Cyclic 2-amino-3-cyanothiophenes and derivatives thereof for treatment of cancer

Abstract

The invention encompasses compounds of formula (I) # imgabs0 # wherein R1a, R1b, R2a, R2b, Z, R3 to R5, A, p, U, V and W have the meanings given in the claims and the description; the use of such compounds as inhibitors of KRAS; pharmaceutical compositions and formulations containing such compounds; and to the use of said pharmaceutical compositions and formulations as medicaments / medical, in particular as agents for the treatment and / or prophylaxis of carcinogenic diseases.

Description

[0001] This application is a divisional application of the Chinese patent application No. 2022800784990 (application date: November 30, 2022, invention name: Cyclic 2-amino-3-cyanothiophene and its derivatives for treating cancer). Technical Field

[0002] The present invention relates to cyclic 2-amino-3-cyanothiophene of formula (I) and its derivatives

[0003]

[0004] where R 1a 、R 1b 、R 2a 、R 2b , Z, R 3 to R 5 , A, p, U, V and W have the meanings given in the claims and the description, the use of the compounds as KRAS inhibitors, pharmaceutical compositions and preparations containing such compounds, and the use of the pharmaceutical compositions and preparations as pharmaceutical agents / medicines, especially for the treatment and / or prevention of carcinogenic diseases, such as cancer. Background Art

[0005] V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) is a small GTPase of the Ras protein family that exists in cells in either a GTP-bound or GDP-bound state (McCormick et al., J. Mol. Med. (Berl)., 2016, 94(3):253-8; Nimnual et al., Sci. STKE., 2002, 2002(145):pe36). Binding of GTPase-activating proteins (GAPs) such as NF1 increases the GTPase activity of Ras family proteins. Binding of guanine nucleotide exchange factors (GEFs), such as SOS1 (Son of Sevenless 1), promotes the release of GDP from Ras family proteins, enabling GTP binding (Chardin et al., Science, 1993, 260(5112):1338-43). When in the GTP-bound state, Ras family proteins are active and engage effector proteins including C-RAF and phosphoinositide 3-kinase (PI3K) to promote the RAF / mitogen- or extracellular signal-regulated kinase (MEK / ERK) pathway, the PI3K / AKT / mammalian target of rapamycin (mTOR) pathway, and the RalGDS (Ral guanine nucleotide dissociation stimulator) pathway (McCormick et al., J. Mol. Med. (Berl)., 2016, 94(3):253-8; Rodriguez-Viciana et al., Cancer Cell. 2005, 7(3): 205-6). These pathways affect different cellular processes, such as proliferation, survival, metabolism, motility, angiogenesis, immunity, and growth (Young et al., Adv. Cancer Res., 2009, 102: 1-17; Rodriguez-Viciana et al., Cancer Cell. 2005, 7(3): 205-6).

[0006] Cancer-associated mutations in Ras family proteins inhibit their intrinsic and GAP-induced GTPase activity, leading to an increase in the population of GTP-bound / active Ras family proteins (McCormick et al., Expert Opin. Ther. Targets., 2015, 19(4):451-4; Hunter et al., Mol. Cancer Res., 2015, 13(9):1325-35). This in turn leads to sustained activation of effector pathways downstream of the mutant Ras family proteins (e.g., RAF / MEK / ERK, PI3K / AKT / mTOR, RalGDS pathways). KRAS mutations (e.g., amino acids G12, G13, Q61, A146) have been found in various human cancers, including lung, colorectal, and pancreatic cancers (Cox et al., Nat. Rev. Drug Discov., 2014, 13(11):828-51). Alterations in Ras family proteins / Ras genes (e.g., mutations, overexpression, gene amplification) have also been described as resistance mechanisms to cancer drugs such as the EGFR antibodies cetuximab and panitumumab (Leto et al., J. Mol. Med. (Berl). 2014 Jul;92(7):709-22) and the EGFR tyrosine kinase inhibitor osimertinib / AZD9291 (Ortiz-Cuaran et al., Clin. Cancer Res., 2016, 22(19):4837-47; Eberlein et al., Cancer Res., 2015, 7 5(12):2489-500).

[0007] In a subset of tumor indications such as gastric cancer, gastroesophageal junction cancer, and esophageal cancer, significant amplification of the wild-type (WT) KRAS proto-oncogene acts as a driving change and makes tumor models carrying this genotype addicted to KRAS in vitro and in vivo (Wong et al. Nat Med., 2018, 24(7): 968-977). In contrast, non-amplified KRAS WT cell lines are independent of KRAS unless they carry secondary changes in genes that indirectly cause KRAS activation (Meyers et al. Nat Genet., 2017, 49: 1779-1784). Based on these data, KRAS targeting agents with KRAS WT targeting activity are expected to have a therapeutic window.

[0008] Genetic changes affecting, for example, codon 12 of KRAS replace the naturally occurring glycine residue at this position with a different amino acid, such as, in particular, aspartic acid (G12D mutation or KRAS G12D), cysteine ​​(G12C mutation or KRASG12C), valine (G12V mutation or KRAS G12V). Similarly, mutations within codons 13, 61, and 146 of KRAS are commonly found in the KRAS gene. In total, KRAS mutations can be detected in 35% of lung cancers, 45% of colorectal cancers, and up to 90% of pancreatic cancers (Herdeis et al., Curr Opin Struct Biol., 2021, 71: 136-147).

[0009] In conclusion, binders / inhibitors of wild-type or mutant KRAS (such as G12D, G12V, and G12C) are expected to exert anti-cancer effects.

[0010] Therefore, there is a need to develop new compounds that are effective in treating cancers mediated by KRAS, particularly cancers mediated by KRAS mutations at positions 12 or 13 and / or cancers mediated by wild-type amplified KRAS, which also possess desirable pharmacological properties, including but not limited to: metabolic stability, plasma protein binding, solubility, and permeability. DETAILED DESCRIPTION

[0011] It has now been surprisingly found that compounds of formula (I)

[0012] in

[0013] R 1a 、R 1b 、R 2a 、R 2b , Z, R 3 to R 5 , A, p, U, V and W have the meanings given below, act as inhibitors of KRAS and are involved in controlling cell proliferation. Therefore, the compounds according to the invention can be used, for example, to treat diseases characterized by excessive or abnormal cell proliferation.

[0014] Surprisingly, it has been found that the compounds described herein have anti-tumor activity and are useful for inhibiting uncontrolled cell proliferation caused by malignant diseases. It is believed that this anti-tumor activity is particularly derived from the inhibition of KRAS mutations at positions 12 or 13, preferably G12D, G12V or G13D mutant KRAS, or the inhibition of WT KRAS, especially amplified KRAS WT. Advantageously, the compounds may be selective for certain KRAS mutants, preferably KRAS G12D, or may be effective against a group of KRAS mutants that includes amplified KRAS wild-type.

[0015] Additionally, the compounds of the present invention advantageously possess desirable pharmacological properties including, but not limited to, metabolic stability, plasma protein binding, solubility, and permeability.

[0016] Therefore, in a first aspect, the present invention relates to a compound of formula (I)

[0017] in

[0018] R 1a and R 1b are independently selected from the group consisting of: hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, halogen, -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, C 3-5 Cycloalkyl and 3-5 membered heterocyclic groups;

[0019] R 2a and R 2b are independently selected from the group consisting of: hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, halogen, -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, C 3-5 Cycloalkyl and 3-5 membered heterocyclic groups;

[0020] and / or optionally R 1a or R 1b One of them and R 2a or R 2b One of them together with the carbon atom to which it is attached forms a cyclopropane ring; Z is -(CR 6a R 6b ) n -;

[0021] Each R 6a and R 6b independently selected from the group consisting of: hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, halogen, -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, C 3-5 Cycloalkyl and 3-5 membered heterocyclic groups;

[0022] or R6a and R 6b Together with the carbon atom to which it is attached, it forms a cyclopropane ring;

[0023] n is selected from the group consisting of 0, 1 and 2;

[0024] R 3 Selected from the group consisting of: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -N3, C 3-10 Cycloalkyl, 3-11 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are all optionally and independently substituted with one or more identical or different R 7 and / or R 8 replace;

[0025] Each R 7 Independently selected from the group consisting of: halogen, -CN, -OR 8 、-NR 8 R 8 、-C(=O)R 8 、-C(=O)OR 8 、-C(=O)NR 8 R 8 、-NHC(=O)OR 8 and a divalent substituent =O;

[0026] Each R 8 independently selected from the group consisting of: hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic group, C 6-10 All aryl and 5-10 membered heteroaryl groups are optionally substituted with one or more identical or different R 9 and / or R 10 replace;

[0027] Each R 9 Independently selected from the group consisting of: -OR 10 、-NR 10 R 10 and -C(O)NR 10 R 10 ;

[0028] Each R 10 independently selected from the group consisting of: hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl and 5-10 membered heteroaryl, wherein the C 1-6 The alkyl group is optionally substituted with a substituent selected from the group consisting of: C 1-6 Alkoxy, C 3-10 Cycloalkyl and optionally C 1-6 an alkyl-substituted 3-11-membered heterocyclic group;

[0029] W is nitrogen (-N=) or -CH=;

[0030] V is nitrogen (-N=) or -CH=;

[0031] U is nitrogen (-N=) or -C(R 11 )=;

[0032] R 11 Selected from hydrogen, halogen and C 1-4 alkoxy;

[0033] Ring A is a ring selected from the group consisting of pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole and triazole;

[0034] If present, each R 4 Independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, cyano-C 1-6 Alkyl, halogen, -OH, -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, -CN, C 3-5 Cycloalkyl and 3-5 membered heterocyclic groups;

[0035] p is selected from the group consisting of 0, 1, 2 and 3;

[0036] R 5 is optionally substituted with one or more identical or different C 1-6 Alkyl, C 1-6 3-11 membered heterocyclic group substituted by alkoxy or 5-6 membered heterocyclic group, wherein C 1-6 The alkyl group is optionally substituted with a cyclopropyl group;

[0037] or R 5 -OC substituted by a 3-11 membered heterocyclic group 1-6 Alkyl, wherein the 3-11 membered heterocyclic group is optionally substituted by one or more identical or different R 12 replace,

[0038] Each R 12 Choose from C 1-6 Alkyl, C 1-6 the group consisting of alkoxy, halogen and 3-11 membered heterocyclic group;

[0039] or a salt thereof.

[0040] In another aspect, the present invention relates to a compound of formula (I) or a salt thereof, wherein R 1a and R 1b are independently selected from hydrogen and C 1-4 A group consisting of alkyl groups.

[0041] In another aspect, the present invention relates to a compound of formula (I) or a salt thereof, wherein R 2a and R 2b are independently selected from the group consisting of hydrogen and halogen.

[0042] In another aspect, the present invention relates to a compound of formula (I) or a salt thereof, wherein R 1a and R 1b are independently selected from the group consisting of hydrogen and methyl.

[0043] In another aspect, the present invention relates to a compound of formula (I) or a salt thereof, wherein R 2a and R 2b are independently selected from the group consisting of hydrogen and fluorine.

[0044] In another aspect, the present invention relates to a compound of formula (I) or a salt thereof, wherein R 1a 、R 1b 、R 2a and R 2b For hydrogen.

[0045] In another aspect, the present invention relates to a compound of formula (I) or a salt thereof, wherein n is 0.

[0046] In another aspect, the present invention relates to a compound of formula (I) or a salt thereof, wherein n is 1; and

[0047] Each R 6a and R 6b independently selected from the group consisting of: hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, halogen, -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, C 3-5 Cycloalkyl and 3-5 membered heterocyclic groups.

[0048] In another aspect, the present invention relates to a compound of formula (I) or a salt thereof, wherein Z is CH2-.

[0049] In another aspect, the present invention relates to a compound of formula (I) or a salt thereof, wherein n is 2;

[0050] Each R 6a and R 6b independently selected from the group consisting of: hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, halogen, -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, C 3-5 Cycloalkyl and 3-5 membered heterocyclic groups.

[0051] In another aspect, the present invention relates to a compound of formula (I) or a salt thereof, wherein p is 0.

[0052] In another aspect, the present invention relates to a compound of formula (I*) or a salt thereof

[0053] in

[0054] R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4 、R 5 , Z, U, V, W, Ring A and p are as defined above or below.

[0055] In another aspect, the present invention relates to a compound of formula (Ia) or a salt thereof

[0056] in

[0057] A, V, U, W, R 3 and R 5 As defined in this article.

[0058] In another aspect, the present invention relates to a compound of formula (Ib) or a salt thereof

[0059] in

[0060] A, V, U, W, R 3 and R 5 As defined in this article.

[0061] In another aspect, the present invention relates to a compound of the present invention or a salt thereof, wherein ring A is a ring selected from the group consisting of imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole and triazole.

[0062] In another aspect, the present invention relates to a compound of the present invention or a salt thereof, wherein ring A is a ring selected from the group consisting of pyrrole, furan, thiophene, imidazole, pyrazole, isoxazole, isothiazole and triazole.

[0063] In another aspect, the present invention relates to a compound of the present invention or a salt thereof, wherein Ring A is selected from the group consisting of:

[0064] and

[0065] In another aspect, the present invention relates to a compound of the present invention or a salt thereof, wherein Ring A is isoxazole or isothiazole.

[0066] In another aspect, the present invention relates to a compound of the present invention or a salt thereof, wherein ring A is selected from

[0067] and

[0068] In another aspect, the present invention relates to a compound of the present invention or a salt thereof, wherein ring A is

[0069]

[0070] In another aspect, the present invention relates to a compound of formula (Ic) or a salt thereof

[0071] in

[0072] V, U, W, R 3 and R 5 As defined herein.

[0073] In another aspect, the present invention relates to a compound of formula (Id) or a salt thereof

[0074] in

[0075] V, U, W, R 3 and R 5 As defined herein.

[0076] In another aspect, the present invention relates to a compound of formula (Ie) or a salt thereof

[0077] in

[0078] V, U, W, R 3 and R5 As defined herein.

[0079] In another aspect, the present invention relates to a compound of formula (If) or a salt thereof

[0080] in

[0081] V, U, W, R 3 and R 5 As defined herein.

[0082] In another aspect, the present invention relates to compounds of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or salts thereof, wherein at least one of W, V, and U is nitrogen.

[0083] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0084] W is nitrogen (-N=);

[0085] V is nitrogen (-N=);

[0086] U = C(R 11 )-;

[0087] R 11 is selected from hydrogen, halogen and C 1-4 Alkoxy.

[0088] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0089] W is -CH=;

[0090] V is nitrogen (-N=);

[0091] U = C(R 11 )-;

[0092] R 11 is selected from hydrogen, halogen and C 1-4 Alkoxy.

[0093] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0094] V is -CH=;

[0095] W is nitrogen (-N=);

[0096] U = C(R11 )-;

[0097] R 11 is selected from hydrogen, halogen and C 1-4 Alkoxy.

[0098] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0099] R 11 Selected from hydrogen, fluorine, chlorine and -O-CH3.

[0100] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0101] V is nitrogen (-N=);

[0102] W is -CH=;

[0103] U is nitrogen (-N=).

[0104] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0105] W is nitrogen (-N=);

[0106] V is -CH=;

[0107] U is nitrogen (-N=).

[0108] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0109] W is -CH=;

[0110] V is -CH=;

[0111] U is nitrogen (-N=).

[0112] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0113] W is nitrogen (-N=);

[0114] V is nitrogen (-N=);

[0115] U is nitrogen (-N=).

[0116] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0117] W is nitrogen (-N=);

[0118] V is nitrogen (-N=);

[0119] U = C(R 11 )-;

[0120] R 11 Selected from hydrogen, halogen and C 1-4 alkoxy;

[0121] or among them

[0122] V is nitrogen (-N=);

[0123] W is -CH=;

[0124] U is nitrogen (-N=).

[0125] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0126] R 5 is optionally substituted with one or more identical or different C 1-6 Alkyl, C 1-6 6-11 membered heterocyclic group substituted by alkoxy or 5-6 membered heterocyclic group, wherein C 1-6 The alkyl group is optionally substituted with a cyclopropyl group.

[0127] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0128] R 5 is optionally substituted with one or more identical or different C 1-4 Alkyl-substituted 7-membered heterocyclic group.

[0129] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0130] R 5 -OC substituted by a 5-8 membered heterocyclic group 1-6 Alkyl, wherein the 5-8 membered heterocyclic group is optionally substituted by one or more identical or different R 12 replace,

[0131] Each R 12Choose from C 1-6 Alkyl, C 1-6 The group consisting of alkoxy, halogen and 5-membered heterocyclic group.

[0132] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0133] R 5 Selected from the group consisting of:

[0134]

[0135] and

[0136] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein R 5 Selected from the group consisting of:

[0137] and

[0138] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0139] R 5 Selected from the group consisting of:

[0140] and

[0141] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0142] R 5 Selected from the group consisting of:

[0143] and

[0144] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0145] R 5 Selected from the group consisting of:

[0146] and

[0147] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0148] R 5 Selected from the group consisting of:

[0149] and

[0150] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0151] R 3 Selected from the group consisting of: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -N3, C 3-10 Cycloalkyl, 3-11 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are all optionally and independently substituted with one or more identical or different R 7 and / or R 8 replace;

[0152] Each R 7 independently selected from the group consisting of: halogen, -CN, -OH, C 1-6 Alkoxy, -NR 8 R 8 、-C(=O)R 8 、-C(=O)OR 8 、-C(=O)NR 8 R 8 、-NHC(=O)OR 8 and a divalent substituent =O;

[0153] Each R 8 independently selected from the group consisting of: hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl, phenyl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, 3-11 membered heterocyclic group and 5-10 membered heteroaryl are all optionally substituted with one or more identical or different R9 and / or R 10 replace;

[0154] Each R 9 Independently selected from -OR 10 the group formed;

[0155] Each R 10 independently selected from the group consisting of: hydrogen, C 1-6 alkyl, 3-11 membered heterocyclyl and 5-10 membered heteroaryl.

[0156] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0157] R 3 Selected from the group consisting of: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -N3, C 3-10 Cycloalkyl, 3-11 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are all optionally and independently substituted with one or more identical or different R 7 and / or R 8 replace;

[0158] Each R 7 Independently selected from the group consisting of: -OR 8 、-NR 8 R 8 , halogen, -CN, -C(=O)R 8 、-C(=O)OR 8 、-C(=O)NR 8 R 8 、-NHC(=O)OR 8 and a divalent substituent =O;

[0159] Each R 8 independently selected from the group consisting of: hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, 3-11 membered heterocyclic group, C 6-10 All aryl and 5-10 membered heteroaryl groups are optionally substituted with one or more identical or different R 9 and / or R10 replace;

[0160] Each R 9 Independently selected from -OR 10 the group formed;

[0161] Each R 10 independently selected from the group consisting of: hydrogen, C 1-6 alkyl, 3-11 membered heterocyclyl and 5-10 membered heteroaryl.

[0162] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein R 3 Selected from halogen, C 1-6 Alkyl, C 1-6 A group consisting of haloalkyl and -N3.

[0163] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein R 3 Selected from the group consisting of chloro, methyl, -CF3 and -N3.

[0164] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0165] R 3 Selected from the group consisting of: 3-11 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein 3-11 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are all optionally and independently substituted with one or more identical or different R 7 and / or R 8 replace;

[0166] Each R 7 independently selected from the group consisting of: halogen, -CN, -OH, C 1-6 Alkoxy, -NR 8 R 8 、-C(=O)R 8 、-C(=O)OR 8 、-C(=O)NR 8 R 8 、-NHC(=O)OR 8 and a divalent substituent =O;

[0167] Each R 8 independently selected from the group consisting of: hydrogen, C 1-6Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic group, C 6-10 All aryl and 5-10 membered heteroaryl groups are optionally substituted with one or more identical or different R 9 and / or R 10 replace;

[0168] Each R 9 Independently selected from the group consisting of: -OR 10 、-NR 10 R 10 and -C(O)NR 10 R 10 ;

[0169] Each R 10 independently selected from the group consisting of: hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl and 5-10 membered heteroaryl, wherein the C 1-6 The alkyl group is optionally substituted with a substituent selected from the group consisting of: C 1-6 Alkoxy, C 3-10 Cycloalkyl and optionally C 1-6 Alkyl-substituted 3- to 11-membered heterocyclic group.

[0170] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0171] R 3 Selected from the group consisting of: 3-11 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein 3-11 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are all optionally and independently substituted with one or more identical or different R 7 and / or R 8 replace;

[0172] Each R 7 independently selected from the group consisting of: halogen, -CN, -OH, C 1-6 Alkoxy, -NR 8 R 8 、-C(=O)R 8 、-C(=O)OR 8 、-C(=O)NR 8 R 8 、-NHC(=O)OR8 and a divalent substituent =O;

[0173] Each R 8 independently selected from the group consisting of: hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, 3-11 membered heterocyclic group, C 6-10 All aryl and 5-10 membered heteroaryl groups are optionally substituted with one or more identical or different R 9 and / or R 10 replace;

[0174] Each R 9 Independently selected from OR 10 the group formed;

[0175] Each R 10 independently selected from the group consisting of: hydrogen, C 1-6 alkyl, 3-11 membered heterocyclyl and 5-10 membered heteroaryl.

[0176] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0177] R 3 Selected from the group consisting of 3-11 membered heterocyclyl and 5-10 membered heteroaryl, wherein the 3-11 membered heterocyclyl and 5-10 membered heteroaryl are all optionally and independently substituted with one or more identical or different R 7 and / or R 8 replace;

[0178] Each R 7 Independently selected from the group consisting of: halogen, -CN, -OR 8 、-NR 8 R 8 、-C(=O)R 8 、-C(=O)OR 8 、-C(=O)NR 8 R 8 、-NHC(=O)OR 8 and a divalent substituent =O;

[0179] Each R 8 independently selected from the group consisting of: hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic group, C 6-10 All aryl and 5-10 membered heteroaryl groups are optionally substituted with one or more identical or different R 9 and / or R 10 replace;

[0180] Each R 9 -OH or C 1-6 alkoxy;

[0181] Each R 10 Independently selected from the group consisting of: C 1-6 alkyl, 3-11 membered heterocyclyl and 5-10 membered heteroaryl.

[0182] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0183] R 3 Selected from the group consisting of 3-11 membered heterocyclyl and 5-10 membered heteroaryl, wherein the 3-11 membered heterocyclyl and 5-10 membered heteroaryl are all optionally and independently substituted with one or more identical or different R 7 and / or R 8 replace;

[0184] Each R 7 independently selected from the group consisting of: halogen, -CN, -OH, C 1-6 Alkoxy, -NR 8 R 8 、-C(=O)R 8 、-C(=O)OR 8 、-C(=O)NR 8 R 8 、-NHC(=O)OR 8 and a divalent substituent =O;

[0185] Each R 8 independently selected from the group consisting of: hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, 3-11 membered heterocyclic group, C 6-10 All aryl and 5-10 membered heteroaryl groups are optionally substituted with one or more identical or different R 9 and / or R 10 replace;

[0186] Each R 9 -OH or C 1-6alkoxy;

[0187] Each R 10 Independently selected from the group consisting of: C 1-6 alkyl, 3-11 membered heterocyclyl and 5-10 membered heteroaryl.

[0188] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0189] R 3 Selected from the group consisting of:

[0190]

[0191] Each of these groups is bound to Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie), or (If) at any ring position by removal of a hydrogen atom, and is optionally and independently connected via one or more identical or different R 7 and / or R 8 Replace, where

[0192] Each R 7 Independently selected from the group consisting of: halogen, -CN, -OR 8 、-NR 8 R 8 、-C(=O)R 8 、-C(=O)OR 8 、-C(=O)NR 8 R 8 、-NHC(=O)OR 8 and a divalent substituent =O;

[0193] Each R 8 independently selected from the group consisting of: hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic group, C 6-10 All aryl and 5-10 membered heteroaryl groups are optionally substituted with one or more identical or different R 9 and / or R 10 replace;

[0194] Each R 9 -OH or C 1-6 alkoxy;

[0195] Each R 10 Independently selected from the group consisting of: C1-6 alkyl, 3-11 membered heterocyclyl and 5-10 membered heteroaryl.

[0196] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0197] R 3 Selected from the group consisting of:

[0198] and

[0199] The groups are each optionally and independently substituted with one or more identical or different R 7 and / or R 8 Replace, where

[0200] Each R 7 Independently selected from the group consisting of: halogen, -CN, -OR 8 、-NR 8 R 8 、-C(=O)R 8 、-C(=O)OR 8 、-C(=O)NR 8 R 8 、-NHC(=O)OR 8 and a divalent substituent =O;

[0201] Each R 8 independently selected from the group consisting of: hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, 3-11 membered heterocyclic group, C 6-10 All aryl and 5-10 membered heteroaryl groups are optionally substituted with one or more identical or different R 9 and / or R 10 replace;

[0202] Each R 9 -OH or C 1-6 alkoxy;

[0203] Each R 10 Independently selected from the group consisting of: C 1-6 alkyl, 3-11 membered heterocyclyl and 5-10 membered heteroaryl.

[0204] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0205] R 3 Selected from the group consisting of:

[0206]

[0207]

[0208]

[0209]

[0210]

[0211] and

[0212] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0213] R 3 is optionally substituted with one or more identical or different R 7 and / or R 8 substituted 3-11 membered heterocyclic group;

[0214] Each R 7 Independently selected from the group consisting of: -OH, C 1-6 Alkoxy, C(=O)R 8 and a divalent substituent =O;

[0215] Each R 8 independently selected from the group consisting of: hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl and 5-10 membered heteroaryl.

[0216] In another aspect, the present invention relates to a compound of formula (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0217] R 3 is optionally substituted with one or more identical or different R 7 and / or R 8 substituted 3-11 membered heterocyclic group;

[0218] Each R 7Independently selected from the group consisting of: -OH, C 1-6 Alkoxy, C(=O)R 8 and a divalent substituent =O;

[0219] Each R 8 independently selected from the group consisting of: hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl and 5-10 membered heteroaryl.

[0220] In another aspect, the present invention relates to a compound of formula (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0221] R 3 is optionally and independently substituted with one or more identical or different R 7 and / or R 8 a substituted nitrogen-containing 5-membered heterocyclic group;

[0222] Each R 7 Independently selected from the group consisting of: -OH, C 1-6 Alkoxy, -NR 8 R 8 , halogen, -CN, -C(=O)R 8 、-C(=O)OR 8 、-C(=O)NR 8 R 8 、-NHC(=O)OR 8 and a divalent substituent =O;

[0223] Each R 8 independently selected from hydrogen, C 1-6 The group consisting of an alkyl group and a 3-11 membered heterocyclic group.

[0224] In another aspect, the present invention relates to a compound of formula (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0225] R 3 is an oxygen-containing 3-11-membered heterocyclic group;

[0226] In another aspect, the present invention relates to a compound of formula (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0227] R 3 Selected from optionally one or more identical or different R 7 and / or R 8 a group consisting of substituted 5-10 membered heteroaryl groups;

[0228] Each R 7 independently selected from the group consisting of: halogen, -OH, C1-6 Alkoxy, -CN, -C(=O)R 8 、-C(=O)OR 8 、-C(=O)NR 8 R 8 and a divalent substituent =O;

[0229] Each R 8 independently selected from the group consisting of: hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl and 5-10 membered heteroaryl are all optionally substituted with one or more identical or different R 10 replace;

[0230] Each R 10 Independently selected from the group consisting of: C 1-6 alkyl, 3-11 membered heterocyclyl and 5-10 membered heteroaryl.

[0231] In another aspect, the present invention relates to a compound of formula (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0232] R 3 Selected from optionally one or more identical or different R 7 and / or R 8 a group consisting of substituted 5-10 membered heteroaryl groups;

[0233] Each R 7 independently selected from the group consisting of: halogen, -OH, C 1-6 Alkoxy, -CN, -C(=O)R 8 、-C(=O)OR 8 、-C(=O)NR 8 R 8 and a divalent substituent =O;

[0234] Each R 8 independently selected from the group consisting of: hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, 3-11 membered heterocyclic group and 5-10 membered heteroaryl are all optionally substituted with one or more identical or different R 10 replace;

[0235] Each R 10 independently selected from the group consisting of: hydrogen, C 1-6alkyl, 3-11 membered heterocyclyl and 5-10 membered heteroaryl.

[0236] In another aspect, the present invention relates to a compound of formula (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0237] R 3 is optionally -C(=O)NR 8 R 8 substituted 5-10 membered heteroaryl;

[0238] Each R 8 independently selected from the group consisting of: hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl and 3-11 membered heterocyclic groups, wherein the C 1-6 The alkyl group is optionally substituted with a 3-11 membered heterocyclic group.

[0239] In another aspect, the present invention relates to a compound of formula (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0240] R 3 for They are optionally and independently C 1-6 Alkyl substitution;

[0241] W is nitrogen (-N=);

[0242] V is nitrogen (-N=);

[0243] U is -C(R 11 )=;where R 11 is hydrogen or fluorine; and

[0244] R 5 for

[0245] In another aspect, the present invention relates to a compound of formula (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0246] R 3 Selected from the group consisting of:

[0247] and

[0248] W is nitrogen (-N=);

[0249] V is nitrogen (-N=);

[0250] U is -CH=;

[0251] R 5 for

[0252] In another aspect, the present invention relates to a compound of formula (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0253] R 3 Selected from the group consisting of:

[0254] and

[0255] W is -N=;

[0256] V is -N=;

[0257] U is -CH=;

[0258] R 5 for

[0259] In another aspect, the present invention relates to a compound of formula (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0260] R 3 is a 3-11 membered heterocyclic group selected from the group consisting of:

[0261] and

[0262] The 3-11 membered heterocyclic groups are each optionally and independently substituted with one or more identical or different R 7 and / or R 8 replace;

[0263] Each R 7 Independently selected from the group consisting of: -OH, C 1-6 Alkoxy, C(=O)R 8 and a divalent substituent =O;

[0264] Each R 8 independently selected from the group consisting of: hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl, 3-11 membered heterocyclyl and 5-10 membered heteroaryl.

[0265] In another aspect, the present invention relates to a compound of formula (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0266] R 3 is a 3-11 membered heterocyclic group or an 8-9 membered heteroaryl group selected from the group consisting of:

[0267] and

[0268] The 3-11 membered heterocyclic group or 8-9 membered heteroaryl group are each optionally and independently substituted with one or more identical or different R 7 and / or R 8 replace;

[0269] Each R 7 Independently selected from the group consisting of: -OR 8 、-NR 8 R 8 , halogen, -CN, -C(=O)R 8 、-C(=O)OR 8 、-C(=O)NR 8 R 8 、-NHC(=O)OR 8 and a divalent substituent =O;

[0270] Each R 8 independently selected from the group consisting of: hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, 3-11 membered heterocyclic group, C 6-10 All aryl and 5-10 membered heteroaryl groups are optionally substituted with one or more identical or different R 9 and / or R 10 replace;

[0271] Each R 9 -OH or C 1-6 alkoxy;

[0272] Each R 10 Independently selected from the group consisting of: C 1-6 alkyl, 3-11 membered heterocyclyl and 5-10 membered heteroaryl.

[0273] In another aspect, the present invention relates to a compound of formula (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0274] R 3 is a 5-10 membered heteroaryl group selected from the group consisting of:

[0275] and

[0276] The 5-10 membered heteroaryl groups are each optionally and independently substituted with one or more identical or different R 7 and / or R8 replace;

[0277] Each R 7 independently selected from the group consisting of: halogen, -CN, -C(=O)R 8 、-C(=O)OR 8 、-C(=O)NR 8 R 8 and a divalent substituent =O;

[0278] Each R 8 independently selected from the group consisting of: hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, 3-11 membered heterocyclic group and 5-10 membered heteroaryl are all optionally substituted with one or more identical or different R 9 replace;

[0279] Each R 9 Independently selected from the group consisting of: C 1-6 alkyl, 3-11 membered heterocyclyl, and 5-10 membered heteroaryl.

[0280] In another aspect, the present invention relates to a compound of formula (Ic), (Id), (Ie) or (If), or a salt thereof, wherein

[0281] R 3 Selected from the group consisting of:

[0282]

[0283]

[0284] and

[0285] Preferred embodiments of the present invention are Example compounds I-1 to I-61, II-1 to II-214, and any subset thereof.

[0286] In particular, preferred embodiments of the present invention are Example compounds I-1 to I-45, II-1 to II-178, and any subset thereof.

[0287] It will be understood that any two or more aspects and / or preferred embodiments of formula (I) or its subformulas may be combined in any manner that results in a chemically stable structure to obtain other aspects and / or preferred embodiments of formula (I) or its subformulas.

