H2O (0-40%) to afford (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[(3R)-6-methyl-7-(pyrimidin-2-yl)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-T-yl]propan-1-one (85 g, 65.3%) as a light yellow solid. 1H NMR (500 MHz, Methanol-d4) 58.82 (dd, J = 5.0, 2.3 Hz, 2H), 7.99 (dd, J = 16.5, 1.6 Hz, 1H), 7.37 - 7.24 (m, 2H), 6.76 (dd, J = 19.5, 4.9 Hz, 1H), 4.23 (dq, J = 42.0, 7.0 Hz, 1H), 3.89 (d, J = 3.3 Hz, 3H), 3.85 - 3.72 (m, 1H), 3.65 - 3.53 (m, 2H), 3.37 (d, J = 12.4 Hz, 1H), 3.24 - 3.14 (m, 1H), 3.05 - 2.99 (m, 1H), 2.50 (d, J = 8.2 Hz, 3H), 2.23 - 2.05 (m, 2H), 1.45 (t, J = 6.7 Hz, 3H).

[0836] LC / MS: mass calcd. for C24H26FN7O2, 463.21 m / z, found 464.20 [M+H]+.

[0837]

[0838] P1 Variant 1 Alt Step 7 Synthesis of Synthesis of (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[(3R)-6-methyl-7-{methyl[2-(morpholin-4-yl)ethyl]amino}-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1 '-yl]propan-1 -one

[0839] To a solution of (2R)-1-[(3R)-7-bromo-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3, 3'-pyrrolidin]-1 '-y l]-2-(3-fluoropy ridin-4-y l)propan-1 -one (100 mg, 0.230 mmol, 1 equiv.) in dioxane (10 mL) was added methyl[2-(morpholin-4-yl)ethyl]amine (49 mg, 0.345 mmol, 1.5 equiv.), EPhos (12 mg, 0.023 mmol, 0.1 equiv.), EPhos Pd G3 (CAS No.: 2940916-90-3) (20 mg, 0.023 mmol, 0.1 equiv.) and Cs2CO3(150 mg, 0.460 mmol, 2 equiv.). The reaction was stirred at 100°C for 4 hours, quenched with H2O (20 mL) and extracted with EA (15 mL x 3). The reaction was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with PE / EA (0-100%) to afford (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[(3R)-6-methyl-7-{methyl[2-(morpholin-4-yl)ethyl]amino}-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-T-yl]propan-1-one (85 mg, 69.96%) as light yellow oil.

[0840] LC / MS: mass calcd. for C27H38FN7O3: 527.07 m / z, found: 528.20 [M+H]+.

[0841]

[0842] P1 Variant 2 Alt Step 7 Synthesis of 1,3-dioxoisoindolin-2-yl bicyclo[1.1.1]pentane-1-carboxylate

[0843] To a solution of bicyclo[1.1.1]pentane-1 -carboxylic acid (300 mg, 2.676 mmol, 1 equiv.) in DCM

[0844] (10 mL) was added DMAP (33 mg, 0.268 mmol, 0.1 equiv.), DIG (338 mg, 2.676 mmol, 1 equiv.) and N-hydroxyphthalimide (436 mg, 2.676 mmol, 1 equiv.). The mixture was stirred at rt for 12h. The reaction was monitored by TLC. The resulting mixture was concentrated under vacuum to yield a crude product which was directly purified by flash chromatography (0-60%PE / EA) to afford 1,3-dioxoisoindol-2-yl bicyclo[1.1.1]pentane-1 -carboxylate (400 mg, 58.12%) as white solid.

[0845] Synthesis of (R)-1-((R)-7-(bicyclo[1.1.1]pentan-1-yl)-6-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)propan-1-one hydrochloride (Example 108)

[0846] A 40 ml_ screwtop glass vial with septum inlet was charged with (2R)-1-[(3R)-7-bromo-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl]-2-(5-fluoro-2-methoxypyridin-4-yl)propan-1-one (76 mg, 0.164 mmol, 1 equiv.), 1, 3-dioxoisoindol-2-yl bicyclo[1.1.1]pentane-1-carboxylate (63 mg, 0.246 mmol, 1.5 equiv.), etidin (HN(MeC=C(CO2Et))2CH2) (83 mg, 0.328 mmol, 2 equiv.), NaHCOs (55 mg, 0.656 mmol, 4 equiv.) and [4,4'-Bis(tert-butyl)-2,2'-bipyridine]nickel dibromide (4 mg, 0.008 mmol, 0.05 equiv.), N, N-dimethylaniline (2 ml_) was added and the

[0847] suspension purged with N2 for 10min. The reaction mixture was sealed and irradiated with a Kessel LED (390nm) at rt for 12h. The resulting mixture was concentrated under vacuum to crude product.

[0848] The residue was purified by Prep-HPLC using a column: XBridge Prep Column: Xselect CSH C18 OBD Column, 30*150 mm, 5pm (eluent: 10% to 40%ACN and Water (0.1% HCI) to give (2R)-1-[(3R)-7-{bicyclo[1.1.1]pentan-1-yl}-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-T-yl]-2-(5-fluoro-2-methoxypyridin-4-yl)propan-1-one hydrochloride (1.5 mg, 1.88%) as a white solid.1H NMR (400 MHz, Methanol-d4) 58.01 (d, J = 12.8 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 6.79-6.71 (m, 1H), 4.28-4.11 (m, 1H), 3.92-3.81 (m, 4H), 3.76-3.50 (m, 3H), 3.45-3.34 (m, 1H), 3.29-3.09 (m, 1H), 2.58 (d, J = 1.5 Hz, 1H), 2.45-2.41 (m, 3H), 2.35-2.08 (m, 8H), 1.50-1.42 (m, 3H).

[0849] LC / MS: mass calcd. for C25H30FN5O2, 451.24 m / z, found 452.25 [M+H]+.

[0850]

[0851] P1 Variant 3 Alt Step 7 Synthesis of (2R)-1-[(3R)-7-(2-cyclopropylethynyl)-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl]-2-(5-fluoro-2-methoxypyridin-4-yl)propan-1-one (Example 41)

[0852] To a stirred mixture of (R)-1-((R)-7-bromo-6-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-T-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)propan-1-one (60 mg, 0.129 mmol, 1 equiv.) and CS2CO3 (126 mg, 0.387 mmol, 3 equiv.) in dioxane (6 mL) were added Pd(dppf)Cl2 (10 mg, 0.013 mmol, 0.1 equiv.) and PPh3(5 mg, 0.019 mmol, 0.15 equiv.) and Cui (3 mg, 0.013 mmol, 0.1 equiv.) and ethynylcyclopropane (9 mg, 0.129 mmol, 1 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90°C for overnight under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched with water (15 mL). The aqueous layer was extracted with EtOAc (3 x 20 mL). The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS19*250mm, 5pm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL / min mL / min; Gradient: 39% B to 64% B In 10min; Wave Length: 254nm nm; RT1(min): 8.77) to afford (2R)-1-[(3R)-7-(2-cyclopropylethynyl)-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-T-yl]-2-(5-fluoro-2-methoxypyridin-4-yl)propan-1-one (6.9 mg, 11.90%) as a white solid.1H NMR (300 MHz, Methanol-d4) 57.99 (dd, J = 8.1, 1.7 Hz, 1H), 6.89-6.52 (m, 2H), 4.25-4.08 (m, 1H), 3.89 (s, 3H), 3.85-3.64 (m, 4H), 3.21-2.81 (m, 2H), 2.30 (d, J = 5.6 Hz, 3H), 2.17-1.99 (m, 2H), 1.54-1.39 (m, 4H), 0.93-0.81 (m, 2H), 0.75-0.64 (m, 2H).19F NMR (282 MHz, MeOD) 5 -147.20.

[0853] LC / MS: mass calcd. For C25H28FN5O2: 449.22, found: 450.25 [M+H]+.

[0854]

[0855] P1 Variant 4 Alt Step 7 Synthesis of (R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((R)-6-methyl-7-(4-methyl-1H-1,2,3-triazol-1 -yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-T-yl)propan-1-one & (R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((S)-6-methyl-7-(4-methyl-1H-1,2,3-triazol-1-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl)propan-1-one & (2R)-2-(5-f luoro-2-methoxypyridin-4-yl)-1 -(6-methyl-7-(4-methyl-2H-1,2,3-triazol-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl)propan-1-one

[0856] To a solution of (2R)-1-{7-bromo-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl}-2-(5-fluoro-2-methoxypyridin-4-yl)propan-1-one (150 mg, 0.323 mmol, 1 equiv.) in 1,4-dioxane (10 mL) was treated with pyrimidin-4-amine (153 mg, 1.615 mmol, 5 equiv.), Ephos (25.91 mg, 0.048 mmol, 0.15 equiv.), Ephos Pd G3 (43 mg, 0.048 mmol, 0.15 equiv.), CS2CO3 (315 mg, 0.969 mmol, 3 equiv.). The reaction was stirred at 100°C for overnight under nitrogen atmosphere. The reaction was quenched with H2O at rt. The aqueous layer was extracted with EA (30 mL x 2). The combined extract was washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by C18 & separated by CHIRAL HPLC using a Column:CHIRALPAK IB 2*25 cm, 5 pm; (eluent: Mobile Phase A: HEX(0.5% 2M NHs-MeOH), Mobile Phase B: IPA) to afford Example 60 (12.2 mg) as an off-white solid.1H NMR (300 MHz, Methanol-d4) δ 7.99 (dd, J = 9.9, 1.7 Hz, 1H), 7.67 (d, J = 1.6 Hz, 1H), 6.84 (d, J = 9.1 Hz, 1H), 6.76 (dd, J = 10.9, 5.0 Hz, 1H), 4.23 (dq, J = 23.5, 6.9 Hz, 1H), 3.89 (d, J = 2.6 Hz, 3H), 3.86 - 3.70 (m, 2H), 3.67 - 3.51 (m, 3H), 3.19 (q, J = 11.2 Hz, 1H), 3.03 (d, J = 2.0 Hz, 1H), 2.39 (d, J = 1.1 Hz, 3H), 2.18 - 2.08 (m, 5H), 1.45 (dd, J = 6.9, 2.7 Hz, 3H).

[0857] LC / MS: mass calcd. for C23H27FN8O2: 466.22, found: 467.20 [M+H]+.

[0858] And Compound 1vA (8.8 mg) as a light pink solid.1H NMR (300 MHz, Methanol-d4) δ 7.99 (dd, J = 9.9, 1.7 Hz, 1H), 7.67 (d, J = 1.6 Hz, 1H), 6.84 (d, J = 9.1 Hz, 1H), 6.76 (dd, J = 10.9, 5.0 Hz, 1H), 4.23 (dq, J = 23.5, 6.9 Hz, 1H), 3.89 (d, J = 2.6 Hz, 3H), 3.86 - 3.70 (m, 2H), 3.67 - 3.51 (m, 2H), 3.32 -3.19 (m, 2H), 3.12 - 3.03 (m, 1H), 2.39 (d, J = 1.1 Hz, 3H), 2.18 - 2.08 (m, 5H), 1.45 (dd, J = 6.9, 2.7 Hz, 3H).

[0859] LC / MS: mass calcd. for C23H27FN8O2: 466.22, found: 467.25 [M+H]+.

[0860]

[0861] P1 Variant Alt Step 8 Synthesis of (3R)-6-methyl-7-(pyrimidin-2-yl)-T-[(2S)-pyrrolidine-2-carbonyl]-2,4-dihydro-1H-spiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidine] (Example 169)

[0862] To a solution of tert-butyl (2S)-2-{[(3R)-6-methyl-7-(py rimidin-2-yl)-2,4-dihydro-1 H-spiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidin]-T-yl] carbonyl} pyrrolidine-1 -carboxylate (90 mg, 0.188 mmol, 1 equiv.) in DCM (10 mL) was added TFA (2 mL). The reaction was stirred at rt for 1h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using a XBridge Prep Shield RP18 OBD Column 30mm x 150 mm x 5 pm column (eluent: 3% to 26% (v / v) ACN and H2O with 10 mmol / L NH4HCO3) to afford (3R)-6-methyl-7-(pyrimidin-2-yl)-1 '-[(2S)-pyrrolid ine-2-carbonyl]-2,4-dihydro-1H-spiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidine] (26.0 mg, 36.51%) as a white solid.1H NMR (400 MHz, Methanol-d4) δ 8.80 (dd, J = 4.9, 0.8 Hz, 2H), 7.41 (d, J = 1.4 Hz, 1H), 7.27(td, J =4.8, 1.1 Hz, 1 H), 3.87(dt, J =10.3, 6.8Hz, 1H), 3.73 - 3.63 (m, 1H), 3.58 (td, J = 9.4, 8.7, 5.3 Hz, 1H), 3.53 - 3.46 (m, 1H), 3.39 - 3.28 (m, 1H), 3.26 (dd, J = 11.1, 8.8 Hz, 1H), 3.07 - 2.99 (m, 1H), 2.99 -2.89 (m, 2H), 2.68 - 2.54 (m, 2H), 2.06 - 1.80 (m, 4H), 1.69 - 1.46 (m, 3H).

[0863] LC / MS: mass calcd. for C20H25N7O: 379.21, found: 380.25 [M+H]+.

[0864]

[0865] Compound 1A Example 25 Example 176P1 SFC separation of Compound 1A Synthesis of (R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((R)-6-methyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl)propan-1-one (Example 25) & (R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((S)-6-methyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-T-yl)propan-1-one (Example 176)

[0866] (2R)-1-(7-bromo-6-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-T-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)propan-1-one (500 mg, 1.07 mmol) was separated by Chiral column (CHIRALPAK IJ 2*25 cm, 5 pm Column (eluent: EtOH, DCM=3: 1(0.1% DEA) to afford (R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((R)-6-methyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3, 3'-pyrrolidin]-1 '-y l)propan-1 -one (261.4 mg, 51.87%) as a light yellow solid.1H NMR (500 MHz, Methanol-d4) 58.82 (dd, J = 4.9, 2.3 Hz, 2H), 7.99 (dd, J = 16.5, 1.6 Hz, 1H), 7.36 - 7.27 (m, 2H), 6.76 (dd, J = 19.5, 4.9 Hz, 1H), 4.23 (dq, J = 42.0, 7.0 Hz, 1H), 3.90 (d, J= 3.3 Hz, 3H), 3.86 - 3.71 (m, 2H), 3.67 - 3.50 (m, 2H), 3.37 (d, J = 12.4 Hz, 1H), 3.25 - 3.13 (m, 1H), 3.08 - 2.97 (m, 1H), 2.50 (d, J = 8.2 Hz, 3H), 2.22 - 2.06 (m, 2H), 1.45 (t, J = 6.7 Hz, 3H). Retention Time: 2.37 min.

[0867] LC / MS: mass calcd. for C24H26FN7O2: 463.21 m / z, found 464.25 [M+H]+.

[0868] And (R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((S)-6-methyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-T-yl)propan-1-one (236.9 mg, 47.00%) as a light yellow solid.1H NMR (500 MHz, Methanol-d4) δ 8.82 (t, J = 5.1 Hz, 2H), 7.96 (dd, J = 42.1, 1.6 Hz, 1H), 7.37 - 7.29 (m, 2H), 6.75 (t, J = 5.1 Hz, 1H), 4.23 (dq, J = 44.5, 6.9 Hz, 1H), 3.97 (m, 1H), 3.89 (d, J = 8.7 Hz, 3H), 3.74 (m, 1H), 3.69 - 3.57 (m, 1H), 3.53 - 3.42 (m, 1H), 3.25 (dd, J = 19.2, 10.8 Hz, 1H), 3.17 - 3.07 (m, 1H), 2.50 (d, J = 9.4 Hz, 3H), 2.23 - 2.00 (m, 2H), 1.46 (dd, J = 18.4, 6.9 Hz, 3H).

[0869] Retention Time: 5.78 min.

[0870] LC / MS: mass calcd. for C24H26FN7O2: 463.21 m / z, found 464.25 [M+H]+.

[0871]

[0872] P1 Variant 1 Step 5 Synthesis of N-[(3R)-T-[(2S)-2-(5-fluoro-2-methoxypyridin-4-yl)propanoyl]-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-7-yl]-2-methoxyacetamide To a solution of (2R)-1-{7-bromo-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-T-yl}-2-(5-fluoro-2-methoxypyridin-4-yl)propan-1-one (150 mg, 0.323 mmol, 1 equiv.) in dioxane (10 mL) was added 2-methoxyacetamide (115 mg, 1.292 mmol, 4 equiv.) and Ephos (17 mg, 0.032 mmol, 0.1 equiv.), Ephos Pd G4 (29 mg, 0.032 mmol, 0.1 equiv.), CS2CO3 (315 mg, 0.969 mmol, 3 equiv.). The reaction was stirred at 100°C. for 1 hours, quenched with water (20 mL) and extracted with EA (20 mL x 3). The combined extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by C18 reversed phase column chromatography, eluted with MeCN / H2O (0% - 100%) to afford N-[(3R)-1'-[(2S)-2-(5-fluoro-2-methoxypyridin-4-yl)propanoyl]-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-7-yl]-2-methoxyacetamide (100 mg crude) as yellow oil.

[0873] LC / MS: mass calcd. for C23H29FN6O4: 472.22, found: 473.25 [M+H]+.

[0874] T jf t-BuXPhos, t-BuXPhos Pd G3 N>V / N-BOCKOTBU DIOXANE 100°C

[0875]

[0876] n — ' P1 Variant 2 Step 5 Synthesis of tert-butyl (3R)-7-(2-methoxyethoxy)-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate

[0877] To a solution of tert-butyl (3R)-7-bromo-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (200 mg, 0.522 mmol, 1 equiv.) in dioxane (10 ml_ ) was added 2-methoxyethanol (59 mg, 0.783 mmol, 1.5 equiv.), t-BuXphos (44 mg, 0.104 mmol, 0.2 equiv.) and t-BuOK (117 mg, 1.044 mmol, 2 equiv.) under N2. The reaction was stirred at 100°C for 2 hours under N2, quenched with H2O (15 mL) and extracted with EA (15 mLx 3). The reaction was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with PE / EA (0-100%) to afford tert-butyl (3R)-7-(2-methoxyethoxy)-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (128 mg, 64.81%) as yellow oil.

[0878] LC / MS: mass calcd. for C19H30N4O4: 378.41 m / z, found: 379.20 [M+H]+.

[0879]

[0880] P1 Variant 3 Step 5 Synthesis of tert-butyl-6-methyl-7-(3-methyl-1,2,4-triazol-1-yl)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate

[0881] To a solution of Tert-butyl-7-bromo-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (500 mg, 1.304 mmol, 1 equiv.) in dioxane (10 mL) was added 3-methyl-1H-1,2,4-triazole (162 mg, 1.956 mmol, 1.5 equiv.), K2CO3 (360 mg, 2.608 mmol, 2 equiv.), t-BuBrettphos Pd G3 (111 mg, 0.130 mmol, 0.1 equiv.) and t-BuBrettPhos (63.23 mg, 0.130 mmol, 0.1 equiv.). The reaction was stirred at 90 °C for 16 hours under N2, quenched with water (10 mL) and extracted with EA (10 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure to provide the crude product, which was purified by column chromatography on silica gel with EA / PE (0-100%) to give tert-butyl-6-methyl-7-(3-methyl-1,2,4-triazol-1-yl)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (120 mg, 23.86%) as a white solid.

[0882] LC / MS: mass calcd. For C19H27N7O2: 385.22 m / z, found:386.20 [M+H]+H N

[0883] t-BuXPhos, t-BuXPhos Pd G3 N— Boc

[0884]

[0885] KOtBu, dioxane / MeOH, 100°C P1 Variant 4 Step 5 Synthesis of tert-butyl (3R)-7-methoxy-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1 '-carboxylate

[0886] To a solution of tert-butyl (3R)-7-bromo-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (300 mg, 0.783 mmol, 1 equiv.) in dioxane / MeOH (5 mL / 5 mL) was added t-BuOK (175 mg, 1.566 mmol, 2 equiv.), t-BuXPhos (33 mg, 0.078 mmol, 0.1 equiv.) and t-BuXPhos Pd G3 (62 mg, 0.078 mmol, 0.1 equiv.) under N2. The reaction was stirred at 100°C for 2 hours under N2, quenched with H2O (10 mL) and extracted with EA (10 mL x 3). The reaction was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with PE / EA (0-100%) to afford tert-butyl (3R)-7-methoxy-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (120 mg, 45.85) as yellow oil.

[0887] LC / MS: mass calcd. for C17H26N4O3: 333.37 m / z, found: 334.42 [M+H]+.

[0888]

[0889] P1 Variant 5 Step 5 Synthesis of tert-butyl (3R)-7-cyano-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-r-carboxylate

[0890] To a stirred solution / mixture of tert-butyl (3R)-7-bromo-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (300 mg, 0.783 mmol, 1 equiv.) and zinc cyanide (92 mg, 0.783 mmol, 1 equiv.) in DMF (5 mL) was added Pd(PPh3)4 (181 mg, 0.157 mmol, 0.2 equiv.) at room temperature under nitrogen atmosphere. The final reaction mixture was irradiated with microwave radiation at 170°C for 2min. The mixture was allowed to cool down to room temperature. The reaction was quenched with water (15 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 x 30 mL). The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl (3R)-7-cyano-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (150 mg, 58.18%) as a white solid.

[0891] LC / MS: mass calcd. for C17H23N5O2: 329.18, found: 330.10 [M+H]+.F

[0892] Et3N, DCM, rt

[0893]

[0894] P1 Variant 1 Step 7 Synthesis of (R)-1'-((3,5-difluorobenzyl)sulfonyl)-6-methyl-7-(pyrimidin-2- yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine] (Example 188)

[0895] To a solution of (3S)-6-methyl-7-(pyrimidin-2-yl)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine- 3, 3'-pyrrolidine] (100 mg, 0.354 mmol, 1 equiv.) in DCM (5 mL) were added EtsN (53 mg, 0.531 mmol, 1.5 equiv.) and (3,5-difluorophenyl)methanesulfonyl chloride (120 mg, 0.531 mmol, 1.5 equiv.). The reaction was stirred for 1h at rt. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC using XBridge Prep Shield RP18 OBD Column, (eluent: 28% B to 53% (V / V), water and MeCN with 10 mmol / L NH4HCO3) to afford (R)-1'-((3,5- difluorobenzyl)sulfonyl)-6-methyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'- pyrrolidine] (7 mg, 4.18%) as a white solid.1H NMR (400 MHz, Methanol-d4) δ 8.83 (d, J = 4.9 Hz, 2H), 7.33 (d, J = 9.9 Hz, OH), 7.28-7.21 (m, 2H), 7.01 (tt, J = 9.1, 2.4 Hz, 1H), 4.48 (s, 2H), 3.63-3.57 (m, 1H), 3.54-3.42 (m, 2H), 3.28-3.19 (m, 2H), 3.12 (d, J = 11.1 Hz, 1H), 2.51 (s, 3H), 2.18 -2.10 (m, 1H), 2.13 - 2.03 (m, 1H).

[0896] LC / MS: mass calcd. for C22H22F2N6O2, 472.15 m / z, found 473.00 [M+H]+.

[0897]

[0898] Example 169

[0899] P1 Variant 2 Step 7 Synthesis of cyclohexyl (3R)-6-methyl-7-(pyrimidin-2-yl)-2,4-dihydro-1H- spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-r-carboxylate (Example 169)

[0900] To a solution of (3S)-6-methyl-7-(pyrimidin-2-yl)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine- 3, 3'-pyrrolidine] (100 mg, 0.354 mmol, 1 equiv.) in DCM (15 ml_) was added TEA (107 mg, 1.062 mmol, 3 equiv.) and cyclohexyl carbonochloridate (63 mg, 0.389 mmol, 1.1 equiv.) at rt. The reaction was stirred for 1h at rt. The reaction was quenched with water (30 ml_), extracted with EA (3 x 30 ml_). The combined organic layer was washed with brine (3x50 ml_). The resulting mixture was concentrated under vacuum. The residue was purified by preparative HPLC using a XSelect CSH Prep C18 OBD Column, 19*250 mm, 5μm Column (eluent: 28% B to 53% (V / V), water and MeCN with 10 mmol / L NH4HCO3) to afford cyclohexyl (3R)-6-methyl-7-(pyrimidin-2-yl)-2,4-dihydro-1H- spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (24.6 mg, 17.00%) as a yellow solid.1H NMR (300 MHz, Methanol-d4) δ 8.83 (d, J = 4.9 Hz, 2H), 7.36 - 7.30 (m, 2H), 4.72 - 4.56 (m, 1H),3.76 - 3.44 (m, 3H), 3.33 - 3.27 (m, 1 H), 3.26 - 3.09 (m, 2H), 2.51 (s, 3H), 2.14 - 2.08 (m, 2H), 1.81 (d, J = 33.9 Hz, 4H), 1.63 - 1.25 (m, 6H).

[0901] LC / MS: mass calcd. for C22H28N6O2: 408.23, found: 409.20 [M+H]+.

[0902] Synthesis Procedure 2 (P2)

[0903]

[0904] P2 Step 1 Synthesis of tert-butyl 6-methyl-2-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1 '-carboxylate (INT -4a)

[0905] To a solution of tert-butyl 7-bromo-6-methyl-2-oxo-1,4-dihydrospiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (230 mg, 0.579 mmol, 1 equiv.) and bis(pinacolato)diboron (441.05 mg, 1.737 mmol, 3 equiv.) in 1,4-dioxane (10 ml_) were added CH3COOK (170 mg, 1.737 mmol, 3 equiv.) and Pd(dppf)Cl2 (42 mg, 0.058 mmol, 0.1 equiv.). After stirring for 10 h at 90 °C under a nitrogen atmosphere. The reaction was quenched with water (10 ml_), extracted with EA (20 mLx 3). The combined extract was washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by C18 reversed phase column chromatography, eluted with MeCN / H2O (10% - 100%) to afford tert-butyl 6-methyl-2-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydrospiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (200 mg, 77.75%) as a yellow solid.