[0288] The present invention further relates to hydrates, solvates, polymorphs, metabolites, derivatives, stereoisomers and prodrugs of compounds of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), including all embodiments thereof.

[0289] The present invention further relates to hydrates of compounds of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), including all embodiments thereof.

[0290] The present invention further relates to solvates of compounds of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), including all embodiments thereof.

[0291] For example, compounds of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If) (including all embodiments thereof) carrying an ester group are potential prodrugs whose esters are cleaved under physiological conditions and are also part of the present invention.

[0292] The present invention further relates to compounds of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If) (including all embodiments thereof).

[0293] The present invention further relates to pharmaceutically acceptable salts of compounds of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie), or (If), including all embodiments thereof, with non-organic or organic acids or bases.

[0294] Pharmaceutical composition

[0295] Another object of the present invention is a pharmaceutical composition comprising a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0296] In one aspect, the pharmaceutical composition optionally comprises one or more other pharmacologically active substances. The one or more other pharmacologically active substances may be pharmacologically active substances or combination partners as defined herein.

[0297] Suitable pharmaceutical compositions for administering a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If) according to the present invention will be clear to those skilled in the art and include, for example, tablets, pills, capsules, suppositories, buccal tablets, dragees, solutions, suspensions (especially solutions, suspensions or other mixtures for injection (subcutaneous, intravenous, intramuscular) and infusion (injectables)), elixirs, syrups, sachets, emulsions, inhalants or dispersible powders. The content of the compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If) should be in the range of 0.1 to 90% by weight, preferably 0.5 to 50% by weight, of the total composition, i.e., in an amount sufficient to achieve the dosage range specified below. If necessary, the specified dosage can be given several times a day.

[0298] Suitable tablets can be obtained, for example, by mixing a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie), or (If) with known pharmaceutically acceptable excipients, such as inert diluents, carriers, disintegrants, adjuvants, surfactants, binders, and / or lubricants. Tablets may also comprise several layers.

[0299] Thus, coated tablets can be prepared by coating a core produced in a similar manner to tablets with excipients commonly used for tablet coatings (e.g., collidone or shellac, gum arabic, talc, titanium dioxide, or sugar). To achieve delayed release or prevent incompatibilities, the core may also consist of multiple layers. Similarly, the tablet coating may consist of multiple layers to achieve delayed release, possibly using the excipients mentioned above for tablets.

[0300] Syrups or elixirs containing one or more compounds of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or in combination with one or more other pharmaceutically active substances, may additionally contain excipients, such as sweeteners, for example saccharin, cyclamate, glycerol or sugar; and flavor enhancers, for example, flavorings, such as vanilla extract or orange extract. They may also contain excipients, such as suspending adjuvants or thickeners, for example sodium carboxymethylcellulose; wetting agents, for example, condensation products of fatty alcohols with ethylene oxide; or preservatives, for example, parabens.

[0301] Solutions for injection and infusion are prepared in a conventional manner, for example by adding excipients such as isotonic agents, preservatives such as p-hydroxybenzoates or stabilizers such as alkali metal salts of ethylenediaminetetraacetic acid, optionally using emulsifiers and / or dispersants, while if water is used as a diluent, for example an organic solvent may optionally be used as a solvating agent or dissolution aid, and transferred to injection vials or ampoules or infusion bottles.

[0302] Capsules containing one or more compounds of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or in combination with one or more other pharmaceutically active substances can be prepared, for example, by mixing the compounds / active substances with an inert excipient, such as lactose or sorbitol, and filling them into gelatin capsules.

[0303] Suitable suppositories can be manufactured, for example, by mixing with excipients provided for this purpose, such as neutral fats or polyethylene glycol or its derivatives.

[0304] Excipients that can be used include, for example, water; pharmaceutically acceptable organic solvents such as paraffins (e.g., petroleum fractions), vegetable oils (e.g., peanut oil or sesame oil), monofunctional or polyfunctional alcohols (e.g., ethanol or glycerol); carriers such as natural mineral powders (e.g., kaolin, clay, talc, chalk), synthetic mineral powders (e.g., highly dispersed silicic acid and silicates), sugars (e.g., sucrose, lactose, and glucose), emulsifiers (e.g., lignin, spent sulfite liquid, methylcellulose, starch, and polyvinyl pyrrolidone), and lubricants (e.g., magnesium stearate, talc, stearic acid, and sodium lauryl sulfate).

[0305] The pharmaceutical composition is administered by conventional methods, preferably orally or transdermally, most preferably orally. For oral administration, the tablets may contain, in addition to the excipients mentioned above, additional excipients such as sodium citrate, calcium carbonate, and calcium hydrogen phosphate, as well as various excipients such as starch (preferably potato starch), gelatin, and the like. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc may be used simultaneously in the tableting process. In the case of aqueous suspensions, the active substance may be combined with various flavor enhancers or colorants in addition to the excipients mentioned above.

[0306] For parenteral use, solutions of the active substance with suitable liquid excipients may be used.

[0307] The dosage range of the compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If) applicable per day is generally 1 mg to 2000 mg, preferably 250 to 1250 mg.

[0308] However, depending on body weight, age, route of administration, severity of the disease, individual response to the drug, the nature of its formulation, and the time or interval of administration of the drug (continuous or intermittent treatment with one or more doses per day), it may sometimes be necessary to deviate from the specified amounts. Thus, in some cases, it may be sufficient to use less than the minimum dose given above, while in other cases the upper limit may be exceeded. When administering larger amounts, it may be advisable to divide them into multiple smaller doses throughout the day.

[0309] Therefore, in another aspect, the present invention relates to a pharmaceutical composition comprising at least one (preferably one) compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0310] The compounds of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising such compounds and salts can also be co-administered with other pharmacologically active substances, for example, other anti-neoplastic compounds (e.g., chemotherapy), i.e., used in combination (see further combination therapy below).

[0311] The units of such combinations can be administered (whether dependently or independently) by methods conventional to those skilled in the art and as they are used in monotherapy, for example, by oral, enteral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, transdermal or subcutaneous injection or implantation), nasal, vaginal, rectal or topical routes of administration and can be formulated separately or together in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable excipients suitable for each route of administration.

[0312] The combination may be administered in a therapeutically effective single or divided daily dose. The active ingredients of the combination may be administered in such doses that are therapeutically effective in monotherapy or in such doses lower than those used in monotherapy, but that when combined result in the desired (joint) therapeutically effective amount.

[0313] However, when the combined use of two or more active substances or ingredients results in a synergistic effect, it is also possible to reduce the amount of one, more or all of the substances or ingredients to be administered, while still achieving the desired therapeutic effect. This can be useful, for example, to avoid, limit or reduce any undesirable side effects associated with the use of one or more of the substances or ingredients when used in their usual amounts, while still achieving the desired pharmacological or therapeutic effect.

[0314] Therefore, in another aspect, the present invention also relates to a pharmaceutical composition comprising a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharmaceutically acceptable salt thereof, and one or more (preferably one or two, most preferably one) other pharmacologically active substances.

[0315] In another aspect, the present invention also relates to a pharmaceutical formulation comprising a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharmaceutically acceptable salt thereof, and one or more (preferably one or two, most preferably one) other pharmacologically active substances.

[0316] Pharmaceutical compositions to be co-administered or used in combination may also be provided in the form of a kit.

[0317] Therefore, in another aspect, the present invention also relates to a kit comprising:

[0318] a first pharmaceutical composition or dosage form comprising a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie), or (If), and optionally one or more pharmaceutically acceptable excipients, and

[0319] - A second pharmaceutical composition or dosage form comprising another pharmacologically active substance and optionally one or more pharmaceutically acceptable excipients.

[0320] In one aspect, such kits comprise a third pharmaceutical composition or dosage form comprising another pharmacologically active substance and, optionally, one or more pharmaceutically acceptable excipients.

[0321] Medical uses-treatment methods

[0322] Indications-Patient groups

[0323] The present invention relates to compounds that inhibit KRAS, preferably KRAS mutated at residue 12, such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12A and KRAS G12R inhibitors, preferably KRAS G12C and / or KRAS G12D inhibitors; or inhibitors that are selective for KRAS G12D; and compounds that inhibit KRAS wild type, preferably amplified KRAS mutated at residue 13, such as KRAS G13D, or KRAS mutated at residue 61, such as KRAS Q61H. In particular, compounds of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), including all embodiments thereof, may be useful for treating and / or preventing diseases and / or conditions mediated by KRAS, preferably KRAS mutated at residue 12 (e.g., KRAS G12C, KRAS G12D, KRAS G12V, more preferably G12D), or by amplification of KRAS wild type, or by KRAS mutated at residue 13 (e.g., KRAS G13D), or by KRAS mutated at residue 61 (such as KRAS Q61H).

[0324] Thus, in another aspect, the present invention relates to a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0325] In another aspect, the present invention relates to a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or a pharmaceutically acceptable salt thereof, suitable for use in a method of treating the human or animal body.

[0326] In another aspect, the invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of diseases and / or conditions mediated by KRAS, preferably by KRAS mutated at residue 12 (e.g., KRAS G12C, KRAS G12D, KRAS G12V, more preferably G12D), or by amplification of KRAS wild type, or by KRAS mutated at residue 13 (e.g., KRAS G13D).

[0327] In another aspect, the invention relates to the use of a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and / or prevention of diseases and / or conditions mediated by KRAS, preferably KRAS mutated at residue 12 (e.g., KRAS G12C, KRAS G12D, KRAS G12V, more preferably G12D), or by amplification of wild-type KRAS, or by KRAS mutated at residue 13 (e.g., KRAS G13D).

[0328] In another aspect, the invention relates to a method for treating and / or preventing diseases and / or conditions mediated by KRAS, preferably by KRAS mutated at residue 12 (e.g., KRAS G12C, KRAS G12D, KRAS G12V, more preferably G12D), or by amplification of wild-type KRAS, or by KRAS mutated at residue 13 (e.g., KRAS G13D), the method comprising administering to a human a therapeutically effective amount of a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof.

[0329] In another aspect, the present invention relates to the use of a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, for treating and / or preventing cancer.

[0330] In another aspect, the present invention relates to a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, for use in a method of treating and / or preventing cancer in the human or animal body.

[0331] In another aspect, the present invention relates to the use of a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and / or prevention of cancer.

[0332] In another aspect, the present invention relates to a method for treating and / or preventing cancer, comprising administering to a human a therapeutically effective amount of a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof.

[0333] Preferably, the cancer as defined herein (above or below) comprises a KRAS mutation. In particular, KRAS mutations include, for example, mutations of the KRAS gene and KRAS protein, such as overexpressed KRAS, amplified KRAS or KRAS, KRAS mutated at residue 12, KRAS mutated at residue 13, KRAS mutated at residue 61, KRAS mutated at residue 146, in particular KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12S, KRAS G13C, KRAS G13D, KRAS G13V, KRAS Q61H, KRAS Q61E, KRAS Q61P, KRAS A146P, KRAS A146T, KRAS A146V. KRAS may present one or more of these mutations / alterations.

[0334] Preferably, in addition to or in place of a KRAS mutation, a cancer as defined herein (above or below) comprises a BRAF mutation. The BRAF mutation is particularly a Class III BRAF mutation, for example as defined in Z. Yao, Nature, 2017, 548, 234-238.

[0335] Preferably, the cancer as defined herein (above or below) comprises, in addition to or instead of a KRAS mutation, a mutation in a receptor tyrosine kinase (RTK), including EGFR, MET and ERBB2 mutations.

[0336] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, for use in treating and / or preventing cancer, wherein the cancer comprises a KRAS mutation, preferably selected from the group consisting of: KRAS G12C, KRAS G12D, KRAS G12V, GKRAS G13D; or amplification of KRAS wild type, amplification of the KRAS gene or overexpression of KRAS.

[0337] In another aspect, the present invention relates to the use of a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and / or prevention of cancer, wherein the cancer comprises a KRAS mutation, preferably selected from the group consisting of KRAS G12C, KRAS G12D, KRAS G12V, GKRAS G13D; or amplification of KRAS wild type, amplification of the KRAS gene or overexpression of KRAS.

[0338] In another aspect, the present invention relates to a method for treating and / or preventing cancer, comprising administering to a human a therapeutically effective amount of a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, wherein the cancer comprises a KRAS mutation, preferably selected from the group consisting of KRAS G12C, KRAS G12D, KRAS G12V, GKRAS G13D; or amplification of KRAS wild type, amplification of the KRAS gene, or overexpression of KRAS.

[0339] In another aspect, the present invention relates to a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, for use in treating and / or preventing cancer, wherein the cancer comprises a KRAS G12D mutation.

[0340] In another aspect, the present invention relates to a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, for use in treating and / or preventing cancer, wherein the cancer comprises a KRAS G12V mutation.

[0341] In another aspect, the present invention relates to a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, for use in treating and / or preventing cancer, wherein the cancer comprises a KRAS G13D mutation.

[0342] In another aspect, the present invention relates to a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, for use in treating and / or preventing cancer, wherein the cancer comprises wild-type amplified KRAS.

[0343] Another aspect is the association between the KRAS mutational status of a patient and their potential susceptibility to treatment with a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie), or (If). KRAS inhibitors, such as compounds of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie), or (If), can then be advantageously used to treat patients with KRAS-dependent diseases that may be resistant to other therapies. This therefore provides the opportunity, methods, and tools to select patients, particularly cancer patients, for treatment with a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie), or (If). This selection is based on whether the tumor cells to be treated have a wild-type, preferably amplified, or mutated KRAS at residue 12, preferably G12C, G12D, or G12V gene, or a mutated KRAS at residue 13, preferably G13D gene. KRAS genetic status can therefore be used as a biomarker to indicate that selection for treatment with a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie), or (If) may be advantageous.

[0344] According to one aspect, a method of selecting a patient for treatment with a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie), or (If) is provided, the method comprising

[0345] Providing a sample containing tumor cells from the patient;

[0346] Determining whether the KRAS gene in the patient's tumor cell-containing sample encodes a wild-type (glycine at position 12) or mutant (cysteine, aspartic acid, valine, alanine, or arginine at position 12, aspartic acid at position 13, amplified and / or overexpressed) KRAS protein; and

[0347] • Selecting a patient for treatment with a compound of Formula (I), (I*), (la), (lb), (lc), (Id), (le), or (If) based on the above.

[0348] The method may or may not include an actual patient sample separation step.

[0349] According to another aspect, a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or a pharmaceutically acceptable salt thereof, is provided for use in treating cancer having tumor cells carrying amplification of KRAS mutations or KRAS wild-type.

[0350] According to another aspect, a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, is provided for use in treating cancer having tumor cells carrying amplification of a G12C mutant, G12D mutant, G12V mutant, G12A mutant, G13D mutant or G12R mutant KRAS gene or KRAS wild type.

[0351] According to another aspect, a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, is provided for use in treating cancer having tumor cells carrying amplification of a G12C mutant, a G12D mutant, a G12V mutant or a G13D mutant KRAS gene or wild-type KRAS.

[0352] According to another aspect, a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, is provided for use in treating cancer having tumor cells carrying a G12D mutant KRAS gene.

[0353] According to another aspect, a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, is provided for use in treating cancer having tumor cells carrying a G12V mutant KRAS gene.

[0354] According to another aspect, a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, is provided for use in treating cancer having tumor cells carrying a G13D mutant KRAS gene.

[0355] According to another aspect, a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or a pharmaceutically acceptable salt thereof, is provided for use in treating cancer having tumor cells harboring wild-type amplified KRAS or overexpressing KRAS.

[0356] According to another aspect, a method of treating cancer having tumor cells carrying a G12C mutant, G12D mutant, G12V mutant, G12A mutant, G13D mutant, or G12R mutant KRAS gene, or KRAS wild-type gene amplification, is provided, comprising administering to a human an effective amount of a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or a pharmaceutically acceptable salt thereof.

[0357] According to another aspect, a method of treating cancer having tumor cells carrying a G12C mutant, G12D mutant, G12V mutant, G12A mutant, or G12R mutant KRAS gene, or KRAS wild-type gene amplification, is provided, comprising administering an effective amount of a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or a pharmaceutically acceptable salt thereof.

[0358] Determining whether a tumor or cancer contains a G12C KRAS mutation can be performed by evaluating the nucleotide sequence encoding the KRAS protein, by evaluating the amino acid sequence of the KRAS protein, or by evaluating the characteristics of a putative KRAS mutant protein. The sequence of wild-type human KRAS is known in the art. Methods for detecting mutations in KRAS nucleotide sequences are known to those skilled in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis, real-time PCR analysis, PCR sequencing, mutant allele-specific PCR amplification (MASA) analysis, direct sequencing, primer extension reaction, electrophoresis, oligonucleotide ligation analysis, hybridization analysis, TaqMan assays, SNP genotyping analysis, high-resolution melting analysis, and microarray analysis. In some embodiments, a sample is assessed for the G12C KRAS mutation by real-time PCR. In real-time PCR, a fluorescent probe specific for the KRAS G12C mutation is used. When the mutation is present, the probe binds and fluorescence is detected. In some embodiments, KRAS G12C mutations are identified using direct sequencing of specific regions in the KRAS gene (e.g., exon 2 and / or exon 3). This technique will identify all possible mutations in the sequenced region. Methods for detecting mutations in KRAS proteins are known to those skilled in the art. These methods include, but are not limited to, detecting KRAS mutants using binding agents (e.g., antibodies) specific for the mutant protein, protein electrophoresis, Western blotting, and direct peptide sequencing.

[0359] Methods for determining whether a tumor or cancer contains a G12C KRAS mutation can use a variety of samples. In some embodiments, the sample is obtained from an individual with a tumor or cancer. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed, paraffin-embedded sample. In some embodiments, the sample is processed into a cell lysate. In some embodiments, the sample is processed into DNA or RNA. In some embodiments, the sample is a liquid biopsy, and a blood sample is tested to look for cancer cells from a tumor circulating in the blood or to look for DNA fragments from tumor cells in the blood.

[0360] Similarly, one can determine whether a tumor or cancer contains KRAS G12D, KRAS G12V, KRAS G12A, KRAS G13D, and KRAS G12R mutations or is KRAS wild-type, preferably amplified.

[0361] Preferably, the disease / condition / cancer / tumor / cancer cell to be treated / prevented by a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharmaceutically acceptable salt thereof as defined and disclosed herein (above and below) is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer, appendix cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcoma.

[0362] Preferably, the disease / condition / cancer / tumor / cancer cell to be treated / prevented by a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharmaceutically acceptable salt thereof according to the methods and uses as defined and disclosed herein (above and below) is selected from the group consisting of pancreatic cancer, lung cancer, ovarian cancer, colorectal cancer (CRC), gastric cancer, gastroesophageal junction cancer (GEJC) and esophageal cancer.

[0363] In another aspect, the disease / condition / cancer / tumor / cancer cell to be treated / prevented by a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharmaceutically acceptable salt thereof according to the methods and uses as defined and disclosed herein (above and below) is selected from the group consisting of pancreatic cancer (preferably pancreatic ductal adenocarcinoma (PDAC)), lung cancer (preferably non-small cell lung cancer (NSCLC)), gastric cancer, bile duct cancer and colorectal cancer (preferably colorectal adenocarcinoma). Preferably, the pancreatic cancer, lung cancer, bile duct cancer, colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC) or colorectal adenocarcinoma comprises a KRAS mutation, in particular a KRAS G12D or KRAS G12V mutation. Preferably (alternatively or in combination with the previous preferred embodiments), the non-small cell lung cancer (NSCLC) comprises a mutation (in particular a loss-of-function mutation) in the NF1 gene.

[0364] In another aspect, the disease / condition / cancer / tumor / cancer cell line to be treated / prevented by a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharmaceutically acceptable salt thereof according to the methods and uses as defined and disclosed herein (above and below) is gastric cancer, ovarian cancer or esophageal cancer, preferably selected from the group consisting of gastric adenocarcinoma (GAC), esophageal adenocarcinoma (EAC) and gastroesophageal junction cancer (GEJC). Preferably, the gastric cancer, ovarian cancer, esophageal cancer, gastric adenocarcinoma (GAC), esophageal adenocarcinoma (EAC) or gastroesophageal junction cancer (GEJC) comprises a KRAS mutation or wild-type amplified KRAS.

[0365] Particularly preferably, the cancer to be treated / prevented with a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharmaceutically acceptable salt thereof according to the methods and uses as defined and disclosed herein (above and below) is selected from the group consisting of:

[0366] Lung adenocarcinoma (preferably non-small cell lung cancer (NSCLC)) with amplification of KRAS mutations at position 12 (preferably G12C, G12D, G12V, G12A, G12R), position 13 (preferably G13D), or KRAS wild-type;

[0367] Colorectal adenocarcinomas harboring amplification of KRAS mutations at position 12 (preferably G12C, G12D, G12V, G12A, G12R), position 13 (preferably G13D), or wild-type KRAS;

[0368] Pancreatic cancer (preferably pancreatic ductal adenocarcinoma (PDAC)) harboring amplification of a RAS mutation at position 12 (preferably KRAS and preferably G12C, G12D, G12V, G12A, G12R mutations), at position 13 (preferably G13D), or KRAS wild type.

[0369] Preferably, "cancer" as used herein (above or below) includes drug-resistant cancers and cancers that have failed one, two or more lines of monotherapy or combination therapy with one or more anticancer agents. In particular, "cancer" (and any embodiment thereof) refers to any cancer (especially cancer species defined above and below) that is resistant to treatment with a KRAS G12C inhibitor.

[0370] Different resistance mechanisms have been reported. For example, the following articles describe resistance in patients treated with KRAS G12C inhibitors: (i) Awad MM, Liu S, Rybkin, II, Arbour KC, Dilly J, Zhu VW, et al. Acquired resistance to KRAS (G12C) inhibition in cancer. N Engl J Med 2021;384:2382-93 and (ii) Tanaka N, Lin JJ, Li C, Ryan MB, Zhang J, Kiedrowski LA, et al. Clinical acquired resistance to KRAS (G12C) inhibition through a novel KRAS switch-II pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation. Cancer Discov 2021;11:1913-22.

[0371] In another aspect, the disease / condition / cancer / tumor / cancer cell line RAS protein family disorder (RASopathy) treated / prevented with a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharmaceutically acceptable salt thereof according to the methods and uses defined and disclosed herein (above and below) is preferably selected from the group consisting of neurofibromatosis type 1 (NF1), Noonan Syndrome (NS), Noonan syndrome with multiple lentigines (NSML) (also known as LEOPARD syndrome), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello Syndrome (CS), cardiofacial-cutaneous syndrome (CFC), Legius Syndrome (also known as NF1-like syndrome) and hereditary gingival fibromatosis.

[0372] In addition, the following cancers, tumors and other proliferative diseases can be treated with compounds of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or pharmaceutically acceptable salts thereof (but not limited thereto). Preferably, the methods of treatment, methods, uses, compounds used therefor and pharmaceutical compositions used therefor as disclosed herein (above and below) are used to treat the following diseases / conditions / cancers / tumors: (i.e., individual cells) having a KRAS mutation at position 12 (preferably a G12C, G12D, G12V, G12A, G12R mutation) or a KRAS wild-type amplification. Or have been identified as having a KRAS mutation at position 12 (preferably a G12C, G12D, G12V, G12A, G12R mutation) or a KRAS wild-type amplification as described and / or referred to herein:

[0373] Cancers / tumors / carcinomas of the head and neck: for example, tumors / carcinomas / cancers of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity (including the lips, gums, alveolar ridges, retromolar trigone, floor of mouth, tongue, hard palate, buccal mucosa), oropharynx (including the base of the tongue, tonsils, tonsillar arches (tonsillar pilars), soft palate, tonsillar fossa, and pharyngeal wall), middle ear, larynx (including the supraglottis, glottis, hypoglottis, and vocal cords), hypopharynx, and salivary glands (including minor salivary glands);

[0374] Lung cancer / tumor / carcinoma: e.g., non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchoalveolar), small cell lung cancer (SCLC) (oat cell carcinoma, intermediate cell carcinoma, combined oat cell carcinoma);

[0375] Neoplasms of the mediastinum: for example, neurogenic tumors (including neurofibroma, neurilemmoma, malignant schwannoma, neurosarcoma, ganglioblastoma, gangliocytoma, neuroblastoma, pheochromocytoma, and paraganglioma), germ cell tumors (including seminoma, teratoma, and non-seminoma), thymic tumors (including thymoma, thymolipoma, thymic carcinoma, and thymic carcinoid), mesenchymal tumors (including fibroma, fibrosarcoma, lipoma, liposarcoma, myxoma, mesothelioma, leiomyoma, leiomyosarcoma, rhabdomyosarcoma, xanthogranuloma, mesenchymal tumor, hemangioma, hemangioendothelioma, hemangiopericytoma, lymphangioma, perilymphatic cell tumor, and lymphangiomyoma);

[0376] Cancers / tumors / carcinomas of the gastrointestinal (GI) tract: for example, tumors / carcinomas / cancers of the esophagus, stomach (gastric cancer), pancreas, liver, and biliary tract (including hepatocellular carcinoma (HCC), such as childhood HCC, fibrolamellar HCC, combined HCC, spindle cell HCC, clear cell HCC, giant cell HCC, carcinosarcoma HCC, sclerosing HCC; hepatoblastoma; bile duct carcinoma; cholangiocarcinoma; hepatic cystadenocarcinoma; angiosarcoma, hemangioendothelioma, leiomyosarcoma, malignant neurilemoma, fibrosarcoma, Klatskin tumor, and cholangiocarcinoma). tumor), gallbladder, extrahepatic bile duct, small intestine (including duodenum, jejunum, ileum), large intestine (including cecum, colon, rectum, anus; colorectal cancer, gastrointestinal stromal tumor (GIST)), genitourinary system (including kidney, such as renal pelvis, renal cell carcinoma (RCC), Wilms' tumor (Wilms' tumor), adrenal tumor, Grawitz tumor; ureter; bladder, such as urachal cancer, urothelial carcinoma; urethra, such as distal, mesangial, prostate; prostate (androgen-dependent, androgen-independent, castration-resistant, hormone-independent, hormone-refractory), penis), gastric cancer;

[0377] Cancer / tumors / carcinomas of the testicles: e.g. seminoma, non-seminoma,

[0378] Gynecological cancers / tumors / cancers: such as tumors / cancers / cancers of the ovaries, fallopian tubes, peritoneum, cervix, vulva, vagina, and uterine corpus (including the endometrium and fundus);

[0379] Breast cancer / tumor / carcinoma: such as breast cancer (invasive ductal carcinoma, colloid carcinoma, invasive lobular carcinoma, ductal carcinoma, adenocystic carcinoma, papillary carcinoma, medullary carcinoma, mucinous carcinoma), hormone receptor-positive breast cancer (estrogen receptor-positive breast cancer, progesterone receptor-positive breast cancer), HER2-positive breast cancer, triple-negative breast cancer, and Paget's disease of the breast;

[0380] Cancer / tumors / carcinomas of the endocrine system: for example, tumors / carcinomas / cancers of the following endocrine glands: thyroid (thyroid carcinomas / tumors; papillary carcinoma, follicular carcinoma, anaplastic carcinoma, medullary carcinoma), parathyroid (parathyroid carcinomas / tumors), adrenal cortex (adrenal cortex carcinomas / tumors), pituitary glands (including prolactinomas, craniopharyngiomas), thymus, adrenal glands, pineal gland, carotid body, islet cell tumors, paraganglia, pancreatic endocrine tumors (PET; non-functional PET, pancreatic polypeptide tumor (PPoma), gastrinoma, insulinoma, vasoactive intestinal polypeptide tumor (VIPoma), glucagonoma, somatostatinoma, growth hormone-releasing factor tumor (GRFoma), adrenocorticotropin tumor (ACTHoma)), carcinoid tumors;

[0381] Soft tissue sarcomas: e.g., fibrosarcoma, fibrohistiocytoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, lymphangiosarcoma, Kaposi's sarcoma, glomus tumor, hemangiopericytoma, synovial sarcoma, giant cell tumor of the tendon sheath, solitary fibrous tumor of the pleura and peritoneum, diffuse mesothelioma, malignant peripheral neural sheath tumor (MPNST), granular cell tumor, clear cell sarcoma, melanocytic schwannoma, plexosarcoma, neuroblastoma, ganglioblastoma, neuroepithelioma, extraskeletal Ewing's sarcoma, paraganglioma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, mesenchymal tumor, soft tissue alveolar sarcoma, epithelioid sarcoma, extrarenal rhabdoid tumor, desmoplastic small cell tumor;

[0382] Bone sarcomas: such as myeloma, reticulum cell sarcoma, chondrosarcoma (including central cell chondrosarcoma, peripheral cell chondrosarcoma, clear cell chondrosarcoma, and mesenchymal chondrosarcoma), osteosarcoma (including parosteal osteosarcoma, periosteal osteosarcoma, high-grade superficial osteosarcoma, small cell osteosarcoma, radiation-induced osteosarcoma, and Paget's sarcoma), Ewing's tumor, malignant giant cell tumor, adamantoma, (fibrous) histiocytoma, fibrosarcoma, chordoma, small round cell sarcoma, hemangioendothelioma, hemangiopericytoma, osteochondroma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, and chondroblastoma;

[0383] Mesothelioma: such as pleural mesothelioma, peritoneal mesothelioma;

[0384] Skin cancer: such as basal cell carcinoma, squamous cell carcinoma, Merkel's cell carcinoma, melanoma (including cutaneous melanoma, superficial spreading melanoma, lentigo maligna melanoma, acral lentigo melanoma, nodular melanoma, and intraocular melanoma), actinic keratosis, and eyelid cancer;

[0385] Tumors of the central nervous system and brain: for example, astrocytomas (cerebral astrocytoma, cerebellar astrocytoma, diffuse astrocytoma, myofibrillar astrocytoma, pleomorphic astrocytoma, pilocytic astrocytoma, protoplasmic large round cell astrocytoma), glioblastoma, glioma, oligodendroglioma, oligoastrocytoma, ependymoma, ependymoblastoma, choroid plexus tumor, medulloblastoma, meningioma, neurilemoma, hemangioblastoma, hemangioma, hemangiopericytoma, neuroma, gangliocytoma, neuroblastoma, retinoblastoma, neuroma (e.g., acoustic neuroma), spinal cord tumors;

[0386] Lymphomas and leukemias, such as B-cell non-Hodgkin's lymphoma (NHL) (including small lymphocytic lymphoma (SLL), lymphoplasmacytoid lymphoma (LPL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large cell lymphoma (DLCL), Burkitt's lymphoma (BL)), T-cell non-Hodgkin's lymphoma (including pleomorphic large cell lymphoma (ALCL), adult T-cell leukemia / lymphoma (ATLL) , cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL)), lymphoblastic T-cell lymphoma (T-LBL), adult T-cell lymphoma, lymphoblastic B-cell lymphoma (B-LBL), immune cell tumor, chronic B-cell lymphocytic leukemia, (B-CLL), chronic T-cell lymphocytic leukemia (T-CLL), B-cell small lymphocytic lymphoma (B-SLL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL ... (B-CLL), chronic T-cell lymphocytic leukemia (T-CLL), B-cell small lymphocytic lymphoma (B-SLL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), lymphoblastic T-cell lymphoma (T-LBL), lymphoblastic B-cell lymphoma (B- LC), primary central nervous system lymphoma (PCNSL), immunoblastoma, Hodgkin's disease (HD) (including nodular lymphocyte-predominant HD (NLPHD), tuberous sclerosis HD (NSHD), mixed cellularity HD (MCHD), lymphocyte-rich classical HD, lymphocyte-depleted HD (LDHD)), large granular lymphocytic leukemia (LGL), chronic myeloid leukemia (CML), acute myeloid / myeloid leukemia (AML), acute lymphoblastic / lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), chronic lymphocytic / lymphoid leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia, chronic myeloid / myeloid leukemia (CML), myeloma, plasmacytoma, multiple myeloma (MM), plasmacytoma, myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML);

[0387] cancer of unknown primary site (CUP);

[0388] All cancers / tumors / carcinomas mentioned above that are characterized by their specific location / origin in the body are intended to include both primary tumors and metastatic tumors derived therefrom.

[0389] All cancers / tumors / carcinomas mentioned above can be further distinguished by their histopathological classification:

[0390] Epithelial cancers, such as squamous cell carcinoma (SCC) (carcinoma in situ, superficially invasive carcinoma, verrucous carcinoma, pseudosarcoma, anaplastic carcinoma, metastatic cell carcinoma, lymphoepithelial carcinoma), adenocarcinoma (AC) (well-differentiated adenocarcinoma, mucinous adenocarcinoma, papillary adenocarcinoma, pleomorphic giant cell adenocarcinoma, ductal adenocarcinoma, small cell adenocarcinoma, signet ring cell adenocarcinoma, spindle cell adenocarcinoma, clear cell adenocarcinoma, oat cell adenocarcinoma, colloid adenocarcinoma, adenosquamous adenocarcinoma, mucoepidermoid adenocarcinoma, adenoid cystic adenocarcinoma), mucinous cystadenocarcinoma, acinar cell carcinoma, large cell carcinoma, small cell carcinoma, neuroendocrine tumors (small cell carcinoma, paraganglioma, carcinoid); oncocytic carcinoma;

[0391] Non-epithelial cancers, such as sarcomas (fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, giant cell sarcoma, lymphosarcoma, fibrohistiocytoma, liposarcoma, angiosarcoma, lymphangiosarcoma, neurofibrosarcoma), lymphoma, melanoma, germ cell tumors, hematological neoplasms, mixed and undifferentiated carcinomas;

[0392] The compounds of the invention may be used in treatment regimens in the setting of first line, second line or any other line of treatment.

[0393] The compounds of the present invention may be used for the prophylaxis, short-term or long-term treatment of the above-mentioned diseases / conditions / cancers / tumors, optionally also in combination with radiotherapy and / or surgery.

[0394] The methods of treatment, methods, uses and compounds for use as disclosed herein (above and below) may be performed using any compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, as disclosed or defined herein, and using any pharmaceutical composition or kit comprising a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof (each including all individual embodiments or general subsets of compounds of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If).

[0395] Combination therapy

[0396] Compounds of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising such compounds or salts may also be co-administered as pre- or post-operative adjuvants with other pharmacologically active substances, such as other anti-neoplastic compounds (e.g., chemotherapy), or used in combination with other treatments, such as radiation or surgical intervention. Preferably, the pharmacologically active substance for co-administration is an anti-neoplastic compound.

[0397] Therefore, in another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, for use as defined above, wherein the compound is administered before, after or together with one or more other pharmacologically active substances.

[0398] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If) for use as defined above, or a pharmaceutically acceptable salt thereof, wherein the compound is administered in combination with one or more further pharmacologically active substances.

[0399] In another aspect, the present invention relates to the use of a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or a pharmaceutically acceptable salt thereof, wherein the compound is administered before, after or together with one or more other pharmacologically active substances.

[0400] In another aspect, the present invention relates to a method as defined above (e.g., a method for treatment and / or prevention), wherein the compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, is administered before, after or together with a therapeutically effective amount of one or more other pharmacologically active substances.

[0401] In another aspect, the present invention relates to a method as defined above (e.g., a method for treatment and / or prevention), wherein a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, is administered in combination with a therapeutically effective amount of one or more other pharmacologically active substances.

[0402] In another aspect, the present invention relates to a method for treating and / or preventing cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of one or more other pharmacologically active substances, wherein the compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, and the one or more other pharmacologically active substances are administered simultaneously, concurrently, sequentially, continuously, alternatingly or separately.

[0403] In another aspect, the present invention relates to a method for treating and / or preventing cancer, comprising administering to a patient in need thereof a therapeutically effective amount of an inhibitor of KRAS mutated at residue 12 or 13, such as a KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12A, KRAS G13D and / or KRAS G12R inhibitor, preferably a KRAS G12C, KRAS G12D or selective KRAS G12D inhibitor or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of one or more other pharmacologically active substances, wherein the inhibitor or a pharmaceutically acceptable salt thereof is administered in combination with the one or more other pharmacologically active substances.

[0404] In another aspect, the present invention relates to a method for treating and / or preventing cancer, comprising administering to a patient in need thereof a therapeutically effective amount of an inhibitor of amplified or overexpressed wild-type KRAS or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of one or more other pharmacologically active substances, wherein the inhibitor or a pharmaceutically acceptable salt thereof is administered in combination with the one or more other pharmacologically active substances.

[0405] In another aspect, the present invention relates to a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of cancer, wherein the compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, is administered simultaneously, concurrently, sequentially, continuously, alternatingly or separately with one or more other pharmacologically active substances.

[0406] In another aspect, the present invention relates to inhibitors of KRAS mutated at residue 12 or 13, such as KRASG12C, KRASG12D, KRASG12V, KRASG12A, KRASG13D and / or KRASG12R inhibitors, preferably KRASG12C, KRASG12D or selective KRASG12D inhibitors or pharmaceutically acceptable salts thereof, for use in treating and / or preventing cancer, wherein the inhibitor or pharmaceutically acceptable salt thereof is administered in combination with one or more other pharmacologically active substances.

[0407] In another aspect, the present invention relates to an inhibitor of amplified or overexpressed KRAS wild-type or a pharmaceutically acceptable salt thereof for use in treating and / or preventing cancer, wherein the inhibitor or a pharmaceutically acceptable salt thereof is administered in combination with one or more other pharmacologically active substances.

[0408] In another aspect, the present invention relates to a kit comprising

[0409] a first pharmaceutical composition or dosage form comprising a compound of Formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients, and

[0410] a second pharmaceutical composition or dosage form comprising another pharmacologically active substance, and optionally one or more pharmaceutically acceptable excipients,

[0411] It is used for the treatment and / or prevention of cancer, wherein the first pharmaceutical composition is to be administered simultaneously, concurrently, sequentially, successively, alternatingly or separately with the second and / or additional pharmaceutical composition or dosage form.

[0412] In one aspect, such a kit for this use comprises a third pharmaceutical composition or dosage form comprising a third pharmaceutical composition or dosage form comprising another pharmacologically active substance and optionally one or more pharmaceutically acceptable excipients.

[0413] In another embodiment of the invention, the components (ie, the combination partners) of the combinations, kits, uses, methods and compounds for use according to the invention (including all embodiments) are administered simultaneously.

[0414] In another embodiment of the invention, the components of the combinations, kits, uses, methods and compounds for use according to the invention (including all embodiments) (ie, combination partners) are administered concurrently.

[0415] In another embodiment of the invention, the components of the combinations, kits, uses, methods and compounds for use according to the invention (including all embodiments) (ie, combination partners) are administered sequentially.

[0416] In another embodiment of the invention, the components of the combinations, kits, uses, methods and compounds for use according to the invention (including all embodiments) (ie, the combination partners) are administered serially.

[0417] In another embodiment of the invention, the components of the combinations, kits, uses, methods and compounds for use according to the invention (including all embodiments) (ie, combination partners) are administered alternately.

[0418] In another embodiment of the invention, the components of the combinations, kits, uses, methods and compounds for use according to the invention (including all embodiments) (ie, the combination partners) are administered separately.

[0419] The pharmacologically active substance used together with / in combination with a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof (including all individual embodiments or general subsets of the compounds), or used in the medical uses, uses, treatments and / or prevention methods as defined herein (above and below), may be selected from any one or more of the following (preferably, there are one or two additional pharmacologically active substances for all these embodiments):

[0420] 1. Inhibitors of EGFR and / or ErbB2 (HER2) and / or ErbB3 (HER3) and / or ErbB4 (HER4) or any mutants thereof

[0421] a. Irreversible inhibitors: such as afatinib, dacomitinib, canertinib, neratinib, avitinib, poziotinib, AV 412, PF-6274484, HKI 357, omotinib, osimertinib, ametinib, neratinib, lazertinib, and pelitinib;

[0422] b. Reversible inhibitors: such as erlotinib, gefitinib, icotinib, sapitinib, lapatinib, varlitinib, vandetanib, TAK-285, AEE788,

[0423] BMS599626 / AC-480, GW 583340;

[0424] c. Anti-EGFR antibodies: such as necitumumab, panitumumab, cetuximab, and amivantamab;

[0425] d. Anti-HER2 antibodies: such as pertuzumab, trastuzumab, and trastuzumab emtansine;

[0426] e. Inhibitors of mutant EGFR;

[0427] f. HER2 inhibitors with exon 20 mutations;

[0428] g. The preferred irreversible inhibitor is afatinib;

[0429] h. Preferably, the anti-EGFR antibody is cetuximab.

[0430] 2. Inhibitors of MEK and / or its mutants

[0431] a. For example, trametinib, cobimetinib, binimetinib, selumetinib, and refametinib;

[0432] b. preferably trametinib

[0433] c. MEK inhibitors as disclosed in WO 2013 / 136249;

[0434] d. MEK inhibitors as disclosed in WO 2013 / 136254

[0435] 3. Inhibitors of SOS1 and / or any mutants thereof (i.e., compounds that modulate / inhibit the GEF functionality of SOS1, e.g., by binding to SOS1 and preventing protein-protein interactions between SOS1 and (mutant) Ras proteins, e.g., KRAS)

[0436] a. For example, BAY-293;

[0437] b. an SOS1 inhibitor as disclosed in WO 2018 / 115380;

[0438] c. an SOS1 inhibitor as disclosed in WO 2019 / 122129;

[0439] d. SOS1 inhibitors as disclosed in WO 2020 / 180768, WO 2020 / 180770, WO 2018 / 172250 and WO 2019 / 201848.

[0440] 4. Inhibitors of YAP1, WWTR1, TEAD1, TEAD2, TEAD3, and / or TEAD4

[0441] a. Reversible inhibitors of TEAD transcription factors (e.g., disclosed in WO 2018 / 204532);

[0442] b. Irreversible inhibitors of TEAD transcription factors (e.g., disclosed in WO 2020 / 243423);

[0443] c. Protein-protein interaction inhibitors of YAP / TAZ::TEAD interactions (e.g., disclosed in WO2021 / 186324);

[0444] d. TEAD palmitoylation inhibitors.

[0445] 5. Oncolytic viruses

[0446] 6. RAS vaccine

[0447] a. For example, TG02 (Targovax).

[0448] 7. Cell cycle inhibitors

[0449] a. For example, inhibitors of CDK4 / 6 and / or any mutants thereof

[0450] i. For example, palbociclib, ribociclib, abemaciclib, trilaciclib, PF-06873600;

[0451] ii. preferably palbociclib and amacoxib;

[0452] iii. Most preferably, it is amacoxib.

[0453] b. For example, vinca alkaloids

[0454] i. For example, vinorelbine.

[0455] c. Inhibitors of, for example, Aurora kinase and / or any mutant thereof

[0456] i. For example, alisertib, barasertib.

[0457] 8. Inhibitors of PTK2 (=FAK) and / or any of its mutants

[0458] a. For example, TAE226, BI 853520.

[0459] 9. Inhibitors of SHP2 and / or any of its mutants

[0460] a. For example, SHP099, TNO155, RMC-4550, RMC-4630, and IACS-13909.

[0461] 10. Inhibitors of PI3 kinase (=PI3K) and / or any mutants thereof

[0462] a. For example, inhibitors of PI3Kα and / or any mutants thereof

[0463] i. For example, alpelisib, serabelisib, GDC-0077, HH-CYH33, AMG 511, buparlisib, dactolisib, pictilisib, taselisib.

[0464] 11. Inhibitors of FGFR1 and / or FGFR2 and / or FGFR3 and / or any mutants thereof

[0465] a. For example, ponatinib, infigratinib, and nintedanib.

[0466] 12. Inhibitors of AXL and / or any of its mutants

[0467] 13. Taxanes

[0468] a. For example, paclitaxel, albumin-bound paclitaxel (nab-paclitaxel), and docetaxel;

[0469] b. Preferably paclitaxel.

[0470] 14. Platinum-containing compounds

[0471] a. For example, cisplatin, carboplatin, oxaliplatin

[0472] b. Oxaliplatin is preferred.

[0473] 15. Antimetabolites

[0474] a. For example, a combination of 5-fluorouracil, capecitabine, floxuridine, cytarabine, gemcitabine, pemetrexed, trifluridine and tipiracil (=TAS102);

[0475] b. Preferably 5-fluorouracil.

[0476] 16. Immunotherapeutic agents

[0477] a. For example, immune checkpoint inhibitors

[0478] i. For example, anti-CTLA4 mAb, anti-PD1 mAb, anti-PD-L1 mAb, anti-PD-L2 mAb, anti-LAG3 mAb, anti-TIM3 mAb;

[0479] ii. preferably anti-PD1 mAb;

[0480] iii. For example, ipilimumab, nivolumab, pembrolizumab, tislelizumab, atezolizumab, avelumab, durvalumab, pidilizumab, PDR-001 (=spartalizumab), AMG-404, ezabenlimab;

[0481] iv. preferably nivolumab, pembrolizumab, ezetanib, and PDR-001 (=spartalizumab);

[0482] v. Most preferred are ezabenb, pembrolizumab and nivolumab.

[0483] 17. Topoisomerase inhibitors

[0484] a. For example, irinotecan, liposomal irinotecan (nal-IRI), topotecan, etoposide;

[0485] b. Most preferably, irinotecan and liposomal irinotecan (nal-IRI) are used.

[0486] 18. Inhibitors of A-Raf and / or B-Raf and / or C-Raf and / or any mutants thereof

[0487] a. For example, encorafenib, dabrafenib, vemurafenib, PLX-8394, RAF-709 (= Example 131 in WO 2014 / 151616), LXH254, sorafenib, LY-3009120 (= Example 1 in WO 2013 / 134243), lifirafenib, TAK-632, agerafenib, CCT196969, RO5126766, RAF265.

[0488] 19. mTOR inhibitors

[0489] a. For example, rapamycin, temsirolimus, everolimus, ridaforolimus, zotarolimus, sapanisertib, Torin 1, dactolisib, GDC-0349, VS-5584, vistusertib, and AZD8055.

[0490] 20. Epigenetic regulators

[0491] a. For example, BET inhibitors

[0492] i. For example, JQ-1, GSK 525762, OTX-015, CPI-0610, TEN-010, OTX-015, PLX51107, ABBV-075, ABBV-744, BMS986158, TGI-1601, CC-90010, AZD5153, I-BET151, and BI 894999;

[0493] 21. Inhibitors of IGF1 / 2 and / or IGF1-R and / or any mutants thereof

[0494] a. For example, xentuzumab (antibody 60833 in WO 2010 / 066868), MEDI-573 (=dusigitumab), linsitinib.

[0495] 22. Inhibitors of Src family kinases and / or any mutants thereof

[0496] a. For example, inhibitors of SrcA subfamily kinases and / or any mutants thereof, ie, inhibitors of Src, Yes, Fyn, Fgr and / or any mutants thereof;

[0497] b. For example, inhibitors of SrcB subfamily kinases and / or any mutants thereof, ie, inhibitors of Lck, Hck, Blk, Lyn and / or any mutants thereof;

[0498] c. For example, inhibitors of Frk subfamily kinases and / or any mutants thereof, ie, inhibitors of Frk and / or any mutants thereof;

[0499] d. For example, dasatinib, ponatinib, bosutinib, vandetanib, KX-01, saracatinib, KX2-391, SU 6656, and WH-4-023.

[0500] 23. Apoptosis regulators

[0501] a. For example, an MDM2 inhibitor, such as an inhibitor of the interaction between p53 (preferably functional p53, most preferably wt p53) and MDM2 and / or any mutant thereof;

[0502] i. For example, HDM-201, NVP-CGM097, RG-7112, MK-8242, RG-7388, SAR405838, AMG-232, DS-3032, RG-7775, and APG-115;

[0503] ii. Preferably HDM-201, RG-7388 and AMG-232;

[0504] iii. MDM2 inhibitors as disclosed in WO 2015 / 155332;

[0505] iv. an MDM2 inhibitor as disclosed in WO 2016 / 001376;

[0506] v. MDM2 inhibitors as disclosed in WO 2016 / 026937;

[0507] vi. MDM2 inhibitors as disclosed in WO 2017 / 060431;

[0508] b. For example, PARP inhibitors;

[0509] c. For example, MCL-1 inhibitors;

[0510] i. For example, AZD-5991, AMG-176, AMG-397, S64315, S63845, A-1210477;

[0511] 24. Inhibitors of c-MET and / or any of its mutants

[0512] a. For example, savolitinib, cabozantinib, and foretinib;

[0513] b. MET antibodies, such as emibetuzumab and amivantamab;

[0514] 25. Inhibitors of ERK and / or any of its mutants

[0515] a. For example, ulixertinib, LTT462;

[0516] 26. Inhibitors of farnesyltransferase and / or any mutant thereof

[0517] a. For example, tipifarnib;

[0518] In another embodiment of the (combination) uses and methods (e.g., methods of treatment and / or prevention) as described above, the further pharmacologically active substance is administered before, after or together with the compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, wherein the further pharmacologically active substance is

[0519] SOS1 inhibitors; or

[0520] MEK inhibitors; or

[0521] Trametinib, or

[0522] anti-PD-1 antibody; or

[0523] ezabenlimab; or

[0524] Cetuximab; or

[0525] afatinib; or

[0526] Standard of care (SoC) for a given indication; or

[0527] PI3 kinase inhibitors; or

[0528] TEAD palmitoylation inhibitors; or

[0529] YAP / TAZ::TEAD inhibitors.

[0530] In another embodiment of the (combination) uses and methods (e.g., methods of treatment and / or prevention) as described above, another pharmacologically active substance is administered in combination with a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, wherein the other pharmacologically active substance is

[0531] SOS1 inhibitors; or

[0532] MEK inhibitors; or

[0533] Trametinib; or

[0534] anti-PD-1 antibody; or

[0535] Ebenlizumab; or

[0536] Cetuximab; or

[0537] afatinib; or

[0538] Standard of care (SoC) for a given indication; or

[0539] PI3 kinase inhibitors; or

[0540] TEAD palmitoylation inhibitors; or

[0541] YAP / TAZ::TEAD inhibitors.

[0542] In another aspect of the (combination) uses and methods (e.g., methods of treatment and / or prevention) as described above, two further pharmacologically active substances are administered before, after or together with the compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof.

[0543] MEK inhibitors and SOS1 inhibitors; or

[0544] Trametinib and an SOS1 inhibitor; or

[0545] Anti-PD-1 antibody (preferably ebenfrucizumab) and anti-LAG-3 antibody; or

[0546] An anti-PD-1 antibody (preferably ebenfrucizumab) and an SOS1 inhibitor; or

[0547] a MEK inhibitor and an inhibitor selected from the group consisting of an EGFR inhibitor and / or an ErbB2 (HER2) inhibitor and / or an inhibitor of any mutant thereof; or

[0548] • an SOS1 inhibitor and an inhibitor selected from the group consisting of an EGFR inhibitor and / or an ErbB2 (HER2) inhibitor and / or an inhibitor of any mutant thereof; or

[0549] MEK inhibitors and afatinib; or

[0550] MEK inhibitor and cetuximab; or

[0551] Trametinib and afatinib; or

[0552] Trametinib and cetuximab; or

[0553] SOS1 inhibitors and afatinib; or

[0554] SOS1 inhibitor and cetuximab; or

[0555] SOS1 inhibitors and TEAD palmitoylation inhibitors; or

[0556] SOS1 inhibitors and YAP / TAZ::TEAD inhibitors.

[0557] In another aspect of the (combination) uses and methods (e.g., methods of treatment and / or prevention) as described above, two further pharmacologically active substances are administered in combination with a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, wherein the two further pharmacologically active substances are

[0558] MEK inhibitors and SOS1 inhibitors; or

[0559] Trametinib and an SOS1 inhibitor; or

[0560] Anti-PD-1 antibody (preferably ebenfrucizumab) and anti-LAG-3 antibody; or

[0561] An anti-PD-1 antibody (preferably ebenfrucizumab) and an SOS1 inhibitor; or

[0562] a MEK inhibitor and an inhibitor selected from the group consisting of an EGFR inhibitor and / or an ErbB2 (HER2) inhibitor and / or an inhibitor of any mutant thereof; or

[0563] an SOS1 inhibitor and an inhibitor selected from the group consisting of an EGFR inhibitor and / or an ErbB2 (HER2) inhibitor and / or an inhibitor of any mutant thereof; or

[0564] MEK inhibitors and afatinib; or

[0565] MEK inhibitor and cetuximab; or

[0566] Trametinib and afatinib; or

[0567] Trametinib and cetuximab; or

[0568] SOS1 inhibitors and afatinib; or

[0569] SOS1 inhibitor and cetuximab; or

[0570] SOS1 inhibitors and TEAD palmitoylation inhibitors; or

[0571] SOS1 inhibitors and YAP / TAZ::TEAD inhibitors.

[0572] Additional pharmacologically active substances that can also be used together with / in combination with a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharmaceutically acceptable salt thereof (including all individual embodiments or generic subsets of compounds of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or for the medical uses, uses, methods of treatment and / or prevention, pharmaceutical compositions, kits as defined herein (above and below) include, but are not limited to, hormones, hormone analogs and anti-hormones (e.g., tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, acetate), finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors (e.g., anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane), LHRH agonists and antagonists (e.g., goserelin acetate), acetate), luprolide), inhibitors of growth factors and / or their corresponding receptors (such as platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), human epidermal growth factor (HER, such as HER2, HER3, HER4) and hepatocyte growth factor (HGF) and / or their corresponding receptors), the inhibitors being, for example, (anti-)growth factor antibodies, (anti-)growth factor receptor antibodies and tyrosine kinase inhibitors,such as cetuximab, gefitinib, afatinib, nintedanib, imatinib, lapatinib, bosutinib, bevacizumab, and trastuzumab); antimetabolites (e.g., antifolates such as methotrexate, raltitrexed, pyrimidine analogs such as 5-fluorouracil (5-FU), nucleoside and deoxynucleoside analogs, capecitabine and gemcitabine, purine and adenosine analogs such as mercaptopurine, thioguanine, cladribine, and pentostatin, cytarabine, and pentostatin); C), fludarabine); antitumor antibiotics (e.g., anthracyclines such as doxorubicin, doxil (pegylated liposomal doxorubicin hydrochloride, myocet (non-pegylated liposomal doxorubicin), daunorubicin, epirubicin, and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, and streptozocin); platinum derivatives (e.g., cisplatin, oxaliplatin, and oxaliplatin); liplatin), carboplatin); alkylating agents (e.g., estramustin, meclorethamine, melphalan, chlorambucil, busulphan, dacarbazin, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as carmustin and lomustin, thiotepa); antimitotic agents (e.g., vinca alkaloids such as vinblastine, vindesine, vinorelbine, and vincristine; and taxanes,such as paclitaxel, docetaxel); angiogenesis inhibitors (e.g., tasquinimod), tubulin inhibitors; DNA synthesis inhibitors, PARP inhibitors, topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantrone), serine / threonine kinase inhibitors (e.g., PDK1 inhibitors, Raf inhibitors, A-Raf inhibitors, B-Raf inhibitors, C-Raf inhibitors, mTOR inhibitors, mTORC1 / 2 inhibitors, PI3K inhibitors, PI3Kα inhibitors, dual mTOR / PI3K inhibitors, STK 33 inhibitors, AKT inhibitors, PLK 1 inhibitors, CDK inhibitors, Aurora kinase inhibitors), tyrosine kinase inhibitors (e.g., PTK2 / FAK inhibitors), protein-protein interaction inhibitors (e.g., IAP inhibitors / SMAC mimetics, Mcl-1, MDM2 / MDMX), MEK inhibitors, ERK inhibitors, FLT3 inhibitors, BRD4 inhibitors, IGF-1R inhibitors, TRAILR2 agonists, Bcl-xL inhibitors, Bcl-2 inhibitors (e.g., venetoclax), Bcl-2 / Bcl-xL inhibitors, ErbB receptor inhibitors, BCR-ABL inhibitors, ABL inhibitors, Src inhibitors, rapamycin analogs (e.g., everolimus, temsirolimus, ridaforolimus), limus), sirolimus), androgen synthesis inhibitors, androgen receptor inhibitors, DNMT inhibitors, HDAC inhibitors, ANG1 / 2 inhibitors, CYP17 inhibitors, radiopharmaceuticals, proteasome inhibitors (e.g., carfilzomib), immunotherapeutics such as immune checkpoint inhibitors (e.g., CTLA4, PD1, PD-L1, PD-L2, LAG3, and TIM3 binding molecules / immunoglobulins, such as ipilimumab, nivolumab, pembrolizumab), ADCC (antibody-dependent cell-mediated cytotoxicity) enhancers (e.g., anti-CD33 antibodies, anti-CD37 antibodies, anti-CD20 antibodies), T cell engagers (e.g., bispecific T cell engagers,

[0014] In some embodiments, the present invention includes but is not limited to the treatment of leukemia, melanoma, and prostate cancer. In some embodiments, the present invention includes but is not limited to the treatment of leukemia, melanoma, prostate cancer, prostate cancer, prostate cancer, prostate cancer, prostate cancer, and prostate cancer. In some embodiments, the present invention includes but is not limited to the treatment of leukemia, melanoma, prostate cancer, prostate cancer, prostate cancer, and prostate cancer.

[0573] It will be understood that the combinations, compositions, kits, methods, uses, pharmaceutical compositions or compounds used according to the present invention may envisage simultaneous, concurrent, sequential, continuous, alternating or separate administration of the active ingredients or components. It will be understood that the compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, and one or more other pharmacologically active substances may be formulated and administered in a dependent or independent manner, such as the compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a pharmaceutically acceptable salt thereof, and one or more other pharmacologically active substances may be administered as part of the same pharmaceutical composition / dosage form or, preferably, in separate pharmaceutical compositions / dosage forms.

[0574] In this context, "combination" or "combined" within the meaning of the present invention includes, but is not limited to, products resulting from the mixing or combining of more than one active ingredient and includes fixed and non-fixed (e.g., free) combinations (including kits) and uses, such as the simultaneous, concurrent, sequential, successively, alternating or separate use of the components or ingredients. The term "fixed combination" means that the active ingredients are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients are administered to a patient simultaneously, concurrently or sequentially in the form of separate entities without specific time limits, wherein such administration provides a therapeutically effective amount of the compounds in the patient.

[0575] The administration of a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharmaceutically acceptable salt thereof and one or more other pharmacologically active substances can be carried out by co-administering the active components or ingredients, such as by simultaneously or concurrently administering the active components or ingredients in a single or two or more separate formulations or dosage forms. Alternatively, the administration of a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a pharmaceutically acceptable salt thereof and one or more other pharmacologically active substances can be carried out by sequential or alternating administration, such as by administering the active components or ingredients in two or more separate formulations or dosage forms.

[0576] For example, simultaneous administration includes administration at substantially the same time. This form of administration may also be referred to as "concomitant" administration. Concurrent administration includes administering the active agent within the same general period (e.g., on the same day but not necessarily at the same time). Alternating administration includes administering one agent during one period (e.g., over the course of a few days or a week), then administering another agent during a subsequent period (e.g., over the course of a few days or a week), and subsequently repeating the pattern for one or more cycles. Sequential or consecutive administration includes administering one agent using one or more doses during a first period (e.g., over the course of a few days or a week), then administering another agent using one or more doses during a second and / or additional period (e.g., over the course of a few days or a week). An overlapping schedule may also be employed, which includes administering the active agent on different days during the treatment period, not necessarily according to a regular sequence. Variations of these general guidelines may also be used, e.g., depending on the agents used and the condition of the individual.

[0577] Definitions

[0578] Terms not specifically defined herein shall be given the meaning that would be given to them by a person skilled in the art in view of the disclosure and the context. However, unless otherwise specified, as used in this specification, the following terms have the indicated meanings and shall conform to the following conventions.

[0579] The prefix C x-y is used, where x and y each represent a positive integer (x < y), indicating that the directly associated specified and mentioned chain or ring structure or combination of chain and ring structures as a whole can consist of a maximum of y carbon atoms and a minimum of x carbon atoms.

[0580] The indication of the number of members in a group containing one or more heteroatoms (e.g., heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl) refers to the total number of all ring members or the total number of all ring and carbon chain members.

[0581] The indication of the number of carbon atoms in a group consisting of a combination of carbon chains and carbon ring structures (e.g. cycloalkylalkyl, arylalkyl) relates to the total number of carbon atoms in all carbon ring and carbon chain members. Obviously, the ring structure has at least three members.

[0582] In general, for groups containing two or more subunits (e.g., heteroarylalkyl, heterocyclylalkyl, cycloalkylalkyl, arylalkyl), the last named subunit is the point of radical attachment, e.g., the substituent aryl-C 1-6 Alkyl means an aryl group bonded to a C 1-6 Alkyl groups, the latter being bonded to the core or the group to which the substituents are attached.

[0583] In groups such as HO, H2N, (O)S, (O)2S, NC (cyano), HOOC, F3C or the like, one skilled in the art can see the point of attachment of the group to the molecule from the free valence of the group itself.

[0584] The expression "compounds of the invention" and grammatical variants thereof encompass compounds of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) and (If), including all salts, aspects and preferred embodiments thereof as defined herein. Any reference to a compound of the invention or a compound of formula (I), (I*), (Ia), (Ib), (Ic), (Id), (Ie) and (If) is intended to include a reference to the respective (sub)aspects and embodiments.

[0585] Alkyl denotes a monovalent saturated hydrocarbon chain which can exist both in straight-chain (unbranched) and branched form. If an alkyl group is substituted, the substitution may be by monosubstitution or polysubstitution, independently of one another, on all hydrogen-carrying carbon atoms.

[0586] The term "C 1-5 "Alkyl" includes, for example, H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-.

[0587] Other examples of alkyl groups are methyl (Me; -CH3), ethyl (Et; -CH2CH3), 1-propyl (n-propyl; n-Pr; -CH2CH2CH3), 2-propyl (i-Pr; isopropyl; -CH(CH3)2), 1-butyl (n-butyl; n-Bu; -CH2CH2CH2CH3), 2-methyl-1-propyl (isobutyl; i-Bu; -CH2CH(CH3)2), 2-butyl (sec-butyl; sec-Bu; -CH(CH3)CH2CH3), 2-methyl-2-propyl (tert-butyl; t-Bu; -C(CH3)3), 1-pentyl (n-butyl; n-Bu; -CH2CH2CH2CH3), Pentyl; -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 3-methyl-1-butyl (isopentyl; -CH2CH2CH(CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 2,2-dimethyl-1-propyl (neopentyl; -CH2C(CH3)3), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (n-hexyl;-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), 2,3- Dimethyl-1-butyl (-CH2CH(CH3)CH(CH3)CH3), 2,2-dimethyl-1-butyl (-CH2C(CH3)2CH2CH3), 3,3-dimethyl-1-butyl (-CH2CH2C(CH3)3), 2-methyl-1-pentyl (-CH2CH(CH3)CH2CH2CH3), 3-methyl-1-pentyl (-CH2CH2CH(CH 3) CH2CH3), 1-heptyl (n-heptyl), 2-methyl-1-hexyl, 3-methyl-1-hexyl, 2,2-dimethyl-1-pentyl, 2,3-dimethyl-1-pentyl, 2,4-dimethyl-1-pentyl, 3,3-dimethyl-1-pentyl, 2,2,3-trimethyl-1-butyl, 3-ethyl-1-pentyl, 1-octyl (n-octyl), 1-nonyl (n-nonyl); 1-decyl (n-decyl), etc.;

[0588] The terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and the like, without any other definition, mean saturated hydrocarbon radicals having the corresponding number of carbon atoms, including all isomeric forms.

[0589] If alkyl is another (combined) group (such as (for example) C x-y Alkylamino or C x-y alkyloxy), the above definition of alkyl also applies.

[0590] The term alkylene can also be derived from alkyl. Unlike alkyl, alkylene is divalent and requires two bonding partners. Formally, the second valency is created by removing a hydrogen atom from an alkyl group. Corresponding groups include, for example, -CH3 and -CH2-, -CH2CH3 and -CH2CH2-, or >CHCH3.

[0591] The term "C 1-4"Alkylene" includes, for example, -(CH2)-, -(CH2-CH2)-, -(CH(CH3))-, -(CH2-CH2-CH2)-, -(C(CH3)2)-, -(CH(CH2CH3))-, -(CH(CH3)-CH2)-, -(CH2-CH(CH3))-, -(CH2-CH2-CH2-CH2)-, -(CH2-CH2-CH(CH3))-, -(CH(CH3)-CH2 -CH2)-, -(CH2-CH(CH3)-CH2)-, -(CH2-C(CH3)2)-, -(C(CH3)2-CH2)-, -(CH(CH3)-CH(CH3))-, -(CH2 -CH(CH2CH3))-, -(CH(CH2CH3)-CH2)-, -(CH(CH2CH2CH3))-, -(CH(CH(CH3))2)-, and -C(CH3)(CH2CH3)-.