[0906] LC / MS: mass calcd. for C22H33BN4O5: 444.25, found: 445.30 [M+H]+.

[0907] P2 Step 2 Synthesis of tert-butyl 6-methyl-2-oxo-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (INT-4b)

[0908] To a solution of tert-butyl 6-methyl-2-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydrospiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (180 mg, 0.405 mmol, 1 equiv.) and 2-bromopyrimidine (322 mg, 2.025 mmol, 5 equiv.) in 1,4-dioxane (10 ml_) were added Na2COs (128 mg, 1.215 mmol, 3 equiv.) and Pd(dppf)Cl2 (59 mg, 0.081 mmol, 0.2 equiv.). After stirring for 10 h at100 °C under a nitrogen atmosphere. The reaction was quenched with water (10 mL), extracted with EA (20 ml_ x 3). The combined extract was washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by C18 reversed phase column chromatography, eluted with MeCN / H2O (10% - 100%) to afford tert-butyl -6-methyl-2-oxo-7-(pyrimidin-2-yl)-1,4-dihydrospiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (50 mg, 31.13%) as a brown solid.

[0909] LC / MS: mass calcd. for C20H24N6O3: 396.19, found: 397.20 [M+H]+.

[0910] P2 Step 3 Synthesis of 6-methyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-2-one TFA salt (INT-4c)

[0911] To a solution of tert-butyl -6-methyl-2-oxo-7-(pyrimidin-2-yl)-1,4-dihydrospiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (50 mg, 0.126 mmol, 1 equiv.) in DCM (5 mL) was added TFA (143 mg, 1.260 mmol, 10 equiv.). The reaction was stirred for 1h at rt. The resulting mixture was concentrated under vacuum to afford (S)-6-methy l-7-( pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-2-one TFA salt (50 mg, crude) as brown solid.

[0912] LC / MS: mass calcd. for C15H16N6O: 296.14, found: 297.25 [M+H]+.

[0913] P2 Step 4 Synthesis of 1'-((R)-2-(5-fluoro-2-methoxypyridin-4-yl)propanoyl)-6-methyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-2-one (Example 58) To a solution of (S)-6-methyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-2-one TFA salt (50 mg, 0.169 mmol, 1 equiv.) in DMF (10 mL) was added (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)propanoic acid (50 mg, 0.254 mmol, 1.5 equiv.), EDCI (48 mg, 0.254 mmol, 1.5 equiv.), DMAP (82 mg, 0.676 mmol, 4 equiv.). The reaction was stirred for 1h at rt. The reaction was quenched with water (10 mL), extracted with EA (10 mL x 3). The combined extract was washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC using a XSelect CSH C18 Column, 19*150mm, 5μm Column (eluent:

[0914] 44% B to 69% (V / V), water(10 mmol / L NH4HCO3) and MeCN) to afford 1'-((R)-2-(5-fluoro-2-methoxypyridin-4-yl)propanoyl)-6-methyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-2-one (13.7 mg, 23.0%) as a white solid.1H NMR (500 MHz, Methanol-d4) δ 8.89 – 8.81(m, 2H), 8.02 - 7.93 (m, 1H), 7.68 - 7.59 (m, 1H), 7.41 - 7.31 (m, 1H), 6.83 -6.71 (m, 1H), 4.33 - 4.10 (m, 2H), 3.90 (d, J = 4.5Hz, 4H), 3.82 - 3.61 (m, 2H), 3.55 - 3.39 (m, 1H), 2.65 - 2.55 (m, 3H), 2.55 - 2.37 (m, 1H), 2.13 (m, 1H), 1.47 - 1.42 (m, 3H).

[0915] LC / MS: mass calcd. for C24H24FN7O3: 477.19, found: 478.20 [M+H]+

[0916] Synthesis Procedure 3 (P3)

[0917]

[0918] P3 Step 1 Synthesis of 7-bromo-N,6-dimethyl-N-(4-(trifluoromethyl)phenyl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1 '-carboxamide (INT-3a)

[0919] To a solution of N-methyl-4-(trifluoromethyl)aniline (204 mg, 1.165 mmol, 1.1 equiv.) in DCE (5 mL) was added Triphosgene (26 mg, 0.088 mmol, 0.5 equiv.) and TEA (321 mg, 3.177 mmol, 3 equiv.) at 0°C. The mixture was stirred for 1 h at 60°C. 7-bromo-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine] (300 mg, 1.059 mmol, 1 equiv.) was added into the mixture at rt. The mixture was stirred for 2 h at rt. The reaction was quenched with water (30 mL) extracted with DCM (3 x 20 mL). The residue was washed with water (3 x 20 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-10% DCM / MeOH) to afford 7-bromo-N,6-dimethyl-N-[4-(trifluoromethyl)phenyl]-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxamide (430 mg, 83.80%).

[0920] LC / MS: mass calcd. for C20H21BrF3N5O: 483.25 m / z, found 484.00 [M+H]+.

[0921] P3 Step 2 Synthesis of (6-methyl-1'-(methyl(4-(trifluoromethyl)phenyl)carbamoyl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-7-yl)boronic acid (INT-3b)

[0922] A solution of 7-bromo-N,6-dimethyl-N-[4-(trifluoromethyl)phenyl]-2,4-dihydro-1 H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]- T-carboxamide (400 mg, 0.826 mmol, 1 equiv.) in dioxane (15 mL) was added Pd(dppf)Cl2 (30 mg, 0.041 mmol, 0.05 equiv.), bis(pinacolato)diboron (251 mg, 0.991 mmol, 1.2 equiv.) and KOAc (242 mg, 2.478 mmol, 3 equiv.) at rt. The mixture was stirred for 4h at 100°C under N2. The mixture was used in the next step directly without further purification.

[0923] LC / MS: mass calcd. For C20H23BF3N5O3: 449.25 m / z, found 450.10 [M+H]+.

[0924] P3 Step 3 Synthesis of N,6-dimethyl-7-(2-methyl-2H-tetrazol-5-yl)-N-(4-(trifluoromethyl)phenyl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1 '-carboxamide (Compound 3A) Add K2CO3 (344 mg, 2.478 mmol, 3 equiv.), Pd(dppf)Cl2 (60 mg, 0.082 mmol, 0.1 equiv.), 5-bromo-2-methyl-2H-tetrazole (134 mg, 0.826 mmol, 1 equiv.) and H2O (2 mL) to the previous reaction solvent at room temperature. The mixture was stirred for 3h at 90°C under N2. After completion of reaction the mixture was cooled to room temperature then quenched with water (10 mL) extracted with ethyl acetate (3 x 10 mL). The combined organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-10% DCM / MeOH) to afford N,6-dimethyl-7-(2-methyl-1,2,3,4-tetrazol-5-yl)-N-[4-(trifluoromethyl)phenyl]-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxamide (140 mg, 34.8%).Compound 3A Example 151 (diastereomer 1)

[0925]

[0926] Example 191 (diastereomers) 191)

[0927] N,6-dimethyl-7-(2-methyl-2H-tetrazol-5-yl)-N-(4-(trifluoromethyl)phenyl)-1,4-dihydro-2H- spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxamide was separated by Chiral-Prep-HPLC (CHIRALPAK OD 2*25 cm, 5 pm; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: EtOH; Gradient (B%): isocratic 50) to afford Example 151 (43.8 mg).1H NMR (300 MHz, Methanol-d4) 57.76-7.67 (m, 3H), 7.39 (d, J = 8.3 Hz, 2H), 4.44 (s, 3H), 3.52-3.36 (m, 3H), 3.29 (s, 3H), 3.26-3.11 (m, 3H), 2.75 (s, 3H), 2.21-2.00 (m, 2H). Retention Time: 1.220 min.

[0928] LC / MS: mass calcd. For C22H24F3N9O: 487.10 m / z, found: 488.25 [M+H]+.

[0929] And Example 191 (41.1 mg).1H NMR (300 MHz, Methanol-d4) 57.76-7.67 (m, 3H), 7.39 (d, J = 8.3 Hz, 2H), 4.44 (s, 3H), 3.52-3.36 (m, 3H), 3.29 (s, 3H), 3.26-3.11 (m, 3H), 2.75 (s, 3H), 2.21-2.00 (m, 2H). Retention Time: 1.688 min.

[0930] LC / MS: mass calcd. For C22H24F3N9O: 487.10 m / z, found: 488.25 [M+H]+.

[0931]

[0932] P3 Alt Prelim Step 1 Synthesis of 5-fluoro-N-isopropyl-2-methoxypyridin-4-amine

[0933] To a mixture of 5-fluoro-2-methoxypyridin-4-amine (300 mg, 2.111 mmol, 1 equiv.) in DMF (10 ml_) under nitrogen atmosphere. And added 60% NaH (169 mg, 4.222 mmol, 2 equiv.) at 0°C. The reaction was stirred at 0°C for 30 min. To this was added 2-iodopropane (717 mg, 4.222 mmol, 2 equiv.) to the mixture at 0°C. The reaction was stirred at rt for 2h. The residue was poured into saturated ammonium chloride solution (20 ml_). The aqueous phase was extracted with EA (2 x 80 ml_). The combined organic phases were washed with brine (3 x 30 ml_), dried over anhydrous sodium sulphate, filtered and concentrated. The crude product which was directly purified by flash chromatography (0-50% EA / PE) to afford 5-fluoro-N-isopropyl-2-methoxypyridin-4-amine (290 mg, 74.58%) as colorless oil.

[0934]

[0935] P3 Alt Prelim Step 2 Synthesis of N-ethyl-5-fluoro-2-methoxypyridin-4-amine

[0936] To a stirred solution of 5-fluoro-2-methoxypyridin-4-amine (500 mg, 3.518 mmol, 1 equiv.) in anhydrous DMF (5 mL) was added acetaldehyde (310 mg, 7.036 mmol, 2 equiv.) and AcOH (634 mg,10.554 mmol, 3 equiv.) followed by NaBH3CN (442 mg, 7.036 mmol, 2 equiv.) at 0°C. The reaction mixture was stirred at room temperature for a period of overnight. After completion of reaction, the reaction mixture was quenched by water (20 ml_) and extracted with EA (50 ml_ x 3). The combined organic phase was washed with brine (100 ml_), dried over anhydrous sodium sulfate. The mixture was concentrated to dryness under reduced pressure to provide the crude product, which was purified by silica gel chromatography (0-100% PE / EA) to afford N-ethyl-5-fluoro-2-methoxypyridin-4-amine (200 mg, 33.4%y ield) as a yellow oil.

[0937] LC / MS: mass calcd. for C8H11FN2O: 170.09 m / z, found 171.00 [M+H]+.

[0938]

[0939] P3 Alt Step 2 / 3 Synthesis of (R)-N,6-dimethyl-N-(4-(trifluoromethyl)phenyl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxamide & (S)-N,6-dimethyl-N-(4-(trifluoromethyl)phenyl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxamide (Examples 104 and S-isomer)

[0940] To a solution of 7-bromo-N,6-dimethyl-N-[4-(trifluoromethyl)phenyl]-2,4-dihydro-1 H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxamide (150 mg, 0.310 mmol, 1 equiv.) in MeOH (10 ml_) was added Pd / C (165 mg) under nitrogen atmosphere in a 50mL round-bottom flask. The mixture was hydrogenated at room temperature for 2h under hydrogen atmosphere using a hydrogen balloon, filtered through a Celite pad and concentrated under reduced pressure. The residue was separated by Chiral-HPLC using a CHIRALPAK IK 25 cm x 2 cm x 5 pm column (eluent: 0.5% 2M NHs-MeOH and EtOH Gradient (B%): isocratic 30) to afford Example 104 (19.4 mg) as a white solid.1H NMR (400 MHz, DMSO-cfe) 57.65 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.3 Hz, 2H), 6.53 (d, J = 7.4 Hz, 2H), 6.19 (d, J = 7.5 Hz, 1H), 5.49 (s, 1H), 3.38-3.34 (m, 1H), 3.24 (d, J = 10.0 Hz, 1H), 3.15 (s, 4H), 2.92-2.81 (m, 3H), 2.11 (s, 3H), 1.81 (d, J= 8.1 Hz, 2H). Retention Time: 2.266 min.

[0941] LC / MS: mass calcd. for C20H22F3N5O: 405.18 m / z, found 406.20 [M+H]+.

[0942] And Example 185 (17.0 mg) as a white solid.1H NMR (400 MHz, DMSO-cfe) 57.65 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.3 Hz, 2H), 6.53 (d, J = 7.4 Hz, 2H), 6.19 (d, J = 7.5 Hz, 1H), 5.49 (s, 1H), 3.38-3.34 (m, 1H), 3.24 (d, J = 10.0 Hz, 1H), 3.15 (s, 4H), 2.92-2.81 (m, 3H), 2.11 (s, 3H), 1.82 (d, J = 8.1 Hz, 2H). Retention Time: 2.931 min.

[0943] LC / MS: mass calcd. for C20H22F3N5O: 405.18 m / z, found 406.15 [M+H]+.Synthesis Procedure 4 (P4)

[0944]

[0945] P4 Step 1 Synthesis of 2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyacetic acid (INT-4a)

[0946] To a stirred solution / mixture of 5-fluoro-2-methoxypyridine-4-carbaldehyde (5 g, 32.231 mmol, 1 equiv.) and KOH (9.95 g, 177.270 mmol, 5.5 equiv.) in MeOH (50 mL) was added tribromomethane (9.78 g, 38.677 mmol, 1.2 equiv.) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for overnight under nitrogen atmosphere. The reaction was quenched with ice water (50 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure to remove MeOH. The residue was dissolved in water (50 mL), extracted with EtOAc (3 x 50 mL). The aqueous phase was acidified to pH 7 with HCI (1 N aq.). The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 column to afford (5-fluoro-2-methoxypyridin-4-yl)(methoxy)acetic acid (3.1 g, 44.70%) as a light yellow solid.

[0947] LC / MS: mass calcd. For C9H10FNO4: 215.05 m / z, found: 216.30 [M+H]+.

[0948] P4 Step 2 Synthesis of methyl 2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyacetate (INT-4b) To a solution of 2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyacetic acid (1 g, 4.65 mmol, 1.0 eq) in MeOH (20 mL) was added SOCI2 (5 mL) at 0 oC. The mixture was stirred for 3 h at 60 °C. The raction was cooled to rt, quchend with NaHCOs aq. Then mixture was extracted by extracted with EA (50 ml_ x 3). The combined extracts were washed with NaHCOs aq, brine, dried over anhydrous Na2SO4, filtered and concentrated to give methyl 2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyacetate (730 mg, 68.2%).

[0949] LC / MS: mass calcd. For C10H12FNO4: 229.21 m / z, found: 230.35 [M+H]+.

[0950] P4 Step 3 SFC Separation of INT-4b Synthesis of methyl (S)-2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyacetate (INT-4c) & methyl (R)-2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyacetate (INT-4d)

[0951] 2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyacetic acid (700 mg) was separated by CHIRAL HPLC using a IG 5 Column (eluent: MeOH / METB) to afford methyl (S)-2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyacetate (280 mg, 40%, irst enantiomer to elute, single known Stereoisomer S, 2.6 min) as a white solid & methyl (R)-2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyacetate (280 mg. 40%, second enantiomer to elute, single known Stereoisomer R, 3.8 min) as a white solid.

[0952] LC / MS: mass calcd. For C10H12FNO4: 229.21 m / z, found: 230.35 [M+H]+.P4 Step 4 Synthesis of (R)-2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyacetic acid (INT-4e) To a solution of methyl (R)-2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyacetate (INT-4d) (280 mg, 1.22 mmol, 1.0 eq) in PBS (PH = 7.0) / DMSO (5 ml_ / 0.5 mL) was added NovoCor AD L enzyme (280 mg). The reaction was stirred overnight at rt. The reaction was acidified with 1N HCI to PH = 5. Then mixture was extracted by extracted with EA (50 ml_ x 3). The combined extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to give (R)-2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyacetic acid 250 mg (95%).

[0953] LC / MS: mass calcd. For C9H10FNO4: 215.18 m / z, found: 216.25 [M+H]+.

[0954] Synthesis Procedure 5 (P5)

[0955] Commercially available

[0956]

[0957] P5 Step 1 Synthesis of tert-butyl 2-(2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)propanoate (INT-5a)

[0958] To a stirred solution of tert-butyl 2-bromopropanoate (1.00 g, 4.803 mmol, 1 equiv.) in DMF (40 mL) was added tert-butyl 2-bromopropanoate (1.00 g, 4.803 mmol, 1 equiv.) and K2CO3 (1.99 g, 14.407 mmol, 3 equiv.). The resulting mixture was stirred at rt for 1h, quenched with water (20 mL) and extracted with EA (20 ml_ x 3). The combined extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by C18 reversed phase column chromatography, eluted with MeCN / H2O (10% - 100%) to afford tert-butyl 2-[2-oxo-4-(trifluoromethyl) pyridin-1-yl] propanoate (1.05 g, 75.06%) as a white solid.

[0959] LC / MS: mass calcd. for C13H16F3NO3: 291.11, found: 236.00 [M-(Bu+H]+.

[0960] P5 Step 2 Synthesis of 2-(2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)propanoic acid (INT-5b)

[0961] To a stirred solution of tert-butyl 2-[2-oxo-4-(trifluoromethyl) pyridin-1-yl] propanoate (100 mg, 0.343 mmol, 1 equiv.) in DCM (10 mL) was added TFA (2 mL). The resulting mixture was stirred at rt for 1h. The resulting mixture was concentrated under reduced pressure. This resulted in 2-[2-oxo-4-(trifluoromethyl) pyridin-1-yl] propanoic acid (130 mg crude) as yellow oil.

[0962] LC / MS: mass calcd. for C9H8F3NO3: 235.05, found: 236.00 [M+H]+.Synthesis Procedure 6 (P6)

[0963] Commercially available INT-6a INT-6b INT-6c

[0964]

[0965] [135325-18-7] P6 Step 1 Synthesis of methyl 2-diazo-2-(4-(trifluoromethyl)phenyl)acetate (INT-6a)

[0966] To a solution of methyl 2-[4-(trifluoromethyl) phenyl] acetate (1 g, 4.583 mmol, 1 equiv.) in ACN (15 mL) was treated with 4-acetamidobenzenesulfonyl azide (1.32 g, 5.500 mmol, 1.2 equiv.) and DBU (1.05 g, 6.875 mmol, 1.5 equiv.) at rt. overnight under nitrogen atmosphere. Desired product could be detected by LCMS. The reaction was quenched by the addition of water (5 mL). The resulting mixture was extracted with EA (10 mL x 3). After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel, eluted with EA / PE (0-60%) to afford methyl 2-diazo-2-[4-(trifluoromethyl) phenyl] acetate (1.1 g, 98.29%) as a white solid.

[0967] LC / MS: mass calcd. for C10H7F3N2O2, 244.05 m / z, found 245.05 [M+H]+.

[0968] P6 Step 2 Synthesis of methyl 2-isopropoxy-2-(4-(trifluoromethyl)phenyl)acetate (INT-6b)

[0969] To a solution of methyl 2-diazo-2-[4-(trifluoromethyl) phenyl] acetate (1.1 g, 4.505 mmol, 1 equiv.) in toluene (15 mL) was treated with isopropyl alcohol (0.30 g, 4.956 mmol, 1.1 equiv.) and bis((acetyloxy)rhodio acetate) (0.01 g, 0.023 mmol, 0.005 equiv.) at 80°C overnight under nitrogen atmosphere. Desired product could be detected by LCMS. The reaction was quenched by the addition of water (5 mL). The resulting mixture was extracted with EA (10 mL x 3). After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel, eluted with EA / PE (0-60%) to afford methyl 2-isopropoxy-2-[4-(trifluoromethyl) phenyl] acetate (600 mg, 48.21%) as a white solid.

[0970] LC / MS: mass calcd. for C13H15F3O3, 276.10 m / z, found 277.10 [M+H]+.

[0971] P6 Step 3 Synthesis of 2-isopropoxy-2-(4-(trifluoromethyl)phenyl)acetic acid (INT-6c)

[0972] To a solution of methyl 2-isopropoxy-2-[4-(trifluoromethyl) phenyl] acetate (600 mg, 2.172 mmol, 1 equiv.) in MeOH (15 mL), H2O (5 mL) and THF (5 mL) was added LiOH (520 mg, 21.720 mmol, 10 equiv.). The reaction was stirred at rt for 1h. Desired product could be detected by LCMS. The reaction was adjusted PH = 5 with 1N HCI. The resulting mixture was extracted with EA (15 mL x 3). After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was used in the next step directly without further purification.

[0973] LC / MS: mass calcd. for C12H13F3O3, 262.08 m / z, found 263.10 [M+H]+.Synthesis Procedure 7 (P7)

[0974]

[0975] P7 Step 1 Synthesis of diethyl 2-(5-fluoro-2-methoxypyridin-4-yl)malonate (INT-7b)

[0976] To a stirred solution of 5-fluoro-4-iodo-2-methoxypyridine (15 g, 59.285 mmol, 1 equiv.) in anhydrous DMSO (300 mL) was added diethyl malonate (11.39 g, 71.142 mmol, 1.2 equiv.), Cs2CO3 (28.97 g, 88.927 mmol, 1.5 equiv.). The reaction was stirred at 100°C for 6h. The reaction progress was monitored by TLC. After completion of reaction, the reaction mixture was cooled to rt, diluted with EtOAc (1 L), washed with water (5 x 300 mL), brine (2 x 200 mL). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give crude product which was further purified by column chromatography using 0% to 40% EA in PE gradient to afford desired compound 1,3-diethyl 2-(5-fluoro-2-methoxypyridin-4-yl)propanedioate (4.5 g, 26.61%) as colorless oil.

[0977] P7 Step 2 Synthesis of ethyl 2-(5-fluoro-2-methoxypyridin-4-yl)acetate (INT-7c)

[0978] To a stirred solution of 1,3-diethyl 2-(5-fluoro-2-methoxypyridin-4-yl)propanedioate (3.4 g, 11.918 mmol, 1 equiv.) in anhydrous DMSO (30 mL) and H2O (3 mL) was added lithium chloride (2.02 g, 47.672 mmol, 4 equiv.). The reaction was stirred at 100°C overnight. The reaction progress was monitored by TLC. After completion of reaction, the reaction mixture was cooled to rt, diluted with EtOAc (200 mL), washed with water (5 x 50 mL), brine (2 x 20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude product which was further purified by column chromatography using 0% to 40% EA in PE gradient to afford desired compound ethyl 2-(5-fluoro-2-methoxypyridin-4-yl)acetate (2 g, 78.71%) as colorless oil.

[0979] P7 Step 3 Synthesis of ethyl 2-diazo-2-(5-fluoro-2-methoxypyridin-4-yl)acetate (INT-7d)

[0980] To a stirred solution of ethyl 2-(5-fluoro-2-methoxypyridin-4-yl)acetate (2.2 g, 10.319 mmol, 1 equiv.) in anhydrous MeCN (40 mL) was added 4-acetamidobenzenesulfonyl azide (3.22 g, 13.415 mmol, 1.3 equiv.), DBU (2.04 g, 13.415 mmol, 1.3 equiv.) at rt and stirred for 24 h at rt. The reaction progress was monitored by TLC. After completion of reaction, it was quenched with water (50 mL), extracted with EtOAc (3 x 100 mL), the organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give crude product which was further purified by column chromatography using 0% to 40% EA in PE gradient to afford desired compound ethyl 2-diazo-2-(5-fluoro-2-methoxypyridin-4-yl)acetate (2.0 g, 81.03%) as light yellow oil.P7 Step 4 Synthesis of ethyl 2-(2-bromoethoxy)-2-(5-fluoro-2-methoxypyridin-4-yl)acetate (INT-7e)

[0981] With an inert atmosphere of nitrogen, to a stirred solution of ethyl 2-diazo-2-(5-fluoro-2-methoxypyridin-4-yl)acetate (1.2 g, 5.017 mmol, 1 equiv.) in anhydrous benzene (30 mL) was added 2-bromoethanol (0.75 g, 6.020 mmol, 1.2 equiv.), bis((acetyloxy)rhodio acetate) (110 mg, 0.251 mmol, 0.05 equiv.). The reaction was stirred at 80°C for 1h. The reaction progress was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure to give crude product which was further purified by column chromatography using 0% to 40% EA in PE gradient to afford desired compound ethyl 2-(2-bromoethoxy)-2-(5-fluoro-2-methoxypyridin-4-yl)acetate (480 mg, 28.46%) as light yellow oil.

[0982] P7 Step 5 Synthesis of ethyl 2-(5-fluoro-2-methoxypyridin-4-yl)oxetane-2 -carboxylate (INT-7f) With an inert atmosphere of nitrogen, to a stirred solution of ethyl 2-(2-bromoethoxy)-2-(5-fluoro-2-methoxypyridin-4-yl)acetate (500 mg, 1.487 mmol, 1 equiv.) in anhydrous THF (20 mL) was added LiHMDS (10 mL, 1.4 equiv., 1M / L) dropwise at rt and stirred for overnight at rt, The reaction progress was monitored by TLC. After completion of reaction, the reaction mixture was quenched with ice / water (30 mL), extracted with EtOAc (3 x 30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude product which was further purified by column chromatography using 0% to 40% EA in PE gradient to afford desired compound ethyl 2-(5-fluoro-2-methoxypyridin-4-yl)oxetane-2-carboxylate (350 mg, 92.19%) as light yellow solid.