[0592] Other examples of alkylene groups are methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene, hexylene, and the like.

[0593] By the generic terms propylene, butylene, pentylene, hexylene etc. without further definition are meant all possible isomeric forms having the corresponding number of carbon atoms, i.e. propylene includes 1-methylethylene and butylene includes 1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene and 1,2-dimethylethylene.

[0594] If alkylene is another (combined) group (such as HO-C x-y Alkyleneamino or H2N-C x-y alkyleneoxy), the above definition of alkylene also applies.

[0595] Unlike alkyl groups, alkenyl groups consist of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C-C double bond, and a carbon atom can only be part of one C-C double bond. If, in an alkyl group having at least two carbon atoms as defined above, two hydrogen atoms on adjacent carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding alkenyl group is formed.

[0596] Examples of alkenyl groups are vinyl (vinyl / ethenyl), prop-1-enyl, allyl (prop-2-enyl), isopropenyl, but-1-enyl, but-2-enyl, but-3-enyl, 2-methyl-prop-2-enyl, 2-methyl-prop-1-enyl, 1-methyl-prop-2-enyl, 1-methyl-prop-1-enyl, 1-methylenepropyl, pent-1-enyl, pent-2-enyl, pent-3-enyl, pent-4-enyl, 3-methyl-but-3-enyl, 3-methyl-but-2-enyl, 1,3-dienyl, hexyl, 1,4-dienyl, pentyl-1,4-dienyl, pentyl-1,3-dienyl, buta-1,3-dienyl, 2,3-dimethylbut-1,3-diene, and the like.

[0597] The generic terms propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, pentadienyl, octadienyl, nonadienyl, decadienyl, etc., without any other definition, mean all possible isomeric forms having the corresponding number of carbon atoms, i.e., propenyl includes prop-1-enyl and prop-2-enyl, and butenyl includes but-1-enyl, but-2-enyl, but-3-enyl, 1-methyl-prop-1-enyl, 1-methyl-prop-2-enyl, etc.

[0598] The alkenyl group may optionally be present in a cis or trans or E or Z orientation relative to the double bond.

[0599] When alkenyl is another (combined) group (such as C x-y Alkenylamino or C x-y When the alkylene group is part of an alkylene group (e.g., an alkylene group or an alkylene group), the above definition of alkylene group also applies.

[0600] Unlike alkylene, alkenylene consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C-C double bond, and a carbon atom can only be part of one C-C double bond. If, in an alkylene group as defined above having at least two carbon atoms, two hydrogen atoms at adjacent carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding alkenylene is formed.

[0601] Examples of alkenylene groups include vinylene, propenylene, 1-methylvinylene, butenylene, 1-methylpropenylene, 1,1-dimethylvinylene, 1,2-dimethylvinylene, pentenylene, 1,1-dimethylpropenylene, 2,2-dimethylpropenylene, 1,2-dimethylpropenylene, 1,3-dimethylpropenylene, and hexenylene.

[0602] The general terms propenylene, butenylene, pentenylene, hexenylene etc., without any further definition, are intended to mean all conceivable isomeric forms having the corresponding number of carbon atoms, i.e. propenylene includes 1-methylvinylene and butenylene includes 1-methylpropenylene, 2-methylpropenylene, 1,1-dimethylvinylene and 1,2-dimethylvinylene.

[0603] The alkenylene group may optionally be present in a cis or trans or E or Z orientation relative to the double bond.

[0604] When alkenylene is part of another (composite) group (as for example in HO-C x-y Alkenyleneamino or H2N-C x-y When the group is alkenyleneoxy, the above definition of alkenylene also applies.

[0605] Unlike alkyl groups, alkynyl groups consist of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together via a C-C triple bond. If, in an alkyl group as defined above having at least two carbon atoms, two hydrogen atoms at adjacent carbon atoms are formally removed in each case and the free valencies are saturated to form two further bonds, the corresponding alkynyl group is formed.

[0606] Examples of alkynyl groups are ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-2-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, 3-methyl-but-1-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, and the like.

[0607] The generic terms propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl etc., without any other definition, are intended to mean all conceivable isomeric forms having the corresponding number of carbon atoms, i.e. propynyl includes prop-1-ynyl and prop-2-ynyl, butynyl includes but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-1-ynyl, 1-methyl-prop-2-ynyl etc.

[0608] If the hydrocarbon chain carries both at least one double bond and at least one triple bond, it belongs to an alkynylene group by definition.

[0609] If the alkynyl group is part of another (composite) group (such as in C x-y Alkynylamino or C x-y alkynyloxy), the above definition of alkynyl also applies.

[0610] Unlike alkylene, alkynylene consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together via a C-C triple bond. If, in an alkylene group as defined above having at least two carbon atoms, two hydrogen atoms at adjacent carbon atoms are formally removed in each case and the free valencies are satisfied to form two further bonds, the corresponding alkynylene group is formed.

[0611] Examples of alkynylene groups are ethynylene, propynylene, 1-methylethynylene, butynylene, 1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene, pentynylene, 1,1-dimethylpropynylene, 2,2-dimethylpropynylene, 1,2-dimethylpropynylene, 1,3-dimethylpropynylene, hexynylene, and the like.

[0612] The generic terms propynylene, butynylene, pentynylene, hexynylene etc. without any further definition are intended to mean all conceivable isomeric forms having the corresponding number of carbon atoms, i.e. propynylene includes 1-methylethynylene and butynylene includes 1-methylpropynylene, 2-methylpropynylene, 1,1-dimethylethynylene and 1,2-dimethylethynylene.

[0613] If the alkynylene group is part of another (composite) group (as for example in HO-C x-y Alkynylideneamino or H2N-C x-y alkynyleneoxy), the above definition of alkynylene also applies.

[0614] Heteroatoms mean oxygen, nitrogen and sulfur atoms.

[0615] Haloalkyl (haloalkenyl, haloalkynyl) is derived from the previously defined alkyl (alkenyl, alkynyl) groups by replacing one or more hydrogen atoms of the hydrocarbon chain independently of one another by halogen atoms, which may be identical or different. If the haloalkyl (haloalkenyl, haloalkynyl) group is further substituted, the substitution may be in each case monosubstituted or polysubstituted, independently of one another, on all hydrogen-carrying carbon atoms.

[0616] Examples of haloalkyl (haloalkenyl, haloalkynyl) are -CF3, -CHF2, -CH2F, -CF2CF3, -CHFCF3, -CH2CF3, -CF2CH3, -CHFCH3, -CF2CF2CF3, -CF2CH2CH3, -CF=CF2, -CCl=CH2, -CBr=CH2, -C≡C-CF3, -CHFCH2CH3, -CHFCH2CF3, etc.

[0617] The previously defined haloalkyl (haloalkenyl, haloalkynyl) groups also derive the term haloalkylene (haloalkenyl, haloalkynyl) group. Unlike haloalkyl (haloalkenyl, haloalkynyl) groups, haloalkylene (haloalkenyl, haloalkynyl) groups are divalent and require two binding partners. Formally, the second valency is formed by removing a hydrogen atom from a haloalkyl (haloalkenyl, haloalkynyl) group.

[0618] Corresponding groups are, for example, -CH2F and -CHF-, -CHFCH2F and -CHFCHF- or >CFCH2F, etc.

[0619] The above definitions also apply if the corresponding halogen-containing group is part of another (composite) group.

[0620] Halogen represents fluorine, chlorine, bromine and / or iodine atoms.

[0621] Cycloalkyl is made up of subunit monocyclic cycloalkyl, bicyclic cycloalkyl and spirocycloalkyl.Ring system is saturated and is formed by the carbon atom that is connected.In bicyclic cycloalkyl, two rings are joined together so that it has at least two shared carbon atoms.In spirocycloalkyl, one carbon atom (spiro atom) belongs to two rings together.

[0622] If cycloalkyl is substituted, the substitution may take place independently of one another on all hydrogen-carrying carbon atoms in the form of mono- or polysubstitutions in each case.Cycloalkyl itself can be bonded to the molecule as a substituent via every suitable position of the ring system.

[0623] Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[4.3.0]nonyl (octahydroindenyl), bicyclo[4.4.0]decyl (decahydronaphthyl), bicyclo[2.2.1]heptyl (norbornyl), bicyclo[4.1.0]heptyl (norcaranyl), bicyclo[3.1.1]heptyl (pinanyl), spiro[2.5]octyl, spiro[3.3]heptyl, and the like.

[0624] If the cycloalkyl group is part of another (composite) group (such as in C x-y Cycloalkylamino, C x-y Cycloalkyloxy or C x-y cycloalkylalkyl), the above definition of cycloalkyl also applies.

[0625] If the free valencies of the cycloalkyl group are saturated, an alicyclic ring is obtained.

[0626] Thus, the term cycloalkylene can be derived from the previously defined cycloalkyl. Unlike cycloalkyl, cycloalkylene is divalent and requires two binding partners. Formally, the second valence is obtained by removing a hydrogen atom from a cycloalkyl. Corresponding groups are, for example:

[0627] Cyclohexyl and (cyclohexylene).

[0628] If cycloalkylene is part of another (composite) group (as for example in HO-C x-y Cycloalkyleneamino or H2N-C x-y cycloalkyleneoxy), the above definition of cycloalkylene also applies.

[0629] Cycloalkenyl groups are composed of the subunits monocyclic cycloalkenyl, bicyclic cycloalkenyl, and spirocycloalkenyl. However, the system is unsaturated, i.e., at least one C-C double bond is present but no aromatic system is present. If, in a cycloalkyl group as defined above, two hydrogen atoms at adjacent ring carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding cycloalkenyl group is obtained.

[0630] If cycloalkenyl is substituted, the substitution may in each case be mono- or polysubstituted, independently of one another, on all hydrogen-carrying carbon atoms.Cycloalkenyl itself can be bonded to the molecule as a substituent via every suitable position of the ring system.

[0631] Examples of cycloalkenyl groups are cycloprop-1-enyl, cycloprop-2-enyl, cyclobut-1-enyl, cyclobut-2-enyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclopent-3-enyl, cyclohex-1-enyl, cyclohex-2-enyl, cyclohex-3-enyl, cyclohept-1-enyl, cyclohept-2-enyl, cyclohept-3-enyl, cyclohept-4-enyl, cyclobuta-1,3-dienyl, cyclopenta-1,4 ...2,4-dienyl, cyclopenta-3-enyl, cyclohex-1,4-dienyl, cyclohex-2, cyclohex-3-enyl, cyclohept-1,4-dienyl, cyclohex-2, cyclohex-3-enyl, cyclohept-2, cyclohept-3-enyl, cyclohept-4-enyl, cyclobuta-1,3-dienyl, cyclopenta-1,4-dienyl, cyclopenta-1,4-dienyl, cyclopenta-2,4-dienyl, cyclopenta-3-enyl, cyclohex-1,4-dienyl, cyclohex-2, cyclohex-3-enyl, cyclohept-1,4-dienyl, cyclohex-2, cyclohex-3-enyl, cyclohept-1,4-dienyl, cyclohex-2, -1,3-dienyl, cyclopenta-2,4-dienyl, cyclohexa-1,3-dienyl, cyclohexa-1,5-dienyl, cyclohexa-2,4-dienyl, cyclohexa-1,4-dienyl, cyclohexa-2,5-dienyl, bicyclo[2.2.1]hept-2,5-dienyl (norbornen-2,5-dienyl), bicyclo[2.2.1]hept-2-enyl (norbornenyl), spiro[4,5]dec-2-enyl, etc.

[0632] When a cycloalkenyl group is part of another (composite) group (such as in C x-y Cycloalkenylamino, C x-y Cycloalkenyloxy or C x-y When the group is cycloalkenyl or cycloalkenylalkyl), the above definition of cycloalkenyl also applies.

[0633] If the free valencies of the cycloalkenyl radical are saturated, an unsaturated alicyclic ring is obtained.

[0634] Thus, the term cycloalkenylene can be derived from the previously defined cycloalkenyl. Unlike cycloalkenyl, cycloalkenylene is divalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a cycloalkenyl. Corresponding groups are, for example:

[0635] Cyclopentenyl and (cyclopentenylene), etc.

[0636] If the cycloalkenylene group is part of another (composite) group (as for example in HO-C x-y Cycloalkenyleneamino or H2N-C x-y cycloalkenyleneoxy), the above definition of cycloalkenylene also applies.

[0637] Aryl represents a monocyclic, bicyclic or tricyclic carbocycle having at least one aromatic carbocycle. Preferably, it represents a monocyclic group having six carbon atoms (phenyl) or a bicyclic group having nine or ten carbon atoms (two six-membered rings or one six-membered ring with a five-membered ring), wherein the second ring may also be aromatic or, however, may also be partially saturated.

[0638] If aryl is substituted, the substitution may take place independently of one another on all hydrogen-carrying carbon atoms in the form of mono- or polysubstitutions in each case.Aryl itself can be bonded to the molecule as a substituent via every suitable position of the ring system.

[0639] Examples of aryl groups include phenyl, naphthyl, dihydroindenyl (2,3-dihydroindenyl), indenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl (1,2,3,4-tetrahydronaphthyl, tetrahydronaphthyl), dihydronaphthyl (1,2-dihydronaphthyl), fluorenyl, etc. Phenyl is most preferred.

[0640] If aryl is part of another (composite) group, as for example in arylamino, aryloxy or arylalkyl, the above definition of aryl also applies.

[0641] If the free valencies of the aryl radical are saturated, an aromatic radical is obtained.

[0642] The term arylene can also be derived from the previously defined aryl. Unlike aryl, arylene is divalent and requires two binding partners. Formally, the second valency is formed by removing a hydrogen atom from an aryl. Corresponding groups are, for example:

[0643] Phenyl and (o-phenylene, m-phenylene, p-phenylene),

[0644] Naphthyl and wait.

[0645] If arylene is part of another (composite) group, as for example in HO-aryleneamino or H2N-aryleneoxy, the above definition of arylene also applies.

[0646] Heterocyclyl refers to a ring system derived from the previously defined cycloalkyl, cycloalkenyl, and aryl groups by replacing one or more -CH2- groups in the hydrocarbon ring independently of one another by -O-, -S-, or -NH- groups, or by replacing one or more =CH- groups by =N- groups. A total of up to five heteroatoms may be present, at least one carbon atom must be present between two oxygen atoms and between two sulfur atoms or between one oxygen atom and one sulfur atom, and the ring as a whole must be chemically stable. Heteroatoms may optionally be present in all possible oxidation stages (sulfur → sulfoxide -SO-, sulfone -SO2-; nitrogen → N-oxide). In heterocyclyl, there are no heteroaromatic rings, i.e., no heteroatoms are part of the aromatic system.

[0647] As a direct consequence of being derived from cycloalkyl, cycloalkenyl and aryl, heterocyclyl is composed of the subunits monocyclic heterocyclyl, bicyclic heterocyclyl, tricyclic heterocyclyl and spiroheterocyclyl, which can exist in saturated or unsaturated form.

[0648] Unsaturated means that there is at least one double bond in the ring system in question, but no heteroaromatic system is formed. In a bicyclic heterocyclyl, the two rings are linked together so that they have at least two shared (hetero)atoms. In a spiroheterocyclyl, one carbon atom (spiro atom) belongs to both rings together.

[0649] If the heterocyclyl is substituted, the substitution may be in each case monosubstituted or polysubstituted form, independently of one another, on all hydrogen-carrying carbon and / or nitrogen atoms. The heterocyclyl itself may be bonded to the molecule as a substituent via every suitable position of the ring system. The substituents on the heterocyclyl do not count towards the number of members of the heterocyclyl.

[0650] Examples of heterocyclic groups are tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, thiazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, oxiranyl, aziridinyl, azetidinyl, 1,4-dioxanyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-dioxide, 1,3-dioxolane , tetrahydropyranyl, tetrahydrothiopyranyl, [1,4]-oxazepanyl, tetrahydrothiophenyl, homothiomorpholinyl-S,S-dioxide, oxazolidinone, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydro-pyrimidinyl, dihydrofuranyl, dihydropyranyl, tetrahydrothiophenyl-S-oxide, tetrahydrothiophenyl-S,S-dioxide, homothiomorpholinyl-S-oxide, 2,3-dihydroazol, 2H-pyrrolyl, 4H-pyranyl, 1,4 -dihydropyridyl, 8-aza-bicyclo[3.2.1]octyl, 8-aza-bicyclo[5.1.0]octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 3,8-diaza-bicyclo[3.2.1]octyl, 2,5-diaza-bicyclo[2.2.1]heptyl, 1-aza-bicyclo[2.2.2]octyl, 3,8-diaza-bicyclo[3.2.1]octyl, 3,9 -diaza-bicyclo[4.2.1]nonyl, 2,6-diaza-bicyclo[3.2.2]nonyl, 1,4-dioxa-spiro[4.5]decyl, 1-oxa-3,8-diaza-spiro[4.5]decyl, 2,6-diaza-spiro[3.3]heptyl, 2,7-diaza-spiro[4.4]nonyl, 2,6-diaza-spiro[3.4]octyl, 3,9-diaza-spiro[5.5]undecyl, 2.8-diaza-spiro[4,5]decyl, and the like.

[0651] Other examples are the structures described below, which can be connected via each hydrogen-carrying atom (exchange with hydrogen):

[0652]

[0653]

[0654]

[0655]

[0656] Preferably, the monocyclic heterocyclyl is 4 to 7 membered and has one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0657] Preferred monocyclic heterocyclic groups are: piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl and azetidinyl.

[0658] Preferably, the bicyclic heterocyclyl is a 6- to 10-membered bicyclic heterocyclyl having one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0659] Preferably, the tricyclic heterocyclyl is a 9-membered tricyclic heterocyclyl and has one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0660] Preferably, the spiroheterocyclyl group is 7 to 11 members and has one or two heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0661] The above definition of heterocyclyl also applies if heterocyclyl is part of another (composite) group, as for example in heterocyclylamino, heterocyclyloxy or heterocyclylalkyl.

[0662] If the free valencies of the cycloalkyl group are saturated, a heterocycle is obtained.

[0663] The term heterocyclylene is also derived from the previously defined heterocyclyl. Unlike heterocyclyl, heterocyclylene is divalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a heterocyclyl. Corresponding groups are, for example:

[0664] Piperidinyl and

[0665] 2,3-dihydro-1H-pyrrolyl and wait.

[0666] The above definition of heterocyclylene also applies if heterocyclylene is part of another (composite) group, as for example in HO-heterocyclyleneamino or H2N-heterocyclyleneoxy.

[0667] Heteroaryl refers to a monocyclic heteroaromatic ring or a polycyclic ring having at least one heteroaromatic ring which, compared to the corresponding aryl or cycloalkyl (cycloalkenyl) group, contains one or more identical or different heteroatoms independently selected from nitrogen, sulfur and oxygen, replacing one or more carbon atoms, provided that the resulting group is chemically stable. The presence of a heteroaryl group presupposes the presence of a heteroatom and a heteroaromatic system.

[0668] If a heteroaryl group is substituted, the substitution may be carried out independently of one another on all hydrogen-carrying carbon atoms and / or nitrogen atoms in the form of mono- or poly-substitutions in each case. A heteroaryl group itself may be bound as a substituent to the molecule via each suitable position (carbon and nitrogen) of the ring system. The substituents on a heteroaryl group do not count towards the number of members of the heteroaryl group.

[0669] Examples of heteroaryl groups are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyridyl-N-oxide, pyrrolyl-N-oxide, pyrimidinyl-N-oxide, pyridazinyl-N-oxide, pyrazinyl-N-oxide, imidazolyl-N-oxide, isoxazolyl-N-oxide, oxazolyl-N-oxide compound, thiazolyl-N-oxide, oxadiazolyl-N-oxide, thiadiazolyl-N-oxide, triazolyl-N-oxide, tetrazolyl-N-oxide, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolyl, quinolyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzotriazinyl, indolizinyl, oxazolopyridinyl, imidazopyridinyl, N-oxide, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, quinolinyl-N-oxide, indolyl-N-oxide, isoquinolinyl-N-oxide, quinazolinyl-N-oxide, quinoxalinyl-N-oxide, phthalazinyl-N-oxide, indolizinyl-N-oxide, indazolyl-N-oxide, benzothiazolyl-N-oxide, benzimidazolyl-N-oxide, and the like.

[0670] Other examples are the structures described below, which can be connected via each hydrogen-carrying atom (exchange with hydrogen):

[0671]

[0672] Preferably, the heteroaryl group is a 5-6 membered monocyclic ring or a 9-10 membered bicyclic ring, each having 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0673] If heteroaryl is part of another (composite) group, as for example in heteroarylamino, heteroaryloxy or heteroarylalkyl, the above definition of heteroaryl also applies.

[0674] If the free valencies of the heteroaryl radical are saturated, a heteroaromatic radical is obtained.

[0675] The term heteroarylene is also derived from the previously defined heteroaryl. Unlike heteroaryl, heteroarylene is divalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a heteroaryl. Corresponding groups are, for example:

[0676] Pyrrolyl and wait.

[0677] If heteroarylene is part of another (composite) group, as for example in HO-heteroaryleneamino or H2N-heteroaryleneoxy, the above definition of heteroarylene also applies.

[0678] Substitution means that a hydrogen atom directly bonded to the atom in question is replaced by another atom or another group of atoms (substituent). Depending on the starting conditions (number of hydrogen atoms), mono- or poly-substitution can be performed on one atom. Substitution with a particular substituent is only possible if the permissible valences of the substituent and the atom to be substituted correspond to each other and if the substitution results in a stable compound (i.e., a compound that does not spontaneously transform, for example, by recombination, cyclization, or elimination).

[0679] Divalent substituents (such as =S, =NR, =NOR, =NNRR, =NN(R)C(O)NRR, =N2, or the like) can only be substituents on carbon atoms, while the divalent substituents =O and =NR can also be substituents on sulfur. In general, substitution by a divalent substituent can only be performed on the ring system and requires the replacement of two geminal hydrogen atoms (i.e., hydrogen atoms bound to the same carbon atom that was saturated before the substitution). Thus, substitution by a divalent substituent can only occur on the group -CH2- or the sulfur atom in the ring system (only =O groups or =NR groups, possibly one or two =O groups or, for example, one =O group and one =NR group, each group replacing a free electron pair).

[0680] Isotopes: It is to be understood that all disclosures of atoms or compounds of the present invention include all suitable isotopic variations. In particular, references to hydrogen also include deuterium.

[0681] Stereochemistry / solvates / hydrates: Unless specifically indicated otherwise, throughout the specification and appended claims, a given chemical formula or name will encompass tautomers and all stereo, optical, and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.) and racemates thereof, as well as mixtures of individual enantiomers in varying proportions, mixtures of diastereomers, or mixtures in which any of the foregoing forms of such isomers and enantiomers are present, and salts thereof (including pharmaceutically acceptable salts thereof) and solvates thereof (such as hydrates), including solvates and hydrates of free compounds or solvates and hydrates of salts of compounds.

[0682] In general, substantially pure stereoisomers can be obtained according to synthetic principles known to those skilled in the art, for example by separation of the corresponding mixtures, by using stereochemically pure starting materials and / or by stereoselective synthesis. It is known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis (e.g., starting from optically active starting materials and / or by using chiral reagents).

[0683] The enantiomerically pure compounds or intermediates of the invention can be prepared by means of asymmetric synthesis, for example by preparing and subsequently isolating appropriate diastereomeric compounds or intermediates which can be separated by known methods (for example by chromatography or crystallization), and / or by using chiral reagents (such as chiral starting materials, chiral catalysts or chiral auxiliaries).

[0684] Furthermore, the person skilled in the art knows how to prepare enantiomerically pure compounds from the corresponding racemic mixtures, such as by chromatographic separation of the corresponding racemic mixtures on a chiral stationary phase, or by resolving the racemic mixtures using suitable resolving agents, for example by means of formation of diastereomeric salts with an optically active acid or base, subsequent resolution of the salts and liberation of the desired compound from the salts, or by derivatization of the corresponding racemic compound with an optically active chiral auxiliary reagent, followed by diastereomeric separation and removal of the chiral auxiliary group, or by kinetic resolution of the racemate (for example by enzymatic resolution); by enantioselective crystallization from aggregates of isotropic crystals under suitable conditions, or by (fractionation) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary.

[0685] Salt: The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0686] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.

[0687] For example, such salts include those derived from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid.

[0688] Other pharmaceutically acceptable salts can be formed with cations derived from ammonia, L-arginine, calcium, 2,2'-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium, and tris(hydroxymethyl)-aminomethane.

[0689] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally speaking, the salts can be prepared by reacting the free acid or free base forms of these compounds with a sufficient amount of a suitable base or acid in water or an organic diluent (such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile or a mixture thereof).

[0690] In addition to those salts mentioned above, salts of other acids (eg, trifluoroacetate) that are useful for purifying or isolating the compounds of the present invention also comprise part of the present invention.

[0691] In diagrams such as the following

[0692]

[0693] The letter A has a ring designation function to easily indicate, for example, that the ring in question is connected to other rings.

[0694] For divalent groups, it is crucial to determine the adjacent groups to which they are bonded and at what valence. For the purpose of clarification, the corresponding binding partners are indicated in brackets when necessary, as shown in the following form:

[0695] or (R 2 )-C(=O)NH- or (R 2 )-NHC(=O)-.

[0696] In the absence of such a description, a divalent group can be bound in both orientations, ie, for example, -C(=O)NH- also includes -NHC(=O)- (and vice versa).

[0697] The groups or substituents are usually selected from the groups having the corresponding group names (e.g., R a 、R b If such groups are used repeatedly in different parts of the molecule to define the compounds of the present invention, it should be noted that each use is to be considered completely independent of each other.

[0698] For purposes of this invention, a therapeutically effective amount means that amount of a substance which is capable of eliminating the symptoms of a disease or preventing or ameliorating such symptoms or prolonging the survival of the patient being treated.

[0699] List of abbreviations

[0700]

[0701]

[0702]

[0703] Example

[0704] The features and advantages of the present invention will become apparent from the following detailed description of the embodiments, which illustrate the principles of the present invention by way of example and without limiting the scope thereof:

[0705] Preparation of the compounds according to the invention

[0706] Overview

[0707] Unless otherwise stated, all reactions were performed using methods commonly used in chemical laboratories in commercially available equipment. Starting materials sensitive to air and / or moisture were stored under protective gas, and corresponding reactions and operations were performed under protective gas (nitrogen or argon).

[0708] If a compound is represented both by a structural formula and by its name, in case of conflict, the structural formula controls.

[0709] The microwave reaction is carried out in an initiator / reactor manufactured by Biotage or in an Explorer manufactured by CEM or in a Synthos 3000 or Monowave 3000 manufactured by Anton Paar, in a sealed vessel (preferably 2, 5 or 20 mL), preferably with stirring.

[0710] Chromatography

[0711] Thin layer chromatography was performed on glass manufactured by Merck (with fluorescent indicator F-254) using ready-made silica gel 60 TLC plates.

[0712] Preparative high pressure chromatography (RP HPLC) of the example compounds of the present invention was performed on a column manufactured by Waters (name: SunFire TM Prep C18,OBD TM 10μm, 50×150mm or SunFire TM Prep C18 OBD TM 5μm, 30×50mm or XBridge TM Prep C18,OBD TM 10μm, 50×150mm or XBridge TM Prep C18,OBD TM 5μm, 30×150mm or XBridge TM Prep C18,OBD TM The results were performed on Agilent or Gilson systems using YMC (name: Actus-Triart Prep C18, 5 μm, 30×50 mm) and YMC (name: Actus-Triart Prep C18, 5 μm, 30×50 mm).

[0713] Compounds were eluted using different gradients of H2O / ACN, while for the Agilent system, 5% acidic modifier (20 mL HCOOH to 1 L H2O / ACN (1 / 1)) was added to water (acidic conditions). For the Gilson system, 0.1% HCOOH was added to water.

[0714] For chromatography under basic conditions on the Agilent system, a HO / ACN gradient was also used, and the water was made basic by adding a 5% basic modifier (50 g NH4HCO3 + 50 mL NH3 (25% in HO) made up to 1 L with HO). For the Gilson system, the water was made basic as follows: 5 mL NH4HCO3 solution (158 g in 1 L HO) and 2 mL NH3 (28% in HO) made up to 1 L with HO.

[0715] Supercritical fluid chromatography (SFC) of the intermediates and example compounds of the present invention was carried out on a JASCO SFC system with the following columns: Chiralcel OJ (250×20 mm, 5 μm), Chiralpak AD (250×20 mm, 5 μm), Chiralpak AS (250×20 mm, 5 μm), Chiralpak IC (250×20 mm, 5 μm), Chiralpak IA (250×20 mm, 5 μm), Chiralcel OJ (250×20 mm, 5 μm), Chiralcel OD (250×20 mm, 5 μm), and Phenomenex Lux C2 (250×20 mm, 5 μm).

[0716] Analytical HPLC (reaction control) of intermediates and final compounds was performed using a Waters (name: XBridge TM C18, 2.5 μm, 2.1 × 20 mm or XBridge TM C18, 2.5 μm, 2.1×30 mm or Aquity UPLC BEH C18, 1.7 μM, 2.1×50 mm), YMC (name: Triart C18, 3.0 μm, 2.0×30 mm), and Phenomenex (name: Luna C18, 5.0 μm, 2.0×30 mm) columns were used. In each case, the analytical instrument was also equipped with a mass detector.

[0717] HPLC-mass spectrometry / UV-spectrometry

[0718] Retention time / MS-ESI curves characterizing the exemplary compounds of the present invention were generated using an HPLC-MS apparatus (high performance liquid chromatography with mass spectrometry detection).+ Compounds eluting at the injection peak are assigned retention times t Ret. =0.00.

[0719] Method A

[0720]

[0721]

[0722] Method B

[0723]

[0724] Method C

[0725]

[0726] Method D

[0727]

[0728]

[0729] Method E

[0730]

[0731] Method F

[0732]

[0733] Method G

[0734]

[0735]

[0736] Method H

[0737]

[0738] Method I

[0739]

[0740] Method J

[0741]

[0742] Method K

[0743]

[0744] Method L

[0745]

[0746] Method M

[0747]

[0748]

[0749] Method N

[0750]

[0751] Method O

[0752]

[0753] Method P

[0754]

[0755]

[0756] Method Q

[0757]

[0758] Method R

[0759]

[0760] Method U

[0761]

[0762]

[0763] Method V

[0764]

[0765] Method W

[0766]

[0767] Method SFC-1

[0768]

[0769]

[0770] Method SFC-2

[0771]

[0772] The compounds and intermediates according to the present invention are prepared by the synthetic methods described below, wherein the substituents of the general formula have the meanings given above. These methods are intended to be illustrative of the present invention and are not intended to limit the scope of the compounds claimed in the subject matter and these embodiments. Where the preparation of the starting compound is not described, it is commercially available or its synthesis is described in the background art or it can be prepared similarly to known background art compounds or the methods described herein, i.e., synthesizing these compounds is within the skill of organic chemists. The substances described in the literature can be prepared according to disclosed synthetic methods. If the following chemical structure is depicted without the exact configuration of a stereocenter (e.g., an asymmetrically substituted carbon atom), both configurations should be deemed to be included and disclosed in the representation. The representation of a stereocenter in racemic form should always be deemed to include and disclose two mirror image isomers (if there are no other defined stereocenters) or all other potential non-mirror image isomers and mirror image isomers (if there are additionally defined or non-limited stereocenters).

[0773] Synthesis of spiroketone intermediate A

[0774] Experimental procedure for the synthesis of A-2a

[0775]

[0776] To a suspension of 5-chlorovaleronitrile (22.9 g, 195 mmol, 1.00 equiv) in EtOH (136 mL) was added acetyl chloride (111 mL, 1.56 mol, 8.00 equiv) dropwise at 0°C. The reaction mixture was warmed to room temperature and stirred for 12 hours. The mixture was concentrated under reduced pressure and washed with Et2O, and the crude product A-2a was used directly in the next step as the HCl salt without further purification (HPLC method: A; t ret =1.03min; [M+H] + =164).

[0777] Experimental procedure for the synthesis of A-3a

[0778]

[0779] Crude A-2a (HCl salt) (28.0 g, 140 mmol, 1.00 equiv) and ethylene glycol (7.38 g, 119 mmol, 0.90 equiv) were dissolved in DCM (300 mL) and stirred at room temperature for 6 days. The resulting suspension was concentrated under reduced pressure, diluted with Et2O (200 mL) and filtered. The filtrate was concentrated under reduced pressure, dissolved in DCM (200 mL) and treated with KOH solution (2 M in water, 150 mL). The mixture was stirred at room temperature overnight, keeping the phases intact. The phases were separated, the aqueous phase was extracted with DCM (2×), and the combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude orthoester A-3a was used in the next step without further purification (HPLC method: A;t ret =1.37min; [M+H] + =163).

[0780] Experimental procedure for the synthesis of A-4a

[0781]

[0782] Crude A-3a (22.3 g, 107 mmol, 1.00 equiv), 1-cyclohexenyloxytrimethylsilane (16.4 mL, 82.3 mmol, 0.80 equiv) and zinc chloride (10.2 g, 74.8 mmol, 0.70 equiv) were dissolved in DCM (120 mL) and stirred at room temperature for 5 hours. The reaction mixture was treated by adding saturated sodium bicarbonate solution. The organic phase was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by NP-chromatography to give the desired compound A-4a (HPLC method: A;t ret =1.25min; [M+H] + =283).

[0783] Experimental procedure for the synthesis of A-5a

[0784]

[0785] A-4a (14.9 g, 57.1 mmol, 1.00 equiv) and sodium iodide (25.9 g, 171 mmol, 3.00 equiv) were dissolved in acetone (120 mL) and stirred at reflux for 16 hours. The reaction mixture was concentrated under reduced pressure, diluted with DCM, and washed with saturated sodium thiosulfate solution. The organic phase was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product A-5a was used in the next step without further purification.

[0786] Experimental procedure for the synthesis of A-6b

[0787]

[0788] A-5a (30.0 g, 85.0 mmol, 1.00 equiv) was dissolved in THF. The mixture was treated with potassium tert-butoxide (28.7 g, 256 mmol, 3.0 equiv) at 0°C and stirred overnight at room temperature. The reaction mixture was quenched by the addition of water (2 mL), diluted by the addition of Et2O and a saturated solution of sodium bicarbonate. The organic phase was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by NP-chromatography to give (racemic) compound A-6a (HPLC method: A;t ret =1.17min; [M+H] + =225).

[0789] The reaction sequence A-1a→A-6a is based on Marko et al., THL 2003, 44, 3333-3336 and Maulide et al., Eur. J. Org. Chem. 2004, 19: 3962-3967.

[0790] The enantiomer A-6b can then be obtained after chiral separation via SFC (using a Lux Cellulose-4 column (250×30 mm, 5 μm), 30° C. column temperature, 90% CO 2 , 10% ACN as a co-solvent), wherein the enantiomer A-6b (HPLC method: A; t ret =1.17min; [M+H] + =225 / SFC method: SFC-1; t ret =2.99 min) eluted as a second peak after the other enantiomer.

[0791] Alternative procedures for the synthesis of A-6b

[0792] Step 1

[0793]

[0794] Toluene (234 L) was charged to a dry and clean reactor under nitrogen (note: 2.5 V of toluene total for this reaction). Water (1.56 kg, 85.5 mol, maintaining HO:Pd = 160:1) was added, followed by rinsing the feed line with 1,1,3,3-tetramethylguanidine (175.5 kg, 1527.6 mol, 2.0 equiv) under nitrogen, and then with toluene (13 L). A-7a (130.0 kg, 763.8 mol) was added under nitrogen, followed by a rinse with toluene (13 L). Allyl acetate (98.8 kg, 992.9 mol, 1.3 equiv) was added under nitrogen and rinsed with toluene (13 L). The mixture was cooled to 10° C. over 0.5 h with stirring. The batch was degassed by bubbling nitrogen through the solution for approximately 30 minutes. (S,S)-DACH-Ph Trost ligand (0.429 kg, 0.619 mol, 0.081 mol%) in degassed toluene (13 L) (note: maintain Pd:ligand = 1:1.15) followed by a rinse with degassed toluene (13 L). Allylpalladium(II) chloride dimer (97.5 g, 267 mol, 0.035 mol%) in degassed toluene (13 L) was added followed by a rinse with degassed toluene (13 L). The batch was held at 10-15° C. for at least 8 hours. After the reaction was complete by HPLC, a solution of N-acetyl-cysteine ​​(3.9 kg, 22.9 mol, 0.03 equiv) in water (260 L) was added at below 25° C. The resulting solution was warmed to 20-25° C. and maintained at 20-25° C. for at least 1 hour. After the phase was cut to discard the bottom aqueous layer, a 10 wt% NH4Cl aqueous solution (260 L) was added. After stirring the mixture for 10 min, the bottom aqueous layer was discharged. The organic phase was further washed with water (130 L). The organic layer was filtered through a very short diatomaceous earth pad and the reactor and diatomaceous earth bed were rinsed with toluene (65 L). The filtrate was loaded into a clean reactor and then toluene was distilled off in a vacuum at 40-50 ° C. The crude product was directly used in the next step or the product was discharged into a container with the help of a minimum amount of toluene (65 L) and stored at 20-23 ° C. 150 kg of A-8a was generally obtained as a light yellow oil with a yield of 96% and an enantiomeric ratio of ≥90:10.

[0795] 1H NMR (500MHz, CDCl3): δ5.75(ddt,J=14.8,9.4,7.5Hz,1H),5.06-5.00(m,2H),4.19(q,J=7.1Hz,2H),2.61(dd,J=13.9,7.1Hz,1H),2 .51-2.43(m,3H),2.33(dd,J=13.9,7.9Hz,1H),2.03-1.98(m,1H),1.78-1.60(m,3H),1.50-1.42(m,1H),1.25(t,J=7.1Hz,3H).13C NMR (125MHz, CDCl3): δ207.7,171.6,133.5,118.4,61.3,61.0,41.3,39.4,35.9,27.7,22.6,14.3.ESI-MS: m / z 211[M+H] + .

[0796] Step 2

[0797]

[0798] To the reactor containing A-8a (150kg, 713.4mol) from step 1 (less than 1V toluene, if used), ethylene glycol (600L) is added to obtain a yellow biphasic mixture. After the mixture is cooled to 10-15°C, TMSCl (193.5kg, 1783.5mol, 2.5 equivalents) is added over a period of no less than 15 minutes to maintain the internal temperature at a rate between 20-30°C (obtaining an orange biphasic mixture). Enough stirring is required to achieve mixing. After the batch is maintained at 20-25°C for 2h, stirring is stopped and maintained at 20-25°C for at least 15min. The batch is cooled to 0-5°C. Water (600L) containing NaOH (96kg, 1854.8mol, 2.6 equivalents) is added at a rate to maintain the internal temperature below 20°C (obtaining a light yellow turbid biphasic mixture). Toluene (300L) is added and the batch is then stirred for 10min. After phase cutting to drain the bottom aqueous layer (caution: some precipitate may form at the interface phase), the organic layer was washed twice with water (300 L). The organic phase was filtered through a short pad of celite to remove insoluble solids / interface phase. The organic solution was charged to a clean and dry reactor and the solvent was then distilled off at 40-50°C to obtain a minimum stirrable volume. The crude product A-9a (189 kg, 95.2 wt%, 100% yield) was discharged to a container with a minimal amount of toluene.

[0799] 1H NMR (500MHz, CDCl3): δ5.65 (ddt, J=14.7, 8.1, 6.6Hz, 1H), 5.07-4.98 (m, 2H), 4.20-4.10 (m, 2H), 3.97-3.88 (m, 4H), 2.8 1(dd,J=13.9,6.6Hz,1H),2.35(dd,J=13.9,8.1Hz,1H),2.04-1.98(m,1H),1.75-1.35(m,7H),1.26(t,J=7.1Hz,3H).13C NMR (125MHz, CDCl3): δ173.7,134.3,117.6,110.9,65.0,64.7,60.5,54.6,36.2,32.3,30.3,23.3,20.9,14.4.ESI-MS: m / z 255[M+H] + .

[0800] Step 3

[0801]

[0802] 9-BBN (688.5 kg, 401 mol, 1.2 equiv) was added to a dry and clean reactor under nitrogen. The solution was cooled to 0-5 ° C to obtain a slurry. A-9a (85.0 kg, 334.2 mol) from step 2 was added at 0-5 ° C and rinsed with THF (40 L). The mixture was allowed to warm to 20-23 ° C within 1 h and maintained at 20-23 ° C for not less than 1 h. Thereafter, the mixture was cooled to -45 to -40 ° C, methyl chloroacetate (69.6 kg, 1.3 equiv) was added in one portion, followed by LiHMDS (909.5 kg, 1102.9 mol) dropwise while maintaining the temperature below -35 ° C. The batch was then warmed to 20-23 ° C within 1 h and then maintained at 20-23 ° C for at least 18 h. Approximately 12-13 V of solvent was removed by distillation under heating (35 ° C) in a vacuum. EtOH (255 kg) was added, followed by a solution of NaOH (13.4 kg) in H 2 O (212.5 L). The mixture was heated at reflux (at 66-70° C.) for at least 14 h.

[0803] Afterwards, about 5-6 V of solvent was removed by distillation under reflux, the batch was cooled to 20-25 ° C and then filtered through a short pad of celite to remove insoluble material and rinsed with heptane (160 L). About 5-6 V of solvent (or most of the residual THF and ethanol) was distilled under vacuum at 40-50 ° C. The batch was cooled to 20-25 ° C. Afterwards, water (255 L) was added and the crude product was extracted twice with heptane (2364.8 kg). The combined heptane layers were washed once with water (85 L). After removing the solvent by distillation under vacuum at 40-50 ° C, the crude product (52.7 kg, 87.5 wt %) was obtained as a yellow oil with a 52.6% analytical yield. The crude product A-6b was used directly in the next step.

[0804] 1 H NMR (500MHz, CDCl3): δ4.01-3.82(m,4H),2.50-2.44(m,1H),2.38-2.34(m,1H),2.28-2.22(m,1H),2.11-2.05(m ,1H),2.01-1.95(m,1H),1.92-1.86(m,1H),1.81-1.58(m,6H),1.54-1.43(m,3H),1.27-1.18(m,1H).ESI-MS:m / z 225[M+H] + .

[0805] Synthetic alcohol, pyrazole and toluenesulfonate intermediate B

[0806] Experimental procedure for synthesizing B-2a

[0807]

[0808] B-1a (4.92 g, 19.1 mmol, 1.00 equiv), N,N'-carbonyldiimidazole (5.14 g, 28.6 mmol, 1.50 equiv), and molecular sieves (3A, 500 mg) were dissolved in DCM (29.5 mL) and stirred at room temperature for 40 min. After complete activation, N,O-dimethylhydroxylamine hydrochloride (2.79 g, 28.6 mmol, 1.50 equiv) was added and the reaction was stirred at room temperature for an additional 2 h. After complete conversion, water (100 mL) and DCM (150 mL) were added and the phases separated, and the aqueous phase was extracted with DCM (2×). The combined organic phases were washed with brine and concentrated under reduced pressure. The residue was purified by NP chromatography to give the product B-2a.

[0809] The following intermediate B-2 (Table 1) can be obtained in a similar manner. If necessary, the crude product is purified by chromatography.

[0810] Table 1

[0811]

[0812] Experimental procedure for the synthesis of B-3a

[0813]

[0814] Under argon atmosphere, B-2a (4.88 g, 16.9 mmol, 1.00 equiv) was dissolved in THF (15 mL) and cooled to -10 ° C. Bromo(methyl)magnesium (3.4 M in MeTHF, 6.46 mL, 22.0 mmol, 1.3 equiv) was added and stirred at -10 ° C for 1 hour. After complete conversion, the reaction mixture was cooled to -20 ° C and quenched by adding brine. The resulting mixture was extracted with DCM (3×). The combined organic phase was concentrated under reduced pressure to obtain B-3a.

[0815] The following intermediate B-3 (Table 2) can be obtained in a similar manner. If necessary, the crude product is purified by chromatography.

[0816] Table 2

[0817]

[0818] Experimental procedure for the synthesis of B-4a

[0819]

[0820] Under an argon atmosphere, (R)-methyloxazole boridine (0.99 g, 3.3 mmol, 0.20 equiv) was dissolved in THF (2 mL) and cooled to -5 ° C. Borane-methyl sulfide complex (1.0 M, 22 mL 22.0 mmol, 1.3 equiv) was added. The mixture was stirred at room temperature for 30 minutes. The mixture was cooled to -5 ° C and B-3a (4.1 g, 17 mmol, 1 equiv) was slowly added dropwise. The reaction was stirred at room temperature for 1 hour. After the starting material was completely converted, the reaction was cooled to -10 ° C and quenched by adding MeOH. The mixture was concentrated under reduced pressure. The residue was dissolved in water (150 mL) and formic acid (0.5 mL) and extracted with DCM (3 ×). The combined organic phase was concentrated under reduced pressure and purified by NP chromatography to obtain product B-4a.

[0821] The following intermediate B-4 (Table 3) can be obtained in a similar manner. If necessary, the crude product is purified by chromatography.

[0822] Table 3

[0823]

[0824]

[0825] Experimental procedure for the synthesis of B-5a

[0826]

[0827] B-4a (306 mg, 12.5 mmol, 1.00 equiv) was dissolved in THF (30.6 mL) under argon atmosphere. Lithium aluminum hydride (1 M in THF, 24.9 mL, 25.0 mmol, 2.00 equiv) was slowly added. The reaction was stirred at 60° C. for 1 h. After complete conversion, the reaction was cooled to room temperature, Rochelle salt solution and KOH were added, and stirred for 1 h. The existing suspension was extracted with DCM (3 times), and the combined organic phases were concentrated under reduced pressure to produce B-5a.

[0828] The following intermediate B-5 (Table 4) can be obtained in a similar manner. Deuterated intermediate B-5 is obtained similarly, but lithium aluminum hydride is exchanged by lithium aluminum deuteride. The crude product is purified by chromatography if necessary.

[0829] Table 4

[0830]

[0831] Experimental procedure for the synthesis of B-7a

[0832]

[0833] B-6a (502 mg, 4.22 mmol, 1.00 equiv) was dissolved in ACN (6 mL), and cesium carbonate (2.04 g, 6.24 mmol, 1.49 equiv) and (2S)-2-hydroxymethyloxirane (420 μL, 5.93 mmol, 1.41 equiv) were added. The reaction was stirred at 80° C. under a nitrogen atmosphere for 18 h. After complete conversion, the reaction mixture was filtered, washed with ACN, and the filtrate was concentrated under reduced pressure. The mixture was purified by RP chromatography to give B-7a.

[0834] Intermediate B-7 (Table 5) can be obtained in a similar manner using the corresponding epoxide or alkyl halide. The crude product is purified by chromatography if necessary.

[0835] Table 5

[0836]

[0837] Experimental procedure for the synthesis of B-8a

[0838]

[0839] B-7a (545 mg, 3.18 mmol, 1.00 equiv) was dissolved in EtOH (40 mL) and palladium (10% on carbon, 40.0 mg, 0.04 mmol, 0.01 equiv) was added. The reaction was stirred at room temperature under a hydrogen atmosphere (3 bar) for 4 h. After complete conversion, the reaction mixture was filtered, washed with EtOH and concentrated under reduced pressure to give B-8a, which was used in the next step without purification.

[0840] Intermediate B-8 (Table 6) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[0841] Table 6

[0842]

[0843]

[0844] Experimental procedure for the synthesis of B-9a

[0845]

[0846] B-8a (222 mg, 1.57 mmol, 1.00 equiv) and bis(pinacolato)diboron (450 mg, 1.73 mmol, 1.10 equiv) were dissolved in ACN (5 mL). tert-Butyl nitrite (504 μL, 4.25 mmol, 2.70 equiv) was added and the reaction was stirred at 80 ° C. under nitrogen atmosphere for 2 h. After complete conversion, the reaction mixture was concentrated under reduced pressure to give B-9a, which was used in the next step without purification.

[0847] Intermediate B-9 (Table 7) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[0848] Table 7

[0849]

[0850] Experimental procedure for the synthesis of B-11a

[0851]

[0852] 1H-Pyrazole-3-carboxylic acid (500 mg, 4.46 mmol, 1.00 equiv) was dissolved in ACN (4.5 mL). Pyrrolidine (745 μL, 8.92 mmol, 2.00 equiv), DIPEA (1.50 mL, 8.92 mmol, 2.00 equiv) and 1-propanephosphonic anhydride (2.00 mL, 6.69 mmol, 1.50 equiv) were added and the reaction mixture was stirred at room temperature for 1 h until complete conversion. The reaction mixture was diluted with saturated NaHCO3 and extracted with DCM, and the organic phase was dried, filtered and the solvent removed in vacuo. The crude product was purified by NP chromatography to obtain B-11a (HPLC method: C, t ret =0.14min; [M+H] + =166).

[0853] Experimental procedure for synthesizing B-13a

[0854]

[0855] To a solution of B-12a (5.00 g, 4.90 mmol, 1.00 equiv) and pyridine (7.75 g, 9.79 mmol, 2.00 equiv) in DCM (50 ml) was added p-toluenesulfonyl chloride (14.0 g, 73.4 mol, 1.5 equiv) at 0°C. The reaction mixture was allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with water and extracted with DCM (2×). The combined organic layers were washed with HCl (1 M) and dried over Na2SO4, then concentrated in vacuo to give the product B-13a.

[0856] Intermediate B-13 (Table 8) can be obtained in a similar manner. The crude product can be purified by chromatography if necessary.

[0857] Table 8

[0858]

[0859] Experimental procedure for synthesizing B-15a

[0860]

[0861] 3-Ethynyloxetan-3-ol (120 mg, 1.16 mmol, 1.00 equiv) and (trimethylsilyl)diazomethane (2M solution in hexanes, 2.00 mL, 4.00 mmol, 3.46 equiv) were combined and stirred in a sealed vial at 50 °C for 3 h until complete conversion. The reaction mixture was cooled to room temperature, diluted with MeOH, and the solvent was removed in vacuo to give crude B-15a (HPLC method: C, t ret =0.08min; [M+H] +=141). The crude product was used in the next step without purification.

[0862] Synthesis of pyrimidine derivative C

[0863] Experimental procedure for the synthesis of intermediate C-2a:

[0864]

[0865] To a solution of 2,4,6-trichloro-5-fluoropyrimidine (1.00 g, 4.87 mmol, 1.00 equiv) and B-5b (739 mg, 487 mmol, 1.00 equiv) in THF (10 mL) was added sodium bis(trimethylsilyl)amide (1 M, 5.00 mL, 5.00 mmol, 1.03 equiv) dropwise at -78 ° C and the mixture was stirred for 10 minutes. After complete conversion, the reaction mixture was quenched with water, extracted with DCM and the organic phase was dried, filtered and concentrated. The crude product was purified by NP chromatography to yield C-2a (HPLC method: B, t ret =1.00min; [M+H] + =312).

[0866] Experimental procedure for the synthesis of intermediate C-3a:

[0867]

[0868] To a solution of C-2a (445 mg, 1.43 mmol, 1.00 equiv) in DMSO (1 mL) was added DIPEA (996 μL, 5.70 mmol, 4.00 equiv) and (S)-5-methyl, 4-7-diazaspiro[2.5]octane dihydrochloride (300 mg, 1.43 mmol, 1.00 equiv). After 72 h at room temperature, complete conversion was observed. The crude product was purified via RP chromatography to yield C-3a. The following intermediate C-3 (Table 9) can be obtained in a similar manner using the corresponding amine. The crude product was purified by chromatography if necessary.

[0869] Table 9

[0870]

[0871] Experimental procedure for the synthesis of C-5a:

[0872]

[0873] To a stirred solution of 2-methoxy-malonic acid dimethyl ester (36.0 g, 222 mmol, 1.00 equiv) and thiourea (25.4 g, 333 mmol, 1.50 equiv) in MeOH (360 mL) was added sodium methoxide (27.8 g, 555 mmol, 2.5 equiv) at room temperature and the mixture was stirred at 80 ° C for 24 h. After complete conversion, iodomethane (41.0 g, 289 mmol, 1.30 equiv) was slowly added at room temperature and the mixture was stirred at room temperature for 16 h. After complete conversion, the reaction mixture was concentrated, water was added and the reaction mixture was stirred for 30 minutes. The product was collected by filtration, washed with water, and dried in vacuo. The crude product C-5a was used in the next step without purification. (HPLC method: H, t ret =0.89min; [M+H] + =189).

[0874] Experimental procedure for the synthesis of intermediate C-6a:

[0875]

[0876] To a stirred mixture of C-5a (3.1 g, 16 mmol, 1.0 eq) and N,N-diethylaniline (0.4 mL) was slowly added POCl (13 g, 81 mmol, 5.0 eq) at 0 ° C. and the resulting mixture was stirred at 90 ° C. for 16 h. After complete conversion, the mixture was cooled to room temperature, excess POCl was evaporated, water was added, and the product was isolated by extraction with EtOAc. The crude product was purified by NP chromatography to obtain C-6a (HPLC method: H, t ret =2.12min; [M+H] + =225).

[0877] Experimental procedure for the synthesis of intermediate C-7a:

[0878]

[0879] To a stirred solution of C-6a (24.0 g, 107 mmol, 1.00 equiv) in DCM (240 mL) at 0° C. was added m-CPBA (55.0 g, 321 mmol, 3.0 equiv) and the mixture was allowed to reach room temperature and stirred for another 16 h. After complete conversion, the mixture was diluted with DCM, washed with saturated NaHCO 3 , and the organic layer was dried, filtered, and concentrated to give C-7a, which was used in the next step without purification. (HPLC method: H, t ret =1.68min; [M+H] + =257).

[0880] Experimental procedure for the synthesis of C-9a:

[0881]

[0882] 6-Hydroxy-2-methylsulfanyl-3H-pyrimidin-4-one (120 g, 0.759 mol, 1.00 equiv) and sodium carbonate (80.4 g, 0.759 mol, 1.00 equiv) were dissolved in water (1898 mL). (Diiodooxy)benzene (244.3 g, 0.759 mol, 1.00 equiv) and sodium carbonate (80.4 g, 0.759 mol, 1.00 equiv) were dissolved in water (1898 mL). The two solutions were combined and stirred at 40° C. for 2 h. The precipitate was filtered, washed with water, and dried to obtain C-8a, which was used in the next step without purification.

[0883] HCl (2.8 M, 140 mL, 0.389 mol, 0.70 eq) was added to a suspension of crude C-8a (200 g, 0.555 mol, 1.00 eq) in ethanol (1000 mL). The reaction mixture was heated to reflux for 20 min, concentrated under reduced pressure, and the obtained residue was washed with petroleum ether to obtain C-9a (HPLC method: H, t ret =0.98min; [M+H] + =193), which was used in the next step without purification.

[0884] Experimental procedure for the synthesis of intermediate C-10a:

[0885]

[0886] Crude C-9a (98.0 g, 0.509 mol, 1.00 equivalent) was added to freshly distilled POCl solution (356 mL, 3.816 mol, 7.50 equivalent). The resulting mixture was heated to reflux and maintained for 16 h. After complete conversion, the mixture was allowed to reach room temperature. The mixture was slowly added to ice-cold water, extracted with EtOAc, and the dried organic layer was filtered and concentrated under reduced pressure. The crude product was purified by NP chromatography to obtain C-10a (HPLC method: G, t ret =2.49min; [M+H] + =229).

[0887] Experimental procedure for the synthesis of intermediate C-11a:

[0888]

[0889] To a stirred solution of C-10a (60.0 g, 261 mmol, 1.00 equiv) in DCM (1200 mL) was added m-CPBA (157.4 g, 915 mmol, 3.50 equiv) at 0°C and the mixture was allowed to reach room temperature and stirred for another 16 h. After complete conversion, the mixture was diluted with DCM, washed with saturated aqueous NaHCO 3 solution, and the organic layer was dried, filtered, and concentrated to give C-11a, which was used in the next step without purification. (HPLC method: V, t ret =10.91min; [M+H] + =260).

[0890] Synthesis of nitrile intermediate D

[0891] Experimental procedure for the synthesis of D-2a:

[0892]

[0893] To a stirred solution of C-7a (24.0 g, 93.4 mmol, 1.0 eq) in ACN (216 mL) and water (24 mL) is added NaCN (5.49 g, 112 mmol, 1.2 eq) under nitrogen at 0° C. and the mixture is allowed to reach room temperature and stirred for another 1 h. After complete conversion, water and EtOAc are added, the organic layer is separated, washed with water, dried, filtered and concentrated, and the crude product is purified by NP chromatography to yield D-2a.

[0894] The following intermediate D-2 (Table 10) can be obtained in a similar manner. If necessary, the crude product is purified by chromatography.

[0895] Table 10

[0896]

[0897]

[0898] Experimental procedure for the synthesis of D-6a:

[0899]

[0900] To a solution of 4,6-dichloropyrimidine-2-carbonitrile D-3a (2000 mg, 10.356 mmol, 90% purity, 1.0 eq) in anhydrous DMSO (5 mL) was added cesium fluoride (6.286 g, 41.382 mmol, 4 eq) and the resulting mixture was stirred at 60 ° C for 1 h until complete conversion of the starting material to 4,6-difluoropyrimidine-2-carbonitrile D-4a was observed. The resulting suspension was filtered and the remaining solid was washed with anhydrous ACN (2 mL). Then, tert-butyl (2S)-2-[(1S)-1-hydroxyethyl]pyrrolidine-1-carboxylate (2449 mg, 11.376 mmol, 1.1 equiv) and DIPEA (3.517 mL, 20.684 mmol, 2 equiv) were added to the filtrate (8 mL), which was stirred at 60° C. for 1 hour and after complete conversion of the starting material was observed, N-methylpiperazine (1.262 mL, 11.376 mmol, 1.1 equiv) was also added to the mixture. The mixture was then stirred at 60° C. for 30 minutes. After complete conversion to D-5a was observed, the reaction was filtered and the crude product was purified via RP chromatography to yield D-6a.

[0901] The following intermediate D-6 (Table 11) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[0902] Table 11

[0903]

[0904]

[0905] Experimental procedure for the synthesis of D-8a

[0906]

[0907] To a solution of D-2b (100 mg, 0.478 mmol, 1.00 equiv) in anhydrous THF (0.5 mL) was added B-5b (80 mg, mmol, 0.527 mmol, 1.10 equiv) and DIPEA (0.10 mL, 0.569 mmol, 1.19 equiv) and the mixture was stirred at 70 ° C for 2 h. After complete conversion to intermediate D-7a was observed, 4-Boc-4,7-diazaspiro[2.5]octane (115 mg, 0.525 mmol, 1.10 equiv) and additional DIPEA (0.10 mL, 0.569 mmol, 1.19 equiv) were added to the mixture. The mixture was then stirred at 70 ° C for 12 h. After complete conversion was observed, the reaction mixture was concentrated and purified by RP chromatography to give the desired product D-8a (HPLC method: A, t ret =1.74min; [M+H]+ =495).

[0908] Experimental procedure for the synthesis of D-10a

[0909]

[0910] 2,6-Dichloropyrimidine-4-carbonitrile D-9a (3.0 g, 0.02 mol, 1.00 equiv) was dissolved in DCM (21.4 mL), DIPEA (5.69 mL, 33.5 mmol, 2.00 equiv) was added and cooled at 0 ° C. 4-Boc-4.7-diazacyclospiro[2.5]octane (3.55 g, 0.02 mol, 1.00 equiv) was added dropwise. The reaction was stirred at room temperature until complete conversion of the starting material was observed. The mixture was concentrated under reduced pressure and purified by NP chromatography to give D-10a (HPLC method: A, t ret =1.47min; [M+H] + =350).

[0911] Experimental procedure for the synthesis of D-11a

[0912]

[0913] D-10a (4.7 g, 0.01 mol, 1.00 equiv) was dissolved in DMSO (10 mL) and (S)-tert-butyl 3-methyl-1,4-diazepane-1-carboxylate (6.30 g, 0.03 mol, 2.10 equiv) and DIPEA (4.69 mL, 0.03 mol, 2.00 equiv) were added. The reaction was stirred at 80° C. overnight. After complete conversion of the starting material was observed, the reaction was concentrated under reduced pressure and purified by RP chromatography to give D-11a (HPLC method: A, t ret =1.72min; [M+H] + =528).

[0914] Experimental procedure for the synthesis of D-13a

[0915]

[0916] 4,6-Dichloropyrimidine-2-carbonitrile D-3a (1.00 g, 5.74 mmol, 1.00 equiv) and (1S)-1-[(2S)-1-methylpyrrolin-2-yl]ethanol (656 mg, 0.01 mol, 1.10 equiv) were dissolved in DMSO (1 mL) and ACN (1 mL). DIPEA (1.62 mL, 0.01 mol, 2.00 equiv) was added and the reaction was stirred at 60° C. for 2 h. After complete conversion of the starting material was observed, the reaction mixture was concentrated under reduced pressure and extracted with DCM / NaHCO 3 . The combined organic phases were concentrated under reduced pressure and purified by RP chromatography to yield D-13a (HPLC method: A, t ret =1.31min; [M+H] + =267).

[0917] Synthetic esters and acids E

[0918] Experimental procedure for the synthesis of intermediate E-1a:

[0919]

[0920] D-2a (7.00 g, 34.3 mmol, 1.0 eq) was added to a stirred solution of HCl (4 M in MeOH, 105 mL, 420 mmol, 12.4 eq) at 0°C. The mixture was allowed to reach room temperature and stirred for another 16 h. After complete conversion, the reaction mixture was concentrated and the crude product was purified by NP chromatography to give the desired product E-1a (HPLC method: H, t ret =1.48min; [M+H] + =237).

[0921] Experimental procedure for the synthesis of intermediate E-2a:

[0922]

[0923] To a solution of D-6a (1.37 g, 3.29 mmol, 1.00 equiv) in MeOH (5 mL) is added a solution of sodium hydroxide (4 M in water, 4.93 mL, 19.7 mmol, 6.00 equiv) and the resulting mixture is stirred for 2 h at 65 ° C. After complete conversion, the solvent is removed under reduced pressure, and the mixture is neutralized and purified by RP chromatography to give the desired product E-2a.

[0924] The following intermediate E-2 (Table 12) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[0925] Table 12

[0926]

[0927] Experimental procedure for the synthesis of intermediate E-3a:

[0928]

[0929] To a solution of D-11a (4.00 g, 7.58 mmol, 1.00 equiv) in MeOH (15 mL) was added a solution of sodium hydroxide (10 M in water, 0.758 mL, 7.58 mmol, 1.00 equiv) and the resulting mixture was stirred at room temperature for 2 hours. After complete conversion, HCl (8 M in water, 3.79 mL, 30.3 mmol, 4.00 equiv) was added and the mixture was stirred at room temperature for 1 hour. After complete conversion to the ester, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with DCM (3×). The organic phase was dried, filtered, and concentrated under reduced pressure to yield E-3a.

[0930] The following intermediate E-3 (Table 13) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[0931] Table 13

[0932]

[0933] Experimental procedure for the synthesis of E-4a

[0934]

[0935] D-13a (400 mg, 1.49 mmol, 1.00 equiv) was dissolved in MeOH (2 mL) and cooled to 0°C. Thionyl chloride (0.13 mL, 0.2 mmol, 1.20 equiv) was added dropwise and stirred at room temperature until complete conversion of the starting material was observed. The reaction mixture was cooled to 0°C and quenched with NaHCO3, then extracted with EtOAc. The combined organic phases were concentrated under reduced pressure and purified by NP chromatography to yield E-4a (HPLC method: K, t ret =1.69min; [M+H] + =300).

[0936] Experimental procedure for the synthesis of E-5a:

[0937]

[0938] To a solution of C-3c (980 mg, 2.01 mmol, 1.00 equiv) in MeOH (15 mL) was added TEA (0.835 mL, 6.03 mmol, 3.0 equiv) and Pd(dppf)Cl CHCl (166 mg, 0.201 mmol, 0.10 equiv). The mixture was stirred at 90 ° C. under CO pressure (150 psi) in a pressure reactor for 22 h. After complete conversion, the reaction mixture was diluted with saturated aqueous NaHCO and extracted with DCM. The organic phase was dried, filtered and concentrated, and the crude product was purified by RP chromatography to yield E-5a.

[0939] The following intermediate E-5 (Table 14) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[0940] Table 14

[0941]

[0942] Experimental procedure for the synthesis of intermediate E-7a:

[0943]

[0944] 2-Chloro-6-(trifluoromethyl)pyrimidine-4-carboxylic acid E-6a (1.00 g, 4.19 mmol, 1.00 equiv) was dissolved in DMSO (2 mL), (S)-tert-butyl 3-methyl-1,4-diazepane-1-carboxylate (1.97 g, 8.81 mmol, 2.1 equiv), and DIPEA (1.83 mL, 0.01 mmol, 2.50 equiv). The reaction was stirred at 80° C. overnight. After complete conversion of the starting material was observed, the mixture was purified by RP chromatography.