[0983] P7 Step 6 Synthesis of 2-(5-fluoro-2-methoxypyridin-4-yl)oxetane-2-carboxylic acid (INT-7g) To a stirred solution of ethyl 2-(5-fluoro-2-methoxypyridin-4-yl)oxetane-2-carboxylate (350 mg, 1.371 mmol, 1 equiv.) in anhydrous methanol (10 mL) and H2O (2 mL) was added LiOH (164 mg, 6.855 mmol, 5 equiv.) at rt and stirred for 1h at rt. The reaction progress was monitored by TLC. After completion of reaction, it was diluted with water (10 mL), the pH was adjusted to 4 with 1N HCI.

[0984] Extracted with EtOAc (3 x 30 mL), dried over Na2SO4, filtered and concentrated under vacuum, to afford 2-(5-fluoro-2-methoxypyridin-4-yl)oxetane-2-carboxylic acid (200 mg) as white oil.

[0985] Synthesis Procedure 8 (P8)

[0986]

[0987] INT-8a INT-8b INT-8c P8 Step 1 Synthesis of ethyl 3-(4-(trifluoromethyl)phenyl)tetrahydrofuran-3-carboxylate (INT-8b)

[0988] To a stirred solution of ethyl 2-[4-(trifluoromethyl)phenyl]acetate (600 mg, 2.584 mmol, 1 equiv.) in anhydrous DMF (40 mL) was added NaH (258 mg, 6.460 mmol, 2.5 equiv., 60%) in portions at 0°C and stirred for 15 min at 0°C. After which 1-chloro-2-(chloromethoxy)ethane (333 mg, 2.584mmol, 1 equiv.) was added to the mixture at 0°C and stirred for 1 h at 0°C. It was quenched with ice / water (30 ml_). The aqueous layer was extracted with EA (3 x 50 ml_). The combined organic phase was washed with brine (2 x 20 ml_), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude product which was further purified by column chromatography using PE / EA: 1 / 1, gradient to afford desired compound ethyl 3-[4-(trifluoromethyl)phenyl]oxolane-3-carboxylate (400 mg, 53.70 %) as a white solid.

[0989] P8 Step 2 Synthesis of 3-(4-(trifluoromethyl)phenyl)tetrahydrofuran-3-carboxylic acid (INT-8c) To a stirred solution of ethyl 3-[4-(trifluoromethyl)phenyl]oxolane-3-carboxylate (400 mg, 1.388 mmol, 1 equiv.) in MeOH (15 ml_) and H2O (3 ml_) was added LiOH (332 mg, 13.880 mmol, 10 equiv.). The reaction was stirred for 2 h. It was diluted with water (10 ml_), pH was adjusted to 4 with 1N HCI, the aqueous layer was extracted with EA (3 x 30 ml_). The combined organic phase was washed with brine (20 ml_), dried over anhydrous sodium sulfate filtered and concentrated under reduced pressure to give crude product which was further purified by column chromatography using EA / PE: 3 / 1 gradient to afford desired compound 3-[4-(trifluoromethyl)phenyl]oxolane-3-carboxylic acid (150 mg, 41.54%) as white solid.

[0990] Synthesis Procedure 9 (P9)

[0991]

[0992] P9 Step 1 Synthesis of S-(3,5-difluorobenzyl) ethanethioate (INT-9b)

[0993] With an inert atmosphere of nitrogen, to a mixture of (3,5-difluorophenyl)methanol (2 g, 13.877 mmol, 1 equiv.) in THF (60 ml_) was added PPh3 (7.28 g, 27.754 mmol, 2 equiv.), Schiff reagent (2.11 g, 27.723 mmol, 2.00 equiv.) and N-[(ethoxycarbonyl)imino]ethoxyformamide (4.83 g, 27.754 mmol, 2 equiv.) at 0°C. The reaction was stirred at 0 °C for 10 min. After which the mixture was allowed to warm to rt and stirred at rt for 2h. Concentrated. The residue was applied onto a silica gel column (80 g, EtOAc / PE: 1 / 5) to give S-(3,5-difluorobenzyl) ethanethioate (1 g, 35.63%) as light yellow oil.

[0994] P9 Step 2 Synthesis of (3,5-difluorophenyl)methanesulfinic chloride (INT-9c)

[0995] With an inert atmosphere of nitrogen, to a mixture of 1 -{[(3,5-difluorophenyl)methyl]sulfanyl}ethanone (700 mg, 3.462 mmol, 1 equiv.) in DCM (30 mL) was added acetic anhydride (0.35 g, 3.428 mmol, 0.99 equiv.) and sulfonyl chloride (0.93 g, 6.891 mmol, 1.99 equiv.) dropwise at -30 °C. The reaction was stirred at -30 °C for 10 min. After which the mixture wasallowed to warm to rt slowly and stirred at rt for 48 h. Concentrated to give crude (3,5-difluorophenyl)methanesulfinyl chloride (600 mg) as light yellow oil.

[0996] Synthesis Procedure 10 (P10)

[0997]

[0998] P10 Step 1 Synthesis of tert-butyl (R)-6-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1.4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (INT-10a)

[0999] To a solution of tert-butyl (R)-7-bromo-6-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (INT-1d)(200 mg, 0.523 mmol, 1 equiv.) in THF (10 mL) was added NBS (111 mg, 0.628 mmol, 1.1 equiv.) at -78 °C. The reaction was stirred for 45 mins at -78 °C. The reaction was quenched with water (10 mL), extracted with EA (10 mL x 3). The combined extract was washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by C18 reversed phase column chromatography, eluted with MeCN / H2O (0% - 100%) to afford tert-butyl (R)-6-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (210 mg, 84.15%) as a yellow solid.

[1000] LC / MS: mass calcd. for C22H35BN4O4: 430.28, found: 431.35 [M+H]+.

[1001] P10 Step 2 Synthesis of tert-butyl (3R)-7-(1,2,3,5,8,8a-hexahydroindolizin-7-yl)-6-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (INT-10b)

[1002] To a solution of 1,2,3,5,8,8a-hexahydroindolizin-7-yl trifluoromethanesulfonate (250 mg, 0.922 mmol, 1 equiv.) and tert-butyl (R)-6-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (793 mg, 1.844 mmol, 2 equiv.) in dioxane (5 mL) and H2O (1 mL) were added K2CO3 (382 mg, 2.766 mmol, 3 equiv.) and Pd(dppf)CI2 (135 mg, 0.184 mmol, 0.2 equiv.). After stirring for 16 h at 100 °C under a nitrogen atmosphere. The reaction was quenched with water (10 mL), extracted with EA (10 mLx 3). The combined extract was washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by C18 reversed phase column chromatography, eluted with MeCN / H2O (0% - 100%) to afford tert-butyl (3R)-7-(1,2,3,5,8,8a-hexahydroindolizin-7-yl)-6-methyl- 1.4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (150 mg, 38.24%) as a yellow solid.

[1003] LC / MS: mass calcd. for C24H35N4O2: 425.28, found: 426.10 [M+H]+.P10 Step 3 Synthesis of tert-butyl (3R)-6-methyl-7-(octahydroindolizin-7-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1 '-carboxylate (INT-10c)

[1004] To a solution of tert-butyl (3R)-7-(1,2,3,5,8,8a-hexahydroindolizin-7-yl)-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (150 mg, 0.352 mmol, 1 equiv.) in MeOH (5 mL) was added Pd / C (187 mg, 1.760 mmol, 5 equiv.) under nitrogen atmosphere in a 100 ml_ Vessel. The mixture was hydrogenated at room temperature for 1 h under hydrogen atmosphere using a hydrogen balloon, filtered through a Celite pad and concentrated under reduced pressure. This resulted in tert-butyl (3R)-6-methyl-7-(octahydroindolizin-7-yl)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (100 mg, 66.35%) as a light yellow solid.

[1005] LC / MS: mass calcd. for C24H37N5O2: 427.29, found: 428.20 [M+H]+.

[1006] P10 Step 4 Synthesis of (3S)-6-methyl-7-(octahydroindolizin-7-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine] (INT-10d)

[1007] To a solution of tert-butyl (3R)-6-methyl-7-(octahydroindolizin-7-yl)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (100 mg, 0.234 mmol, 1 equiv.) in DCM (2 mL) / MeOH (1 mL) was added HCI in 1,4-dioxane (4.0 M) (1 mL). The reaction was stirred at room temperature for 4 h. The resulting mixture was concentrated under vacuum to afford (3S)-6-methyl-7-(octahydroindolizin-7-yl)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine] (100 mg, crude) as a yellow solid.

[1008] LC / MS: mass calcd. for C19H29N5: 327.24, found: 328.30 [M+H]+.

[1009] P10 Step 5 Synthesis of (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((3R)-6-methyl-7-(octahydroindolizin-7-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl)propan-1-one (Example 80)

[1010] To a solution of (3S)-6-methyl-7-(octahydroindolizin-7-yl)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine] (50 mg, 0.153 mmol, 1 equiv.) in DMF (2 mL) was added (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)propanoic acid (46 mg, 0.229 mmol, 1.5 equiv.), TCFH (64 mg, 0.229 mmol, 1.5 equiv.), NMI (75 mg, 0.918 mmol, 6 equiv.). The reaction was stirred for 1h at rt. The reaction was quenched with water (30 mL), extracted with EA (3 x 30 mL). The combined organic layer was washed with brine (3 x 50 mL). The resulting mixture was concentrated under vacuum. The residue was purified by preparative HPLC using a XBridge Prep OBD C18 Column, 30*150 mm, 5μm Column (eluent: 10% B to 40% (V / V), water (10mmol / L NH4HCO3) and MeCN) to afford (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[(3R)-6-methyl-7-(octahydroindolizin-7-yl)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl]propan-1-one (2.6 mg, 3.35%) as an off-white solid. 1H NMR (500 MHz, Methanol-d4) 57.98 (dd, J = 16.0, 1.6 Hz, 1H), 6.83-6.70 (m, 2H), 4.21 (dq, J = 47.0, 6.9 Hz, 1H), 3.89 (s, 3H), 3.85-3.70 (m, 1H), 3.69-3.52(m, 2H), 3.50-3.46 (m, 1H), 3.26-3.20(m, 1H), 3.19-3.08 (m, 2H), 3.03-2.94(m, 1H), 2.76-2.68 (m, 1H), 2.31-2.20 (m, 5H), 2.18-1.93 (m, 4H), 1.93-1.78 (m, 3H), 1.78-1.64 (m, 2H), 1.54-1.32 (m, 5H).

[1011] LC / MS: mass calcd. for C28H37FN6O2: 508.30, found: 509.30 [M+H]+.Synthesis Procedure 12 (P12)

[1012]

[1013] P12 Step 1 Synthesis of (2R)-1-(7-bromo-6-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-r-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)propan-1-one (INT-12a)

[1014] To a solution of 7-bromo-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine] (180 mg, 0.636 mmol, 1 equiv.) in DMF (10 mL) were added (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)propanoic acid (189.92 mg, 0.954 mmol, 1.5 equiv.), NMI (156.57 mg, 1.908 mmol, 3 equiv.) and TCFH (267.53 mg, 0.954 mmol, 1.5 equiv.). The reaction was stirred for 1h at rt. The reaction was quenched with water (20 mL), extracted with EA (20 mL x 3). The combined extract was washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by C18 reversed phase column chromatography, eluted with MeCN / H2O (10% - 100%) to afford (2R)-1-{7-bromo-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-T-yl}-2-(5-fluoro-2-methoxypyridin-4-yl)propan-1-one (130 mg, 44.04%) as a yellow solid.

[1015] LC / MS: mass calcd. for C20H23BrFN5O2: 463.10, found:464.2 [M+H]+.

[1016] P12 Step 2 Synthesis of (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-(6-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl)propan-1-one (INT-12b)

[1017] To a solution of (2R)-1-(7-bromo-6-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-T-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)propan-1-one (300 mg, 0.646 mmol, 1 equiv.) in dioxane (10mL) I H2O (1mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,2-oxaborolan-2-yl)-1,3,2-dioxaborolane (250 mg, 0.992 mmol, 1.54 equiv.), AcOK (190 mg, 1.936 mmol, 3.00 equiv.) and Pd(dppf)CI2 (236 mg, 0.323 mmol, 0.50 equiv.). The mixture was stirred at 90°C overnight under N2 atmosphere. The reaction was quenched with water (20 mL) and extracted with EA (20 mL x 3). The combined extract was washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by C18 reversed phase column chromatography, eluted with MeCN / H2O (10% - 100%) to afford (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[6-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,4-dihydro-1H-spiro[pyrido[2,3-b] pyrazine-3, 3'-pyrrolidin]-1 '-y I] propan-1-one (250 mg, 75.5%) as a purple solid.

[1018] LC / MS: mass calcd. C26H35BFN5O4 for: 511.28, found: 512.25 [M+H]+.

[1019] P12 Step 3 Synthesis of (2R)-1-(7-(5-(difluoromethyl)-1-methyl-1H-1,2,4-triazol-3-yl)-6-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-r-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)propan-1-one (Example 21)To a solution of (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[6-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl]propan-1-one (50 mg, 0.098 mmol, 1 equiv.) in dioxane (5 ml_) / H2O (0.5 ml_) was added 3-bromo-5-(difluoromethyl)-1-methyl-1,2,4-triazole (41 mg, 0.196 mmol, 2 equiv.), K3PO4 (62 mg, 0.294 mmol, 3 equiv.), bis(adamantan-1-yl)(butyl)phosphane (17.53 mg, 0.049 mmol, 0.5 equiv.) and cataCXium-A-Pd-G3 (35 mg, 0.049 mmol, 0.5 equiv.) under N2 atmosphere. The resulting mixture was stirred at 100°C overnight under N2 atmosphere. The reaction was quenched with water (20 ml_) and extracted with EA (20 ml_ x 3). The combined extract was washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC using a XBridge Prep Shield RP18 OBD Column, 30*150 mm, 5μm Column (eluent: 8% B to 38% (V / V), water and MeCN with 0.05% TFA) to afford (2R)-1 -(7-(5-(difluoromethyl)-1 -methyl-1 H-1,2,4-triazol-3-yl)-6-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-T-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)propan-1-one (4.2 mg, 7.47%) as a light yellow solid.1H NMR (400 MHz, Methanol-d4) 57.99 -7.86 (m, 1H), 7.70 (dd, J = 10.9, 1.6 Hz, 1H), 7.28 - 7.03 (m, 1H), 6.77 -6.61 (m, 1H), 4.32 - 4.15 (m, 1H), 4.13 - 3.98 (m, 3H), 3.86 (d, J = 11.6 Hz, 3H), 3.79 - 3.52 (m, 3H), 3.39 (m, 1H), 3.23 - 3.07 (m, 2H), 2.74 (dd, J = 6.2, 1.2 Hz, 3H), 2.29 - 2.13 (m, 2H), 1.44 (dt, J = 9.5, 6.8 Hz, 3H), 1.29 (s, 1H).

[1020] LC / MS: mass calcd. C24H27F3N8O2 for: 516.22, found: 517.30 [M+H]+.

[1021] Synthesis Procedure 13 (P13)

[1022]

[1023] P13 Step 1 Synthesis of tert-butyl 5-((R)-T-((R)-2-(5-fluoro-2-methoxypyridin-4-yl)propanoyl)-6-methyl-7-(pyrimidin-2-yl)-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1 (4H)-yl)-1H-pyrazole- 1 -carboxylate (INT-13a)

[1024] To a solution of tert-butyl (R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((R)-6-methyl-7-(pyrimidin- 2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl)propan-1-one (382 mg, 1.0 mmol, 1 equiv.) and tert-butyl 3-bromo-1H-pyrazole-1 -carboxylate (500 mg, 2.0 mmol, 2.0 equiv.) in Tol (10 ml_) were added Cs2CO3 (722 mg, 2.0 mmol, 2.0 equiv.), Xphos Pd (80 mg, 0.1 mmol, 0.1 equiv.). After stirring for 16 h at 100 °C under a nitrogen atmosphere, quenched with water (20 ml_) and extracted with EA (30 ml_ x 3). The combined extract was washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by C18 reversed phase column chromatography, eluted with MeCN / H2O (10% - 100%) to afford tert-butyl 5-((R)-1 '-((R)-2-(5-fluoro-2-methoxypyridin-4-yl)propanoyl)-6-methyl-7-(pyrimidin-2-yl)-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1(4H)-yl)-1H-pyrazole-1-carboxylate (310 mg, 51%) as a yellow solid.

[1025] LC / MS: mass calcd. for C32H36FN9O4, 629.3 m / z, found 630.00 [M+H]+.

[1026] P13 Step 2 Synthesis of (R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((R)-6-methyl-1-(1H-pyrazol-5-yl)-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl)propan-1-one (Example 70)

[1027] A solution of tert-butyl 5-((R)-T-((R)-2-(5-fluoro-2-methoxypyridin-4-yl)propanoyl)-6-methyl-7-(pyrimidin-2-yl)-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1(4H)-yl)-1H-pyrazole-1-carboxylate (75 mg, 0.119 mmol, 1 equiv.) in DCM (6 mL) was added TFA (2 mL). The reaction was stirred for 2h at rt. The resulting mixture was concentrated under vacuum to afford (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[(3R)-6-methyl-1-(1H-pyrazol-3-yl)-7-(pyrimidin-2-yl)-2,4-dihydrospiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl]propan-1-one as red brown oil. The residue was separated by preparative HPLC using a XBridge Prep OBD C18 Column, 30*150 mm, 5pm; column (eluent: 14% B to 44% B (V / V), Water(10mmol / L NH4HC03+0.05%NH3H20) ) to afford (R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((R)-6-methyl-1-(1H-pyrazol-5-yl)-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl)propan-1-one (21.2 mg, 33.61%) as a white solid.1H NMR (300 MHz, Methanol-d4) 5 8.78 (d, J = 5.0 Hz, 2H), 8.06-7.78 (m, 2H), 7.60 (dd, J = 14.4, 2.5 Hz, 1H), 7.29 (t, J = 4.9 Hz, 1H), 6.68 (dd, J = 41.7, 4.9 Hz, 1H), 6.16 (dd, J = 50.6, 2.5 Hz, 1H), 4.10 (dq, J = 36.0, 6.9 Hz, 1H), 3.88 (s, 1H), 3.84 (s, 2H), 3.76 (d, J = 7.5 Hz, 2H), 3.68-3.50 (m, 3H), 3.39 (dd, J = 12.2, 3.7 Hz, 1H), 2.55 (d, J = 3.7 Hz, 3H), 2.26-2.02 (m, 2H), 1.40 (dd, J = 10.4, 6.9 Hz, 3H).

[1028] LC / MS: mass calcd. for C27H28FN9O2, 529.20 m / z, found: 530.30 [M+H]+.

[1029] Synthesis Procedure 14 (P14)

[1030]

[1031] P14 Step 1 Synthesis of tert-butyl (R)-7-bromo-1-((1-(tert-butoxycarbonyl)-1H-pyrazol-3-yl)methyl)-6-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (INT-14a)

[1032] To a stirred solution of tert-butyl (3R)-7-bromo-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidine]-1'-carboxylate (300 mg, 0.783 mmol, 1 equiv.) in DMF (10 mL) was added NaH (158 mg, 3.950 mmol, 5.05 equiv., 60%) at 0 °C. The resulting mixture was stirred at 0°C for 1h. Then was added tert-butyl 3-(bromomethyl) pyrazole-1 -carboxylate (615 mg, 2.355 mmol, 3.01 equiv.) at 0 °C. The reaction was stirred at rt for 1 h, quenched with water (30 mL) and extracted with EA (30 mLx 3). The combined extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by C18 reversed phase column chromatography,eluted with MeCN / H₂O (10% - 100%) to afford tert-butyl (3R)-7-bromo-1-{[2-(tert-butoxycarbonyl) pyrazol-3-yl] methyl}-6-methyl-2,4-dihydrospiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1 '-carboxylate (200 mg, 45.35%yield) as a yellow solid.

[1033] LC / MS: mass calcd. for C25H35BrN6O4: 562.19, found: 563.00 [M+H]+.

[1034] P14 Step 2 Synthesis of tert-butyl (R)-1-((1-(tert-butoxycarbonyl)-1H-pyrazol-3-yl)methyl)-6-methyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-r-carboxylate (INT-14b)

[1035] To a stirred solution of tert-butyl (3R)-7-bromo-1-{[2-(tert-butoxycarbonyl) pyrazol-3-yl] methyl}-6-methyl-2,4-dihydrospiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidine]-1'-carboxylate (200 mg, 0.355 mmol, 1 equiv.) in dioxane (10 mL) was added 2-(tributylstannyl) pyrimidine (262 mg, 0.710 mmol, 2.00 equiv.), [P(tBu)3] Pd(crotyl)CI (50 mg) at N2 atmosphere. The resulting mixture was stirred at 100°C for 3h under N2 atmosphere. The mixture was concentrated. The residue was purified by C18 reversed phase column chromatography, eluted with MeCN / H2O (10% - 70%) to afford tert-butyl (3R)-1-{[2-(tert-butoxycarbonyl)pyrazol-3-yl]methyl}-6-methyl-7-(pyrimidin-2-yl)-2,4-dihydrospiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidine]-1'-carboxylate (150 mg, 75.11%) as a yellow solid.

[1036] LC / MS: mass calcd. for C24H30BrFN6O4: 564.15, found: 565.00 [M+H]+.

[1037] P14 Step 3 Synthesis of (S)-1-((1H-pyrazol-5-yl)methyl)-6-methyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine] (INT-14c)

[1038] To a stirred solution of tert-butyl (3R)-1-{[2-(tert-butoxycarbonyl) pyrazol-3-yl] methyl}-6-methyl-7-(pyrimidin-2-yl)-2,4-dihydrospiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (150 mg, 0.267 mmol, 1 equiv.) in DCM (10 mL) was added TFA (2 mL). The resulting mixture was stirred at rt for 1h. The resulting mixture was concentrated under reduced pressure. This resulted in (3S)-6-methyl-1-(2H-pyrazol-3-ylmethyl)-7-(pyrimidin-2-yl)-2,4-dihydrospiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidine] (150 mg crude) as yellow oil.

[1039] LC / MS: mass calcd. for C19H22N8: 362.20, found: 363.25 [M+H]+.

[1040] P14 Step 4 Synthesis of 1-((R)-1-((1H-pyrazol-5-yl)methyl)-6-methyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-r-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyethan-1-one (Compound 14A)

[1041] To a stirred solution of (3S)-6-methyl-1-(2H-pyrazol-3-ylmethyl)-7-(pyrimidin-2-yl)-2,4-dihydrospiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidine] (150 mg, 0.414 mmol, 1 equiv.) in DMF (5 mL) was added (5-fluoro-2-methoxypyridin-4-yl) (methoxy)acetic acid (89 mg, 0.414 mmol, 1.00 equiv.), DIEA (535 mg, 4.139 mmol, 10.00 equiv.) and HATU (236 mg, 0.621 mmol, 1.50 equiv.). The resulting mixture was stirred at rt for 1 h, quenched with water (20 mL) and extracted with EA (20 mL x 3). The combined extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by C18 reversed phase column chromatography, eluted with MeCN / H2O (10% - 100%) to afford 2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxy-1-[(3R)-6-methyl-1-(2H-py razol-3-ylmethyl)-7-(pyrimidin-2-yl)-2,4-dihydrospiro[pyrido[2,3-b] py razine-3, 3'-pyrrolidin]-1 '-y I] ethanone (50 mg, 21.59%) as a yellow solid.

[1042] LC / MS: mass calcd. for C28H30FN9O3: 559.25, found: 560.20[M+H]+.

[1043]

[1044] Example 14 (diastereomer 1)

[1045] Example 122 (diastereomer 2)

[1046] P14 SFC Separate Synthesis of (R)-1-((R)-1-((1H-pyrazol-5-yl)methyl)-6-methyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyethan-1-one & (S)-1-((R)-1-((1H-pyrazol-5-yl)methyl)-6-methyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyethan-1-one (Examples 14 and 122)

[1047] 1-((R)-1-((1H-pyrazol-5-yl)methyl)-6-methyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-T-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyethan-1-one (70 mg, 0.125 mmol, 1 equiv.) was separated by CHIRAL HPLC (CHIRALPAK IA,2*25 cm, 5 pm Column (eluent: EtOH, MTBE (0.5% 2M NH3-MeOH)) to afford Example 14 (14.2 mg, 20.29%), first enantiomer to elute) as an off-white solid. 1 H NMR (300 MHz, Methanol-d4) 58.81 (dd, J = 4.9, 1.3 Hz, 2H), 8.02 (dd, J = 3.9, 1.6 Hz, 1H), 7.55 (d, J = 5.0 Hz, 2H), 7.30 (td, J = 4.9, 1.2 Hz, 1H), 6.85 (dd, J = 9.0, 4.6 Hz, 1H), 6.27 (dd, J = 19.3, 2.2 Hz, 1H), 5.25 (d, J = 22.0 Hz, 1H), 4.55-4.44 (m, 1H), 4.51 (d, J = 11.5 Hz, 1H), 3.88 (d, J = 9.4 Hz, 3H), 3.80 - 3.67 (m, 2H), 3.66-3.58 (m, 1H), 3.55-3.37 (m, 4H), 3.19 -2.94 (m, 2H), 2.50 (d, J = 4.3 Hz, 3H), 2.21 - 1.97 (m, 2H), 1.35-1.24 (m, 1H).

[1048] Retention Time: 2.374 min.

[1049] LC / MS: mass calcd. for C28H30FN9O3: 559.25, found: 560.30 [M+H]+.