[0945] The following intermediate E-7 (Table 15) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[0946] Table 15

[0947]

[0948] Experimental procedure for the synthesis of intermediate E-9a:

[0949]

[0950] 4,6-Dichloropyrimidine-2-carboxylic acid E-8a (900 mg, 4.66 mmol, 1.00 equiv) was dissolved in DMSO (2 mL) and DIPEA (1.5 mL, 8.8 mmol, 2.0 equiv) and (S)-tert-butyl 3-methyl-1,4-diazepane-1-carboxylate (1.04 g, 4.896 mmol, 95% purity, 1.05 equiv) were added dropwise. The reaction mixture was then stirred at 40 ° C for 18 h. The mixture was diluted with ACN and purified by RP chromatography to give the desired product E-9a (HPLC method: A, t ret =0.82min; [M+H] + =371).

[0951] Experimental procedure for the synthesis of intermediate E-11a:

[0952]

[0953] E-10a (3.00 g, 14.5 mmol, 1.00 equiv) was dissolved in DCM (30 mL) and DIPEA (5.34 mL, 29 mmol, 2.0 equiv) and B-5b (3.20 g, 21.8 mmol, 1.5 equiv) were added. The reaction mixture was then stirred at room temperature for 18 h. After complete conversion, the mixture was concentrated, water was added, and the mixture was extracted with EtOAc. The organic phase was washed with brine, dried, filtered, and concentrated. The crude product was purified by NP chromatography to yield E-11a.

[0954] The following intermediate E-11 (Table 16) can be obtained in a similar manner. The crude product E-11 is purified by chromatography if necessary.

[0955] Table 16

[0956]

[0957] Experimental procedure for the synthesis of E-11e:

[0958]

[0959] B-5a (100 mg, 0.48 mmol, 1.00 equiv) was dissolved in THF (500 ° C), LiHMDS (591 μL, 0.59 mmol, 1.10 equiv) was added and stirred for 5 minutes. At the same time, 4,6-dichloropyrimidine-2-carboxylic acid methyl ester (170 mg, 0.81 mmol, 1.5 equiv) was dissolved in THF (500 μL). The solution of B-5a was added dropwise to the 4,6-dichloropyrimidine-2-carboxylic acid methyl ester solution over 5 min. The reaction was stirred for 25 minutes. After observing the complete conversion of the starting material, the reactant was filtered and purified by RP chromatography to give E-11e (HPLC method: A, t ret =1.08min; [M+H] + =330).

[0960] Experimental procedure for the synthesis of intermediate E-12a:

[0961]

[0962] 4,6-dichloropyrimidine-2-methylformate (450mg, 21.4mmol, 1 equivalent) was dissolved in THF (18mL). In a second flask, imidazole (1.42mg, 20.7mmol, 0.97 equivalent) was dissolved in THF (18mL) and cooled to 0°C, and LiHMDS (20.1mL, 20.1mmol, 0.94 equivalent) was added dropwise. At -30°C, LiHMDS / imidazole solution was added dropwise to the solution of E-10a. The reactant was stirred at room temperature for 30 minutes. After observing complete conversion, the reactant was concentrated under reduced pressure and purified by NP chromatography to obtain E-12a (HPLC method: C, t ret =0.23min; [M+H] + =239).

[0963] Experimental procedure for synthesizing E-13a

[0964]

[0965] To a stirred mixture of E-11c (50.0 mg, 0.166 mmol, 1.00 equiv), 2-furan-3-yl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.04 g, 0.206 mmol, 1.2 equiv) and cesium carbonate (81.5 mg, 0.25 mmol, 1.50 equiv) in dioxane (4.5 mL) in a sealed tube was purged with argon for 10 minutes, followed by the addition of Pd(dppf)Cl2 (36.6 mg, 0.05 mmol, 0.30 equiv) at room temperature and the reaction was heated to 90°C for 18 h. After complete conversion of the starting material was observed, the mixture was filtered through celite and washed with DCM. The filtrate was concentrated under reduced pressure and purified by NP chromatography to give the desired product, E-13a.

[0966] Intermediate E-13 (Table 17) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[0967] Table 17

[0968]

[0969]

[0970] Experimental procedures for the synthesis of E-14a and E-14b

[0971]

[0972] E-13a (6.10 g, 0.02 mol, 1.00 equiv) was dissolved in MeOH, palladium (10% on carbon, 5.88 mg, 0.06 mmol, 3.00 equiv) was added and the reaction was stirred at room temperature for 48 h under a hydrogen atmosphere. After complete conversion of the starting material was observed, the mixture was filtered and washed with 10% MeOH / DCM. The filtrate was concentrated under reduced pressure to give the crude product.

[0973] Intermediate E-14 (Table 18) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[0974] The diastereomeric mixture E-14a / b was purified by chiral HPLC (column / size: Lux Amylose-2 (250×30) mm, 5 μm; solvent: n-hexane / ethanol (75:25); column temperature: ambient) to give diastereomeric isomers E-14a and E-14b (E-14a eluted as peak 1, followed by E-14b eluting as peak 2).

[0975] Table 18

[0976]

[0977] Experimental procedure for the synthesis of intermediate E-15a

[0978]

[0979] To a solution of E-3a (4.20 g, 7.49 mmol, 1.00 equiv) in ACN (5 mL) was added sodium hydroxide solution (1 M in water, 10.5 mL, 10.5 mmol, 1.40 equiv) and the resulting reaction mixture was stirred at room temperature for 1.5 h. After complete conversion, the solvent was removed under reduced pressure and the remaining aqueous solution was carefully neutralized with aqueous HCl (8 M). The mixture was diluted with ACN and purified by acidic RP chromatography to give the desired product, E-15a.

[0980] The following intermediate E-15 (Table 19) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[0981] Table 19

[0982]

[0983] Experimental procedure for synthesizing E-16a

[0984]

[0985] To a solution of methyl 4,6-dichloropyrimidine-2-carboxylate E-10A (2.50, 11.8 mmol, 1.00 equiv) in DMSO (2.00 mL) was added DIPEA (4.02 mL, 23.6 mmol, 2.00 equiv) and a solution of imidazole (885 mg, 13.0 mmol, 1.10 equiv) in ACN (2.00 mL). Complete conversion was observed after 2 h at 45 ° C and (S)-3-methyl-1,4-diazepane-1-carboxylate (2.90 g, 13.0 mmol, 1.10 equiv) was added. The resulting reaction mixture was stirred at 45 ° C overnight. The reaction mixture was diluted with brine and extracted with DCM. The combined organic phases were concentrated under reduced pressure and purified by RP chromatography to give the desired product E-16a (HPLC method: A, t ret =1.16min; [M+H] + =417).

[0986] Synthesis of diketone F

[0987] When multiple HPLC retention times are reported, this means that different tautomers are present.

[0988] Experimental procedure for the synthesis of F-1a

[0989]

[0990] Under an argon atmosphere, E-2a (832 mg, 1.91 mmol, 1.0 equiv) and 1-(1H-imidazole-1-carbonyl)-1H-imidazole (620 mg, 3.82 mmol, 2.0 equiv) were dissolved in THF (5 mL) and stirred at room temperature for 1 h. After complete acid activation, a solution of A-6b (473 mg, 2.01 mmol, 1.1 equiv) and LiHMDS (1.0 M in THF, 4 mL, 4.01 mmol, 2.1 equiv) was added to the reaction mixture and washed with THF (5 mL). The resulting mixture was stirred at 60° C. overnight. After complete conversion, the reaction was diluted with saturated aqueous NaHCO 3 solution and extracted three times with DCM. The organic phases were combined, dried, filtered, and concentrated under reduced pressure to give the crude product. The crude product was dissolved in ACN and water, filtered, and purified by basic RP chromatography to give the desired product F-1a.

[0991] Intermediate F-1 (Table 20) can be obtained in a similar manner. The crude product F-1 can be purified by chromatography if necessary.

[0992] Table 20

[0993]

[0994]

[0995] Experimental procedure for synthesizing F-2a

[0996]

[0997] E-14a (203 mg, 0.58 mmol, 1.00 equiv) was dissolved in THF (10 mL) and activated molecular sieves were added. The mixture was stirred at 50°C for 20 minutes under an argon atmosphere, and then magnesium bromide ethyl etherate (225 mg, 0.87 mmol, 1.5 equivalents) was added and the mixture was further stirred at 50°C for 30 minutes.

[0998] At the same time, use the activated molecular sieve at 50 ° C A second solution of A-6b (152 mg, 0.67 mmol, 1.17 eq) pre-dried for 20 min in THF (5 ml) was prepared. LiHMDS (1 M in THF, 1.6 mL, 1.6 mmol, 2.77 eq) was then added and stirred for 15 min. Afterwards, the second solution was added to the first solution and stirred at 50 °C for 1 h until complete conversion to product was observed.

[0999] The mixture was carefully quenched with NaHCO 3 , concentrated under reduced pressure and extracted with DCM / water. The combined organic phases were concentrated under reduced pressure and purified by RP chromatography to give F-2a.

[1000] The following intermediate F-2 (Table 21) can be obtained in a similar manner. If necessary, the crude product is purified by chromatography.

[1001] Table 21

[1002]

[1003]

[1004] Experimental procedure for synthesizing F-4a

[1005]

[1006] A-6b (1.4 g, 5.31 mmol, 1.1 equiv) and magnesium bromide diethyl etherate (2.5 g, 9.66 mmol, 2.0 equiv) were dissolved in DCM (10.0 mL). F-3a (1.0 g, 4.83 mmol, 1.0 equiv) dissolved in DCM (10 mL) was added dropwise. DIPEA (2.1 mL, 12.08 mmol, 2.5 equiv) was added and the reaction mixture was stirred at room temperature for 7 h. The reaction was quenched with 1 M HCl, diluted with DCM and water. The organic phase was separated, evaporated and the resulting residue was purified by RP chromatography to give F-4a (HPLC method: C, t ret =0.633min; [M+H] + =399).

[1007] Experimental procedure for the synthesis of F-5a

[1008]

[1009] Methyl 4,6-dichloropyrimidine-2-carboxylate (2.00 g, 9.67 mmol, 1.00 equiv) was dissolved in anhydrous ACN (5 mL) under a nitrogen atmosphere. A solution of magnesium bromide diethyl etherate (2.99 g, 11.6 mmol, 1.20 equiv), A-6b (2.38 g, 10.6 mmol, 1.10 equiv) in ACN (5 mL) and DIPEA (2.67 mL, 14.5 mmol, 1.50 equiv) were added and the reaction mixture was stirred at 50 ° C for 20 h. After complete conversion, the reaction mixture was carefully quenched with HCl (1 M), diluted with water, extracted with DCM, and the organic phase was dried, filtered and concentrated to give crude F-5a. The crude compound was purified by normal phase chromatography (HPLC-method: H, t ret=2.50 min; [M+H]=399 / 401) purification.

[1010] Experimental procedure for synthesizing F-6a

[1011]

[1012] A-6b (3.71 g, 0.02 mol, 1.05 eq) was dissolved in THF (10 mL) and LiHMDS (1 M in THF, 31.3 mL, 31.3 mmol, 2 eq) was added at room temperature and stirred for 10 minutes. E-12a (3.73 g, 0.02 mol, 1 eq) and magnesium bromide diethyl etherate (1.63 g, 6.25 mmol, 0.4 eq) were dissolved in THF (40 mL) and stirred at 50° C. under argon atmosphere. The solution from A-6b was added at 50° C.

[1013] The reaction mixture was stirred at 50 ° C for 1 h. After complete conversion, the reaction mixture was concentrated under reduced pressure. Water was added and acidified with formic acid, filtered through celite and extracted with DCM. The combined organic phases were concentrated under reduced pressure and purified by RP chromatography to give F-6a (HPLC method: C, t ret =0.45,0.62,0.71min; [M+H] + =431).

[1014] Experimental procedure for the synthesis of F-7a

[1015]

[1016] F-4a (2.8 g, 7.01 mmol, 1 eq) was dissolved in DMSO (10 mL), tert-butyl (2S,6S)-2,6-dimethylpiperazine-1-carboxylate (1.7 g, 7.71 mmol, 1.1 eq) and DIPEA (3.6 mL, 21.0 mmol, 3.0 eq) were added, and the solution was stirred at 60 ° C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with DCM and water. The organic phase was separated, evaporated, and the resulting residue was purified by NP chromatography to obtain F-7a.

[1017] The following intermediate F-7 (Table 22) can be obtained in a similar manner using different starting materials.

[1018] Table 22

[1019]

[1020] Experimental procedure for synthesizing F-8a

[1021]

[1022] F-4a (1.27 g, 2.77 mmol, 1.0 eq) was dissolved in dioxane (10 mL) and cesium carbonate aqueous solution (2 M, 3.46 mL, 6.93 mmol, 2.5 eq) was added and stirred at 80 ° C for 15 minutes. Pyridine-4-boronic acid (357 mg, 2.91 mmol, 1.1 eq) and Pd (dppf) Cl CHCl (238 mg, 0.28 mmol, 0.1 eq) were then added to the reaction mixture and stirred at 90 ° C for 30 minutes until complete conversion of the starting material was observed. The reaction mixture was filtered and diluted with water and extracted three times with DCM. The organic phase was evaporated, and the residue was dissolved in DMF and purified by RP chromatography to give the desired product F-8a (HPLC-method: C, t ret =0.80 / 86min; [M+H]=440).

[1023] Experimental procedure for synthesizing F-9a

[1024]

[1025] F-5a (10.0 g, 19.4 mmol, 1.00 equiv) was dissolved in DMSO (10 mL), (1S)-1-[(2S)-1-methylpyrrolidin-2-yl]ethanol (2.76 g, 21.4 mmol, 1.10 equiv) and DIPEA (6.78 mL, 38.8 mmol, 2.0 equiv) were added, and the solution was stirred at room temperature overnight. The reaction mixture was diluted with DCM and water. The organic phase was separated, evaporated, and the resulting residue was purified by RP chromatography to obtain F-9a. (HPLC-Method: A, t ret =1.58 / 1.66min; [M+H]=492).

[1026] Experimental procedure for the synthesis of F-10a

[1027]

[1028] (1S)-1-[(2S)-1-Methylpyrrolidin-2-yl]ethanol (245 mg, 1.71 mmol, 1.10 equiv) was dissolved in DMSO (2 mL) and DIPEA (542 μL, 3.11 mmol, 2.00 equiv) was added. F-5a (1.00 g, 2.50 mmol, 1.00 equiv) dissolved in DMSO (2 mL) was added dropwise. The reaction mixture was stirred overnight.

[1029] 4-Oxo-7-azaspiro[2.5]octane (281 mg, 2.48 mmol, 1.60 equiv) and DIPEA (271 μL, 1.55 mmol, 1.00 equiv) were added and the reaction was stirred at 50° C. for 2 days. After complete conversion of the starting material was observed, the mixture was concentrated under reduced pressure and purified by RP chromatography to give F-10a (HPLC-method: C, t ret =0.82 / 0.89min; [M+H]=569).

[1030] Experimental procedure for synthesizing F-11a

[1031]

[1032] Under argon atmosphere, E-9a (1.05 g, 2.83 mmol, 1.00 equiv) and 1-(1H-imidazole-1-carbonyl)-1H-imidazole (918 mg, 5.66 mmol, 2.00 equiv) were dissolved in THF (5 mL) and stirred at room temperature for 1 h. After complete acid activation, a solution of A-6b (1.34 mg, 5.98 mmol, 2.00 equiv) and LiHMDS (1.0 M in THF, 5.95 mL, 5.95 mmol, 2.10 equiv) was added to the reaction mixture and washed with THF (5 mL). The resulting mixture was stirred at 60° C. overnight. After complete conversion, the reaction mixture was diluted with saturated aqueous NaHCO 3 solution and extracted three times with DCM. The organic phases were combined, dried, filtered, and concentrated under reduced pressure. The crude product was dissolved in ACN and water, filtered and purified by basic RP chromatography to give the desired product F-11a (HPLC-method: C, t ret =0.888 / 0.936 / 0.978min; [M+H]=557).

[1033] Experimental procedure for synthesizing F-12a

[1034]

[1035] E-11e (1.80 g, 0.01 mol, 1 equivalent) was dissolved in THF (18 mL) and activated molecular sieves were added. (200 mg before 1 ml solvent) and stirred at 50 ° C under argon atmosphere for 20 minutes. Then magnesium bromide ethyl etherate (2.11 g, 0.01 mol, 1.5 equivalents) was added and further stirred at 50 ° C for 30 minutes. At the same time, a mixture containing activated molecular sieves was used at 50 ° C. A second solution of A-6b (1.47 g, 0.01 mmol, 1.5 equivalents) in THF (8 ml) pre-dried for 20 min was prepared. LiHMDS (1 M in THF, 13.7 mL, 0.01 mol, 2.5 equivalents) was then added and stirred for 15 minutes. Thereafter, the second solution was added to the first solution and stirred at 50 ° C for 1 h. After complete conversion, the reaction mixture was carefully quenched with water and THF was removed under reduced pressure. The residue pH was adjusted to 7-8 by using 1N HCl and extracted with 5% MeOH / DCM (2 ×), the combined organic layers were washed with brine solution, dried over Na2SO4, filtered and concentrated to obtain crude F-12a. The crude compound was purified by NP chromatography.

[1036] The following intermediate F-12 (Table 23) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1037] Table 23

[1038]

[1039]

[1040] Synthesis of isoxazole-intermediate G

[1041] Experimental procedure for the synthesis of G-4a

[1042]

[1043] F-1h (944 mg, 1.25 mmol, 1.00 equiv) was dissolved in dioxane (5 mL) and hydroxylamine solution (50% in water, 0.15 mL, 2.51 mmol, 2.00 equiv) was added. The reaction was stirred at 80 ° C. under N2 atmosphere overnight. After complete conversion, the reaction mixture was concentrated under reduced pressure and purified by RP chromatography to give a mixture of G-1a and G-2a.

[1044] A mixture of G-1a and G-2a (522 mg, 0.679 mmol, 1.00 equiv) was dissolved in DCM (5 mL) and DIPEA (260 μL, 1.5 mmol, 2.20 equiv) and methanesulfonyl chloride (54.2 μL, 0.71 mmol, 1.04 equiv) were added. The resulting solution was stirred at room temperature until complete conversion was observed. The reaction was evaporated and extracted with DCM / water. The organic solvent was evaporated and the resulting residue was purified by RP chromatography to give G-3a and G-4a.

[1045] The following intermediates G-3 and G-4 (Table 24) can be obtained in a similar manner. The crude product can be purified by chromatography if necessary.

[1046] Table 24

[1047]

[1048] Experimental procedures for the synthesis of G-7a and G-8a

[1049]

[1050] F-1a (541 mg, 0.843 mmol, 1.0 equiv) was dissolved in dioxane (5 mL) and hydroxylamine (50% in water, 103 μL, 1.69 mmol, 2.0 equiv) was added. The reaction mixture was stirred at 80° C. overnight. After complete conversion of the starting material, the reaction was diluted with saturated aqueous NaHCO 3 and extracted with DCM (3×). The organic phases were combined, dried, filtered, and concentrated under reduced pressure to give the crude product.

[1051] A mixture of crude G-5a and G-6a (116 mg, 0.18 mmol, 1 eq) was dissolved in dioxane (1.5 mL) and HCl (4 M in dioxane, 177 μL, 0.71 mmol, 4.00 eq) was added. The reaction was stirred at 60° C. for 4 h. After complete conversion, the mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by RP chromatography to give G-7a and G-8a.

[1052] The following intermediates G-7 and G-8 (Table 25) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1053] Table 25

[1054]

[1055]

[1056] Experimental procedures for the synthesis of G-9a and G-10a

[1057]

[1058] F-11a (1.10 g, 1.91 mmol, 1.0 equiv) was dissolved in 1,4-dioxane (3 mL) and hydroxylamine (50% in water, 140 μL, 2.29 mmol, 1.2 equiv) was added. The reaction mixture was stirred at room temperature overnight. After complete conversion, the reaction mixture was diluted with saturated aqueous NaHCO₃ and extracted three times with DCM. The organic phases were combined, dried, filtered, and concentrated under reduced pressure to give the crude product.

[1059] The crude mixture of G-9a and G-10a (1.0 g, 1.68 mmol, 1.0 equivalent) was dissolved in 1,4-dioxane (6 mL) and HCl (4 M in water, 2.11 mL, 8.44 mmol, 5.0 equivalent) was added. The reaction mixture was stirred at room temperature for 3 h. After complete conversion, the reactants were diluted with saturated aqueous NaHCO3 and extracted three times with DCM. The organic phases were combined, dried, filtered, and concentrated under reduced pressure to give the crude product. The crude product was dissolved in ACN and water, filtered, and purified by basic RP chromatography to give the desired products G-11a and G-12a.

[1060] The following intermediates G-11 and G-12 (Table 26) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1061] Table 26

[1062]

[1063]

[1064] Experimental procedure for synthesizing A-10a

[1065]

[1066] To a dry and clean reactor under nitrogen was charged 9-BBN (387 mL, 193.5 mmol, 1.2 eq., 0.5 M in THF). The solution was cooled to 0-5°C to obtain a slurry. A-9a (41.0 g, 161.2 mmol) was added at 0-5°C and rinsed with THF (20.5 mL). The mixture was allowed to warm to 20-23°C over 1 h and maintained at 20-23°C for no less than 1 h. After the mixture was cooled to -45 to -40°C, methyl chloroacetate was added in one portion followed by the dropwise addition of LiHMDS (355 mL, 532.0 mol, 3.3 eq.) while maintaining the temperature below -35°C. The batch was then warmed to 20-23°C over 1 h and then maintained at 20-23°C for at least 18 h. The batch was cooled to 5-10°C and AcOH (30.4 mL, 3.3 eq) was added below 20°C, followed by water (41 mL) at below 20°C. AcOH (30.4 mL, 3.3 eq) was added below 20°C to reach a pH of approximately 6-7. Approximately 15-16 V of THF was removed under vacuum below 35°C. MTBE (246 mL) and water (205 mL) were added. After phase splitting to discard the bottom aqueous layer, the mixture was cooled to 0-5°C and a solution of sodium percarbonate (37.2 g, 322.4 mmol, 2.0 eq) in water (320 mL) was added below 20°C. After 1 h at 20-23°C, 20 wt% sodium sulfite solution (31 mL) was added. After 15 minutes at 20-23°C, the bottom aqueous layer was separated and discarded. The organic layer was washed with 5% ammonium chloride solution (123 mL) and water (328 mL). The organic layer was treated with 5% activated carbon for 30 min before filtration. After removing about 4-5 V of the solvent in vacuo at less than 35 ° C, the crude product A-10a (80% yield, HPLC method: C, t ret =0.84min; [M+H] + =283).

[1067] Experimental procedure for the synthesis of G-70a

[1068]

[1069] A reactor was charged with A-10a (45.5 g, 161.2 mmol), ethanol (91.0 mL), NaOAc (39.7 g, 483.6 mmol, 3.0 equiv), water (45.5 mL), and NH2OH·HCl (33.6 g, 483.6 mmol, 3.0 equiv). The mixture was heated at 73-78°C for not less than 16 h. After the batch was cooled to 20-23°C, water (227.6 mL) was added over 0.5 h. MTBE (136.5 mL) was then added over 0.5 h, followed by heptane (113.8 mL) over 1 h. After 0.5 h at 20-23°C, the solid was collected by filtration. The solid was washed successively with MTBE (45 mL) and water (91.0 mL). The solid was dried in vacuo to give the product G-70a in 40% yield as an off-white solid (18.27 g, 93.2 wt%).

[1070] 1 H NMR(500MHz,DMSO-d6):δ11.48(br s,1H),4.04(q,J=6.0Hz,1H),3.89-3.80(m,2H),3.60(q,J=6.8Hz,1H),2.10-1.95(m,2H),1.92-1.76(m,4H),1.69-1.39(m,8H).ESI-MS:m / z 266[M+H] + .

[1071] Experimental procedure for the synthesis of G-71a

[1072]

[1073] A clean reactor was charged with G-70a (100.0 g, 376.9 mmol, 1.0 equiv) and K 3 PO 4 (240.0 g, 1130.8 mmol, 3.0 equiv) in water (499.0 g, 500.0 mL) and toluene (432.5 g, 500.0 mL). The biphasic mixture was stirred until thoroughly mixed. After the mixture was cooled to 0-5° C., Tf 2 O (186.0 g, 110.9 mL, 659.6 mmol, 1.750 equiv) was added at below 5° C. over 2 h using a syringe pump. After phase separation, the organic layer was filtered through a celite bed with Na 2 SO 4 . After rinsing with toluene (50 mL), the crude product G-71a (149.8 g, 100% yield) was used directly in the next step.

[1074] 1H NMR (500MHz, CDCl3): δ3.95-3.91(m,3H),3.77-3.74(m,1H),2.51-2.44(m,2H),2.16-1.80(m,4H),1.77-1.48(m,8H).ESI-MS: m / z 398[M+H] + .

[1075] Experimental procedure for synthesizing G-72a

[1076]

[1077] A dry and clean autoclave reactor was charged with G-71a (750 g, 1.89 mol, 1 eq), Pd(OAc)2 (8.48 g, 37.7 mmol, 0.02 eq), rac-BINAP (23.5 g, 37.7 mmol, 0.02 eq), 2-MeTHF (3 L), EtOH (870 g, 18.9 mol, 10 eq), and DIPEA (293 g, 2.26 mol, 1.2 eq). The reactor was purged twice with nitrogen (100 psi) and then twice with CO (100 psi). The reactor was pressurized to 200 psi CO and heated at 55-60°C for no less than 12 h. The mixture was transferred to the reactor and the autoclave reactor was flushed with 2-MeTHF (0.75 L) into the reactor. The mixture was washed with water (3.75 L). After filtration through a short pad of celite, the solvent was removed by vacuum distillation to give the crude product G-72a (531.9 g, 87.7% yield), which was used in the next step without purification.

[1078] 1 H NMR (400MHz, CDCl3): δ4.38(q,J=7.1Hz,2H),3.95-3.85(m,3H),3.76-3.73(m,1H),2.85(dt,J=17.5,5.5Hz,1H),2.64(d dd,J=17.5,9.6,6.0Hz,1H),2.22-2.14(m,1H),2.04-1.88(m,3H),1.78-1.45(m,8H),1.37(t,J=7.1Hz,3H).ESI-MS:m / z 322[M+H] + .

[1079] Experimental procedure for synthesizing G-73a

[1080]

[1081] G-72a (482.0 g, 1.5 mol, 1 equivalent) and EtOH (3 V) were charged to a dry and clean reactor and vacuum distilled for about 3 V to remove residual 2-MeTHF from the aforementioned carbonylation step. EtOH (1.45 L) and NH OH (1.93 L) were added. The mixture was kept at 20-25 ° C for not less than 15 h. Water (1.69 L) was added over 30 min. After 30 min at 20-25 ° C, the solid was collected and washed with 1: 2 EtOH / water (0.96 L) and water (0.48 L). The solid was slurried in 1: 1 MTBE / hexane (0.96 L) for 1 hour. The solid was collected by filtration and dried overnight in a vacuum at 40-45 ° C to obtain the product G-73a (332.4 g, 75.8% yield, based on Karl Fischer titration water content ≤ 0.5%) as a brown solid.

[1082] 1 H NMR (500MHz, DMSO-d6): δ8.05(s,1H),7.78(s,1H),3.94-3.72(m,4H),2.78(dt,J=17.1,5.0Hz ,1H),2.54-2.48(m,1H),2.20-2.14(m,1H),1.93-1.78(m,3H),1.70-1.42(m,8H).ESI-MS:m / z 293[M+H] + .

[1083] Experimental procedure for synthesizing G-74a

[1084]

[1085] A dry and clean reactor was charged with G-73a (383 g, 86.7 wt%, 1.137 mol, 1 eq), MeCN (1.15 L), and pyridine (216 g, 0.19 L, 2.4 eq). After the mixture was cooled to 0-5°C, trifluoroacetic anhydride (287 g, 1.36 mol, 1.2 eq) was added below 5°C. After 5 minutes at 0-5°C, water (1.54 L) was added below 15°C. The product was extracted with MTBE (1.92 L) and washed with 5% sodium bicarbonate solution (1.15 L). The organic layer was filtered through a silica gel pad (380 g) and rinsed with MTBE (0.58 L). After removing the solvent by vacuum distillation, the product G-74a (421.8 g, 97.8% yield) was obtained as a reddish-brown oil.

[1086] 1H NMR (500MHz, CDCl3): δ3.98-3.85(m,3H),3.80-3.75(m,1H),2.72(dt,J=17.0,5.2Hz,1H),2.60(d dd,J=17.0,9.5,5.8Hz,1H),2.20-2.12(m,1H),2.07-1.94(m,3H),1.82-1.48(m,8H).ESI-MS:m / z 275[M+H] + .

[1087] Experimental procedure for the synthesis of G-76a

[1088]

[1089] A dry flask was charged with crude G-74a (265 g, 72.3 wt%, 698.4 mmol) in MeOH (1590 mL) and catalyst NaOMe (8.0 mL, 25% in MeOH, 34.9 mmol). The mixture was stirred at room temperature for 1 h to achieve >99% conversion. After adding solid NHCl (52.0 g, 977.8 mmol, 1.4 eq), the resulting mixture was stirred at room temperature to achieve >95% conversion (otherwise, more NHCl was added). After adding dimethyl malonate (168 g, 1047.7 mmol, 1.5 eq) at room temperature, NaOMe (377 g, 25% in MeOH, 2.5 eq) was added. The resulting mixture was heated to reflux and maintained for 4 h to achieve >95% conversion. After the mixture was cooled to 23 ° C, water (795 mL) was added, followed by the slow addition of 6N HCl (349 mL) at below 20 ° C to reach a pH of approximately 3. MTBE (530 mL) was added to the slurry. After 1 h at room temperature, the solid was collected by filtration, washed with 3V water (796 mL) and MTBE (530 mL) to give the product G-76a (178 g) as an off-white solid with a crude yield of 71%. The crude product was used directly in the next step.

[1090] 1 H NMR (500MHz, CDCl3): δ5.82(s,1H),3.96-3.74(m,4H),2.74-2.70(m,1H),2.62-2 .59(m,1H),2.22-2.10(m,1H),2.12-1.90(m,3H),1.80-1.48(m,8H).ESI-MS:m / z 360[M+H] + .

[1091] Experimental procedure for the synthesis of G-77a

[1092]

[1093] G-76a (80.0 g, 253.7 mmol), DMAP (4.0 g), tetramethylammonium chloride (4.0 g) and POCl (400 mL) were charged into a dry flask. The mixture was heated at 80 ° C for 1.5 h to obtain a conversion rate of > 99%. POCl was removed in vacuo to obtain a viscous light yellow slurry. MTBE (160 mL) was added. The mixture was then cooled to 5 ° C. Water (800 mL) was slowly added. The resulting white slurry was stirred at 23 ° C for 1 h. The solid was collected by filtration and then washed with water (480 mL) and MTBE (160 mL) in sequence. After vacuum drying at 60 ° C overnight, 84.3 g of product G-77a was isolated as a white solid with a purity of > 99% and an approximately 93% yield.

[1094] 1 H NMR (600MHz, DMSO-d6): δ8.05(s,1H),2.96-2.91(m,1H),2.76-2.69(m,2H),2.53-2.48(m,2H),2 .37-2.34(m,1H),1.97-1.96(m,2H),1.88-1.82(m,4H),1.70-1.61(m,1H),1.52-1.41(m,1H).13C NMR (125MHz, DMSO-d6): δ209.8,164.3,161.4,157.3,155.7,120.8,120.2,50.3,38.1,37.5,31.0,26.6,20.7,19.9,18.0.ESI-MS: m / z 353[M+H] + .