[1050] Example 122 (10.9 mg, 15.57%), was the second enantiomer to elute) as an off-white solid.1H NMR (300 MHz, Methanol-d4) 58.81 (dd, J = 5.0, 3.2 Hz, 2H), 8.01 (dd, J = 20.8, 1.6 Hz, 1H), 7.61 - 7.40 (m, 2H), 7.30 (td, J = 4.9, 2.8 Hz, 1H), 6.84 (dd, J = 4.7, 2.3 Hz, 1H), 6.28 (dd, J = 18.0, 2.2 Hz, 1H), 5.25 (d, J = 22.3 Hz, 1H), 4.60 - 4.46 (m, 2H), 4.04 - 3.77 (m, 4H), 3.75 - 3.56 (m, 1H), 3.51 - 3.33 (m, 5H), 3.17 - 2.96 (m, 2H), 2.51 (d, J = 2.2 Hz, 3H), 2.20 - 2.09 (m, 1H), 2.07 - 1.93 (m, 1H), 1.35-1.21 (m, 1H). Retention Time: 4.688 min.

[1051] LC / MS: mass calcd. for C28H30FN9O3: 559.25, found: 560.30 [M+H]+.Synthesis Procedure 15 (P15)

[1052]

[1053] P15 Step 1 Synthesis of tert-butyl (R)-7-bromo-1-(1-methoxy-2-methyl-1-oxopropan-2-yl)-6-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-r-carboxylate (INT-15a)

[1054] To a solution of tert-butyl (3R)-7-bromo-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidine]-T-carboxylate (1 g, 2.609 mmol, 1 equiv.) in DMF (15 mL) was added sodium hydride (0.19 g, 7.827 mmol, 3 equiv.) at 0°C, the reaction was stirred for 1h. Then methyl 2-bromo-2-methylpropanoate (2.36 g, 13.045 mmol, 5 equiv.) was added, and the reaction was stirred for 1h at rt. The reaction was quenched with water (30 mL), extracted with EA (3 x 30 mL). The combined organic layer was washed with brine (3 x 50 mL). The resulting mixture was concentrated under vacuum. The residue was purified by C18 reversed phase column chromatography, eluted with MeCN / H2O (10% - 100%) to afford tert-butyl (3R)-7-bromo-1-(1-methoxy-2-methyl-1-oxopropan-2-yl)-6-methyl-2,4-dihydrospiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (300 mg, 23.79%) as a white solid.

[1055] LC / MS: mass calcd. for C21H31BrN4O4: 482.15, found: 483.40 [M+H]+.

[1056] P15 Step 2 Synthesis of tert-butyl (R)-7-bromo-1-(1-hydroxy-2-methylpropan-2-yl)-6-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (INT-15b)

[1057] To a solution of tert-butyl (3R)-7-bromo-1-(1-methoxy-2-methyl-1-oxopropan-2-yl)-6-methyl-2,4-dihydrospiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (300 mg, 0.621 mmol, 1 equiv.) in tetrahydrofuran (15 mL) was added lithium borohydride (135 mg, 6.210 mmol, 10 equiv.) at rt. The reaction was stirred for 1h at rt. The reaction was quenched with water (30 mL), extracted with EA (3 x 30 mL). The combined organic layer was washed with brine (3 x 50 mL). The resulting mixture was concentrated under vacuum. The residue was purified by C18 reversed phase column chromatography, eluted with MeCN / H2O (10% - 100%) to afford tert-butyl(3R)-7-bromo-1-(1-hydroxy-2-methylpropan-2-yl)-6-methyl-2,4-dihydrospiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (80 mg) as a white solid.

[1058] LC / MS: mass calcd. for C20H31BrN4O3: 454.15, found: 455.15 [M+H]+.

[1059] P15 Step 3 Synthesis of (S)-2-(7-bromo-6-methyl-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1(4H)-yl)-2-methylpropan-1-ol (INT-15c)

[1060] To a solution of tert-butyl (3R)-7-bromo-1-(1-hydroxy-2-methylpropan-2-yl)-6-methyl-2,4-dihydrospiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidine]-1'-carboxylate (80 mg, 0.176 mmol, 1 equiv.) in DCM (6 mL) was added TFA (2 mL). The reaction was stirred for 1h at rt. The resulting mixture was concentrated under vacuum to afford 2-[(3S)-7-bromo-6-methyl-2,4-dihydrospiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidin]-1-yl]-2-methylpropan-1-ol (80 mg, crude) as light-yellow oil.LC / MS: mass calcd. for C15H23BrN4O: 354.10, found: 355.28 [M+H]+.

[1061] P15 Step 4 Synthesis of (R)-1-((R)-7-bromo-1-(1-hydroxy-2-methylpropan-2-yl)-6-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)propan-1-one (INT-15d)

[1062] To a solution of 2-[(3S)-7-bromo-6-methyl-2,4-dihydrospiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolid in]-1-yl]-2-methylpropan-1 -ol (80 mg, 0.225 mmol, 1 equiv.) in DMF (15 mL) was added (2R)-2-(5-fluoro-2-methoxypyridin-4-yl) propanoic acid (44 mg, 0.225 mmol, 1 equiv.), DMAP (82 mg, 0.675 mmol, 3 equiv.), EDCI (69 mg, 0.450 mmol, 2 equiv.). The reaction was stirred for 1h at rt. The reaction was quenched with water (30 mL), extracted with EA (3 x 30 mL). The combined organic layer was washed with brine (3 x 50 mL). The resulting mixture was concentrated under vacuum. The residue was purified by C18 reversed phase column chromatography, eluted with MeCN / H2O (10% -100%) to afford {4-[(2R)-1-[(3R)-7-bromo-1-(1-hydroxy-2-methylpropan-2-yl)-6-methyl-2,4-dihydrospiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidin]-T-yl]-1-oxopropan-2-yl]-5-fluoropyridin-2-yl}methyl-Iambda3-oxidanyl (50 mg) as a white solid.

[1063] LC / MS: mass calcd. for C24H31BrFN5O3: 535.15, found: 536.44 [M+H]+.

[1064] P15 Step 5 Synthesis of (R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((R)-1-(1-hydroxy-2-methylpropan-2-yl)-6-methyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl)propan-1-one (Example 36)

[1065] To a solution of (2R)-1-[(3R)-7-bromo-1-(1-hydroxy-2-methylpropan-2-yl)-6-methyl-2,4-dihydrospiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidin]-T-yl]-2-(5-fluoro-2-methoxypyridin-4-yl) propan-1-one (80 mg, 0.149mmol, 1 equiv.) in dioxane (10 mL) was added [P(tBu)3] Pd(crotyl)CI (14 mg, 0.030 mmol, 0.2 equiv.) and 2-(tributy Istanny I) pyrimidine (138 mg, 0.298 mmol, 2equiv.). The mixture was stirred at 90°C for 1h. The reaction was quenched with water (30 mL), extracted with EA (3 x 30 mL). The combined organic layer was washed with brine (3 x 50 mL). The resulting mixture was concentrated under vacuum. The residue was purified by preparative HPLC using a XSelect CSH Prep C18 OBD Column, 30*150 mm, 5μm Column (eluent: 11% B to 41% (V / V), water and MeCN with 10mmol / L NH4HC03+0.05%NH3. H20) to afford (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[(3R)-1-(1-hydroxy-2-methylpropan-2-yl)-6-methyl-7-(pyrimidin-2-yl)-2,4-dihydrospiro[pyrido[2,3-b] pyrazine-3, 3'-pyrrolidin]-1 '-y I] propan-1-one (20.6 mg, 20.63%) as yellow semi-solid.1H NMR (300 MHz, Methanol-d4) 58.88 - 8.80 (m, 2H), 8.04 - 7.96 (m, 1H), 7.42 - 7.29 (m, 2H), 6.82 - 6.70 (m, 1H), 4.32 - 4.11 (m, 1H), 3.93 - 3.88 (m, 3H), 3.88 - 3.73 (m, 1H), 3.65 - 3.56 (m, 2H), 3.51 - 3.43 (m, 2H), 3.42 - 3.31 (m, 1H), 3.29 - 3.14 (m, 2H), 3.14 - 3.04 (m, 1H), 3.03 - 2.98 (m, 1H), 2.54 - 2.47 (m, 3H), 2.26 - 1.95 (m, 3H), 1.51 - 1.39 (m, 3H), 1.03 (d, J = 6.7 Hz, 1H), 0.96 - 0.87 (m, 2H).

[1066] LC / MS: mass calcd. for C28H34FN7O3: 535.27 m / z, found: 536.25 [M+H]+.Synthesis Procedure 16 (P16)

[1067] INT-6S

[1068]

[1069] step 4

[1070] P16 Step 1 Synthesis of (R)-2-(7-bromo-1'-(tert-butoxycarbonyl)-6-methyl-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1(4H)-yl)acetic acid (INT-16a)

[1071] To a solution of tert-butyl (3R)-7-bromo-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidine]-1'-carboxylate (300 mg, 0.783 mmol, 1 equiv.) in MeOH (10 ml_) was added glyoxalate (1.16 g, 15.660 mmol, 20 equiv.). The reaction was stirred at room temperature for 1 h. Then was added NaBH3CN (245 mg, 3.915 mmol, 5 equiv.) at 0°C. The reaction was stirred at rt for 1 h, quenched with water (30 ml_) and extracted with EA (30 ml_ x 3). The combined extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. This resulted in (3R)-7-bromo-T-(tert-butoxycarbonyl)-6-methyl-2,4-dihydrospiro[pyrido[2,3-b] py razine-3, 3'-pyrrolidin]-1-ylacetic acid (300 mg crude) as a yellow semi-solid.

[1072] LC / MS: mass calcd. for C18H25BrN4O4: 440.11, found: 441.05 [M+H]+.

[1073] P16 Step 2 Synthesis of tert-butyl (R)-7-bromo-1-(2-(dimethylamino)-2-oxoethyl)-6-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (INT-16b)

[1074] To a stirred solution of (3R)-7-bromo-T-(tert-butoxycarbonyl)-6-methyl-2,4-dihydrospiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidin]-1-ylacetic acid (300 mg, 0.680 mmol, 1 equiv.) in DMF (15 ml_) was added dimethylamine (306.47 mg, 6.800 mmol, 10 equiv.), DIEA (263 mg, 2.040 mmol, 3 equiv.) and HATU (387 mg, 1.020 mmol, 1.5 equiv.). The resulting mixture was stirred at rt for 1 h, quenched with water (30 ml_) and extracted with EA (30 ml_ x 3). The combined extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by C18 reversed phase column chromatography, eluted with MeCN / H2O (10% - 60%) to afford tert-butyl (3R)-7-bromo-1-[(dimethylcarbamoyl)methyl]-6-methyl-2,4-dihydrospiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidine]-1'-carboxylate (290 mg, 91.08%) as a yellow solid.

[1075] LC / MS: mass calcd. for C20H30BrN5O3: 467.15, found: 468. 10[M+H]+.P16 Step 3 Synthesis of (S)-2-(7-bromo-6-methyl-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1(4H)-yl)-N, N-dimethylacetamide (INT-16c)

[1076] To a stirred solution of tert-butyl (3R)-7-bromo-1-[(dimethylcarbamoyl)methyl]-6-methyl-2,4-dihydrospiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidine]-T-carboxylate (240 mg, 0.512 mmol, 1 equiv.) in DCM (10 ml_) was added TFA (2 ml_). The resulting mixture was concentrated under reduced pressure. This resulted in 2-[(3S)-7-bromo-6-methyl-2,4-dihydrospiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidin]-1-yl]-N, N-dimethylacetamide (240 mg crude) as yellow solid.

[1077] LC / MS: mass calcd. for C15H22BrN5O: 367.10, found: 368.20 [M+H]+.

[1078] P16 Step 4 Synthesis of 2-((3R)-7-bromo-1'-(2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyacetyl)-6-methyl-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1 (4H)-yl)-N, N-di methylacetamide (INT-16d)

[1079] To a stirred solution of 2-[(3S)-7-bromo-6-methyl-2,4-dihydrospiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidin]-1-yl]-N, N-dimethylacetamide (210 mg, 0.570 mmol, 1 equiv.) in DMF (10 ml_) was added (5-fluoro-2-methoxypyridin-4-yl) (methoxy)acetic acid (122 mg, 0.570 mmol, 1 equiv.), DMAP (696 mg, 5.700 mmol, 10 equiv.) and EDCI (132 mg, 0.855 mmol, 1.5 equiv.). The resulting mixture was stirred at rt for 1 h, quenched with water (30 ml_) and extracted with EA (30 ml_ x 3). The combined extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by C18 reversed phase column chromatography, eluted with MeCN / H2O (10% -60%) to afford 2-[(3R)-7-bromo-T-[2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyacetyl]-6-methyl-2,4-dihydrospiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1 -yl]-N, N-dimethylacetamide (300 mg, 93.04%) as a yellow solid.

[1080] LC / MS: mass calcd. for C24H30BrFN6O4: 564.15, found: 565.00 [M+H]+.

[1081] P16 Step 5 Synthesis of 2-((3R)-1'-(2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyacetyl)-6-methyl-7-(pyrimidin-2-yl)-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1 (4H)-yl)-N, N-di methylacetamide (Compound 16A)

[1082] To a stirred solution of 2-[(3R)-7-bromo-1'-[2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyacetyl]-6-methyl-2,4-dihydrospiro[pyrido[2,3-b] py razine-3,3'-py rrolidin]-1-yl]-N, N-dimethylacetamide (150 mg, 0.265 mmol, 1 equiv.) in dioxane (10 mL) was added 2-(tributy Istanny I) pyrimidine (200 mg, 0.542 mmol, 2.04 equiv.) and [P(tBu)3] Pd(crotyl)CI (40 mg, 0.100 mmol, 0.38 equiv.). The reaction was stirred at 100°C under N2 atmosphere. The resulting mixture was concentrated. The residue was purified by C18 reversed phase column chromatography, eluted with MeCN / H2O (10% - 70%) to afford 2-[(3R)-1'-[2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyacetyl]-6-methyl-7-(pyrimidin-2-yl)-2,4-dihydrospiro[pyrido[2,3-b] py razine-3, 3'-pyrrolidin]-1 -yl]-N, N-dimethylacetamide (110 mg, 73.44%yield, 98%purity) as a yellow solid.

[1083] LC / MS: mass calcd. for C28H33FN8O4: 564.26, found: 565.20 [M+H]+.Example 37 (diastereomer 1)

[1084]

[1085] Compound 16B (diastereomer 2) P16 Step SFC Separation Synthesis of 2-((R)-1'-((R)-2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyacetyl)-6-methyl-7-(pyrimidin-2-yl)-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1(4H)-yl)-N, N-dimethylacetamide AND 2-((R)-1'-((S)-2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyacetyl)-6-methyl-7-(pyrimidin-2-yl)-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1(4H)-yl)-N, N-dimethylacetamide (Example 37 and compound 16b)

[1086] 2-((3R)-T-(2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyacetyl)-6-methyl-7-(pyrimidin-2-yl)-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1(4H)-yl)-N, N-dimethylacetamide (110 mg, 0.195 mmol, 1 equiv.) was separated by CHIRAL HPLC using a CHIRALPAK IA, 2*25 cm, 5 pm Column (eluent: EtOH-HPLC, MTBE(0.5% 2M NH3-MeOH— HPLC)) afford Example 37 (19.4 mg, 17.64%) as a yellow solid.1H NMR (300 MHz, Methanol-d4) 58.79 (dd, J = 4.9, 2.3 Hz, 2H), 8.03 (t, J = 2.2 Hz, 1H), 7.28 (td, J = 4.9, 2.2 Hz, 1H), 7.16 (d, J = 13.6 Hz, 1H), 6.86 (t, J = 4.3 Hz, 1H), 5.31 (d, J = 11.7 Hz, 1H), 4.39-4.17 (m, 1H), 4.07-3.70 (m, 6H), 3.66-3.48 (m, 2H), 3.43 (d, J = 8.1 Hz, 4H), 3.11 (d, J = 5.6, 4.0 Hz, 4H), 2.91 (d, J = 5.1 Hz, 3H), 2.51 (d, J = 5.3 Hz, 3H), 2.27-1.96 (m, 2H). Retention Time: 1.447 min.

[1087] LC / MS: mass calcd. for C28H33FN8O4: 564.26, found: 565.35 [M+H]+.

[1088] And Compound 16b (21 mg, 19.09%) second enantiomer to elute) as a yellow solid.1H NMR (300 MHz, Methanol-d4) 58.80 (dd, J = 4.9, 3.5 Hz, 2H), 8.01 (dd, J = 19.2, 1.6 Hz, 1H), 7.29 (td, J = 4.9, 3.1 Hz, 1H), 7.17 (d, J = 4.2 Hz, 1H), 6.86 (t, J = 4.4 Hz, 1H), 5.33 (d, J = 8.7 Hz, 1H), 4.39 - 4.09 (m, 2H), 4.02 (dd, J = 11.1, 2.4 Hz, 1H), 3.88 (d, J = 4.1 Hz, 3H), 3.79 - 3.53 (m, 2H), 3.49-3.45 (m, 4H), 3.36-3.30 (m, 1H), 3.26-3.18 (m, 1H), 3.16 (d, J = 11.2 Hz, 1H), 3.11 (d, J = 8.3 Hz, 3H), 2.91 (d, J = 12.4 Hz, 3H), 2.51 (d, J = 2.1 Hz, 3H), 2.19 (t, J = 7.4 Hz, 1H), 2.11 - 1.92 (m, 1H).

[1089] Retention Time: 2.402 min.

[1090] LC / MS: mass calcd. for C28H33FN8O4: 564.26, found: 565.30 [M+H]+.

[1091] F F BH3Me2S THF, 70°C

[1092]

[1093] EtjN, DCM

[1094] P16 Alt Step 1a Synthesis of tert-butyl 7-bromo-1-(2,2-difluoroacetyl)-6-methyl-2,4-dihydrospiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidine]-1 '-carboxylateTo a stirred solution of tert-butyl 7-bromo-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidine]-T-carboxylate (300 mg, 0.783 mmol, 1 equiv.) in DCM (10 mL) was added Et3N (7.8 mL, 15.600 mmol, 19.93 equiv.) and 2,2-difluoroacetyl 2,2-difluoroacetate (2043 mg, 11.745 mmol, 15 equiv.). The resulting mixture was stirred at rt for 1h. The reaction was quenched with water (20 mL) and extracted with DCM (20 mLx 3), filtered and concentrated. The residue was purified by column chromatography on silica gel, eluted with EA / PE (0-100%) to afford tert-butyl 7-bromo-1-(2,2-difluoroacetyl)-6-methyl-2,4-dihydrospiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidine]-1'-carboxylate (360 mg, 73.5%) as a yellow solid.

[1095] LC / MS: mass calcd. for C18H23BrF2N4O3: 460.09, found: 462.95 [M+H]+.

[1096] P16 Alt Step 1b Synthesis of tert-butyl 7-bromo-1-(2,2-difluoroethyl)-6-methyl-2,4-dihydrospiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-r-carboxylate

[1097] To a stirred tert-butyl 7-bromo-1-(2,2-difluoroacetyl)-6-methyl-2,4-dihydrospiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidine]-T-carboxylate (580 mg, 0.780 mmol, 1 equiv.) in THF (3 mL) was added Borane-dimethyl sulfide complex (94%) (4 mL). The resulting mixture was stirred at 70 °C for 2 h. The mixture was allowed to cool down to 0 °C, quenched by the addition of MeOH (3 ml) at 0 °C, filtered and concentrated. The residue was purified by C18 reversed phase column chromatography, eluted with MeCN / H₂O (10% - 100%) to afford tert-butyl 7-bromo-1-(2,2-difluoroethyl)-6-methyl-2,4-dihydrospiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (380 mg, 72.2%) as a yellow solid.

[1098] Synthesis Procedure 17 (P17)

[1099]

[1100] P17 Step 1 Synthesis of tert-butyl (R)-7-bromo-1-(2-methoxyacetyl)-6-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-r-carboxylate (INT-17a)

[1101] To a stirred solution of tert-butyl (3R)-7-bromo-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidine]-T-carboxylate (500 mg, 1.304 mmol, 1 equiv.) in DCM (10 mL) was added methoxyacetyl chloride (212 mg, 1.956 mmol, 1.5 equiv.) and TEA (2 mL, 4.000 mmol, 3.07 equiv.).

[1102] The resulting mixture was stirred at rt for 2h. The mixture was quenched by water (20 mL), extractedwith DCM (30 ml_ x 3). Concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluted with EA / PE (0-60%) to afford tert-butyl (3R)-7-bromo-1-(2-methoxyacetyl)-6-methyl-2,4-dihydrospiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidine]-T-carboxylate (450 mg, 75.76%) as light yellow semi-solid.

[1103] LC / MS: mass calcd. for C19H27BrN4O4: 454.12, found: 455.05 [M+H]+.

[1104] P17 Step 2 Synthesis of tert-butyl (R)-7-bromo-1-(2-methoxyethyl)-6-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-r-carboxylate (INT-17b)

[1105] To a stirred solution of tert-butyl (3R)-7-bromo-1-(2-methoxyacetyl)-6-methyl-2,4-dihydrospiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidine]-T-carboxylate (440 mg, 0.966 mmol, 1 equiv.) in THF (5 mL) was added Borane-tetrahydrofuran complex (1.0M in THF) (2 mL, 2.000 mmol, 2.07 equiv.). The resulting mixture was stirred at 60°C for 2h. The mixture was allowed to cool down to rt. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluted with EA / PE (0-60%) to afford tert-butyl (3R)-7-bromo-1-(2-methoxyethyl)-6-methyl-2,4-dihydrospiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidine]-T-carboxylate (340 mg, 79.72%) as light green oil.

[1106] LC / MS: mass calcd. forC19H29BrN4O3:440.14, found: 441.10 [M+H]+.

[1107] P17 Step 3 Synthesis of tert-butyl (R)-1-(2-methoxyethyl)-6-methyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (INT-17c)

[1108] To a stirred solution of tert-butyl (3R)-7-bromo-1-(2-methoxyethyl)-6-methyl-2,4-dihydrospiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidine]-1'-carboxylate (320 mg, 0.725 mmol, 1 equiv.) in dioxane (10 mL) was added 2-(tributylstannyl) pyrimidine (538 mg, 1.457 mmol, 2.01 equiv.) and [P(tBu)3] Pd(crotyl)Cl (58 mg, 0.145 mmol, 0.20 equiv.). The resulting mixture was stirred at 100°C for 2h under N2 atmosphere. The mixture was allowed to cool down to rt. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 reversed phase column chromatography, eluted with ACN / H₂O (10% - 100%) to afford tert-butyl (3R)-1-(2-methoxyethyl)-6-methyl-7-(pyrimidin-2-yl)-2,4-dihydrospiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidine]-1'-carboxylate (264 mg, 82.65%) as a light yellow solid.

[1109] LC / MS: mass calcd. for C23H32N6O3: 440.25, found: 441.35 [M+H]+.

[1110] P17 Step 4 Synthesis of (S)-1-(2-methoxyethyl)-6-methyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine] (INT-17d)

[1111] To a stirred solution of tert-butyl (3R)-1-(2-methoxyethyl)-6-methyl-7-(pyrimidin-2-yl)-2,4-dihydrospiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidine]-1'-carboxylate (100 mg, 0.227 mmol, 1 equiv.) in dioxane (1 mL) was added HCL in 1,4-dioxane (4.0 M) (5 mL). The resulting mixture was stirred at rt for 1h. The resulting mixture was concentrated under reduced pressure. This resulted in (3S)-1-(2-methoxyethyl)-6-methyl-7-(pyrimidin-2-yl)-2,4-dihydrospiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidine] (110 mg crude) as a light yellow solid.

[1112] LC / MS: mass calcd. forC18H24N6O: 340.20, found: 341.00 [M+H]+.P17 Step 5 Synthesis of (S)-1-(2-methoxyethyl)-6-methyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine] (Compound 17A)

[1113] To a stirred solution of(3S)-1-(2-methoxyethyl)-6-methyl-7-(pyrimidin-2-yl)-2,4-dihydrospiro[pyrido[2,3-b] pyrazine-3, 3'-pyrrolidine] (80 mg, 0.235 mmol, 1 equiv.) in DMF (5 ml_) was added (5-fluoro-2-methoxypyridin-4-yl) (methoxy)acetic acid (50 mg, 0.235 mmol, 1 equiv.), NMI (115 mg, 1.410 mmol, 6 equiv.) and TCFH (98 mg, 0.352 mmol, 1.5 equiv.). The resulting mixture was stirred at rt for 1h, quenched with water (20 ml_) and extracted with EA (20 ml_ x 3). The combined extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC using a XSelect CSH C18 OBD Column, 19*250 mm, 5μm Column (eluent: 24% B to 44% (V / V), water and MeCN with 10mmol / L NH4HCO3) to afford 2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxy-1-[(3R)-1-(2-methoxyethyl)-6-methyl-7-(pyrimidin-2-yl)-2,4-dihydrospiro[pyrido[2,3-b] pyrazine-3, 3'-py rrolidin]-1 '-y I] ethanone (43 mg, 34.04%) as an off-white solid.

[1114] LC / MS: mass calcd. for C27H32FN7O4: 537.25, found: 538. 50 [M+H]+.

[1115] Example 28 (diastereomer 1)

[1116]

[1117] Compound 17B (diastereomer 2) P17 Step SFC Separation Synthesis of (R)-2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxy-1-((R)- 1-(2-methoxyethyl)-6-methyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl)ethan-1-one & (S)-2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxy-1-((R)-1-(2-methoxyethyl)-6-methyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl)ethan-1-one (Example 28 and Compound 17B)

[1118] 2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxy-1-((R)-1-(2-methoxyethyl)-6-methyl-7-(pyrimidin- 2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl)ethan-1-one (40 mg, 0.074 mmol, 1 equiv.) was separated by CHIRAL HPLC using a Amylose-C NEO Column (eluent: CO2, MEOH(0.1% 7M NH3-MeOH) to afford Example 28 (7.8 mg, 19.50%) as a white solid.1H NMR (300 MHz, Methanol-c / 4) 58.73 (dd, J = 5.0, 2.6 Hz, 2H), 8.09-7.78 (m, 1H), 7.30-7.10 (m, 2H), 6.82-6.56 (m, 1H), 5.19 (d, J = 29.5 Hz, 1H), 4.50 (b, 1H), 3.92-3.58 (m, 5H), 3.56-3.27 (m, 7H), 3.24 (m, 4H), 2.41 (d, J = 4.9 Hz, 3H), 2.13-1.88 (m, 2H), 1.33 (dd, J = 9.1, 6.9 Hz, 1H). Retention Time: 1.566 min.

[1119] LC / MS: mass calcd. for C27H32FN7O4: 537.25, found: 538.25 [M+H]+.

[1120] And Compound 17b (5.2 mg, 13.00%) as a white solid.1H NMR (300 MHz, Methanol-c / 4) 5 8.82 (t, J = 4.7 Hz, 2H), 8.00 (dd, J = 23.3, 1.6 Hz, 1H), 7.40-7.14 (m, 2H), 6.86 (dd, J = 10.3, 4.7 Hz, 1H), 5.30 (d, J = 28.2 Hz, 1H), 4.10-3.84 (m, 4H), 3.80-3.38 (m, 10H), 3.36 (s, 2H), 3.23 (d, J = 27.7 Hz, 3H), 2.50 (d, J = 1.7 Hz, 3H), 2.19-1.98 (m, 2H).Retention Time: 1.928 min.

[1121] LC / MS: mass calcd. for C27H32FN7O4: 537.25, found: 538.25 [M+H]+.

[1122] Synthesis Procedure 18 (P18)

[1123] [6704-31-0] NaBH(OAc)3Compound 1A DCE, CH3COOH step 1

[1124]

[1125] P18 Step 1 Synthesis of (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[(3R)-6-methyl-1-(oxetan-3-yl)-7-(pyrimidin-2-yl)-2,4-dihydrospiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-T-yl]propan-1-one (Example 5)

[1126] A solution of (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[(3R)-6-methyl-7-(pyrimidin-2-yl)-2,4-dihydro-1 H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl]propan-1-one (70 mg, 0.151 mmol, 1 equiv.) in DCE (10 ml_) was treated with 3-oxetanone (21 mg, 0.302 mmol, 2 equiv.) and HOAc (0.05 ml_, 0.001 mmol, 0.01 equiv.) at rt for 2.5h followed by the addition of STAB (96 mg, 0.453 mmol, 3 equiv.) dropwise portions at rt. Desired product could be detected by LCMS. The reaction was quenched with H2O at RT. The aqueous layer was extracted with EA (2 x 20 ml_). The combined extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC using a XBridge Prep Shield RP18 OBD C18 Column, 30*150 mm, 5μm Column (eluent: 10% B to 40% (V / V), water and MeCN with Water(10mmol / L NH4HCO3) to afford (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[(3R)-6-methyl-1-(oxetan-3-yl)-7-(pyrimidin-2-yl)-2,4-dihydrospiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl]propan-1-one (28.8 mg, 36.70%) as a white solid.1H NMR (400 MHz, Methanol-d4) 58.82(d, J = 4.9 Hz, 2H), 8.01 -7.95(m, 1H), 7.31(td, J = 4.9, 1.3 Hz, 1H), 6.94 (d, J = 18.2 Hz, 1H), 6.79(t, J = 5.3 Hz, 1H), 4.95 (dt, J = 13.7, 6.5 Hz, 1H), 4.79 - 4.56 (m, 2H), 4.48 (dd, J = 6.8, 4.3 Hz, 1H), 4.30-4.20 (m, 2H), 3.97 - 3.76(m, 5H), 3.71 - 3.51(m, 2H), 2.98 (dd, J = 66.6, 11.1 Hz, 2H), 2.54 (d, J = 6.9 Hz, 3H), 2.33-2.04 (m, 3H), 1.47 (t, J = 6.6 Hz, 3H).

[1127] LC / MS: mass calcd. for C27H30FN7O3: 519.24 m / z, found: 520.30 [M+H]+.

[1128] NaBH3CN, MgSO4MeOH. AcOH, 65°C

[1129]

[1130] P18 Variant 1 Step 1 Synthesis of (2R)-1-[(3R)-1-cyclopropyl-6-methyl-7-(pyrimidin-2-yl)-2,4-dihydrospiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl]-2-(5-fluoro-2-methoxypyridin-4-yl)propan-1-one (Example 23)

[1131] To a mixture of (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[(3R)-6-methyl-7-(pyrimidin-2-yl)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl]propan-1-one (20 mg, 0.043 mmol, 1 equiv.) in MeOH (1 ml_) and HOAc (0.1 ml_) was added (l-ethoxycyclopropoxy)trimethylsilane (37 mg, 0.215 mmol, 5 equiv.) and MgSO4 (26 mg, 0.215 mmol, 5 equiv.). The reaction was stirred at rt for 30 min. After which NaBH3CN (27.11 mg, 0.430 mmol, 10 equiv.) was added to the mixture. The resulting mixture was stirred at rt for 5h. Desired product could be detected by LCMS. The mixture was concentrated and purified by column chromatography using DCM / MeOH: 10 / 1 to give a crude product which was further purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: MEOH; Gradient: 40% B to 70% B in 10min) to afford desired compound (2R)-1-[(3R)-1-cyclopropyl-6-methyl-7-(pyrimidin-2-yl)-2,4-dihydrospiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-T-yl]-2-(5-fluoro-2-methoxypyridin-4-yl)propan-1-one (5.1 mg, 7.82%) as white solid.1H NMR (300 MHz, Methanol-d4) 58.82 (d, J = 4.9 Hz, 2H), 7.98 (t, J = 1.5 Hz, 1H), 7.73 (d, J = 12.6 Hz, 1H), 7.31 (td, J = 4.9, 1.5 Hz, 1H), 6.74 (dd, J = 9.1, 5.0 Hz, 1H), 3.88 (d, J = 4.0 Hz, 3H), 3.80 (d, J = 8.7 Hz, 1H), 3.65-3.52 (m, 1H), 3.51-3.36 (m, 2H), 3.26-3.18 (m, 1H), 3.12-2.96 (m, 1H), 2.96-2.84 (m, 1H), 2.50 (d, J = 4.7 Hz, 3H), 2.28-2.18 (m, 1H), 2.18-1.96 (m, 2H), 1.43 (dd, J = 13.4, 6.9 Hz, 3H), 1.00-0.81 (m, 2H), 0.48-0.34 (m, 1H), 0.29-0.24 (m, 1H)

[1132] LC / MS: mass calcd. for C27H30FN7O2, 503.24 m / z, found 504.30 [M+H]+.

[1133] Synthesis Procedure 19 (P19)

[1134]

[1135] P19 Step 1 Synthesis of tert-butyl 7-bromo-1,4-bis(4-methoxybenzyl)-6-methyl-2-oxo-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (INT-19a)

[1136] (S)-7-bromo-6-methyl-2-oxo-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (2 g, 5.034 mmol, 1 equiv.) in THF (20 ml_) was added 60% NaH (1.2 g, 30.204 mmol, 6 equiv.) at 0 °C under air atmosphere. The mixture was stirred for 30 minutes at rt. Then 1-(chloromethyl)-4-methoxybenzene (4.73 g, 30.204 mmol, 6 equiv.) was added to the above mixture and stirred at 70°C for 2 hours. Desired product could be detected by LCMS. The mixture wasallowed to cool down to rt. The reaction was quenched by the addition of H2O (50 mL) at 0°C. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with saturation NaCI solution (1x100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0-50%) to afford tert-butyl 7-bromo-1,4-bis(4-methoxybenzyl)-6-methyl-2-oxo-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (2.4 g, 74.77%) as a yellow solid.

[1137] LC / MS: mass calcd. for C32H37BrN4O5: 636.19 m / z, found 637.15 [M+H]+.

[1138] P19 Step 2 Synthesis of tert-butyl 7-bromo-1,4-bis(4-methoxybenzyl)-2,6-dimethyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-r-carboxylate (INT-19b)

[1139] 7-bromo-1,4-bis(4-methoxybenzyl)-6-methyl-2-oxo-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (2.43 g, 3.811 mmol, 1 equiv.) in anhydrous THF (30 mL) was treated with a solution of MeMgBr (2.27 g, 19.055 mmol, 5 equiv.) dropwise under N2 atmosphere at 0 °C. After heating at 65 °C under nitrogen for 2 hours, the reaction mixture was cooled to 0 °C, and HOAc (8.01 g, 133.385 mmol, 35 equiv.) and NaBH4 (0.29 g, 7.622 mmol, 2 equiv.) were added subsequently. The mixture was allowed to warm up to room temperature and stirred overnight. The reaction mixture was concentrated to remove the solvent, and 10 ml of saturated aqueous NaHCOs solution were added. A small amount of solid Na2COs was also added to neutralize acetic acid. BOC2O was then added. The mixture was stirred at room temperature for 2 hours and then extracted with EtOAc (3 x 50 mL). The extracts were washed with brine (10 ml), and the organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with EA in PE (0-30%) to afford tert-butyl 7-bromo-1,4-bis(4-methoxybenzyl)-2,6-dimethyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (1.4 g, 57.61%) as a yellow solid.

[1140] LC / MS: mass calcd. for C33H41BrN4O4: 636.23m / z, found 637.15[M+H]+.

[1141] P19 Step 3 Synthesis of 7-bromo-2,6-dimethyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine] (INT-19c)

[1142] A solution of tert-butyl 7-bromo-1,4-bis(4-methoxybenzyl)-2,6-dimethyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (150 mg, 0.235 mmol, 1 equiv.) in mixture solvent (TFA (1 mL) ) was stirred at 60°C for 12 hours under air atmosphere. Desired product could be detected by LCMS. The mixture was allowed to cool down to rt. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification.

[1143] LC / MS: mass calcd. for C16H20N6: 296.17 m / z, found 297.10 [M+H]+.P19 Step 4 Synthesis of 1-((3S)-7-bromo-2,6-dimethyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyethan-1-one (INT-19d)

[1144] A solution of 7-bromo-2,6-dimethyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine] (100 mg, 0.336 mmol, 1 equiv.) and (5-fluoro-2-methoxypyridin-4-yl)(methoxy)acetic acid (72 mg, 0.336 mmol, 1 equiv.) in DMF (2 mL) was treated with NMI (116 mg, 1.0 mmol, 3 equiv.) and TCFH (280 mg, 1.0 mmol, 3 equiv.) at rt for 2 hours under air atmosphere. Desired product could be detected by LCMS. The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with saturation NaCI solution (1 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0-20%) to afford 1-(7-bromo-2,6-dimethyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-T-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyethan-1-one (100 mg, 60.6%) as a yellow solid.

[1145] LC / MS: mass calcd. for C21H25BrFN5O3: 493.11 m / z, found 494.15[M+H]+.

[1146] P19 Step 5 Synthesis of 1-(2,6-dimethyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyethan-1-one (Compound 19A)

[1147] A mixture of 1-(7-bromo-2,6-dimethyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-T-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyethan-1-one (100 mg, 0.202 mmol, 1 equiv.) and 2-(tributylstanny l)py rimidine (449 mg, 0.606 mmol, 3 equiv.) in dioxane (4 mL) was added Chloro(crotyl)(tri-tert-butylphosphine)palladium(ll) (8 mg, 0.02 mmol, 0.1 equiv. JWith an inert atmosphere of nitrogen, the above mixture was stirred at 100°C for 2 hours. Desired product could be detected by LCMS. The mixture was allowed to cool down to rt. The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with saturation NaCI solution (1 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0-50%) & Prep-HPLC to afford 1 -((3S)-2,6-dimethyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-T-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyethan-1-one (9.2 mg) as a yellow solid.

[1148] LC / MS: mass calcd. for C25H28FN7O3: 493.22 m / z, found 494.20 [M+H]+.

[1149]

[1150] P19 Step r1 Synthesis of tert-butyl (S)-7-bromo-1,4-bis(4-methoxybenzyl)-6-methyl-2-oxo-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate

[1151] A solution of tert-butyl (S)-7-bromo-6-methyl-2-oxo-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (2 g, 5.034 mmol, 1 equiv.) in THF (20 ml_) was added 60% NaH (1.2 g, 30.204 mmol, 6 equiv.) at 0 °C under air atmosphere. The mixture was stirred for 30 minutes at rt. Then 1-(chloromethyl)-4-methoxybenzene (4.73 g, 30.204 mmol, 6 equiv.) was added to the above mixture and stirred at 70 °C for 2 hours. Desired product could be detected by LCMS. The mixture was allowed to cool down to rt. The reaction was quenched by the addition of H2O (50 ml_) at 0°C. The resulting mixture was extracted with EA (3 x 100 ml_). The combined organic layers were washed with saturation NaCI solution (1x100 ml_), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0-50%) to afford tert-butyl (S)-7-bromo-1,4-bis(4-methoxybenzyl)-6-methyl-2-oxo-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (2.4 g, 74.77%) as a yellow solid.

[1152] LC / MS: mass calcd. for C32H37BrN4O5: 636.19 m / z, found 637.15 [M+H]+.

[1153] P19 Step r2 Synthesis of tert-butyl (3S)-7-bromo-1,4-bis(4-methoxybenzyl)-2,6-dimethyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate

[1154] tert-butyl (S)-7-bromo-1,4-bis(4-methoxybenzyl)-6-methyl-2-oxo-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (2.43 g, 3.811 mmol, 1 equiv.) in anhydrous THF (30 ml_) was treated with a solution of MeMgBr (2.27 g, 19.055 mmol, 5 equiv.) dropwise under N2 atmosphere at 0°C. After heating at 65 °C under nitrogen for 2 hours, the reaction mixture was cooled to 0°C, and HOAc (8.01 g, 133.385 mmol, 35 equiv.) and NaBH4 (0.29 g, 7.622 mmol, 2 equiv.) were added subsequently. The mixture was allowed to warm up to room temperature and stirred overnight. The reaction mixture was concentrated to remove the solvent, and 10 ml of saturated aqueous NaHCOs solution were added. A small amount of solid Na2CO3was also added to neutralize acetic acid. BOC2O was then added. The mixture was stirred at room temperature for 2 hours and then extracted with EtOAc (3 x 50 ml_). The extracts were washed with brine (10 ml), and the organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purifiedby silica gel column chromatography, eluted with EA in PE (0-30%) to afford tert-butyl (3S)-7-bromo-1,4-bis(4-methoxybenzyl)-2,6-dimethyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (1.4 g, 57.61%) as a yellow solid.

[1155] LC / MS: mass calcd. for C33H41BrN4O4: 636.23 m / z, found 637.15 [M+H]+.

[1156] P19 Step r3 Synthesis of tert-butyl (2S,3S)-7-bromo-1,4-bis(4-methoxybenzyl)-2,6-dimethyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate & tert-butyl (2R,3S)-7-bromo-1,4-bis(4-methoxybenzyl)-2,6-dimethyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1 '-carboxylate

[1157] tert-butyl (3S)-7-bromo-1,4-bis(4-methoxybenzyl)-2,6-dimethyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (1.4 g, 2.196 mmol, 1 equiv.) was seperated by silica gel column, eluted with EA in PE (0-30%) to afford tert-butyl (2R,3S)-7-bromo-1,4-bis(4-methoxybenzyl)-2,6-dimethyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate. LC / MS: mass calcd. for C33H41BrN4O4: 636.23 m / z, found 637.15 [M+H]+. TLC=0.4 (PE / EA=1:1).

[1158] And tert-butyl (2S,3S)-7-bromo-1,4-bis[(4-methoxyphenyl)methyl]-2,6-dimethyl-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (600 mg) as yellow solids. LC / MS: mass calcd. for C33H41BrN4O4: 636.23 m / z, found 637.20 [M+H]+. TLC=0.5 (PE / EA=1:1).

[1159] P19 Step r4 Synthesis of tert-butyl (2S,3S)-1,4-bis(4-methoxybenzyl)-2,6-dimethyl-7-(pyrimidin-2-y l)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1 '-carboxylate

[1160] A mixture of tert-butyl (2S,3S)-7-bromo-1,4-bis(4-methoxybenzyl)-2,6-dimethyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (400 mg, 0.627 mmol, 1 equiv.) and 2-(tributylstannyl)pyrimidine (347 mg, 0.941 mmol, 1.5 equiv.) in dioxane (4 mL) was added Chloro(crotyl)(tri-tert-butylphosphine)palladium(ll) (25 mg, 0.063 mmol, 0.1 equiv. JWith an inert atmosphere of nitrogen, the above mixture was stirred at 100 °C for 2 hours. Desired product could be detected by LCMS. The mixture was allowed to cool down to rt. The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with saturation NaCI solution (1 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0-50%) to afford tert-butyl (2S,3S)-1,4-bis(4-methoxybenzyl)-2,6-dimethyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (300 mg, 75.10%) as a yellow solid.

[1161] LC / MS: mass calcd. for C37H44N6O4: 636.342 m / z, found 637.25 [M+H]+.

[1162] P19 Step r5 Synthesis of (2S,3S)-2,6-dimethyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]

[1163] A solution of tert-butyl (2S,3S)-1,4-bis(4-methoxybenzyl)-2,6-dimethyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (300 mg, 0.471 mmol, 1 equiv.) in mixture solvent (TFA (1 mL) ) was stirred at 70 °C for 12 hours under air atmosphere. Desiredproduct could be detected by LCMS. The mixture was allowed to cool down to rt. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification.

[1164] LC / MS: mass calcd. for CieH2oNe: 296.17 m / z, found 297.10 [M+H]+.

[1165] P19 Step r6 Synthesis of 1-((2S,3S)-2,6-dimethyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyethan -1 -one

[1166] A solution of (2S,3S)-2,6-dimethyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine] (140 mg, 0.472 mmol, 1 equiv.) and (5-fluoro-2-methoxypyridin-4-yl)(methoxy)acetic acid (101 mg, 0.472 mmol, 1 equiv.) in DMF (2 mL) was treated with NMI (116 mg, 1.416 mmol, 3 equiv.) and TCFH (397 mg, 1.416 mmol, 3 equiv.) at rt for 2 hours under air atmosphere. Desired product could be detected by LCMS. The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with saturation NaCI solution (1 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0-20%) to afford 1-[(2S,3S)-2,6-dimethyl-7-(pyrimidin-2-yl)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-T-yl]-2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyethanone (160 mg, 68.63%) as a yellow solid.

[1167] LC / MS: mass calcd. for C25H28FN7O3: 493.22 m / z, found 494.15 [M+H]+.

[1168] P19 SFC resolution 1 Synthesis of (R)-1-((2S,3S)-2,6-dimethyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-r-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyethan-1-one & (S)-1-((2S,3S)-2,6-dimethyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-r-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyethan-1-one (Examples 31 and 45)

[1169] 1-[(2S,3S)-2,6-dimethyl-7-(pyrimidin-2-yl)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-T-yl]-2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyethanone (140 mg, 0.283 mmol, 1 equiv.) was seperated by (Column: CHIRALPAK IK 2*25 cm, 5 pm; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: IPA: DCM=1: 1, Gradient (B%): isocratic 30%) to afford Example 31as a off-white solid (16.6 mg, 11.85%).1H NMR (300 MHz, Methanol-c / 4) 58.81 (dd, J = 5.0, 2.5 Hz, 2H), 8.04 (dd, J = 4.0, 1.5 Hz, 1H), 7.27 - 7.37 (m, 2H), 6.88 (dd, J = 15.1, 4.6 Hz, 1H), 5.33 (d, J = 18.6 Hz, 1H), 3.92 - 4.03 (m, 1H), 3.89 (d, J = 10.5 Hz, 3H), 3.52 - 3.83 (m, 3H), 3.44 (d, J = 3.8 Hz, 3H), 3.33 - 3.42 (m, 1H), 2.50 (d, J = 7.5 Hz, 3H), 1.90 -2.25 (m, 2H), 1.11 (dd, J = 24.2, 6.4 Hz, 3H).19F NMR (282 MHz, Methanol-c / 4) 5 -146.40, -146.42, -146.45, -146.46, -146.47. Retention Time: 1.171 min.

[1170] LC / MS: mass calcd. for C25H28FN7O3: 493.22 m / z, found 494.25 [M+H]+.

[1171] And Example 45 as an off-white solid (7.6 mg, 11.85%).1H NMR (300 MHz, Methanol-c / 4) 5 8.80-8.95(m, 2H), 7.93 - 8.09 (m, 1H), 7.79 - 7.91 (m, 1H), 7.33 - 7.47 (m, 1H), 6.83 (dd, J = 15.7, 4.6 Hz, 1H), 5.28 (d, J = 43.4 Hz, 1H), 3.91 - 4.15 (m, 1H), 3.79 - 3.90 (m, 3H), 3.66 - 3.77 (m, 2H),3.63 (s, 1H), 3.38 - 3.58(m, 4H), 2.68 - 2.83 (m, 3H), 1.94 -2.45(m, 2H), 1.11 - 1.25 (m, 3H).19F NMR (282 MHz, Methanol-d4) 6 -76.84, -77.14, -77.78, -145.34, -146.38. Retention Time: 2.518 min.

[1172] LC / MS: mass calcd. for C25H28FN7O3: 493.22m / z, found 494.25[M+H]+.

[1173]

[1174] P19 Step r7 Synthesis of tert-butyl (2R,3S)-1,4-bis(4-methoxybenzyl)-2,6-dimethyl-7-(pyrimidin-2-y l)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1 '-carboxylate

[1175] A mixture of tert-butyl (2R,3S)-7-bromo-1,4-bis(4-methoxybenzyl)-2,6-dimethyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (400 mg, 0.627 mmol, 1 equiv.) and 2-(tributy Istanny l)pyrimidine (347 mg, 0.941 mmol, 1.5 equiv.) in dioxane (4 mL) was added Chloro(crotyl)(tri-tert-butylphosphine)palladium(ll) (25 mg, 0.063 mmol, 0.1 equiv. JWith an inert atmosphere of nitrogen, the above mixture was stirred at 100°C for 2 hours. Desired product could be detected by LCMS. The mixture was allowed to cool down to rt. The resulting mixture was extracted with EA (3 x 20mL). The combined organic layers were washed with saturation NaCI solution (1 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0-50%) to afford tert-butyl (2R,3S)-1,4-bis(4-methoxybenzyl)-2,6-dimethyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (160 mg, 40.05%) as a yellow solid.

[1176] LC / MS: mass calcd. for C37H44N6O4: 636.342 / z, found 637.30[M+H]+.

[1177] P19 Step r8 Synthesis of (2R,3S)-2,6-dimethyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]

[1178] A solution of tert-butyl (2R,3S)-1,4-bis(4-methoxybenzyl)-2,6-dimethyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (150 mg, 0.236 mmol, 1 equiv.) ) in mixture solvent (TFA (1 mL) ) was stirred at 70°C for 12 hours under air atmosphere.

[1179] Desired product could be detected by LCMS. The mixture was allowed to cool down to rt. The resulting mixture was concentrated under reduced pressure. The crude product (2R,3S)-2,6-dimethyl-7-(py rimidin-2-y l)-1,4-dihydro-2H-spiro[pyrido[2, 3-b]pyrazine-3, 3'-pyrrolidine] was used in the next step directly without further purification.

[1180] LC / MS: mass calcd. for C16H20N6: 296.17m / z, found 297.10[M+H]+.P19 Step r9 Synthesis of 1-((2R,3S)-2,6-dimethyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyethan -1 -one

[1181] A solution of (2R,3S)-2,6-dimethyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine] (70 mg, 0.236 mmol, 1 equiv.) and (5-fluoro-2-methoxypyridin-4-yl)(methoxy)acetic acid (50.82 mg, 0.236 mmol, 1 equiv.) in DMF (3 ml_) was treated with NMI (58 mg, 0.708 mmol, 3 equiv.) and TCFH (198 mg, 0.708 mmol, 3 equiv.) at rt for 2 hours under air atmosphere. Desired product could be detected by LCMS. The resulting mixture was extracted with EA (3 x 20mL). The combined organic layers were washed with saturation NaCI solution (1 x 50 ml_), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0-20%) to afford 1-((2R,3S)-2,6-dimethyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-T-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyethan-1-one (100 mg, 85.79%) as a yellow solid.

[1182] LC / MS: mass calcd. for C25H28FN7O3: 493.22 m / z, found: 494.15 [M+H]+.

[1183] P19 Resolution 2 Synthesis of (R)-1-((2R,3S)-2,6-dimethyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-r-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyethan-1-one & (S)-1-((2R,3S)-2,6-dimethyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-r-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyethan-1-one (Examples 152 and 184)

[1184] 1-[(2R,3S)-2,6-dimethyl-7-(pyrimidin-2-yl)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-T-yl]-2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyethanone (100 mg, 0.202 mmol, 1 equiv.) was seperated by (Column: CHIRALPAK IK 2*25 cm, 5 pm; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: EtOH; Gradient (B%): isocratic 50) to afford Example 152 as a off-white solid (17.9 mg).1H NMR (300 MHz, Methanol-c / 4) 58.81 (dd, J = 4.9, 3.5 Hz, 2H), 7.99 (dd, J = 22.9, 1.6 Hz, 1H), 7.27 - 7.34 (m, 2H), 6.87 (dd, J = 4.6, 1.8 Hz, 1H), 5.30 (d, J = 17.8 Hz, 1H), 3.81 -4.02 (m, 4H), 3.54 - 3.77 (m, 2H), 3.48 (s, 2H), 3.42 - 3.45 (m, 2H), 3.33 - 3.41 (m, 1H), 2.49 (d, J = 3.9 Hz, 3H), 1.89 - 2.21 (m, 2H), 1.14 (dd, J = 24.7, 6.4 Hz, 3H).19F NMR (282 MHz, Methanol-c / 4) 5 -146.23, -146.24, -146.25, -146.68, -146.69, -146.70.