[1095] Experimental procedure for the synthesis of G-78a

[1096]

[1097] To a dry and clean reactor was charged LiHMDS (1 M in THF) (406.4 kg, 456.1 mol, 1.1 eq). The solution was cooled to 0-5 °C, crude A-6b (93.0 kg, 414.6 mol) was added below 5 °C and rinsed with THF (46.5 kg) to aid transfer. After 30 minutes at 0-5 °C, diethyl oxalate (72.5 kg, 497.5 mol, 1.2 eq) was added below 5 °C. After the mixture was warmed to 20-25 °C over 1 h, the mixture was maintained at 20-25 °C for no less than 3 h. After the batch was cooled to 10-15°C, a cooled HCl solution [prepared by adding acetyl chloride (73.6 kg, 932.9 mol, 2.25 equiv) to EtOH (293.9 kg) at 0-5°C] was added to the batch at below 25°C to achieve a final pH of the yellow slurry of approximately 6-7. Solid NH2OH·HCl (28.8 kg, 414.4 mol, 1.05 equiv) was added in one portion, and the resulting mixture was heated to reflux at 66-70°C and maintained for 6-10 h. Thereafter, 5V of solvent was removed by distillation at reflux at 66-70°C. Residual THF was removed using EtOH (73.5 kg). Water (372.0 kg) and EtOH (293.9 kg) were added. After 3-6 hours at 70-75°C, the mixture was cooled to 30-35°C. Seeded with 0.5-1% G-78a crystals. After 2-4 h at 30-35 ° C, heptane (63.2 kg) was added over not less than 1 h. After 60 min at 20-25 ° C, water (279.0 kg) was added over 4-6 h. After 1 h at 20-25 ° C, the solid was collected and washed twice with 1:2 EtOH / water (51.2 kg EtOH and 130.2 kg water) and then with heptane (63.2 kg). The solid was dried under vacuum under a stream of nitrogen to give the product G-78a (93.0 kg) with a 65% yield.

[1098] 1 H NMR (500MHz, CDCl3): δ4.42(q,J=7.1Hz,2H),2.73(dt,J=16.8,5.1Hz,1H),2.64(dt,J=14.3,6.0Hz,1H),2.60-2.51(m,2H),2. 43-2.30(m,2H),2.09-1.96(m,3H),1.91-1.81(m,3H),1.76-1.67(m,1H),1.65-1.58(m,1H),1.40(t,J=7.1Hz,3H).ESI-MS:m / z 278[M+H] + .

[1099] Experimental procedure for the synthesis of G-79a

[1100]

[1101] A dry and clean reactor was charged with G-78a (72.0 kg, 259.6 mol), EtOH (56.9 kg), and NH4OH (aqueous solution) (280.8 kg). The mixture was maintained at 20-25°C for no less than 16 h. After adding water (144.0 kg) over 30 minutes, the slurry was maintained at 20-25°C for 30 minutes. The solid was collected by filtration, washed with 1:3 EtOH / water (28.5 kg EtOH and 108 kg water) and then with heptane (97.9 kg). After vacuum drying at 23°C for 1 hour, the solid was dried at 50-55°C overnight to give the product G-79a (61.4 kg, 87.2% yield, enantiomeric ratio ≥95:5 (254 nm), water content ≤0.5% based on Karl Fischer titration).

[1102] A dry and clean reactor was charged with crude G-79a (60.0 kg, 1.0 equivalent), 1,4-dioxane (240.0 kg) and activated carbon (3.0 kg, 5 wt %). The mixture was stirred at 55-65°C for 2-4 hours. After filtration at high temperature (55-65°C), the filter cake was washed with 1,4-dioxane (33.0 kg). The filtrate was transferred to a clean reactor. The temperature was adjusted to 45-55°C and stirred at 45-55°C for 1-2 hours. Water (240.0 kg) was added over 2 hours. The temperature was adjusted to 45-55°C and stirred at 45-55°C for 1-2 hours. The mixture was cooled to 35-45°C and stirred at 35-45°C for 2-4 hours. Water (87.0 kg) was added over 4 hours. The mixture was cooled to 15-25°C and stirred at 15-25°C for 12-14 hours. The solid was collected by centrifuge, washed with water (120.0 kg) and dried under vacuum at 50-55° C. overnight to give the product G-79a (44.8 kg, 71% yield) as a light yellow to off-white solid. The undesired isomer should be less than 0.5%.

[1103] 1 H NMR (500MHz, DMSO-d6): δ7.99(s,1H),7.71(s,1H),2.80-2.69(m,1H),2.60-2.53(m,1H),2.50-2. 42(m,1H),2.40-2.28(m,2H),2.26-2.18(m,1H),2.05-1.70(m,7H),1.48-1.39(m,1H).ESI-MS:m / z 249[M+H] + .

[1104] Experimental procedure for the synthesis of G-80a

[1105]

[1106]

[0147] A dry and clean reactor was charged with G-79a (40.0 kg, 161.1 mol), MeCN (96.0 kg) and pyridine (30.8 kg, 386.6 mol, 2.4 equiv). After the mixture was cooled to 0-5°C, TFAA (40.8 kg, 193.3 mol, 1.2 equiv) was added slowly at below 5°C. After 5 minutes at 0-5°C, water (120.0 kg) was added over 30 minutes at 0-5°C and seeded with 0.5% G-80a crystals. After 15 minutes at 0-5°C, water (120.0 kg) was added over 30 minutes. After 30 minutes at 0-5°C, the solid was collected by filtration, washed with 1:3 MeCN / water (15.6 acetonitrile and 60.0 kg water) and then with water (80.0 kg). The solid was dried in vacuo to give the crude product as a tan solid (33.0 kg, 93.6% yield).

[1107] To a dry and clean reactor was charged crude G-80a (32.5 kg, 1.0 equiv) and MTBE (48.1 kg) and the slurry was stirred at 20-25° C. for 30 minutes. Heptane (132.6 kg) was added over 1 hour. After 30 minutes at 20-25° C., the solid was collected and dried in vacuo to give the product G-80a (26.6 kg, 82.0% yield) as a white solid with a >99:1 enantiomeric ratio (254 nm) and >98% purity (220 nm).

[1108] 1 H NMR (500MHz, DMSO-d6): δ2.83-2.73(m,1H),2.60-2.40(m,3H),2.34-2.20(m,2H),2.06-1.75(m,7H),1.53-1.43(m,1H).ESI-MS:m / z 231[M+H] + .

[1109] Experimental procedure for synthesizing G-82a

[1110]

[1111] To a stirred solution of G-80a (25.0 g, 108.6 mmol, 1.0 equiv) in MeOH (150 mL) was added NaOMe (30% in MeOH, 4.89 g, 27.1 mmol, 0.25 equiv) and the resulting mixture was stirred at room temperature for 2 h. NHCl (6.39 g, 119.4 mmol, 1.1 equiv) was then added and the mixture was stirred at room temperature for 16 h. After complete conversion to the desired amidine, the mixture was filtered through a bed of Celite and concentrated. The residue was dissolved in DMF (125 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (32.3 g, 212.3 mmol, 2.1 equiv) and diethyl malonate (13.4 g, 101.1 mmol, 1.0 equiv) were added at 0 °C and the resulting mixture was stirred at 90 °C for 16 h. After complete conversion, ice-cold water was added, the mixture was acidified with 1N HCl and the precipitate was collected by filtration. The precipitate was dried under reduced pressure to yield crude G-82a (HPLC-method: H, t ret =1.51 min; [M+H]=316), which was used in the next step without purification.

[1112] Experimental procedure for synthesizing G-83a

[1113]

[1114] G-82a (10.0 g, 30.1 mmol, 1.0 equiv) and POCl (48.0 g, 310.0 mmol, 10.3 equiv) were combined at 0° C. and stirred for 5 minutes. DIPEA (8.2 g, 63.2 mmol, 2.1 equiv) was added and the resulting mixture was stirred at 80° C. for 3 hours. After complete conversion, ice-cold water (1 L) was slowly added to the mixture at 0° C., and the mixture was then allowed to reach room temperature and stirred for 1 hour. The precipitate was collected by filtration, washed with water and hexanes, and dried under vacuum to yield G-83a (HPLC-method: H, t ret =2.22 min; [M+H]=352 / 354). The crude product was used in the next step without purification.

[1115] Experimental procedure for synthesizing G-84a

[1116]

[1117] B-5d (694 mg, 4.09 mmol, 1.2 equivalents) was dissolved in anhydrous THF (13 mL) and cooled to 0 ° C. LiHMDS (1.0 M in THF, 5.11 mL, 5.11 mmol, 1.5 equivalents) was added dropwise at 0 ° C and the mixture was stirred for another 15 min. G-77a (1.20 g, 3.41 mmol, 1.0 equivalents) was dissolved in anhydrous THF (13 mL) and added dropwise at 0 ° C. The mixture was stirred at 65 ° C for 1.5 h. After complete conversion, the mixture was diluted with saturated NaHCO3 aqueous solution and extracted three times with DCM. The organic phases were combined, filtered and concentrated under reduced pressure to obtain G-84a. The crude product was used in the next step without purification.

[1118] The following intermediate G-84 (Table 27) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1119] Table 27

[1120]

[1121]

[1122] Experimental procedure for synthesizing G-15a

[1123]

[1124] F-8a (356 mg, 0.804 mmol, 1.0 equiv) was dissolved in dioxane (2 mL) and hydroxylamine solution (50% in water, 98.6 μL, 1.61 mmol, 2.0 equiv) was added. The resulting solution was stirred at 40 °C until complete conversion was observed. The solvent was evaporated and the resulting residue was purified by RP chromatography to give G-13a (G-14a was observed as a side product and was isolated by chromatography). G-13a (136.0 mg, 0.29 mmol, 1.0 equiv) was dissolved in DCM (2 mL) and DIPEA (114.38 μL, 0.65 mmol, 2.2 equiv) and methanesulfonyl chloride (34.2 μL, 0.45 mmol, 1.5 equiv) were added. The resulting solution was stirred at room temperature until complete conversion was observed. The reaction mixture was concentrated under reduced pressure and extracted with DCM (3×) and water. The organic solvent is evaporated and the resulting residue is purified by RP chromatography to afford G-15a.

[1125] The following intermediate G-15 (Table 28) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1126] Table 28

[1127]

[1128]

[1129] Experimental procedure for synthesizing G-18a

[1130]

[1131] F-7a (740 mg, 1.28 mmol, 1.00 equiv) was dissolved in pyridine (5.0 mL), hydroxylamine hydrochloride (135 mg, 1.92 mmol, 1.5 equiv) was added, and the solution was stirred at 80 ° C for 2 h. After cooling to room temperature, the reaction mixture was acidified with 2M HCl and extracted with DCM (2×). The combined organic phases were washed with 1M HCl, the solvent was evaporated, and the resulting residue was purified by NP chromatography to give G-16a. G-17a was observed as a byproduct and was not isolated.

[1132] G-16a (425 mg, 0.65 mmol, 1.00 equiv) was dissolved in acetic acid (1.0 mL) and stirred at 50° C. overnight. The reaction mixture was quenched with saturated Na 2 CO 3 . The suspension was extracted with DCM, the organic phase was separated, evaporated, and the resulting residue was purified by NP chromatography to give G-18a.

[1133] The following intermediate G-18 (Table 29) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1134] Table 29

[1135]

[1136]

[1137] Experimental procedure for synthesizing G-21a

[1138]

[1139] F-6a (1.98 g, 4.60 mmol, 1 eq) was dissolved in dioxane (40 mL) and MeOH (10 mL), and formic acid (250 μL, 6.63 mmol, 1.44 mmol) and hydroxylamine solution (50% in water, 310 μL, 5.05 mmol, 1.44 eq) were added and stirred overnight. After complete conversion, the reaction was concentrated under reduced pressure and purified by NP chromatography to give the products G-19a and G-20a.

[1140] G-19a (350 mg, 0.78 mmol, 1.00 equiv) was dissolved in HCl (4 M in dioxane, 2.5 mL) and stirred at room temperature for 5 min. HCl (4 M, 2.5 mL) was then added and the reaction was stirred at room temperature for 30 min. After complete conversion, the reaction mixture was alkalized with NaHCO and extracted with DCM. The combined organic phases were concentrated under reduced pressure to give the product G-21a.

[1141] The following intermediates G-21 and G-22 (Table 30) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1142] Table 30

[1143]

[1144]

[1145] Experimental procedure for the synthesis of G-25a

[1146]

[1147] F-1e (350 mg, 0.54 mmol, 1.00 equiv) was dissolved in pyridine (3 mL) and hydroxylamine hydrochloride (56.9 mg, 0.81 mmol, 1.5 equiv) was added. The reaction was stirred at 90 ° C for 3 days. After observing complete conversion of the starting material, the reaction was concentrated under reduced pressure and extracted with NaHCO / DCM. The combined organic phase was concentrated under reduced pressure and purified by RP chromatography to give G-25a. G-26a was observed as a minor byproduct and was not isolated (HPLC-method: C, t ret =1.01 min; [M+H]=639).

[1148] Experimental procedure for synthesizing G-27a

[1149]

[1150] (1S)-1-[(2S)-1-Methylpyrrolidin-2-yl]ethan-1-ol (1.78 g, 10.5 mmol, 3.0 equiv) and potassium tert-butoxide (1.17 g, 10.5 mmol, 3.0 equiv) were dissolved in 1-4-dioxane (500 mL) and stirred at 50° C. for 30 min. G-18a (2.0 g, 3.48 mmol, 1 equiv) was added and the solution was stirred at 85° C. for 3 h. The solvent was evaporated and the resulting residue was purified by NP chromatography to give G-27a (HPLC-method: A, t ret =1.92 min; [M+H]=667).

[1151] Experimental procedure for synthesizing G-28a

[1152]

[1153] G-15a (114 mg, 0.260 mmol, 1.0 equiv) was dissolved in DMSO (1 mL) and DIPEA (90.4 μL, 0.519 mmol, 2.0 equiv) was added. (S)-tert-butyl 3-methyl-1,4-diazepane-1-carboxylate (121 mg, 0.545 mmol, 2.1 equiv) was then added to the reaction mixture and stirred at 70 ° C for 17 h until complete conversion of the starting material was observed. The reaction mixture was diluted with water and extracted three times with DCM. The organic solvent was evaporated and the resulting residue was purified by RP chromatography to give G-28a (HPLC-method: C, t ret =1.06 min; [M+H]=617).

[1154] Experimental procedure for synthesizing G-29a

[1155]

[1156] (1S)-1-[(2S)-1-Methylpyrrolidin-2-yl]ethan-1-ol (122 μL mg, 0.865 mmol, 3.0 equiv) and potassium tert-butoxide (97.0 mg, 0.865 mmol, 3.0 equiv) were dissolved in THF (2 mL) and stirred at 50° C. for 30 min. G-15b (165 mg, 0.28 mmol, 1 equiv) was added and the solution was stirred at 85° C. for 3 h. The solvent was evaporated and the resulting residue was purified by RP chromatography to give G-29a (HPLC-method: C, t ret =1.12 min; [M+H]=665).

[1157] Experimental procedure for the synthesis of G-30a

[1158]

[1159] G-29a (183 mg, 275 μmol, 1.0 eq) and HCl (8 M, 172 μL, 1.38 mmol, 5.0 eq) were dissolved in MeOH (2.0 mL) and stirred at 60° C. until complete conversion. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc / NaHCO 3 . The combined organic phases were concentrated under reduced pressure to give G-30a (HPLC method: A, t ret =1.41 min; [M+H]=521).

[1160] Experimental procedure for the synthesis of G-31a

[1161]

[1162] G-11b (3.00 g, 6.45 mmol, 1.0 eq) was dissolved in DMF (7 mL), sodium azide (504 mg, 7.74 mmol, 1.2 eq) was added and the reaction was stirred at 50 ° C for 18 h. After competitive conversion of the starting material, the reaction was cooled to room temperature and extracted with DCM / water. The combined organic phases were concentrated under reduced pressure to give G-31a (HPLC-method: C, t ret =0.88 min; [M+H]=452).

[1163] Experimental procedure for synthesizing G-32a

[1164]

[1165] G-15c (80.0 mg, 0.139 mmol, 1.0 equiv) was dissolved in DMSO (1 mL) and DIPEA (47.4 μL, 0.279 mmol, 2.0 equiv) and N-methylpiperazine (20.9 mg, 0.209 mmol, 1.5 equiv) were added. The reaction mixture was stirred at 90° C. until complete conversion was observed. The mixture was diluted with a saturated aqueous solution of NaHCO 3 and extracted three times with DCM. The organic phases were combined, filtered and concentrated under reduced pressure. The resulting residue was dissolved in ACN and purified by basic RP chromatography (gradient elution: 40% to 98% ACN / water) to give the desired product 32a (HPLC method: C, t ret =0.953min; [M+H] + =638).

[1166] Experimental procedure for synthesizing G-33a

[1167]

[1168] G-32a (139 mg, 0.225 mmol, 1.0 equiv) was dissolved in dioxane (1 mL) and HCl solution (2 M in water, 0.79 mL, 1.58 mmol, 7.0 equiv) was added. The resulting solution was stirred at 60 ° C for 2 h until complete conversion of the starting material was observed. The reaction mixture was diluted with a saturated aqueous solution of NaHCO 3 and extracted three times with DCM. The organic solvent was evaporated and the resulting residue was purified by RP chromatography to give G-33a.

[1169] The following intermediate G-33 (Table 31) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1170] Table 31

[1171]

[1172]

[1173] Experimental procedure for synthesizing G-34a

[1174]

[1175] G-12b (100 mg, 0.22 mmol, 1.0 equiv), (S)-5-methyl-4,7-diazaspiro[2.5]octane 2HCl (141 mg, 0.67 mmol, 3.0 equiv), and DIPEA (230 μL, 0.67 mmol, 6.0 equiv) were dissolved in DMSO (1 mL). The reaction was stirred at 90° C. for 18 h. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by basic RP chromatography to provide the desired product, G-34a.

[1176] The following intermediate G-34 (Table 32) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1177] The diastereomeric mixture G-34c can be separated via chiral HPLC (Chiralpack IE, 250×20 mm, 5 μ; solvent: ethanol / heptane, 60:40% + 0.1% diethylamine) to obtain G-34c1 (eluting first as Peak 1) and G-34c2 (eluting later as Peak 2).

[1178] Table 32

[1179]

[1180]

[1181]

[1182]

[1183] Experimental procedure for synthesizing G-35a

[1184]

[1185] G-12b (140 mg, 0.31 mmol, 1.0 equiv) was dissolved in dioxane (2 mL). [1-(Oxetan-3-yl)-1H-pyrazol-3-yl]boronic acid (B-9c) (66.3 mg, 0.38 mmol, 1.19 equiv), XPHOS PD G3 (29.9 mg, 0.03 mmol, 0.1 equiv) and cesium carbonate (400 μl, 0.80 mmol, 2.54 equiv) were added. The reaction was stirred at 80 ° C. under argon atmosphere for 10 min. After complete conversion was observed, the reaction was extracted with DCM / water. The combined organic phases were concentrated under reduced pressure, dissolved in ACN / water and purified by RP chromatography to give the desired product G-35a.

[1186] The following intermediate G-35 (Table 33) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1187] Table 33

[1188]

[1189]

[1190]

[1191] Experimental procedure for the synthesis of G-35n

[1192] G-12b (118 mg, 0.27 mmol, 1.0 equiv), 1-methyl-1H-1,2,3-triazole-4-boronic acid and 1,1,1-tris(hydroxymethyl)ethane lithium salt (69.0 mg, 0.32 mmol, 1.20 equiv), Pd(dppf)Cl2 DCM (45.6 mg, 0.05 mol, 0.20 equiv) were dissolved in dioxane (1.5 ml) and cesium carbonate (190 mg, 0.58 mol, 2.2 equiv) dissolved in water (165 μL) were added to the reaction. The reaction was stirred at 90 ° C for 18 h. After complete conversion, the reaction mixture was filtered and extracted with DCM (3×). The combined organic phases were concentrated under reduced pressure and purified by RP chromatography to give G-35n (HPLC-method: A, t ret =1.41 min; [M+H]=492).

[1193] Experimental procedure for synthesizing G-36a

[1194]

[1195] G-351 (61.0 mg, 0.1 mmol, 1.0 equiv) was dissolved in dioxane (1 mL) and HCl (4 M, 101 μL, 0.4 mmol, 4.0 equiv) was added. The reaction was stirred at 50 ° C for 3 h. After the starting material was completely consumed, the reaction was quenched by adding NaHCO 3 and extracted with DCM (3×). The combined organic phase was filtered and concentrated under reduced pressure. The residue was dissolved in ACN and purified by RP chromatography to give the desired product G-36a (HPLC-method: C, t ret =0.72 min; [M+H]=503).

[1196] Experimental procedure for synthesizing G-37a

[1197]

[1198] G-34f (157 mg, 0.25 mmol, 1.0 equiv) was dissolved in MeOH (2 mL) and palladium (10% on carbon, 26.7 mg, 0.1 equiv) was added. The reaction was stirred at room temperature under 5 bar of hydrogen for 17 h. After complete conversion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was dissolved in DMF and purified by RP chromatography to give the product G-37a (HPLC method: C, t ret =0.67 min; [M+H]=537).

[1199] Experimental procedure for synthesizing G-38a

[1200]

[1201] G-34g (185 mg, 0.29 mmol, 1.0 eq) was dissolved in DCM (3 mL) and TFA (110 μL, 1.48 mmol, 5.07 eq) was added. The reaction was stirred at 40° C. for 20 h. After complete conversion of the starting material, the reaction was concentrated under reduced pressure, basified, dissolved in DMSO, and purified by RP chromatography to give the product G-38a (HPLC-Method C, t ret =0.80 min; [M+H]=535).

[1202] Experimental procedure for synthesizing G-39a

[1203]

[1204] G-33a (52.0 mg, 0.105 mmol, 1.0 equiv) was dissolved in DCM (2 mL) under argon and cooled to 0 ° C. Formaldehyde (9.47 μL, 0.126 mmol, 1.2 equiv) was added, followed by sodium triacetoxyborohydride (94.0 mg, 0.443 mmol, 4 equiv). The solution was stirred at 0 ° C for 30 min. After the starting material was completely consumed, the reactant was quenched by adding water. The aqueous phase was extracted with DCM (3×). The combined organic phase was filtered and concentrated under reduced pressure. The residue was purified by RP chromatography to obtain the desired product G-39a (HPLC method: C, t ret =0.72min; [M+H] + =508).

[1205] Experimental procedure for synthesizing G-40a

[1206]

[1207] G-11a (500 mg, 1.07 mmol, 1.00 equiv) was dissolved in MeOH (10 mL), and formaldehyde (403 μL, 5.36 mmol, 5 equiv) and acetic acid (27 μL, 0.54 mmol, 0.50 equiv) were added, followed by sodium cyanoborohydride (142 mg, 2.14 mmol, 2.00 equiv). The solution was stirred at room temperature for 1 h. After the starting material was completely consumed, the reaction was quenched by adding water and saturated NaHCO 3 . The aqueous phase was extracted with DCM (3×). The combined organic phases were filtered and concentrated under reduced pressure. The residue was dissolved in ACN and purified by RP chromatography to give the desired product G-40a (HPLC method: A, t ret =1.39min; [M+H] + =444).

[1208] Experimental procedure for synthesizing G-41a

[1209]

[1210] G-27a (1.00 g, 1.50 mmol, 1.00 equiv) was dissolved in DCM (3.0 mL), TFA (500 μL, 6.48 mmol, 4.32 equiv) was added and the solution was stirred at 50 ° C for 1 h. The solvent was evaporated and the resulting residue was dissolved in DCM and saturated aqueous Na2CO3. The organic phase was separated and the remaining aqueous phase was extracted with DCM (2×). The combined organic phases were dried over magnesium sulfate, the solvent was evaporated and the resulting residue was purified by RP chromatography to give G-41a (HPLC method: A, t ret =1.34min; [M+H] + =523).

[1211] Experimental procedure for synthesizing G-42a

[1212]

[1213] G-4a (114 mg, 0.152 mmol, 1.0 equiv) was dissolved in dioxane (2 mL) and 2M aqueous HCl (0.38 mL, 0.76 mmol, 5.0 equiv). The resulting solution was stirred at 60° C. for 2 h until complete conversion of the starting material was observed. The reaction mixture was diluted with saturated aqueous NaHCO and extracted three times with DCM. The organic solvent was evaporated, and the resulting residue was purified by RP chromatography to afford G-42a.

[1214] The following intermediate G-42 (Table 34) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1215] Table 34

[1216]

[1217] Experimental procedure for synthesizing G-43a

[1218]

[1219] G-18b (1.15 g, 1.64 mmol, 1.0 equiv) was treated with HCl (4 N in 1,4-dioxane, 15 mL, 60.0 mmol, 36.6 equiv) and the mixture was stirred at 80 ° C for 1 hour. After complete conversion, the reaction mixture was diluted with saturated aqueous NaHCO 3 and extracted three times with DCM. The organic phase was dried, filtered and evaporated. The resulting residue was purified by RP chromatography to give G-43a.

[1220] The following intermediate G-43 (Table 35) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1221] Table 35

[1222]

[1223] Experimental procedure for synthesizing G-44a

[1224]

[1225] G-12b (120 mg, 0.269 mmol, 1.0 equiv), 1H-1,2,3-triazole (37.3 mg, 0.539 mmol, 2.0 equiv) and cesium carbonate (220 mg, 0.67 mmol, 2.5 equiv) were dissolved in DMSO (1 mL) and stirred at 80 ° C for 1 hour. After complete conversion, DCM was added and the reaction was washed with water. The organic phase was concentrated under reduced pressure and purified by RP chromatography to give the desired product G-44a.

[1226] The following intermediate G-44 (Table 36) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1227] Table 36

[1228]

[1229] Experimental procedure for synthesizing G-45a

[1230]

[1231] G-11a (217 mg, 0.505 mmol, 1.0 equiv) was dissolved in DMSO (2 mL) and DIPEA (172 μL, 1.01 mmol, 2.0 equiv) and N-methylpiperazine (75.8 mg, 0.757 mmol, 1.5 equiv) were added. The reaction mixture was stirred at 90° C. until complete conversion was observed. The mixture was diluted with a saturated aqueous solution of NaHCO 3 and extracted three times with DCM. The organic phases were combined, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in ACN and purified by basic RP chromatography to give the desired product, G-45a.

[1232] The following intermediate G-45 (Table 37) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1233] The diastereomeric mixture G-451 was separated by chiral HPLC (column: Chiralpack IE, 250×20 mm, 5 μ; solvent: ethanol / heptane 1:1 + 0.1% diethylamine) to obtain G-45I1 (eluted first as peak 1) and G-45I2 (eluted later as peak 2).

[1234] Table 37

[1235]

[1236]

[1237]

[1238]

[1239]

[1240]

[1241]

[1242] Experimental procedure for synthesizing G-46a

[1243]

[1244] 4-(1H-pyrazol-3-yl)pyridine (73.4 mg, 0.51 mmol, 1.50 equiv) was dissolved in DMF (1 mL), NaH (51.7 mg, 1.35 mmol, 4.0 equiv) was added and stirred at room temperature for 20 min. G-11b (150 mg, 0.34 mmol, 1.0 equiv) was added and the reaction was stirred at 40 ° C for 1 h. After complete conversion, the reaction was extracted with EtOAc / water. The organic phase was concentrated under reduced pressure and purified by RP chromatography to give the desired product G-46a.

[1245] The following intermediate G-46 (Table 38) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1246] Table 38

[1247]

[1248]

[1249] Experimental procedure for synthesizing G-47a

[1250]

[1251] G-11b (150 mg, 271.7 μmol, 1.0 eq), 2-hydroxypyrazine (31.3 mg, 326.1 μmol, 1.2 eq) and t-BuONa (2 M in THF, 190.20 μL, 0.38 mmol, 1.4 eq) were dissolved in THF (2 mL) and stirred at 65 ° C for 18 h. After complete conversion, the reaction was extracted with DCM / water. The combined organic phases were concentrated under reduced pressure and purified by RP chromatography to give the desired product G-47a (HPLC-method: A, t ret =1.39 min; [M+H]=505).

[1252] Experimental procedure for synthesizing G-48a

[1253]

[1254] G-11d (150 mg, 0.32 mmol, 1.0 equiv) was dissolved in dioxane (1.5 mL). 1-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyrazole (82.7 mg, 0.39 mmol, 1.2 equiv), XPHOS PDG3 (26.0 mg, 0.03 mmol, 0.09 equiv) and cesium carbonate (0.4 mL, 0.80 mmol, 2.46 equiv) were added. The reaction was stirred at 80° C. for 2 h. After complete conversion was observed, the reaction was extracted with DCM / water. The combined organic phases were concentrated under reduced pressure, dissolved in ACN / water and purified by RP chromatography to give the desired product, G-48a.

[1255] The following intermediate G-48 (Table 39) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1256] Table 39

[1257]

[1258]

[1259]

[1260]

[1261]

[1262]

[1263]

[1264] Experimental procedure for synthesizing G-49a

[1265]

[1266] G-11b (50 mg, 0.10 mmol, 1.0 equiv), 2-(4,4,5,5-tetramethyl-1,3,4-dioxaborolan-2-yl)pyridine (41.39 mg, 0.19 mmol, 2.0 equiv), Pd(dppf)Cl2 (7 mg, 0.01 mmol, 0.1 equiv), copper(I) chloride (9.68 mg, 0.10 mmol, 1.0 equiv) and cesium carbonate (128 mg, 0.38 mmol, 4.0 equiv) were dissolved in DMF (1 mL) and stirred at 90 ° C. under argon atmosphere for 18 h. The reaction was extracted with DCM / water, the organic phase was concentrated under reduced pressure and purified by RP chromatography to give the desired product G-49a (HPLC-method: A, t ret=1.56 min; [M+H]=488).

[1267] Experimental procedure for the synthesis of G-50a

[1268]

[1269] G-11b (148 mg, 0.30 mmol, 1 eq.), 5-bromothiazole (50 mg, 0.30 mmol, 1.0 eq.), bis(pinacolato)diboron (163 mg, 0.63 mmol, 2.10 eq.), APhos PD G3 mesylate (10.4 mg, 0.02 mmol, 0.06 eq.), potassium acetate (60.3 mg, 0.61 mmol, 2.06 eq.) and tripotassium phosphate (4 M in water, 161 μL, 0.64 mmol, 2.15 eq.) were dissolved in dioxane (1 mL) and stirred at 90 ° C. under nitrogen for 18 h. After complete conversion, the reaction mixture was extracted with EtOAc / water, the organic phase was concentrated under reduced pressure and purified by RP chromatography to give the desired product G-50a (HPLC-method: C, t ret =0.79 min; [M+H]=494).

[1270] Experimental procedure for synthesizing G-51a

[1271]

[1272] G-11b (150 mg, 0.34 mmol, 1.0 eq) was dissolved in dioxane (18 mL) and 2-oxazolidinone (59.9 mg, 0.67 mmol, 2.0 eq), Pd(dppf)Cl2 (24.7 mg, 0.03 mmol, 0.1 eq) and NaOtBu (2.0 M in THF, 185 μL, 0.37 mmol, 1.1 eq) were added. The reaction was stirred at 60 ° C for 3 days. After complete conversion was observed, the reaction was filtered and concentrated under reduced pressure. The residue was extracted with DCM / water. The combined organic phases were concentrated under reduced pressure and purified by RP chromatography to give G-51a (HPLC-method: C, t ret =0.78 min; [M+H]=496).

[1273] Experimental procedure for synthesizing G-52a

[1274]

[1275] G-11b (120 mg, 0.27 mmol, 1.0 equiv), 1-methylimidazolin-2-one (81.0 mg, 0.81 mmol, 3.0 equiv), Xantphos PD G3 (16.15 mg, 0.02 mmol, 0.06 equiv), cesium carbonate (131 mg, 0.40 mmol, 1.5 equiv) were dissolved in dioxane (960 μL) and stirred at 110 ° C. under argon atmosphere for 16 hours. After complete conversion, the reaction mixture was filtered and purified by RP chromatography to give the desired product G-52a.

[1276] The following intermediate G-52 (Table 40) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1277] Table 40

[1278]

[1279] Experimental procedure for synthesizing G-53a

[1280]

[1281] G-11b (300 mg, 617 μmol, 1 eq), 2-hydroxythiazole (125 mg, 1.23 mmol, 2 eq) and cesium carbonate (402 mg, 1.23 mmol, 2 eq) were dissolved in DMSO (3 mL). The reaction was stirred at 85° C. for 2 h. After complete conversion, DCM was added and the solution was washed with water. The organic phase was concentrated under reduced pressure and purified by RP chromatography to obtain G-53a.

[1282] The following intermediate G-53 (Table 41) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1283] Table 41

[1284]

[1285]

[1286] Experimental procedure for synthesizing G-54a

[1287]

[1288] G-11b (200 mg, 449 μmol, 1.0 equiv), tert-butyl 6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (148 mg, 629 μmol, 1.4 equiv), cesium carbonate (293 mg, 0.899 mmol, 2.0 equiv), CuI (17.1 mg, 90 μmol, 0.20 equiv) and 4,7-dimethoxy-1,10-phenanthroline were dissolved in DMF (1 mL). The mixture was purged with argon and stirred at 80 ° C for 24 h. After complete conversion, the reaction mixture was treated with a few drops of aqueous ammonia and the product was isolated by RP chromatography to obtain G-54a.