[1185] Retention Time: 1.176 min.

[1186] LC / MS: mass calcd. for C25H28FN7O3: 493.22m / z, found 494.25[M+H]+.

[1187] And Example 184 as a off-white solid (7.6 mg,).1H NMR (300 MHz, Methanol-c / 4) 58.82 (dd, J = 7.3, 4.9 Hz, 2H), 7.93 (dd, J = 58.2, 1.6 Hz, 1H), 7.24 - 7.40 (m, 2H), 6.84 (dd, J = 12.6, 4.6 Hz, 1H), 5.25 (d, J = 51.5 Hz, 1H), 3.91 -4.15(m, 1H), 3.82 - 3.91(m, 3H), 3.39 - 3.80(m, 5H), 3.33 -3.38(m, 2H), 2.50 (d, J = 4.0 Hz, 3H), 1.80 -2.27 (m, 2H), 1.12 (dd, J = 6.3, 5.0 Hz, 3H).19F NMR (282 MHz, Methanol-c / 4) 5 -144.53, -145.18, -145.29, -145.91, -146.49, -146.73, -146.74. Retention Time: 4.327 min.

[1188] LC / MS: mass calcd. for C25H28FN7O3: 493.22m / z, found 494.25[M+H]+.Synthesis Procedure 20 (P20)

[1189]

[1190] P20 Step 1 Synthesis of tert-butyl 7-bromo-2-cyano-6-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1 '-carboxylate (INT -20a)

[1191] With an inert atmosphere of nitrogen, to a mixture of 1, 1 ',4-tri-tert-buty I 7-bromo-6-methyl-2-oxospiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1,1',4-tricarboxylate (393 mg, 0.658 mmol, 1 equiv.) in THF (20 mL) was added a solution of diethoxy(lithio)alumane (995 mg, 7.893 mmol, 12.00 equiv.) in Et20 (25 mL) dropwise at 0°C over 15 min, it was stirred at 0°C for 3h. After which AcOH (790 mg, 13.160 mmol, 20 equiv.) and a solution of KCN (257 mg, 3.948 mmol, 6 equiv.) in H2O (4 mL) was added to the mixture. The resulting mixture was warmed to 50 °C and stirred at 50 °C overnight.

[1192] Desired product could be detected by LCMS. After cooling down to rt, it was quenched with saturated sodium bicarbonate aqueous solution (100 mL), extracted with EtOAc (3 x 100 mL), the organic phase was dried over Na2SO4, filtered and concentrated. The residue was applied onto a silica gel column(40g, EtOAc / PE: 1 / 3) to give tert-butyl 7-bromo-2-cyano-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (180 mg, 67.03%) as light yellow solid.

[1193] LC / MS: mass calcd. for C17H18BrN5O2: 407.10 m / z, found: 408.20, 410.20 [M+H, M+H+2]+.

[1194] P20 Step 2 Synthesis of tert-butyl 2-cyano-6-methyl-7-(pyrimidin-2-yl)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-r-carboxylate (INT-20b)

[1195] To a stirred solution / mixture of tert-butyl 7-bromo-2-cyano-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (180 mg, 0.441 mmol, 1 equiv.) and 2-(tributylstannyl)pyrimidine (488 mg, 1.323 mmol, 3 equiv.) in dioxane (10 mL) was added [P(tBu)3] Pd(crotyl)CI (9 mg, 0.044 mmol, 0.1 equiv.) dropwise / in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 4 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched with water at room temperature. The aqueous layer was extracted with EtOAc (3 x 20 mL). The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford tert-butyl 2-cyano-6-methyl-7-(pyrimidin-2-yl)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (120 mg, 66.80%) as a yellow solid.

[1196] LC / MS: mass calcd. For C21H25N7O2: 407.20, found: 408.30[M+H]+.

[1197] P20 Step 3 Synthesis of 6-methyl-7-(pyrimidin-2-yl)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-2-carbonitrile hydrochloride (INT-20c)

[1198] To a solution of tert-butyl 2-cyano-6-methyl-7-(pyrimidin-2-yl)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (120 mg, 0.294 mmol, 1 equiv.) in dioxane (3 mL) wasadded a solution of 4N HCI in dioxane (5 ml_). The reaction was stirred at room temperature for 2h under air atmosphere. It was concentrated to give 100 mg of 6-methyl-7-(pyrimidin-2-y l)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-2-carbonitrile hydrochloride as light yellow solid.

[1199] LC / MS: mass calcd. For C9H10FNO4: 307.36, found: 308.30 [M+H]+.

[1200] P20 Step 4 Synthesis of 1'-[2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyacetyl]-6-methyl-7-(pyrimidin-2-yl)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-2 -carbonitrile formate (Compound 20A)

[1201] To a stirred mixture of 6-methyl-7-(pyrimidin-2-yl)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3, 3'-pyrrolidine]-2-carbonitrile hydrochloride (100 mg, 0.245 mmol, 1 equiv.) and TCFH (137 mg, 0.490 mmol, 2 equiv.) in DMF (5 ml_) were added NMI (201 mg, 2.449 mmol, 10 equiv.) and (5-fluoro-2-methoxypyridin-4-yl)(methoxy)acetic acid (53 mg, 0.245 mmol, 1 equiv.) at room temperature under air atmosphere. The reaction was quenched with water at room temperature. The aqueous layer was extracted with EtOAc (3 x 30 ml_). The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column, 30*150 mm, 5pm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 3% B to 22% B in 10min; Wave Length: 254nm / 220nm nm;

[1202] RT1(min): 10.23) to afford 1'-[2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyacetyl]-6-methyl-7-(pyrimidin-2-yl)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-2-carbonitrile formate (45 mg, 28.1%) as a yellow solid.

[1203] LC / MS: mass calcd. for C25H25FN8O3: 504.20, found: 505.25 [M+H]+.

[1204]

[1205] P20 SFC Separation Synthesis of (2R)-T-((R)-2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyacetyl)-6-methyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-2 -carbonitrile AND (3S)-1'-(2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyacetyl)-6-methyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-2-carbonitrile & (3R)-1'-(2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyacetyl)-6-methyl-7-(pyrimidin-2-yl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-2 -carbonitrile (Example 84, compound 20B and compound 20C)

[1206] T-[2-(5-fluoro-2-methoxypyridin-4-yl)-2-methoxyacetyl]-6-methyl-7-(pyrimidin-2-yl)-2,4-dihydro-1 H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-2-carbonitrile (40 mg, 0.073 mmol, 1 equiv.) was separated by Prep-Chiral HPLC with the following conditions (Column: CHIRALPAK IH 2*25 cm,5 pm; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: EtOH, Gradient (B%): isocratic 50) to afford Compound 20B (6.1 mg) as a white solid.1H NMR (300 MHz, Methanol-c / 4) 58.91-8.81 (m, 2H), 8.08-7.86 (m, 1H), 7.55-7.47 (m, 1H), 7.41-7.25 (m, 1H), 6.98-6.79 (m, 1H), 5.38-5.16 (m, 1H), 4.54 (dd, J = 19.3, 4.3 Hz, 1H), 3.95-3.87 (m, 3H), 3.87-3.53 (m, 3H), 3.52-3.47 (m, 3H), 3.39 (s, 1H), 2.54 (s, 3H), 2.46-1.88 (m, 2H). Retention Time: 1.867 min.

[1207] LC / MS: mass calcd. For C25H25FN8O3: 504.20, found: 505.30 [M+H]+.

[1208] And Example 84 (5.9 mg) as a white solid.1H NMR (300 MHz, Methanol-c / 4) 58.97-8.81 (m, 2H), 8.11-7.95 (m, 1H), 7.52 (d, J= 7.0 Hz, 1H), 7.40-7.28 (m, 1H), 6.97-6.79 (m, 1H), 5.41-5.18 (m, 1H), 4.60-4.44 (m, 1H), 3.95-3.89 (m, 3H), 3.87-3.58 (m, 3H), 3.54-3.44 (m, 3H), 3.39 (s, 1H), 2.64-2.52 (m, 3H), 2.38-1.97 (m, 2H). Retention Time: 2.751 min.

[1209] LC / MS: mass calcd. For C25H25FN8O3: 504.20, found: 505.30 [M+H]+.

[1210] And Compound 20C (10.8 mg) as a white solid.1H NMR (300 MHz, Methanol-c / 4) 58.91-8.81 (m, 2H), 8.11-7.97 (m, 1H), 7.56-7.47 (m, 1H), 7.47-7.25 (m, 1H), 6.97-6.79 (m, 1H), 5.41-5.15 (m, 1H), 4.65-4.44 (m, 1H), 3.99-3.89 (m, 3H), 3.88-3.55 (m, 3H), 3.54-3.44 (m, 3H), 3.42-3.37 (m, 1H), 2.61-2.52 (m, 3H), 2.38-1.95 (m, 2H). Retention Time: 4.591 min.

[1211] LC / MS: mass calcd. For C25H25FN8O3: 504.20, found: 505.30 [M+H]+.

[1212] Synthesis Procedure 21 (P21)

[1213] -

[1214]

[1215] P21 Step 1 Synthesis of 1 '-(tert-butyl) 7-methyl (R)-6-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1',7-dicarboxylate (INT-21a)

[1216] To a solution of tert-butyl (3R)-7-bromo-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (500 mg, 1.304 mmol, 1 equiv.) in MeOH (10 mL) and 1,4-dioxane (10 mL) was added Mo(CO)6 (67 mg, 0.326 mmol, 0.25 equiv.), K3PO4 (276 mg, 1.304 mmol, 1 equiv.), DMAP (79 mg, 0.652 mmol, 0.5 equiv.), Xantphos (75 mg, 0.130 mmol, 0.1 equiv.), and Pd(OAc)2 (14 mg, 0.065 mmol, 0.05 equiv.). The reaction was stirred at 100°C for 3 h. Quenched with water (50 mL) and extracted with EA (3 x 50 mL). The combined extracts were washed with water, brine, driedover Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel with EA / PE (0-100%) to give 1 '-tert-butyl 7-methyl (3R)-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidine]-1',7-dicarboxylate (300 mg, 63.45%) as a yellow solid.

[1217] LC / MS: mass calcd. for C18H26N4O4: 362.19, m / z, found: 363.43 [M+H]+.

[1218] P21 Step 2 Synthesis of methyl (S)-6-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-7 -carboxylate (INT -21 b)

[1219] To a solution of 1 '-tert-butyl 7-methyl (3R)-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidine]-T,7-dicarboxylate (300 mg, 0.828 mmol, 1 equiv.) in DCM (10 mL) was added TFA (2 mL). The reaction was stirred for 1h at rt. The resulting mixture was concentrated under vacuum to afford methyl (3R)-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-7-carboxylate (350 mg crude) as light yellow oil.

[1220] LC / MS: mass calcd. for C13H18N4O2: 262.14, found: 263.15 [M+H]+.

[1221] P21 Step 3 Synthesis of methyl (R)-1'-((R)-2-(5-fluoro-2-methoxypyridin-4-yl)propanoyl)-6-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-7 -carboxylate (INT-21c) To a solution of methyl (3R)-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidine]-7-carboxylate (272 mg, 1.037 mmol, 1 equiv.) in DMF (15 mL) was added (2R)-2-(5-fluoro-2-methoxypyridin-4-yl) propanoic acid (206 mg, 1.037 mmol, 1 equiv.), DMAP (380 mg, 3.111 mmol, 3 equiv.), EDCI (321 mg, 2.074 mmol, 2 equiv.) at room temperature. The reaction was stirred at rt for 2 h. The aqueous layer was extracted with EA (50 mL x 2). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (0-50%) to afford methyl (3R)-1'-[(2R)-2-(5-fluoro-2-methoxypyridin-4-yl) propanoyl]-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidine]-7-carboxylate (304 mg, 66.11 %) as a white solid.

[1222] LC / MS: mass calcd. for C22H26FN5O4: 443.19, found: 444.22 [M+H]+.

[1223] P21 Step 4 Synthesis of (R)-1'-((R)-2-(5-fluoro-2-methoxypyridin-4-yl)propanoyl)-6-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-7-carboxylic acid (INT-21d)

[1224] To a solution of methyl (3R)-1'-[(2R)-2-(5-fluoro-2-methoxypyridin-4-yl) propanoyl]-6-methyl-2,4-dihydro-1 H-spiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidine]-7-carboxylate (100 mg, 0.225 mmol, 1 equiv.) in MeOH / H2O (10 mL / 2 mL) was added NaOH (45 mg, 1.125 mmol, 5 equiv.). The reaction was stirred for 1h at rt. The resulting mixture was diluted with H2O (10 mL). The mixture was acidified to 5-6 with HCI. The aqueous layer was extracted with EA (2 x 20 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 reversed phase column chromatography, eluted with MeCN / H2O (10% - 100%) to afford (3R)-1'-[(2R)-2-(5-fluoro-2-methoxypyridin-4-yl)propanoyl]-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-7-carboxylic acid (80 mg, 82.61 %) as white solid.

[1225] LC / MS: mass calcd. for C21H24FN5O4: 429.18, found: 430.15 [M+H]+.P21 Step 5 Synthesis of (R)-1'-((R)-2-(5-fluoro-2-methoxypyridin-4-yl)propanoyl)-N, N,6-trimethyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-7 -carboxamide (Compound 14A)

[1226] To a stirred solution of (3R)-T-[(2R)-2-(5-fluoro-2-methoxypyridin-4-yl) propanoyl]-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidine]-7-carboxylic acid (80 mg, 0.186 mmol, 1 equiv.) in DMF (10 ml_) was added dimethylamine (41 mg, 0.930 mmol, 5 equiv.), DIEA (72.23 mg, 0.558 mmol, 3 equiv.), HATU (141 mg, 0.372 mmol, 2 equiv.) at room temperature, the reaction was quenched with water (15 ml_) and extracted with EA (20 ml_ x 3). The combined extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC using a XSelect CSH Prep C18 OBD Column, 30*150 mm, 5μm Column (eluent: 3% B to 27% (V / V), water and MeCN with 0.05% 10 mmol / L NH4HCO3 + 0.05% NH3. H2O) to afford the (3R)-1'-[(2R)-2-(5-fluoro-2-methoxypyridin-4-yl) propanoyl]-N, N, 6-trimethyl-2,4-dihydro-1H-spiro[pyrido[2,3-b] pyrazine-3,3'-pyrrolidine]-7-carboxamide hydrochloride (2.7 mg, 3.14%) as a yellow solid.

[1227] 1H NMR (400 MHz, Methanol-d4) 56.84 - 6.53 (m, 1H), 3.96 - 3.84 (m, 2H), 3.65 - 3.56 (m, 10H), 3.14 - 3.07 (m, 2H), 3.02 -2.91 (m, 2H), 2.68 (t, J = 5.6 Hz, 2H), 2.32 - 1.88 (m, 3H), 1.50 -1.40 (m, 2H), 1.39 - 1.29 (m, 3H), 1.19 - 1.12 (m, 1H), 0.93 (t, J = 6.8 Hz, 1H).

[1228] LC / MS: mass calcd. for C23H29FN6O3: 456.23, found: 457.30 [M+H]+.

[1229] Synthesis Procedure 22 (P22)

[1230]

[1231] P22 Step 1 Synthesis of tert-butyl (3R)-1,4-dibenzyl-7-bromo-6-methyl-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (INT-22a)

[1232] To a mixture of tert-butyl (3R)-7-bromo-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (1 g, 2.609 mmol, 1 equiv.) in DMF (30 ml_) was added and 60% NaH (0.52 g, 13.045 mmol, 5 equiv.) in portions at 0°C and stirred at 0°C for 30min under nitrogen atmosphere. After which BnBr (0.89 g, 5.218 mmol, 2 equiv.) was added to the mixture at 0°C. Theresulting mixture was stirred at room temperature for 2h. The reaction was quenched with ice water (40 mL). The aqueous layer was extracted with EtOAc (3 x 50 mL). The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl (3R)-1,4-dibenzyl-7-bromo-6-methyl-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (900 mg, 61.21%) as a light yellow solid.

[1233] LC / MS: mass calcd. For C30H35BrN4O2: 562.20, found: 563.30 [M+H]+.

[1234] P22 Step 2 Synthesis of tert-butyl (3R)-1,4-dibenzyl-7-fluoro-6-methyl-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate ( INT-22b)

[1235] With an inert atmosphere of nitrogen, to a mixture of tert-butyl (3R)-1,4-dibenzyl-7-bromo-6-methyl-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (760 mg, 1.349 mmol, 1 equiv.) in THF (30 mL) was added n-BuLi (3.24 mL, 8.100 mmol, 6.01 equiv.) dropwise at -78°C, it was stirred at -78°C for 30 min. After which a solution of N-(benzenesulfonyl)-S-phenylfluoranesulfonamido (2126 mg, 6.745 mmol, 5 equiv.) in THF (15 mL) was added dropwised to the mixture over 30 min. The reaction was stirred at -78°C for 30 min, allowed to warm to rt over 2h. The resulting mixture was stirred at rt overnight. Desired product could be detected by LCMS. It was quenched with saturated ammonium chloride aqueous solution (50 mL), extracted with EtOAc (3 x 50 mL), the organic phase was dried over Na2SO4, filtered and concentrated. The residue was applied onto a silica gel column(40g, EtOAc / PE: 1 / 3) to give tert-butyl (3R)-1,4-dibenzyl-7-fluoro-6-methyl-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (500 mg, 73.76%) as light yellow solid.

[1236] LC / MS (ESI): mass calcd. for C30H35FN4O2: 502.27 m / z, found: 503.45 [M+H]+.

[1237] P22 Step 3 Synthesis of tert-butyl (3R)-7-fluoro-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-r-carboxylate ( INT-22c)

[1238] To a stirred mixture of tert-butyl (3R)-1,4-dibenzyl-7-fluoro-6-methyl-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (120 mg, 0.239 mmol, 1 equiv.) in MeOH (10 mL) was added Pd / C (50.81 mg, 0.478 mmol, 2 equiv.) and con. HCI (10 mg) at room temperature. The reaction was stirred at rt under hydrogen atmosphere for 1h. The resulting mixture was filtered, the filter cake was washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tertbutyl (3R)-7-fluoro-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-T-carboxylate (70 mg, 91%) as a light yellow oil. LC / MS: mass calcd. For C16H23FN4O2: 322.20, found: 323.25 [M+H]+.

[1239] P22 Step 4 Synthesis of (S)-7-fluoro-6-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine] hydrochloride (INT-22d)

[1240] To a mixture of 1 -benzyl 1 '-tert-butyl (2R)-4-hydroxy-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydrospiro[1,8-naphthyridine-2,3'-pyrrolidine]-1, T-dicarboxylate (70 mg, 0.132 mmol, 1 equiv.) in dioxane (3 mL) was added a solution of 4N HCI in dioxane (5 mL). The reaction was stirred at rt for 1h. It was concentrated to give 56 mg of (S)-7-fluoro-6-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine] hydrochloride as light yellow solid.

[1241] LC / MS: mass calcd. For C16H19N5O: 222.20, found: 223.25 [M+H]+.P22 Step 5 Synthesis of (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[(3R)-7-fluoro-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl]propan-1-one (Example 141)

[1242] To a stirred mixture of (S)-7-fluoro-6-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine] hydrochloride (56 mg, 0.216 mmol, 1 equiv.) and TCFH (121 mg, 0.433 mmol, 2 equiv.) in DMF (5 ml_) were added NMI (177 mg, 2.164 mmol, 10 equiv.) and (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)propanoic acid (43 mg, 0.216 mmol, 1 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2h under air atmosphere. The mixture was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water(10mmol / L NH4HC03+0.05%NH3H20), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 21% B to 51% B) to afford (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[(3R)-7-fluoro-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl]propan-1-one (30 mg, 34.3%) as a light yellow solid. 1H NMR (300 MHz, Methanol-d4) 57.99 (d, J = 9.1 Hz, 1H), 6.85-6.66 (m, 1H), 6.66-6.47 (m, 1H), 4.31-4.08 (m, 1H), 3.89 (d, J = 0.8 Hz, 3H), 3.84-3.67 (m, 1H), 3.67-3.53 (m, 1H), 3.51 (d, J = 2.7 Hz, 1H), 3.23-3.02 (m, 1H), 2.99 (d, J = 3.0 Hz, 1H), 2.19 (dd, J = 5.8, 2.9 Hz, 3H), 2.14-1.93 (m, 2H), 1.52-1.38 (m, 3H).

[1243] LC / MS: mass calcd. For C20H23F2N5O2: 403.18, found:404.25 [M+H]+.

[1244] P22 Step 6 Synthesis of (R)-1-((R)-7-fluoro-1,6-dimethyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-r-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)propan-1-one (Example 143) To a mixture of (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[(3R)-7-fluoro-6-methyl-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl]propan-1-one (30 mg, 0.074 mmol, 1 equiv.) in MeOH (5 ml_) was added 30% formaldehyde (0.2 ml_), it was stirred at room temperature for 10min. After which NaBH3CN (14 mg, 0.222 mmol, 3 equiv.) was added to the mixture at room temperature. The resulting mixture was stirred at room temperature for 1h under nitrogen atmosphere. The reaction was quenched with water (15 ml_). The aqueous layer was extracted with EtOAc (3 x 30 ml_). The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water(10mmol / L NH4HC03+0.05%NH3H20), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient (B%): 30% B to 51% B in 9 min; Wave Length: 254nm / 220nm nm;

[1245] RT1(min): 7.08) to afford (R)-1-((R)-7-fluoro-1,6-dimethyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)propan-1-one (2.4 mg, 7.73%) as a yellow solid.

[1246] 1H NMR (300 MHz, Methanol-d4) 58.00 (s, 1H), 6.74 (dd, J = 14.2, 4.9 Hz, 1H), 6.61 (dd, J = 16.6, 10.9 Hz, 1H), 4.32-4.05 (m, 1H), 3.90 (s, 3H), 3.88-3.41 (m, 4H), 3.19-3.00 (m, 1H), 2.90 (s, 1H), 2.86 (d, J = 4.3 Hz, 1H), 2.66 (s, 2H), 2.25-2.15 (m, 3H). 19F NMR (282 MHz, MeOD) 5 -140.89, -147.56.

[1247] LC / MS: mass calcd. For C21H25F2N5O2: 417.19, found: 418.20 [M+H]+.Synthesis Procedure 23 (P23)

[1248]

[1249] P23 Step 1 Synthesis of 2-amino-5-methoxybenzaldehyde (INT-23a)

[1250] With an inert atmosphere of nitrogen, a solution of 5-methoxy-2-nitrobenzaldehyde (5 g, 27.60 mmol, 1 equiv.) in EA (100 mL) was added NaOAc (1 g, 12.190 mmol, 0.44 equiv.) and PtO2 (1 g, 4.404 mmol, 0.16 equiv.). Then the mixture was stirred at rt for 30 minutes under H2 atmosphere. The resulting mixture was filtered and washed with EA (1 x 50 mL). The aqueous layer was extracted with EA and H2O (3 x 100ml_). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0-30%) to afford 2-amino-5-methoxybenzaldehyde (3 g, 71.90%) as a yellow solid.

[1251] LC / MS: mass calcd. for C8H9NO2: 151.06 m / z, found: 152.10 [M+H]+.

[1252] P23 Step 2 Synthesis of 6-methoxy-3-nitroquinolin-2(1H)-one (INT-23b)

[1253] A solution of 2-amino-5-methoxybenzaldehyde (0.7 g, 4.631 mmol, 1 equiv.) and nitroacetic acid ethyl ester (0.92 g, 6.947 mmol, 1.5 equiv.) in mixture solution (H2O (31 mL) and HOAc (10 mL) ) was stirred at 100°C for 2 hours under air atmosphere. The mixture was allowed to cool down to rt. The reaction was quenched with H2O (40 mL) at rt. The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with H2O (1x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (20-50%) to afford 6-methoxy-3-nitroquinolin-2(1H)-one (0.7 g, 68.65%) as a red solid.

[1254] LC / MS: mass calcd. for C10H8N2O4: 220.04 m / z, found: 221.00 [M+H]+.

[1255] P23 Step 3 Synthesis of 2-chloro-6-methoxy-3-nitroqu incline (INT-23c)

[1256] A solution of 6-methoxy-3-nitroquinolin-2(1H)-one (0.7 g, 3.179 mmol, 1 equiv.) in phosphoroyl trichloride (15 mL) was stirred at 95°C for 2 hours under air atmosphere. The mixture was allowed to cool down to rt. The reaction was quenched with cold water at 0°C. The aqueous layer was extracted with EA (3 x 50mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA in PE (0-50%) to afford 2-chloro-6-methoxy-3-nitroquinoline (0.68 g, 89.63%) as a yellow solid.

[1257] LC / MS: mass calcd. for C10H7CIN2O3: 238.01 m / z, found: 239.00 [M+H]+.

[1258] P23 Step 4 Synthesis of 1-(tert-butoxycarbonyl)-3-((6-methoxy-3-nitroquinolin-2-yl)amino)pyrrolidine-3-carboxylic acid (INT-23d)

[1259] A solution of 2-chloro-6-methoxy-3-nitroquinoline (1.3 g, 5.448 mmol, 1 equiv.) and 3-amino-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (2.51 g, 10.896 mmol, 2 equiv.) in DMF (120 mL) was treated with Cs2CO3 (5.32 g, 16.344 mmol, 3 equiv.) at 120°C for 2 hours under air atmospher.The mixture was allowed to cool down to rt. The reaction was quenched by the addition of cold water (100 mL) at 0°C. The resulting mixture was extracted with EA (3 x 40 mL). The combined organic layers were washed with saturation NaCI solution (1x100 ml), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0-20%) to afford 1-(tert-butoxycarbonyl)-3-((6-methoxy-3-nitroquinolin-2-yl)amino)pyrrolidine-3-carboxylic acid (1.2 g, 50.94%yield, 95%purity) as a red solid.

[1260] LC / MS: mass calcd. for C20H24N4O7: 432.16 m / z, found: 433.15 [M+H]+.

[1261] P23 Step 5 Synthesis of tert-butyl 8-methoxy-2-oxo-1,4-dihydro-2H-spiro[pyrazino[2,3-b]quinoline-3,3'-pyrrolidine]-r-carboxylate (INT-23e)

[1262] A solution of 1-(tert-butoxycarbonyl)-3-((6-methoxy-3-nitroquinolin-2-yl)amino)pyrrolidine-3-carboxylic acid (1.2 g, 2.775 mmol, 1 equiv.) and Tetrahydroxydiboron (1.24 g, 13.875 mmol, 5 equiv.) in DMF (24 mL) was treated with 4, 4'-Bipy ridine (0.03 g, 0.222 mmol, 0.08 equiv.) at 0°C for 10 minutes under air atmosphere. Then the mixture was stirred at rt for 4 hours. Desired product could be detected by LCMS. The reaction was quenched with water at rt. The resulting mixture was extracted with EA (340 mL). The combined organic layers were washed with saturation NaCI solution (1 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0-20%) to afford tert-butyl 8-methoxy-2-oxo-1,4-dihydro-2H-spiro[pyrazino[2,3-b]quinoline-3,3'-pyrrolidine]-1'-carboxylate (0.8 g, 74.99%) as a yellow solid.

[1263] LC / MS: mass calcd. for C20H24N4O4: 384.18 m / z, found: 385.15 [M+H]+.

[1264] P23 Step 6 Synthesis of tert-butyl 8-methoxy-1,4-dihydro-2H-spiro[pyrazino[2,3-b]quinoline-3,3'-pyrrolidine]-T-carboxylate (INT-23f)

[1265] A solution of tert-butyl 8-methoxy-2-oxo-1,4-dihydro-2H-spiro[pyrazino[2,3-b]quinoline-3,3'-pyrrolidine]-1'-carboxylate (0.9 g, 2.341 mmol, 1 equiv.) in THF (10 mL) was treated with Boranetetrahydrofuran complex(1.0M in THF) (1.21 g, 14.046 mmol, 6 equiv.) at 65°C for 2 hours under air atmosphere. The mixture was allowed to cool down to rt. Desired product could be detected by LCMS. The reaction was quenched with MeOH at 0°C. The resulting mixture was extracted with EA (3 x 40 mL). The combined organic layers were washed with aq. NaCI (1x100 ml), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0-20%) to afford tert-butyl 8-methoxy-1,4-dihydro-2H-spiro[pyrazino[2,3-b]quinoline-3,3'-pyrrolidine]-T-carboxylate (0.7 g, 73.25%) as a yellow solid.

[1266] LC / MS: mass calcd. for C20H26N4O3: 370.20 m / z, found: 371.20 [M+H]+.P23 Step 7 Synthesis of 8-methoxy-1,4-dihydro-2H-spiro[pyrazino[2,3-b]quinoline-3,3'-pyrrolidine] (INT-23g)

[1267] A solution of tert-butyl 8-methoxy-1,4-dihydro-2H-spiro[pyrazino[2,3-b]quinoline-3,3'-pyrrolid ine]-1 '-carboxylate (0.81 g, 2.187 mmol, 1 equiv.) and HCI in 1,4-dioxane (4.0 M) (4 ml_) in solution MeOH (4 ml_) & DCM (8 ml_ ) was stirred at rt for 3 hours under air atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure.

[1268] 8-methoxy-1,4-dihydro-2H-spiro[pyrazino[2,3-b]quinoline-3,3'-pyrrolidine] (0.5 g, 53.19%) was obtained.

[1269] LC / MS: mass calcd. for C15H18N4O: 270.14 m / z, found: 271.15 [M+H]+.

[1270] P23 Step 8 Synthesis of 2-(5-fluoro-2-methoxypyridin-4-yl)-1-(8-methoxy-1,4-dihydro-2H-spiro[pyrazino[2,3-b]quinoline-3,3'-pyrrolidin]-T-yl)propan-1-one (Compound 23A)

[1271] A solution of 8-methoxy-1,4-dihydro-2H-spiro[pyrazino[2,3-b]quinoline-3,3'-pyrrolidine] (150 mg, 0.555 mmol, 1 equiv.) and 2, 5-dioxopyrrolidin-1 -yl 2-(5-fluoro-2-methoxypyridin-4-yl)propanoate (180 mg, 0.611 mmol, 1.1 equiv.) in DMF (10 ml_) was treated with DIEA (717 mg, 5.550 mmol, 10 equiv.) at rt for 2 hours under air atmosphere. The resulting mixture was extracted with EA and H2O (3x30mL). The combined organic layers were washed with H2O (1X50mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (0-20%) to afford crude product 2-(5-fluoro-2-methoxypyridin-4-yl)-1-(8-methoxy-1,4-dihydro-2H-spiro[pyrazino[2,3-b]quinoline-3,3'-pyrrolidin]-T-yl)propan-1-one (200 mg).

[1272]

[1273] P23 SFC Separation Synthesis of (R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((R)-8-methoxy-1,4-dihydro-2H-spiro[pyrazino[2,3-b]quinoline-3,3'-pyrrolidin]-r-yl)propan-1-one 81 (S)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((R)-8-methoxy-1,4-dihydro-2H-spiro[pyrazino[2,3-b]quinoline-3,3'-pyrrolidin]-1'-yl)propan-1-one, (R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((S)-8-methoxy-1,4-dihydro-2H-spiro[pyrazino[2,3-b]quinoline-3,3'-pyrrolidin]-r-yl)propan-1-one, AND (S)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((S)-8-methoxy-1,4-dihydro-2H-spiro[pyrazino[2,3-b]quinoline-3,3'-pyrrolidin]-1'-yl)propan-1-one (Examples 7, 52, 129 and 134)

[1274] The crude product was separated by Chiral column (Column: (R, RJ-WHELK-0 1 5pm Kromasil, 2.11*25 cm, 5 pm; Mobile Phase A: MtBE(0.5% 2M NH3-MeOH), Mobile Phase B: IPA- HPLC; Gradient (B%): isocratic 30) to afford (R)-Example 134 (13.6 mg, 8.14%) was obtained as a white solid.1H NMR (300 MHz, Methanol-d4) 57.92 (dd, J = 47.7, 1.7 Hz, 1H), 7.29-7.40 (m, 1H), 6.86-7.04 (m, 3H), 6.70-6.79 (m, 1H), 4.11-4.32 (m, 1H), 3.87-3.94 (s, 2H), 3.82-3.86 (m, 5H), 3.67-3.80 (m, 1H), 3.51-3.66 (m, 1H), 3.41-3.50 (m, 1H), 3.25 (d, J = 12.4 Hz, 1H), 3.18 (d, J = 10.5 Hz, 1H), 1.92-2.82(m, 2H), 1.45 (dd, J = 11.6, 6.9 Hz, 3H).19F NMR (282 MHz, Methanol-d4) 5 -147.32, -147.54. Retention Time: 1.837 min.LC / MS: mass calcd. for C24H26FN5O3: 451.20 m / z, found: 452.25 [M+H]+.

[1275] And Example 52 (13.8 mg, 6.90%) as a off-white solid.1H NMR (300 MHz, Methanol-d4) 5 7.90 (d, J = 47.3 Hz, 1H), 7.33 (t, J= 8.1 Hz, 1H), 6.98 (d, J = 6.7 Hz, 1H), 6.84 - 6.94 (m, 2H), 6.72 (t, J = 5.5 Hz, 1H), 4.11 - 4.30 (m, 1H), 3.88 (s, 2H), 3.81 - 3.84 (m, 4H), 3.66-3.78 (m, 1H), 3.4 -3.64 (m, 2H), 3.01 - 3.26 (m, 3H), 1.97 - 2.25 (m, 2H), 1.37 - 1.50(m, 3H).19F NMR (282 MHz, Methanol-c / 4) 5 -147.35, -147.58. Retention Time: 2.044 min.

[1276] LC / MS: mass calcd. for C24H26FN5O3: 451.20 m / z, found: 452.15 [M+H]+.

[1277] And 2-(5-fluoro-2-methoxypyridin-4-yl)-1-((S)-8-methoxy-1,4-dihydro-2H-spiro[pyrazino[2,3-b]quinoline-3,3'-pyrrolidin]-T-yl)propan-1-one. The product was separated by Chiral column (CHIRALPAK IA, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH), Mobile Phase B: EtOH; Gradient (B%): isocratic 40) to get Example 7 (9.9 mg, 4.93%) as a white solid.1H NMR (300 MHz, Methanol-c / 4) 57.99 (dd, J= 9.3, 1.7 Hz, 1H), 7.36 (t, J = 8.4 Hz, 1H), 6.86 - 7.03 (m, 3H), 6.76 (dd, J = 10.2, 5.0 Hz, 1H), 4.09 - 4.33 (m, 1H), 3.90 (s, 3H), 3.70 - 3.85 (m, 5H), 3.48 - 3.68 (m, 2H), 3.18 -3.29 (m, 1H), 2.92 - 3.17 (m, 1H), 2.02 - 2.27 (m, 2H), 1.45 (t, J = 6.7 Hz, 3H).19F NMR (282 MHz, Methanol-c / 4) 5 -147.18, -147.19, -147.32, -147.49, -147.54. Retention Time: 1.738 min.

[1278] LC / MS: mass calcd. for C24H26FN5O3: 451.20 m / z, found: 452.25 [M+H]+.

[1279] And Example 129 (9.2 mg, 4.57%) as a white solid.1H NMR (300 MHz, Methanol-c / 4) 57.97 (dd, J = 8.8, 1.7 Hz, 1H), 7.34 (t, J= 7.9 Hz, 1H), 6.85 - 7.06 (m, 3H), 6.74 (dd, J = 9.3, 4.9 Hz, 1H), 4.10 - 4.31 (m, 1H), 3.88 (s, 3H), 3.70 - 3.85 (m, 4H), 3.48 - 3.66 (m, 2H), 3.16 - 3.27 (m, 2H), 2.99 -3.15 (m, 1H), 1.90 - 2.31(m, 2H), 1.43 (dd, J = 6.9, 5.5 Hz, 3H).19F NMR (282 MHz, Methanol-c / 4) 5 -147.22, -147.52. Retention Time: 2.658 min.

[1280] LC / MS: mass calcd. for C24H26FN5O3: 451.20 m / z, found: 452.15 [M+H]+.

[1281] Synthesis Procedure 24 (P24)

[1282]

[1283] P24 Step 1 Synthesis of 1-(tert-butoxycarbonyl)-3-((6-(methoxycarbonyl)-3-nitropyridin-2-yl)amino)pyrrolidine-3-carboxylic acid (INT-24a)

[1284] To a mixture of 3-amino-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (15 g, 65.143 mmol, 1 equiv.) and CS2CO3 (42.45 g, 130.287 mmol, 2.00 equiv.) in DMF (200 mL) was added methyl 6-chloro-5-nitropyridine-2-carboxylate (14.11 g, 65.149 mmol, 1.00 equiv.) in portions. The reaction was stirred at rt overnight. Desired product could be detected by LCMS. The mixture was poured into ice / water (1.5 L), The mixture was acidified to pH 5 with 2N HCI. The solid was collected by filtration to give 1-(tert-butoxycarbonyl)-3-{[6-(methoxycarbonyl)-3-nitropyridin-2-yl]amino}pyrrolidine-3-carboxylic acid (15 g, 56.11%) as off-white solid.P24 Step 2 Synthesis of 1 '-(tert-butyl) 6-methyl 2-oxo-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1',6-dicarboxylate (INT-24b)

[1285] To a mixture of 1-(tert-butoxycarbonyl)-3-{[6-(methoxycarbonyl)-3-nitropyridin-2-yl]amino}pyrrolidine-3-carboxylic acid (14 g, 34.114 mmol, 1 equiv.) in DMF (300 mL) was added (dihydroxyboranyl)boronic acid (9.18 g, 102.342 mmol, 3 equiv.) and 4-( py ridin-4-y l)py ridine (0.27 g, 1.706 mmol, 0.05 equiv.) at 0°C. The reaction mixture was stirred at rt for 12h. It was diluted with EA (600 mL), washed with water (3 x 150 mL), brine (150 mL). The organic phase was dried over Na2SO4, filtered and concentrated. The crude product which was directly purified by flash chromatography (0-20% DCM / MeOH) to afford 1'-tert-butyl 6-methyl 2-oxo-1,4-dihydrospiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1',6-dicarboxylate (10 g, 80.89%yield, 95.029%purity) as yellow solid.

[1286] LC / MS: mass calcd. for C17H22N4O5, 362.15 m / z, found 385.00 [M+Na]+.

[1287] P24 Step 3 Synthesis of tert-butyl 6-(hydroxymethyl)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (INT-24c)

[1288] To a solution of 1'-tert-butyl 6-methyl 2-oxo-1,4-dihydrospiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1',6-dicarboxylate (500 mg, 1.380 mmol, 1 equiv.) in THF (10 mL) under nitrogen atmosphere was added Borane-tetrahydrofuran complex (1.0M in THF) (13.80 mL, 13.800 mmol, 10 equiv.) at 0°C. The mixture was stirred at 60°C for 4h. After cooling down to 0°C, It was quenched with MeOH (30 mL). The resulting mixture was concentrated under vacuum to yield a crude product which was directly purified by flash chromatography (0-10% DCM / MeOH) to afford tert-butyl 6-(hydroxymethyl)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (200 mg, 45.24%) as yellow green solid.

[1289] LC / MS: mass calcd. for C16H24N4O3, 320.18 m / z, found 321.20 [M+H]+.

[1290] P24 Step 4 Synthesis of (3S)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-6-ylmethanol hydrochloride (INT-24d)

[1291] To a mixture of tert-butyl 6-(hydroxymethyl)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carboxylate (150 mg, 0.468 mmol, 1 equiv.) in dioxane (4 mL) was added HCI in 1,4-dioxane (4.0 M) (4 mL). The reaction mixture was stirred at rt for 4h. The resulting mixture was concentrated under vacuum to give (3S)-2,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-6-ylmethanol hydrochloride (120 mg) as yellow soild.

[1292] LC / MS: mass calcd. for C11H16N4O, 220.13 m / z, found 221.15 [M+H]+.

[1293] P24 Step 5 Synthesis of 2-(5-fluoro-2-methoxypyridin-4-yl)-1-(6-(hydroxymethyl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl)propan-1-one (INT-24e)

[1294] A solution of (1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-6-yl)methanol (110 mg, 0.428 mmol, 1 equiv.) in DMF (5 mL) was treated with DIEA (166 mg, 1.284 mmol, 3 equiv.) and 2,5-dioxopyrrolidin-1-yl 2-(5-fluoro-2-methoxypyridin-4-yl)propanoate (127 mg, 0.428 mmol, 1equiv.). The reaction mixture was stirred at rt for 1h. The compound was purified by reverse phase flash with the following conditions (0-60% Water (0.05%NH₄HCO₃) / ACN) to give 2-(5-fluoro-2-methoxypyridin-4-yl)-1-(6-(hydroxymethyl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl)propan-1-one (100 mg, 58.14%) as yellow solid.

[1295] LC / MS: mass calcd. for C20H24FN5O3, 401.18 m / z, found 402.15 [M+H]+.

[1296] P24 Step 6 Synthesis of 2-(5-fluoro-2-methoxypyridin-4-yl)-1-[6-(hydroxymethyl)-1-methyl-2,4-dihydrospiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl]propan-1-one (Example 182)

[1297] To a mixture of 2-(5-fluoro-2-methoxypyridin-4-yl)-1-(6-(hydroxymethyl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl)propan-1-one (90 mg, 0.224 mmol, 1 equiv.) in MeOH (5 ml_) was added Formaldehyde solution (68 mg, 2.240 mmol, 10 equiv.). The reaction mixture was stirred at rt for 30min. After, NaBH3CN (141 mg, 2.240 mmol, 10 equiv.) was added to the mixture. The reaction mixture was stirred at rt for 20min. It was quenched with water (10 ml_), extracted with EA (3 x 30 ml_), the organic phase was dried over Na₂SO₄, filtered and concentrated. The residue was applied onto a silica gel column (0-10% DCM / MeOH) to give a crude product which was further purified by Prep-HPLC using a Column: XBridge Prep C18 OBD Column, 30*150 mm, 5pm(eluent: 3% to 26%ACN and Water(0.1% FA) to give 2-(5-fluoro-2-methoxypyridin-4-yl)-1-(6-(hydroxymethyl)-1-methyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidin]-1'-yl)propan-1-one (2.2 mg, 2.26%) as white solid.1H NMR (400 MHz, Methanol-d4) 58.06-7.83 (m, 1H), 6.89-6.61 (m, 3H), 4.65-4.51 (m, 1H), 4.50-4.36 (m, 2H), 4.23-4.08 (m, 1H), 3.85 (d, J = 7.4 Hz, 3H), 3.81-3.36 (m, 3H), 3.27-2.95 (m, 2H), 2.95-2.80 (m, 3H), 2.66 (s, 1H), 2.12-1.95 (m, 2H), 1.48-1.41 (m, 3H).

[1298] LC / MS: mass calcd. for C21H26FN5O3, 415.20 m / z, found 416.20 [M+H]+.

[1299] EXAMPLES

[1300] Synthesis Examples 1 -213

[1301] Table 3. Method of Synthesis and physiochemical data for Examples 1 -213

[1302] Example Compound Method of1H NMR (400 MHz, methanol-d4) X; Number Synthesis Mass spec, observed ion m / z [M+H]+

[1303] (R)-2-(5-fluoro-2- Run following 1H NMR (300 MHz, Methanol-d4) 5 methoxy-4-py ridy l)-1 - Procedure 1. steps 8.81 (d, J = 4.9 Hz, 2H), 8.09-7.93 (m, [(R)-4-methyl-7-methyl- 1 and 7 run with 1H), 7.40-7.17 (m, 2H), 6.73 (dq, J = 6-(2-py rimidiny I)- enantiopure starting 15.4, 5.0 Hz, 1H), 4.20 (dq, J = 30.4, 1,1',4,8-tetraaza-3,4- materials to provide 6.8 Hz, 1H), 3.88 (s, 3H), 3.73 (m, J = dihydro-1H- an analog of 13.0, 4.3 Hz, 1H), 3.62-3.46 (m, 2H), spiro[naphthalene-2,3'- Example 193, 3.36 (d, J = 12.1 Hz, 1H), 3.09 (d, J = pyrrolidin]-1 '-y l]-1 - isolated as a single 18.4 Hz, 1H), 2.95 (s, 1H), 2.84 (s, 1H), propanone isomer 2.69 (s, 2H), 2.50 (d, J = 3.3 Hz, 3H),

[1304] 2.21-1.97 (m, 2H), 1.43 (m, J = 8.8, 6.9Example Compound Method of1H NMR (400 MHz, methanol-d4) X; Number Synthesis Mass spec, observed ion m / z [M+H]+

[1305] Hz, 3H); Mass spec, observed ion m / z [M+H]+ 478.1

[1306] 2 1-[6-[5-(difluoromethyl)- Run following 1H NMR (400 MHz, Methanol-d4) 5 1-methyl-1H-1,2,4- Procedure 12. Step 7.31 (d, J = 2.6 Hz, 1H), 7.13 (td, J = triazol-3-yl]-7-methyl- 1 run with 52.4, 2.2 Hz, 1H), 6.96-6.77 (m, 3H), 1,1',4,8-tetraaza-3,4- alternative known 4.08 (d, J = 1.7 Hz, 3H), 3.88 (ddd, J = dihydro-1H- acid [105184-38-1] 10.8, 8.1, 5.8 Hz, 1H), 3.79-3.38 (m, spiro[naphthalene-2,3'- to provide an analog 6H), 3.24-3.06 (m, 2H), 2.54 (d, J = 1.5 pyrrolidin]-1'-yl]-2-(3,5- of Example 21, Hz, 3H), 2.25-2.02 (m, 2H); Mass spec, difluorophenyl)-1 - isolated as a single observed ion m / z [M+H]+ 490.15 ethanone diastereomer isomer following

[1307] 2 SFC purification

[1308] p-fluorophenyl 6-[5- Run following 1H NMR (400 MHz, Methanol-d4) 5 (difluoromethyl)-1- Procedure 10. Step 7.41-6.92 (m, 5H), 4.08 (d, J = 1.1 Hz, methyl-1H-1,2,4-triazol- 2 run using 3H), 3.97-3.71 (m, 2H), 3.69 -3.58 (m, 3-yl]-7-methyl-1,1',4,8- [1185320-36-8], 1H), 3.57-3.47 (m, 1H), 3.41 (d, J = tetraaza-3,4-dihydro-1 H- skipping step 3 and 11.2 Hz, 1H), 3.29-3.15 (m, 1H), 2.56 spiro[naphthalene-2,3'- step 5 run using the (s, 3H), 2.32-2.07 (m, 2H), 1.31 (s, 1H); py rrolidine]-1 '- chloroformate Mass spec, observed ion m / z [M+H]+ carboxylate [38377-38-7] and in 474.2

[1309] diastereomer 1 a manner similar to

[1310] that of Example 148

[1311] to provide an analog

[1312] of Example 80,

[1313] isolated as a single

[1314] isomer following

[1315] SFC purification

[1316] 4 2-(5-fluoro-2-methoxy-4- Run following 1H h IMR (300 MHz, Methanol-d4) 5 pyridyl)-1-[(R)-4-(2- Procedures 15. Int- 8.89- ■8.80 (m, 2H), 8.10-7.99 (m, 1H), hydroxy-1,1- 1d used as a single 7.41- ■7.37 (m, 1H), 7.37-7.30 (m, 1H), dimethylethyl)-7-methyl- enantiomer in step 6.88 (dd, J = 12.7, 4.7 Hz, 1H), 5.43- 6-(2-py rimidiny I)- 1c, step 5c run 5.20 (m, 1H), 4.02-3.83 (m, 3H), 3.83- 1,1',4,8-tetraaza-3,4- using INT-4a to 3.60 (m, 3H), 3.60-3.51 (m, 2H), 3.49- dihydro-1H- provide an analog of 3.40 (m, 4H), 3.33 (p, J = 1.6 Hz, 3H), spiro[naphthalene-2,3'- Example 36, 3.22- ■2.94 (m, 1H), 2.56-2.47 (m, 3H), pyrrolidin]-1'-yl]-2- isolated as a single 2.28- ■2.03 (m, 3H), 1.07-0.95 (m, 3H);Example Compound Method of1H NMR (400 MHz, methanol-d4) X; Number Synthesis Mass spec, observed ion m / z [M+H]+

[1317] methoxy-1 -ethanone isomer following Mass spec, observed ion m / z [M+H]+ diastereomer 1 SFC purification 552.35

[1318] 5 (R)-2-(5-fluoro-2- Run following 1H NMR (400 MHz, Methanol-d4) 5 methoxy-4-py ridy l)-1 - Procedure 18. Run 8.82(d, J = 4.9 Hz, 2H), 8.01-7.95(m, [(R)-7-methyl-4-(3- using enantiopure 1H), 7.31(td, J = 4.9, 1.3 Hz, 1H), oxetanyl)-6-(2- starting materials to 6.94(d, J = 18.2 Hz, 1H), 6.79(t, J = 5.3 pyrimidiny l)-1, 1 ',4,8- provide an analog of Hz, 1H), 4.95(dt, J = 13.7, 6.5 Hz, 1H), tetraaza-3,4-dihydro-1 H- Example 5, isolated 4.79-4.56 (m, 2H), 4.48(dd, J = 6.8, 4.3 spiro[naphthalene-2,3'- as a single isomer Hz, 1H), 4.30-4.20(m, 2H), 3.97-3.76(m, pyrrolidin]-1'-yl]-1- 5H), 3.71-3.51(m, 2H), 2.98(dd, J = propanone 66.6, 11.1 Hz, 2H), 2.54(d, J = 6.9 Hz,

[1319] 3H), 2.33-2.04(m, 3H), 1.47(t, J = 6.6 Hz, 3H); Mass spec, observed ion m / z [M+H]+ 520.3

[1320] 6 N-(5-fluoro-2-methoxy- Run following 1H NMR (400 MHz, Methanol-d4) 5 4-pyridyl)-N-methyl-(R)- Procedure 3. Step 1 8.90 (d, J = 4.9 Hz, 2H), 8.19 (d, J = 4.8 4-methyl-7-methyl-6-(2- run using Hz, 1H), 7.80 (s, 1H), 7.43 (t, J = 4.9 pyrimidiny l)-1, 1 ',4,8- enantiopure INT-1f Hz, 1H), 6.80 (d, J = 6.1 Hz, 1H), 4.06 tetraaza-3,4-dihydro-1 H- and [3033067-95-4], (s, J = 0.9 Hz, 3H), 3.74-3.61 (m, 3H), spiro[naphthalene-2,3'- step 3 run with 3.57 (d, J = 22.1 Hz, 1H), 3.35 (s, 3H), pyrrolidine]-1'- [56423-63-3] to 3.28 (s, 1H), 3.24-3.16 (m, 2H), 3.06 (s, carboxamide provide an analog of 3H), 2.77 (s, 3H), 2.32-2.21 (m, 2H);

[1321] compound 3a, Mass spec, observed ion m / z [M+H]+ isolated as a single 479.15

[1322] isomer

[1323] 7 2-(5-fluoro-2-methoxy-4- Run following 1H NMR (300 MHz, Methanol-d4) 5 pyridyl)-1-[6-methoxy- Procedure 23. to 7.99 (dd, J = 9.3, 1.7 Hz, 1H), 7.36 (t, J 1,1',4,9-tetraaza-3,4- provide an analog of = 8.4 Hz, 1H), 7.03-6.86 (m, 3H), 6.76 dihydro-1H- compound 23a, (dd, J =10.2, 5.0 Hz, 1H), 4.22 (dq, J = spiro[anthracene-2,3'- isolated as a single 26.7, 6.8 Hz, 1H), 3.90 (s, 3H), 3.88- py rrolidin]-1 '-yl]-1- isomer following 3.71 (m, 5H), 3.70-3.48 (m, 2H),3.30- propanone diastereomer SFC purification 3.18 (m, 1H), 3.17-3.02 (m, 1H), 2.25- 2 2.16 (m, 1H), 2.11 (t, J = 7.7 Hz, 2H),

[1324] 1.45 (t, J = 6.7 Hz, 3H), 1.29 (d, J = 7.3Hz, 1H); Mass spec, observed ion m / z [M+H]+ 452.25Example Compound Method of1H NMR (400 MHz, methanol-d4) X; Number Synthesis Mass spec, observed ion m / z [M+H]+

[1325] 8 N-methyl-N-3,4,5- Run following 1H NMR (400 MHz, Methanol-d4) 5 trifluorophenyl-(R)-7- Procedure 3. Step 1 8.84 (d, J = 4.9 Hz, 2H), 8.36 (s, 1H), methyl-6-(2-pyrimidinyl)- run using 7.48-7.30 (m, 2H), 7.12-6.99 (m, 2H), 1,1',4,8-tetraaza-3,4- enantiopure INT-1f 3.56-3.47 (m, 1H), 3.42-3.30 (m, 2H), dihydro-1H- and [853767-19-8], 3.21 (s, 3H), 3.17-3.04 (m, 2H), 2.57 (s, spiro[naphthalene-2,3'- step 3 run with 3H), 2.08-2.00 (m, 2H); Mass spec, py rrolidine]-1 '- [56423-63-3] to observed ion m / z [M+H]+ 470.2 carboxamide provide an analog of

[1326] compound 3a,

[1327] isolated as a single

[1328] isomer

[1329] 9 N-3,5-dimethoxyphenyl- Run following 1H NMR (300 MHz, Methanol-d4) 5 N-methyl-(R)-7-methyl- Procedure 3. Step 1 8.79 (d, J = 4.9 Hz, 2H), 7.33-7.21 (m, 6-(2-py rimidiny I)- run using 2H), 6.32 (d, J = 1.5 Hz, 3H), 3.76 (s, 1,1',4,8-tetraaza-3,4- enantiopure INT-1f 6H), 3.43 (m, J = 12.5, 6.5 Hz, 2H), dihydro-1H- and [1797132-05-8, 3.17 (m, 4H), 3.06-2.96 (m, 3H), 2.46 spiro[naphthalene-2,3'- step 3 run with (s, 3H), 1.94 (t, J = 7.3 Hz, 2H); Mass pyrrolidine]-1 '- [56423-63-3] to spec, observed ion m / z [M+H]+ 476.2 carboxamide provide an analog of

[1330] compound 3a,

[1331] isolated as a single

[1332] isomer

[1333] 10 2-(3,5-difluorophenyl)-1- Run following 1H NMR (500 MHz, Methanol-d4) 5

[1334] [7-methyl-6-(2- Procedure 1. Step 7 8.85 (dd, J = 4.9, 1.7 Hz, 2H), 7.50 (d, J py rimidiny l)-1, 1 ',4, 8- run with alternative = 9.8 Hz, 1 H), 7.35 (t, J = 4.9 Hz, 1 H), tetraaza-3,4-dihydro-1 H- known acid 6.98-6.79 (m, 3H), 3.96-3.66 (m, 5H), spiro[naphthalene-2,3'- [105184-38-1] to 3.52 (dd, J = 49.6, 11.4 Hz, 1H), 3.27- pyrrolidin]-1'-yl]-1- provide an analog of 3.13 (m, 2H), 2.59 (d, J = 3.7 Hz, 3H), ethanone diastereomer Example 25, 2.23 (t, J = 7.3 Hz, 1H), 2.14 (td, J = 1 isolated as a single 8.0, 7.0, 2.2 Hz, 1H); Mass spec, isomer following observed ion m / z [M+H]+ 437.2 SFC purification

[1335] N-methyl[(R)-1'-[2-(5- Run following 1H NMR (300 MHz, Methanol-d4) 5 fluoro-2-methoxy-4- Procedures 16. 8.81 (d, J = 5.0 Hz, 2H), 8.02 (dd, J = pyridy l)-2- Step 1d used INT- 11.8, 1.6 Hz, 1H), 7.39-7.19 (m, 2H), methoxyacetyl]-7- 1d as a single 6.86 (dd, J = 7.2, 4.7 Hz, 1H), 5.32 (d, JExample Compound Method of1H NMR (400 MHz, methanol-d4) X; Number Synthesis Mass spec, observed ion m / z [M+H]+

[1336] methyl-6-(2-pyrimidinyl)- enantiomer, step 2d = 10.8 Hz, 1H), 4.02-3.54 (m, 9H), 3.45 1,1',4,8-tetraaza-3,4- was run with (d, J = 3.0 Hz, 3H), 3.34-3.31 (m, 1H), dihydro-1H- methylamine to 3.28-3.16 (m, 1H), 2.73 (d, J = 5.6 Hz, spiro[naphthalene-2,3'- provide an analog of 3H), 2.55 (d, J = 3.0 Hz, 3H), 2.26-2.05 pyrrolidin]-4- compound 16a, (m, 2H); Mass spec, observed ion m / z yl]acetamide isolated as a single [M+H]+ 551.3

[1337] diastereomer 1 isomer following

[1338] SFC purification

[1339] 2-(5-fluoro-2-methoxy-4- Run following 1H NMR (400 MHz, Methanol-d4) 5 py ridy l)-2-methoxy-1 - Procedures 1 and 4. 8.95-8.83 (m, 2H), 8.04 (d, J = 14.0 Hz, [(R)-7-methyl-6-(2- Step 1 run with 1H), 7.33 (s, 2H), 6.89 (d, J = 12.0, 1H), py rimidiny l)-1, 1 ',4, 8- enantiopure starting 5.32 (d, J = 33.4 Hz, 1H), 4.66-4.58 (m, tetraaza-3,4-dihydro-1 H- material, step 7 run 1H), 3.92 (s, 1H), 3.89 (s, 2H), 3.85- spiro[naphthalene-2,3'- using the acid INT- 3.71 (m, 1H), 3.61-3.59 (m, 1H), 3.50- pyrrolidin]-1'-yl]-1- 4a from Procedure 3.47 (m, 1H), 3.45-3.42 (m, 3H), 3.27- ethanone diastereomer 4, to provide an 3.04 (m, 2H), 2.51 (d, J = 8.0 Hz, 3H), 1 analog of Example 2.19-2.15 (m, 1H), 2.10-2.03 (m, 1H),

[1340] 25, isolated as a 1.35-1.31 (m, 1H); Mass spec, single isomer observed ion m / z [M+H]+ 480.25 following SFC

[1341] purification

[1342] 13 N-3,5-dimethoxyphenyl- Run following 1H NMR (400 MHz, Methanol-d4) 5 N-methyl-6-[5- Procedure 3. Run 7.29-6.98 (m, 2H), 6.35 (s, 3H), 4.07 (s, (difluoromethyl)-1- using [1797132-05- 3H), 3.78 (s, 7H), 3.51-3.40 (m, 1H), methyl-1H-1,2,4-triazol- 8] for step 1 and 3.35 (s, 1H), 3.19 (s, 3H), 3.08-2.96 (m, 3-yl]-7-methyl-1, 1 ',4,8- [2172595-12-7] for 3H), 2.52 (s, 3H), 1.95 (t, J = 7.5 Hz, tetraaza-3,4-dihydro-1 H- step 3 to provide an 2H); Mass spec, observed ion m / z spiro[naphthalene-2,3'- analog of compound [M+H]+ 529.3

[1343] py rrolidine]-1 '- 3a, isolated as a

[1344] carboxamide mixture of

[1345] stereoisomers

[1346] 14 2-(5-fluoro-2-methoxy-4- Run following 1H NMR (300 MHz, Methanol-d4) 5 py ridy l)-2-methoxy-1 - Procedure 14. Step 8.81 (dd, J = 4.9, 1.3 Hz, 2H), 8.02 (dd, [(R)-7-methyl-4-[(5- 1b used INT-1d as a J = 3.9, 1.6 Hz, 1H), 7.55 (d, J = 5.0...

Claims

What is claimed is:CLAIMS1. A compound of Formula I:or a diastereomer or enantiomer thereof, or a pharmaceutical salt thereof,whereinR1is -S(O)2(RA) or -C(O)(RA);each R2is independently H, C1-6 alkyl, oxo, -CN, C3-6 cycloalkyl, C3-6 heterocyclyl, C1-6 alkyl C3-6 heterocyclyl;R3is H, optionally substituted C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 heterocyclyl, optionally substituted C3-6 heteroaryl, -C(O)-C3-6 cycloalkyl, -C(O)-C3-6 heterocyclyl or optionally substituted C1-6 alkyl C3-6 heteroaryl;R5is H, halogen, -CN, optionally substituted C1-6 alkyl, optionally substituted alkynyl, C3-10 cycloalkyl, optionally substituted C1-10 heteroaryl, optionally substituted C3-10 heterocyclyl, -C(O)(RA), or -QA-RB;R6is C1-6 alkyl, -CH2OH, -CH2-O-(C1-6 alkyl);or R5and R6together with the atom to which both are attached, combine to form an optionally substituted C6aryl;QAis CH2, CH(RB), N(RN), or O;RAis –QB–RB,, optionally substituted C1-6 alkyl, optionally substituted C5-6 aryl, optionally substituted C3-10 cycloalkyl, optionally substituted C6 aryl, optionally substituted C8-12 bicyclic aryl, optionally substituted C5-6 heteroaryl, or optionally substituted C3-10 heterocyclyl;QBis CH2, CH(RB), N(RN), or O;RBis independently selected from -OH, -O-(Ci-e alkyl), optionally substituted C-i-e alkyl, optionally substituted Ci-e haloalkyl, optionally substituted Ce aryl, optionally substituted C8-12bicyclic aryl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkyl Ce aryl, optionally substituted Ci-e alkyl Ce aryl, optionally substituted C3-10 heterocyclyl, or optionally substituted Ci-e heteroaryl, or optionally substituted Ce-n bicyclic heteroaryl;RNis H, optionally substituted C1-6 alkyl, or RNand RBtogether with the atom to which both are attached, combine to form an optionally substituted C3-10 heterocyclyl or optionally substituted C6-11 bicyclic heterocyclyl;wherein each optionally substituted group is optionally substituted with one, two, three, or four groups independently selected from a group consisting of: halogen, oxo, C1-6 alkyl, Cs-e cycloalkyl, C1-6 haloalkyl, Cs-e aryl, substituted Cs-e aryl substituted with one, two, or three groups independently selected from halogen or C1-6 haloalkyl, C2-10 heteroaryl, C3-6 heterocyclyl, -OH, -O-(Ci-e alkyl), -O-(C3-8 cycloalkyl), -O-(Ci-e heterocycloalkyl), -O-(Ci-e haloalkyl), -C(O)NH2, -C(O)NH(Ci-e alkyl), and –C(O)N(C1-6alkyl)2;wherein each heterocyclyl or heteroaryl comprises of one, two, three, or four heteroatoms independently selected from a group consisting of nitrogen, oxygen, and sulfur.

2. The compound of claim 1, wherein R1is selected from a group consisting of:whereinn is 0, 1, 2, 3, or 4;each R1Ais independently, halogen, C1-6 alkyl, C1-6 haloalkyl, -O-(optionally substituted C1-6 alkyl), -O-(optionally substituted C3-8 cycloalkyl), -O-(C1-6 optionally substituted heterocycloalkyl), or -O-(C1-6 haloalkyl);R1Bis H, C1-6 alkyl, -OH, -O-(C1-6 alkyl), -O-(C3-8 cycloalkyl), or -O-(C1-6 heterocycloalkyl); andeach X is independently CH, C(R1A), or N.

3. The compound of claim 2, wherein R1Ais selected from a group consisting of: F, -CH3, -O-CH3,4. The compound of claim 2, wherein R1Bis selected from a group consisting of: H, -CH3, -CH2CH3, -OH, -O-CH3,5. The compound of claim 1, wherein the compound is of Formula la:whereinR1is -S(O)2(RA) or -C(O)(RA);R3is H, optionally substituted C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 heterocyclyl, optionally substituted C3-6 heteroaryl, -C(O)-Cs-6 cycloalkyl, -C(O)-C3-e heterocyclyl or optionally substituted C1-6 alkyl C3-6 heteroaryl;R5is H, halogen, -CN, optionally substituted C1-6 alkyl, optionally substituted alkynyl, C3-10 cycloalkyl, optionally substituted C1-10 heteroaryl, optionally substituted C3-10 heterocyclyl, -C(O)(RA), or -QA-RB;R6is C1-6 alkyl, -CH2OH, -CH2-O-(C1-6alkyl);or R5and R6together with the atom to which both are attached, combine to form an optionally substituted C6aryl;QAis CH2, CH(RB), N(RN), or O;< ~RBtoptionally substituted C1-6 alkyl, optionally substituted C5-6 aryl, optionally substituted C3-10 cycloalkyl, optionally substituted C6 aryl, optionally substituted C8-12 bicyclic aryl, optionally substituted C5-6 heteroaryl, or optionally substituted C3-10 heterocyclyl;QBis CH2, CH(RB), N(RN), or O;RBis independently selected from -OH, -O-(Ci-e alkyl), optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalky I, optionally substituted Ce aryl, optionally substituted C8-12bicyclic aryl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkyl Ce aryl, optionally substituted C1-6 alkyl Ce aryl, optionally substituted C3-10 heterocyclyl, or optionally substituted Ci-e heteroaryl, or optionally substituted Ce-n bicyclic heteroaryl;RNis H, optionally substituted C1-6 alkyl, or RNand RBtogether with the atom to which both are attached, combine to form an optionally substituted C3-10 heterocyclyl or optionally substituted C6-11 bicyclic heterocyclyl;wherein each optionally substituted group is optionally substituted with one, two, three, or four groups independently selected from a group consisting of: halogen, oxo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C5-6 aryl, substituted C5-6 aryl substituted with one, two, or three groups independently selected from halogen or Ci-e haloalkyl, C2-10 heteroaryl, Cs-e heterocyclyl, -OH, -O-(Ci-e alkyl), -O-(Cs-8 cycloalkyl), -O-(Ci-e heterocycloalkyl), -O-(Ci-e haloalkyl), -C(O)NH2, -C(O)NH(Ci-e alkyl), and –C(O)N(C1-6alkyl)2;wherein each heterocyclyl or heteroaryl comprises of one, two, three, or four heteroatoms independently selected from a group consisting of nitrogen, oxygen, and sulfur.

6. The compound of claim 1, wherein the compound is of Formula (lb):whereinR1is–S(O)2(RA) or–C(O)(RA);R5is H, halogen, -CN, optionally substituted C1-6 alkyl, optionally substituted alkynyl, C3-10 cycloalkyl, optionally substituted C1-10 heteroaryl, optionally substituted C3-10 heterocyclyl, -C(O)(RA), or -QA-RB;R6is C1-6 alkyl, -CH2OH, -CH2-O-(C1-6 alkyl);or R5and R6together with the atom to which both are attached, combine to form an optionally substituted C6aryl;QAis CH2, CH(RB), N(RN), or O;RB, optionally substituted Ci-e alkyl, optionally substituted Cs-e aryl, optionally substituted C3-10 cycloalkyl, optionally substituted Cearyl, optionally substituted Ce-12 bicyclic aryl, optionally substituted C3-6 heteroaryl, or optionally substituted C3-10 heterocyclyl;QBis CH2, CH(RB), N(RN), or O;RBis independently selected from -OH, -O-(Ci-e alkyl), optionally substituted Ci-e alkyl, optionally substituted C1-6haloalkyl, optionally substituted C6aryl, optionally substituted C8-12bicyclic aryl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkyl Ce aryl, optionally substituted Ci-e alkyl Ce aryl, optionally substituted C3-10 heterocyclyl, or optionally substituted Ci-e heteroaryl, or optionally substituted Ce-n bicyclic heteroaryl;RNis H, optionally substituted C1-6 alkyl, or RNand RBtogether with the atom to which both are attached, combine to form an optionally substituted C3-10 heterocyclyl or optionally substituted C6-11 bicyclic heterocyclyl;wherein each optionally substituted group is optionally substituted with one, two, three, or four groups independently selected from a group consisting of: halogen, oxo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C5-6 aryl, substituted C5-6 aryl substituted with one, two, or three groups independently selected from halogen or Ci-e haloalkyl, C2-10 heteroaryl, Cs-e heterocyclyl, -OH, -O-(Ci-e alkyl), -O-(Cs-8 cycloalkyl), -O-(Ci-e heterocycloalkyl), -O-(Ci-e haloalkyl), -C(O)NH2, -C(O)NH(Ci-e alkyl), and –C(O)N(C1-6alkyl)2;wherein each heterocyclyl or heteroaryl comprises of one, two, three, or four heteroatoms independently selected from a group consisting of nitrogen, oxygen, and sulfur.

7. The compound of claim 6, wherein the compound is of Formula lb’:whereinR1is –S(O)2(RA), –C(O)(RA); andR5is H, halogen, -CN, optionally substituted C1-6 alkyl, optionally substituted alkynyl, C3-10 cycloalkyl, optionally substituted C1-10 heteroaryl, optionally substituted C3-10 heterocyclyl, -C(O)(RA), or -QA-RB.

8. The compound of claim 1, wherein the compound is of Formula (Ic):or a pharmaceutically acceptable salt thereof,whereinR1is -S(O)2(RA) or -C(O)(RA);R5is H, halogen, -CN, optionally substituted C1-6 alkyl, optionally substituted alkynyl, C3-10 cycloalkyl, optionally substituted C1-10 heteroaryl, optionally substituted C3-10 heterocyclyl, -C(O)(RA), or -QA-RB;R6is C1-6 alkyl, -CH2OH, -CH2-O-(C1-6 alkyl);or R5and R6together with the atom to which both are attached, combine to form an optionally substituted C6aryl;QAis CH2, CH(RB), N(RN), or O;RB, optionally substituted C1-6 alkyl, optionally substituted Cs-earyl, optionally substituted C3-10 cycloalkyl, optionally substituted Cearyl, optionally substituted C8-12bicyclic aryl, optionally substituted C5-6heteroaryl, or optionally substituted C3-10 heterocyclyl;QBis CH2, CH(RB), N(RN), or O;RBis independently selected from -OH, -O-(Ci-e alkyl), optionally substituted C-i-e alkyl, optionally substituted C1-6 haloalky I, optionally substituted Ce aryl, optionally substituted Cs-12 bicyclic aryl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkyl Ce aryl, optionally substituted Ci-e alkyl Ce aryl, optionally substituted C3-10 heterocyclyl, or optionally substituted Ci-e heteroaryl, or optionally substituted Ce-n bicyclic heteroaryl;RNis H, optionally substituted C1-6 alkyl, or RNand RBtogether with the atom to which both are attached, combine to form an optionally substituted C3-10 heterocyclyl or optionally substituted C6-11 bicyclic heterocyclyl;wherein each optionally substituted group is optionally substituted with one, two, three, or four groups independently selected from a group consisting of: halogen, oxo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C5-6 aryl, substituted C5-6 aryl substituted with one, two, or three groups independently selected from halogen or Ci-e haloalkyl, C2-10 heteroaryl, Cs-e heterocyclyl, -OH, -O-(Ci-e alkyl), -O-(Cs-8 cycloalkyl), -O-(Ci-e heterocycloalkyl), -O-(Ci-e haloalkyl), -C(O)NH2, -C(O)NH(Ci-e alkyl), and –C(O)N(C1-6alkyl)2;wherein each heterocyclyl or heteroaryl comprises of one, two, three, or four heteroatoms independently selected from a group consisting of nitrogen, oxygen, and sulfur.

9. The compound of claim 1, wherein the compound is of Formula (Id):whereinn is 0, 1, or 2;each Rcis independently -OH or -O-(Ci-e alkyl);R1is -S(O)2(RA) or -C(O)(RA);each R2is independently H, C1-6 alkyl, oxo, -CN, C3-6 cycloalkyl, C3-6 heterocyclyl, or C1-6 alkyl C3-6 heterocyclyl;R3is H, optionally substituted C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 heterocyclyl, optionally substituted C3-6 heteroaryl, -C(O)-C1-6 alkyl, -C(O)-C3-6 cycloalkyl, -C(O)-C3-6 heterocyclyl or optionally substituted C1-6 alkyl C3-6 heteroaryl;RB, optionally substituted C1-6 alkyl, optionally substituted Cs-e aryl, optionally substituted C3-10 cycloalkyl, optionally substituted Cearyl, optionally substituted C8-12bicyclic aryl, optionally substituted C5-6heteroaryl, or optionally substituted C3-10 heterocyclyl;QBis CH2, CH(RB), N(RN), or O;RBis independently selected from -OH, -O-(Ci-e alkyl), optionally substituted Ci-e alkyl, optionally substituted C1-6 haloalkyl, optionally substituted Ce aryl, optionally substituted Cs-12 bicyclic aryl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkyl Ce aryl, optionally substituted Ci-e alkyl Ce aryl, optionally substituted C3-10 heterocyclyl, or optionally substituted Ci-e heteroaryl, or optionally substituted Ce-n bicyclic heteroaryl;RNis H, optionally substituted C1-6 alkyl, or RNand RBtogether with the atom to which both are attached, combine to form an optionally substituted C3-10 heterocyclyl or optionally substituted C6-11 bicyclic heterocyclyl;wherein each optionally substituted group is optionally substituted with one, two, three, or four groups independently selected from a group consisting of: halogen, oxo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C5-6 aryl, substituted C5-6 aryl substituted with one, two, or three groups independentlyselected from halogen or C1-6 haloalkyl, C2-10 heteroaryl, C3-6 heterocyclyl, -OH, -O-(Ci-e alkyl), -O-(C3-8 cycloalkyl), -O-(Ci-e heterocycloalkyl), -O-(Ci-e haloalkyl), -C(O)NH2, -C(O)NH(Ci-e alkyl), and –C(O)N(C1-6alkyl)2;wherein each heterocyclyl or heteroaryl comprises of one, two, three, or four heteroatoms independently selected from a group consisting of nitrogen, oxygen, and sulfur.

10. The compound of claim 9, wherein the compound is of Formula (Id’):

11. The compound of claim 1, wherein the compound is of Formula (le):whereinR1is -S(O)2(RA) or -C(O)(RA);each R2is independently H, Ci-e alkyl, oxo, -CN, C3-6 cycloalkyl, C3-6 heterocyclyl, or C1-6 alkyl C3-6 heterocyclyl.R3is H, optionally substituted C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 heterocyclyl, optionally substituted C3-6 heteroaryl, -C(O)-C3-6 cycloalkyl, -C(O)-C3-6 heterocyclyl or optionally substituted C1-6 alkyl C3-6 heteroaryl;R5is H, halogen, -CN, optionally substituted C1-6 alkyl, optionally substituted alkynyl, C3-10 cycloalkyl, optionally substituted C1-10 heteroaryl, optionally substituted C3-10 heterocyclyl, -C(O)(RA), or -QA-RB;QAis CH2, CH(RB), N(RN), or O;RB, optionally substituted C1-6 alkyl, optionally substituted C5-6 aryl, optionally substituted C3-10 cycloalkyl, optionally substituted C6 aryl, optionally substituted C8-12 bicyclic aryl, optionally substituted C5-6 heteroaryl, or optionally substituted C3-10 heterocyclyl;QBis CH2, CH(RB), N(RN), or O;RBis independently selected from -OH, -O-(Ci-e alkyl), optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalky I, optionally substituted Ce aryl, optionally substituted Cs-12 bicyclic aryl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkyl Ce aryl, optionally substituted C1-6 alkyl Ce aryl, optionally substituted C3-10 heterocyclyl, or optionally substituted Ci-e heteroaryl, or optionally substituted Ce-n bicyclic heteroaryl;RNis H, optionally substituted C1-6 alkyl, or RNand RBtogether with the atom to which both are attached, combine to form an optionally substituted C3-10 heterocyclyl or optionally substituted C6-11 bicyclic heterocyclyl;wherein each optionally substituted group is optionally substituted with one, two, three, or four groups independently selected from a group consisting of: halogen, oxo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C5-6 aryl, substituted C5-6 aryl substituted with one, two, or three groups independently selected from halogen or C1-6 haloalkyl, C2-10 heteroaryl, C3-6 heterocyclyl, -OH, -O-(Ci-e alkyl), -O- (C3-8 cycloalkyl), -O-(Ci-e heterocycloalkyl), -O-(Ci-e haloalkyl), -C(O)NH2, -C(O)NH(Ci-e alkyl), and –C(O)N(C1-6alkyl)2;wherein each heterocyclyl or heteroaryl comprises of one, two, three, or four heteroatoms independently selected from a group consisting of nitrogen, oxygen, and sulfur.stereoisomer thereof., or a stereoisomer thereof.

14. The compound of any one of claims 1 to 11, wherein R1is,15. The compound of any one of claims 1 to 11, wherein R1is16. The compound of any one of claims 1 to 15, wherein R5is17. The compound of any one of claims 1 to 15, wherein R5is18. The compound of any one of claims 1 to 15, wherein R5is19. The compound of claim 1, wherein the compound is selected from a group consisting of:

20. The compound of claim 19, wherein the compound is:

21. A compound selected from Table 1 or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising the compound of any one of claims 1-21 and a pharmaceutically acceptable excipient.

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