[1289] The following intermediate G-54 (Table 42) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1290] Table 42

[1291]

[1292] Experimental procedure for the synthesis of G-55a

[1293]

[1294] To a stirred solution of G-11b (700 mg, 1.57 mmol, 1.0 equiv) in ACN (14.0 mL) was added tetraethylammonium cyanide (368.1 mg, 2.36 mmol, 1.50 equiv) at 0 ° C under argon, followed by 1,4-diazabicyclo[2.2.2]octane (52.9 mg, 0.47 mmol, 0.3 equiv). The reaction mixture was stirred at room temperature overnight until TLC showed complete conversion. The solvent was removed under reduced pressure. The crude product was purified by NP chromatography to obtain G-55a (HPLC method: A, t ret =1.48min; [M+H] + =436).

[1295] Experimental procedure for synthesizing G-56a

[1296]

[1297] To a stirred solution of G-55a (300 mg, 0.69 mmol, 1.0 equiv) in THF (2.0 mL) and water (2.0 mL) was added NaOH (83 mg, 2.1 mmol, 3.0 equiv) at room temperature, and the reaction mixture was stirred at 50 ° C for 90 min until TLC showed complete conversion. The solvent was removed under reduced pressure. The crude product was purified by NP chromatography to obtain G-56a (HPLC method: A, t ret =0.97min; [M+H]+ =455).

[1298] Experimental procedure for synthesizing G-57a

[1299]

[1300] To a stirred mixture of G-56a (100 mg, 0.22 mmol, 1.0 equiv) and HATU (126 mg, 0.33 mmol, 1.50 equiv) in dioxane (2.0 mL) was added DIPEA (112 μL, 0.66 mmol, 3.0 equiv) at room temperature, and the reaction mixture was then stirred at room temperature for 30 minutes. Morpholine (21.1 μL, 0.242 mmol, 1.10 equiv) was added and the mixture was stirred at room temperature overnight until complete conversion. The crude product was purified by RP chromatography to give the product G-57a (HPLC method: D; t ret =0.67min; [M+H] + =524).

[1301] Experimental procedure for synthesizing G-58a

[1302]

[1303] G-31a (150 mg, 0.28 mol, 1.0 eq) was dissolved in DCM (2 mL) and N,N-dimethylprop-2-ynamide (30,2 mg, 0.31 mmol, 1.1 eq), copper (I) iodide (10.8 mg, 0.06 mol, 0.2 eq) and DIPEA (98.9 μL, 0.56 mmol, 2 eq) were added. The reaction was stirred at room temperature for 20 min. After complete conversion, the reaction was extracted with DCM / NaHCO. The organic phase was concentrated under reduced pressure and purified by RP chromatography to yield G-58a.

[1304] The following intermediate G-58 (Table 43) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1305] Table 43

[1306]

[1307]

[1308] Experimental procedure for the synthesis of G-59a

[1309]

[1310] G-21a (144 mg, 0.36 mmol, 1.0 equiv) and B-5b (80.0 mg, 0.49 mmol, 1.37 equiv) were dissolved in dioxane (1.4 mL) and degassed with argon. [BrettPhos Pd(butenyl)]OTf (24 mg, 0.03 mmol, 0.08 equiv) was added and NaOtBu (222 μL, 0.44 mmol, 1.25 equiv) was added at room temperature. The reaction was stirred at 60° C. for 30 h. After complete conversion, the solution was filtered and purified by RP chromatography to give the desired product, G-59a.

[1311] The following intermediate G-59 (Table 44) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1312] Table 44

[1313]

[1314] Experimental procedure for the synthesis of G-60a

[1315]

[1316] G-8f (2.4 g, 0.01 mol, 1 eq) was dissolved in THF (100 mL), triethylamine (2.09 mL, 0.02 mol, 3.0 eq) and dimethylaminopyridine (122 mg, 1.0 mmol, 0.2 eq) were added and the reaction was stirred at room temperature for 5 min. The reaction was cooled to 0 ° C. and Boc-anhydride (2.18 g, 0.01 mol, 2.0 eq) was added. The reaction was stirred at room temperature for 16 hours. After complete conversion, water was added and the reaction was extracted with DCM. The combined organic phases were concentrated under reduced pressure and purified by NP chromatography to produce the desired product G-60a as a mixture of diastereomers. The diastereomeric mixture G-60a was separated by SFC (column: (R,R) Whelk-01 (250×30, 5 μm); 55% CO 2 , 45% cosolvent = 0.5% isopropylamine / isopropanol, flow rate: 100 g / min, temperature: 30° C.) to produce G-60a1 and G-60a2 (Table 45).

[1317] Table 45

[1318]

[1319] Experimental procedure for the synthesis of G-61a

[1320]

[1321] G-45b (204 mg, 0.335 mmol, 1.0 equivalent) was dissolved in MeOH (1 mL) and 4M HCl (0.42 mL, 1.67 mmol, 5.0 equivalent) was added. The reaction was stirred at 60 ° C for 3 h. After complete conversion, the reaction mixture was quenched by adding NaHCO 3 and extracted with DCM. The combined organic phase was filtered and concentrated under reduced pressure. The residue was purified by RP chromatography to obtain the desired product G-61a.

[1322] The following intermediate G-61 (Table 46) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1323] Table 46

[1324]

[1325]

[1326]

[1327] Experimental procedure for synthesizing G-62a

[1328]

[1329] G-45w (135 mg, 217 μmol, 1.0 eq) was dissolved in DCM (1.0 mL) and trifluoroacetic acid (0.50 mL, 6.49 mmol, 30 eq). The reaction was stirred at room temperature for 1 hour. After complete conversion, the solvent was removed under reduced pressure. The residue was dissolved in DCM and extracted with saturated Na2CO3 aqueous solution. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by RP chromatography to give G-62a (HPLC method: B; t ret =0.93min; [M+H] + =521).

[1330] Experimental procedure for synthesizing G-63a

[1331]

[1332] Under argon, G-45a (124 mg, 0.251 mmol, 1.0 equivalent) was dissolved in DCM (10 mL) and cooled to 0 ° C. Formaldehyde (22.5 μL, 0.301 mmol, 1.2 equivalents) was added, followed by sodium triacetoxyborohydride (224 mg, 1.01 mmol, 4.0 equivalents). The solution was stirred at 0 ° C for 30 min. After the starting material was completely consumed, the reactant was quenched by adding water. The aqueous phase was extracted with DCM. The combined organic phase was dried, filtered and concentrated under reduced pressure. The residue was purified by RP chromatography to obtain the desired product G-63a.

[1333] The following intermediate G-63 (Table 47) can be obtained in a similar manner. Deuterated intermediate G-63 is obtained similarly, but sodium triacetoxyborohydride is exchanged for sodium triacetoxyborodeuteride. The crude product is purified by chromatography if necessary.

[1334] Table 47

[1335]

[1336]

[1337] Experimental procedure for synthesizing G-64a

[1338]

[1339] G-48af (272 mg, 0.48 mmol, 1 eq) was dissolved in MeOH (2 mL) and HCl (4 M in dioxane, 363 μL, 1.45 mmol, 3.0 eq) was added. The reaction was stirred at room temperature for 1.5 h. After complete conversion, the reaction was filtered and extracted with NaHCO 3 / DCM (3×). The combined organic phases were concentrated under reduced pressure and purified by RP chromatography to give the product G-64a (HPLC method: A; t ret =1.10min; [M+H] + =478).

[1340] Experimental procedure for the synthesis of G-65a

[1341]

[1342] G-45p (150 mg, 0.24 mmol, 1 eq) was dissolved in ACN (2 mL). The reaction was stirred at 150 ° C for 4 h under microwave. After complete conversion, the reaction was concentrated under reduced pressure and purified by RP chromatography to give the desired product G-65a (HPLC method: C, t ret =0.659; [M+H] + =537).

[1343] Experimental procedure for the synthesis of G-66a

[1344]

[1345] G-8a (87.0 mg, 0.176 mmol, 1.0 equiv) was dissolved in ACN (1 mL) and DIPEA (121.0 μL, 0.704 mmol, 4.0 equiv) and (3S)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate (139 mg, 0.528 mmol, 3.0 equiv) was added. The reaction mixture was stirred at 70° C. until complete conversion was observed. The mixture was diluted with saturated aqueous NaHCO 3 solution and extracted with DCM. The organic phases were combined, filtered and concentrated under reduced pressure. The resulting residue was dissolved in DMF and purified by RP chromatography to give the desired product G-66a (HPLC method: A, t ret =1.48min; [M+H] + =565).

[1346] Experimental procedure for the synthesis of G-67a

[1347]

[1348] G-61c (60.0 mg, 0.13 mmol, 1.0 equivalent) is dissolved in ACN (0.5 mL), cesium carbonate (82.0 mg, 0.25 mmol, 2.0 equivalent) is added and the mixture is stirred at room temperature for 30 minutes. B-13a (65.9 mg, 0.25 mmol, 2.0 equivalent) is added. The reaction mixture is stirred at 85 ° C for 2 h. After complete conversion, the reaction is extracted with DCM / water. The organic phase is concentrated under reduced pressure and purified by RP chromatography to obtain the desired product G-67a.

[1349] The following intermediate G-67 (Table 48) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1350] Table 48

[1351]

[1352] Experimental procedure for the synthesis of G-68a

[1353]

[1354] G-61c (60 mg, 0.13 mmol, 1 eq), 2-(chloromethyl)oxazole (23.4 mg, 0.19 mmol, 1.5 eq) and KCO (34.8 mg, 0.25 mmol, 2.0 eq) were dissolved in DMF (0.5 mL) and stirred at 60° C. for 30 min. After complete conversion, the reaction mixture was extracted with DCM / water. The organic phase was concentrated under reduced pressure and purified by RP chromatography to give the desired product, G-68a.

[1355] The following intermediate G-68 (Table 49) can be obtained in a similar manner using the appropriate alkyl halide. The crude product is purified by chromatography if necessary.

[1356] Table 49

[1357]

[1358] Experimental procedure for the synthesis of G-69a

[1359]

[1360] G-48ac (152 mg, 0.31 mmol, 1.0 equiv) was dissolved in DCM (6 mL) and palladium (10% / charcoal, 60 mg) was added. The reaction was stirred at room temperature under 7 bar H2 for 4 h. After complete conversion, the reaction was filtered and concentrated under reduced pressure. The residue was purified by RP chromatography to give the desired product, G-69a.

[1361] The following intermediate G-69 (Table 50) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1362] Table 50

[1363]

[1364]

[1365] Experimental procedure for the synthesis of G-85a

[1366]

[1367] G-53k (600 mg, 1.10 mmol, 1.0 eq) was dissolved in DMSO (4.0 mL), cesium carbonate (539 mg, 1.66 mmol, 1.5 eq) and B-13c (269 mg, 1.10 mmol, 1.0 eq) were added, and the reaction mixture was stirred at 65° C. for 12 h. After complete conversion, the desired product was isolated by RP chromatography to obtain G-85a.

[1368] The following intermediate G-85 (Table 51) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1369] Table 51

[1370]

[1371] Experimental procedure for the synthesis of G-86a

[1372]

[1373] G-12b (2.00 g, 4.23 mmol, 1 eq), ethyl 1H-pyrazole-5-carboxylate (936 mg, 6.34 mmol, 1.5 eq), and cesium carbonate (4.59 g, 8.46 mmol, 2 eq) were dissolved in THF (20 mL). The reaction was stirred at 70° C. for 2 h. After complete conversion, DCM was added and the solution was washed with water. The organic phase was concentrated under reduced pressure and purified by RP chromatography to obtain G-86a.

[1374] The following intermediate G-86 (Table 52) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1375] Table 52

[1376]

[1377]

[1378] Experimental procedure for synthesizing G-88a

[1379]

[1380] G-11b (4.00 g, 8.99 mmol, 1 equiv), 2-(1H-pyrazol-3-yl)acetic acid hydrochloride (1.73 g, 10.34 mmol, 1.15 equiv), and cesium carbonate (8.79 g, 26.97 mmol, 3 equiv) were dissolved in DMSO (20 mL). The reaction was stirred at 90° C. for 1.5 h. After complete conversion to the desired intermediate, the reaction mixture was cooled to room temperature, isopropylamine (1.55 mL, 17.98 mmol, 2.0 equiv), 1-methylimidazole (1.43 mL, 17.98 mmol, 2.0 equiv), and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (5.15 g, 17.98 mmol, 2.0 equiv) were added, and the mixture was stirred at room temperature for 15 min. After complete conversion, DCM was added, and the solution was washed with water and brine. The organic phase was concentrated under reduced pressure and purified by RP chromatography to obtain G-88a.

[1381] The following intermediate G-88 (Table 53) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1382] Table 53

[1383]

[1384]

[1385] Synthesis of aminocyanothiophene I and II

[1386] Experimental procedure for the synthesis of I-1

[1387]

[1388] G-12b (76.1 mg, 0.157 mmol, 1.00 equiv) and molecular sieves were added under argon atmosphere. Malononitrile (14.5 mg, 0.209 mmol, 1.33 equiv), sulfur (10.1 mg, 0.312 mmol, 2.00 equiv) and β-alanine (19.4 mg, 0.218 mmol, 1.40 equiv) were added to a solution in MeOH (2 mL). The reaction mixture was stirred at 80 ° C overnight. After complete conversion, the reaction mixture was cooled to room temperature, filtered and extracted with DCM and saturated aqueous NaHCO 3 solution. The organic phases were combined and concentrated under reduced pressure. The residue was dissolved in ACN and water and purified by basic RP chromatography to give the desired product I-1 (HPLC method: A, t ret =2.16min; [M+H] + =525).

[1389] Experimental procedure for the synthesis of I-2

[1390]

[1391] G-30a (80.0 mg, 154 μmol, 1.00 equiv), malononitrile (64.2 mg, 953 μmol, 6.20 equiv), sulfur (23.1 mg, 791 μmol, 4.70 equiv), β-alanine (60.9 mg, 684 μmol, 4.50 equiv) and magnesium sulfate (23.5 mg, 195 μmol, 1.30 equiv) were suspended in EtOH (2.0 mL) and stirred at 80 ° C for 18 h. The reaction mixture was diluted with EtOAc, filtered and washed with saturated aqueous NaHCO 3 solution. The organic phase was separated and the remaining aqueous phase was extracted with EtOAc (2×). The combined organic phases were dried over magnesium sulfate, evaporated and the resulting residue was purified by RP chromatography to give I-2.

[1392] The following final compounds I (Table 54) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1393] Table 54

[1394]

[1395]

[1396]

[1397]

[1398]

[1399]

[1400]

[1401] Experimental procedure for the synthesis of I-37

[1402]

[1403] G-34h (91.0 mg, 0.160 mmol, 1.00 equiv), ammonium acetate (26.3 mg, 0.320 mmol, 2.00 equiv) and sulfur (10.3 mg, 0.320 mmol, 2.00 equiv) were suspended in EtOH (1.0 mL) and stirred at 60° C. for 15 min. Malononitrile (22.3 mg, 0.320 mmol, 2.00 equiv) was added. The reaction was stirred at 80° C. for 5 h. After complete conversion, the mixture was diluted with DMSO, filtered and purified by RP chromatography to give I-37.

[1404] The following final compounds I (Table 55) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1405] Table 55

[1406]

[1407]

[1408] Experimental procedure for the synthesis of I-40

[1409]

[1410] I-2 (52 mg, 87 μmol, 1.0 eq) was dissolved in DCM (1.0 mL) and formaldehyde (6.2 μL, 82 μmol, 1.0 eq) was added. The solution was stirred at room temperature for 4 h, then sodium triacetoxyborohydride (23 mg, 0.10 mmol, 1.2 eq) was added and the suspension was stirred for 2 h. The reaction mixture was quenched with water, diluted with DCM and washed with water. The organic phase was separated and the remaining aqueous phase was extracted with DCM (2×). The combined organic phase was washed with brine, dried over magnesium sulfate, evaporated and the resulting residue was purified by RP chromatography to give I-40.

[1411] The following final compounds I (Table 56) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1412] Table 56

[1413]

[1414] Experimental procedure for the synthesis of I-44

[1415]

[1416] I-3 (51 mg, 83 μmol, 1.0 eq) was dissolved in THF and cooled with an ice / water bath for 15 minutes, followed by the addition of NaH (60% in mineral oil, 6.5 mg, 0.16 mmol, 2.0 eq) and stirred for 10 minutes. Iodomethane (5.7 μL, 9.2 μmol, 1.1 eq) was added, the reaction was warmed to room temperature and stirred at room temperature for 18 h. After complete conversion, the reaction mixture was extracted with EtOAc (3×). The combined organic phases were filtered and concentrated under reduced pressure. The residue was dissolved in DMSO and purified by RP chromatography to give the desired product I-44 (HPLC-method: A, t ret =1.69 min; [M+H]=629).

[1417] Experimental procedure for the synthesis of I-45

[1418]

[1419] I-38 (225 mg, 0.31 mmol, 1.0 equiv) was dissolved in DCM / TFA (1:1, 2.0 mL) and the reaction was stirred at room temperature for 3 h. After complete conversion, the reaction mixture was concentrated in vacuo and purified by RP chromatography to yield I-45 (HPLC-method: A, t ret =1.47 min; [M+H]=619).

[1420] Experimental procedure for the synthesis of I-51

[1421]

[1422] To a suspension of I-46 (2.73 g, 4.14 mmol, 1.0 equiv) in ethanol (47 mL) was added potassium hydroxide (1.91 g, 29.0 mmol, 7.0 equiv) dissolved in water (53 mL) and the mixture was stirred at room temperature for 2 h. After complete conversion, the mixture was acidified to pH 6, ethanol was removed under reduced pressure, and the resulting precipitate was collected by repeated centrifugation and washing with water and dried under reduced pressure to give the desired product, I-51. The crude product was used without further purification.

[1423] The following final compounds I (Table 57) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1424] Table 57

[1425]

[1426] Experimental procedure for the synthesis of I-53

[1427]

[1428] To a solution of I-51 (90.1 mg, 0.14 mmol, 1.0 equiv) in DMSO (0.7 mL) was added (R)-tetrahydrofuran-3-amine hydrochloride (21.9 mg, 0.17 mmol, 1.2 equiv), 1-methylimidazole (45.6 μL, 0.57 mmol, 4.0 equiv) and chloro-N,N,N',N'-tetramethylformamidinium-hexafluorophosphate (57.3 mg, 0.20 mmol, 1.4 equiv) and the mixture was stirred at room temperature for 1 hour. After complete conversion, the mixture was diluted with ACN and the product was isolated via RP chromatography to give the desired product, I-53.

[1429] The following final compounds I (Table 58) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1430] Table 58

[1431]

[1432]

[1433]

[1434] Experimental procedure for the synthesis of II-1

[1435]

[1436] G-11c (1.20 g, 2.59 mmol, 1.00 equiv), ammonium acetate (319 mg, 4.15 mmol, 1.60 equiv), sulfur (133 mg, 4.15 mmol, 1.60 equiv) were dissolved in EtOH (12 mL) and stirred at 60 ° C for 15 minutes. Malononitrile (8 mL / h) was slowly added dropwise as a solution in EtOH (3.77 mL, 4.28 mmol, 1.65 equiv). The reaction was stirred at 80 ° C for 5 hours. After complete conversion, the reaction was concentrated and purified by NP chromatography. The product fractions were concentrated and extracted with DCM and saturated NaHCO 3. The organic phase was concentrated under reduced pressure to obtain II-1.

[1437] The following final compounds II (Table 59) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1438] Table 59

[1439]

[1440]

[1441] Experimental procedure for the synthesis of II-5

[1442]

[1443] II-3 (100 mg, 0.152 mmol, 1.00 equiv) was dissolved in DMF (1 mL) and sodium azide (17.8 mg, 0.274 mmol, 1.80 equiv) was added and the reaction was stirred at 50 ° C for 16 h. After complete conversion, the reaction was extracted with DCM / water. The organic phase was concentrated under reduced pressure to give II-5 (HPLC method: A, t ret =1.63min; [M+H] + =532).

[1444] Experimental procedure for the synthesis of II-6

[1445]

[1446] II-5 (40 mg, 0.068 mmol, 1.0 equiv), 3-ethynyl-4-methylpyridine (10 mg, 0.088 mmol, 1.3 equiv) and copper (I) iodide (2.6 mg, 0.01 mmol, 0.20 equiv) were dissolved in DCM (500 μL) and DIPEA (24 μL, 0.14 mmol, 2.0 equiv) was added. The brown solution was stirred at room temperature. After 30 minutes, 3-ethynyl-4-methylpyridine (10 mg, 0.088 mmol, 1.3 equiv) was added. The reaction mixture was stirred at room temperature for 18 h. After complete conversion, the reaction mixture was extracted with DCM and ammonium chloride solution, dried, filtered and concentrated. The resulting residue was purified by RP chromatography to give the desired final product II-6 (HPLC method: A, t ret =1.56min; [M+H] + =649).

[1447] Experimental procedure for the synthesis of II-7

[1448]

[1449] II-3 (100 mg, 0.190 mmol, 1.00 equiv) was suspended in EtOH (700 μl). DIPEA (116 μl, 0.667 mmol, 3.00 equiv) and N,N-dimethylazetidin-3-amine dihydrochloride (41.6 mg, 0.229 mmol, 1.20 equiv) were added and the reaction mixture was stirred at 80° C. overnight. After complete conversion, the reaction mixture was filtered and purified by RP chromatography to give the desired final product II-7.

[1450] The following final compounds II (Table 60) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1451] Table 60

[1452]

[1453]

[1454]

[1455] Experimental procedure for the synthesis of II-17

[1456]

[1457] II-1 (0.10 g, 0.18 mmol, 1.0 eq) was suspended in DMSO (0.50 ml). DIPEA (0.11 mL, 0.57 mmol, 3.1 eq) and (R)-5-methyl-4,7-diazaspiro[2.5]dihydrochloride (42 mg, 0.20 mmol, 1.1 eq) were added and the reaction mixture was stirred at 80° C. for 2 h. After complete conversion, the reaction mixture was purified by RP chromatography.

[1458] The following final compounds II (Table 61) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1459] Table 61

[1460]

[1461]

[1462] Experimental procedure for the synthesis of II-19

[1463]

[1464] II-3 (80 mg, 0.15 mmol, 1.0 equiv) and B-11a (50.3 mg, 0.31 mmol, 2.0 equiv) were dissolved in THF (1.0 mL), cesium carbonate (123 mg, 0.38 mmol, 2.5 equiv) was added and the mixture was stirred at 65 ° C for 3 h. After complete conversion, saturated NaHCO solution was added and the product was extracted with DCM. The organic phase was dried, filtered and concentrated under reduced pressure. The crude product was purified by RP chromatography to give the desired final product II-19.

[1465] The following final compounds II (Table 62) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1466] Table 62

[1467]

[1468]

[1469] Experimental procedure for the synthesis of II-24

[1470]

[1471] To a solution of II-23 (100 mg, 0.159 mmol, 1.0 equiv) in 1-propanol (1 mL) was added sodium hydroxide (4 M in water, 99.4 μL, 0.40 mmol, 2.5 equiv) and the mixture was stirred at room temperature for 30 min. After complete conversion, saturated NaHCO was added, the mixture was washed with DCM, and the aqueous phase was then acidified with HCl and extracted with DCM. The organic phase was dried, filtered, and concentrated, and the crude product was purified by RP chromatography to give the desired product II-24.

[1472] The following final compound II (Table 63) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1473] Table 63

[1474]

[1475]

[1476] Experimental procedure for the synthesis of II-25

[1477]

[1478] To a solution of II-24 (40 mg, 0.067 mmol, 1.0 equiv) in DMF (0.4 mL) was added oxetan-3-amine hydrochloride (15 mg, 0.133 mmol, 2.0 equiv), DIPEA (22.3 μL, 0.166 mmol, 2.5 equiv) and 1-propanephosphonic anhydride (29.7 μL, 1.00 mmol, 1.5 equiv) and the mixture was stirred at room temperature for 3 h. After complete conversion, saturated NaHCO was added and the mixture was extracted with DCM. The organic phase was dried, filtered and concentrated, and the crude product was purified by RP chromatography to give the desired product II-25.

[1479] The following final compound II (Table 64) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1480] Table 64

[1481]

[1482]

[1483]

[1484]

[1485] Experimental procedure for the synthesis of II-27

[1486]

[1487] II-1 (70 mg, 0.1 mmol, 1.0 equiv) was dissolved in dioxane (1 mL), cesium carbonate (2 M, 131 μL, 0.26 mmol, 2.5 equiv) was added, and the resulting suspension was stirred at 80° C. for 10 min. 1-Methyl-3-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (32.7 mg, 0.16 mmol, 1.5 equiv) and XPhos-Pd-G3 (9.34 mg, 0.01 mmol, 0.1 equiv) were added. The reaction was stirred under argon for 10 min, and then the reaction mixture was heated at 80° C. for 18 h. After complete conversion, the reaction mixture was extracted with NaHCO3 and DCM. The organic phase was concentrated under reduced pressure, dissolved in DMSO, and purified by RP chromatography to give the desired product II-27.

[1488] The following final compound II (Table 65) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1489] Table 65

[1490]

[1491]

[1492] Experimental procedure for the synthesis of II-30

[1493]

[1494] G-63a (94.0 mg, 0.18 mmol, 1.0 equivalent) and molecular sieves were added under argon atmosphere. Malononitrile (64.4 mg, 0.97 mmol, 5.0 equiv), sulfur (23.8 mg, 0.74 mmol, 4.0 equiv) and β-alanine (69.5 mg, 0.78 mmol, 4.0 equiv) were added to a solution in anhydrous EtOH (2 mL). The reaction mixture was stirred at 80° C. overnight. After complete conversion, the mixture was cooled to room temperature, filtered and extracted with DCM and saturated aqueous NaHCO 3 . The organic phases were combined and concentrated under reduced pressure. The residue was dissolved in ACN and water and purified by basic RP chromatography to give the desired product II-30.

[1495] The following final compounds II (Table 66) can be obtained in a similar manner. The crude product is purified by chromatography if necessary. In the case of II-87, Boc deprotection was observed during the reaction using G-48r as the starting material.

[1496] Table 66

[1497]

[1498]

[1499]

[1500]

[1501]

[1502]

[1503]

[1504]

[1505]

[1506]

[1507]

[1508]

[1509]

[1510]

[1511]

[1512]

[1513]

[1514]

[1515]

[1516]

[1517] Experimental procedure for the synthesis of II-143

[1518]

[1519] G-51a (90 mg, 0.18 mmol, 1.0 equiv), ammonium acetate (22.4 mg, 0.29 mmol, 1.6 equiv) and sulfur (9.32 mg, 0.29 mmol, 1.6 equiv) were dissolved in EtOH (1.20 mL) and stirred at 60 ° C for 15 min. Malononitrile as a solution in EtOH (0.26 mL, 0.3 mmol, 1.65 equiv) was slowly added dropwise. The reaction was stirred at 80 ° C for 5 h. After complete conversion, DCM was added and extracted with water three times. The combined organic phases were concentrated under reduced pressure, dissolved in DMF / ACN / water and purified by RP chromatography to give II-143.

[1520] The following final compounds II (Table 67) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1521] Table 67

[1522]

[1523]

[1524]

[1525]

[1526]

[1527]

[1528] Experimental procedure for the synthesis of II-160

[1529]

[1530] To a solution of II-146 (210 mg, 0.29 mmol, 1.0 equiv) in dioxane (3 mL) was added HCl (4 M in dioxane, 0.29 mL, 1.17 mmol, 4.0 equiv) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was heated to 50 ° C and stirred for 6 h. The solvent was removed and the residue was purified by RP chromatography to obtain II-160.

[1531] The following final compound II (Table 68) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1532] Table 68

[1533]

[1534]

[1535] Experimental procedure for the synthesis of II-166

[1536]

[1537] II-137 (148 mg, 0.21 mmol, 1.0 equiv) was dissolved in DCM (1 mL). TFA (60 μL, 0.83 mmol, 4 equiv) was added and the reaction was stirred at room temperature for 3 h. After complete conversion, the reaction mixture was concentrated in vacuo and purified by RP chromatography to yield II-166.

[1538] The following final compound II (Table 69) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1539] Table 69

[1540]

[1541] Experimental procedure for the synthesis of II-169

[1542]

[1543] II-142 (70 mg, 0.129 mmol, 1.0 equiv) was dissolved in DCM (1.0 mL), and acetone (100 μL, 1.36 mmol, 10.5 equiv) and acetic acid (1.48 μL, 0.03 mmol, 0.2 equiv) were added. The resulting solution was cooled to 0 ° C and stirred for 10 minutes. Then sodium triacetoxyborohydride (115 mg, 0.52 mmol, 4.0 equiv) was added and the suspension was stirred for 1 hour. The reaction mixture was quenched with water and the aqueous phase was extracted with DCM. The combined organic phase was evaporated and the resulting residue was purified by RP chromatography to obtain II-169.

[1544] Intermediate II (Table 70) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1545] Table 70

[1546]

[1547] Experimental procedure for the synthesis of II-171

[1548]

[1549] II-54 (50.0 mg, 0.083 mmol, 1.0 equivalent) was dissolved in DCM (1 mL) under argon and cooled to -30 ° C. Formaldehyde (7.48 μL, 0.100 mmol, 1.3 equivalents) was added, followed by sodium triacetoxyborohydride (74.2 mg, 0.333 mmol, 4.0 equivalents). The solution was stirred at -30 ° C for 30 min. After the starting material was completely consumed, the reactant was quenched by adding water. The aqueous phase was extracted with DCM (3 ×). The combined organic phase was filtered and concentrated under reduced pressure. The residue was dissolved in ACN and purified by RP chromatography (gradient elution: 60% to 98% ACN / water) to obtain the desired product II-171.

[1550] The following final product II (Table 71) can be obtained in a similar manner. If necessary, the crude product is purified by chromatography.

[1551] Table 71

[1552]

[1553]

[1554] Experimental procedure for the synthesis of II-177

[1555]

[1556] II-6 (40 mg, 0.07 mmol, 1 eq) was dissolved in acetone (720 μL) and an aqueous solution of potassium carbonate (27.5 mg, 0.2 mmol, 3.0 eq) in water (280 μL) was added. Acetyl chloride (1 M in acetone, 51.8 mg, 0.07 mmol, 1 eq) was added to the reaction and the reaction mixture was stirred at room temperature for 3 h. After complete conversion, the reaction mixture was concentrated under reduced pressure, dissolved in DMF / water and purified by RP chromatography to give II-177.

[1557] The following final compounds II (Table 72) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1558] Table 72

[1559]

[1560] Experimental procedure for the synthesis of II-210

[1561]

[1562] II-188 (76 mg, 0.13 mmol, 1 eq), 4-azidooxane (19.8 mg, 0.15 mmol, 1.1 eq) and CuI (2.6 mg, 0.013 mmol, 0.1 eq) were suspended in DCM (2.0 mL). DIPEA (53.2 mg, 0.27 mmol, 2.0 eq) was added and the reaction mixture was stirred at 40 ° C for 12 h. After complete conversion, the reaction mixture was concentrated under reduced pressure, dissolved in DMF and purified by RP chromatography to give II-210.

[1563] The following final compounds II (Table 73) can be obtained in a similar manner. The crude product is purified by chromatography if necessary.

[1564] Table 73

[1565]

[1566]

[1567] The following examples illustrate the biological activities of the compounds according to the present invention, but the present invention is not limited to these examples.

[1568] KRAS::SOS1 Alpha Screening Binding Assay

[1569] This assay can be used to examine the potency of compounds according to the invention in binding to (mutated) KRAS to inhibit the protein-protein interaction between SOS1 and (mutated) KRAS, e.g., KRAS WT, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G13D. This inhibits the GEF function of SOS1 and locks the corresponding (mutated) KRAS protein in its inactive GDP-bound state. The lower IC in this assay setting 50 Values ​​indicate stronger inhibition of the protein-protein interaction between SOS1 and KRAS:

[1570] Description of the analysis:

[1571] These assays measure the inhibitory effects of compounds on KRAS mutant protein-protein interactions using Perkin Elmer's Alpha Screen technology.

[1572] The following (mutant) enzyme forms of KRAS and interacting proteins were used in these assays at the indicated concentrations:

[1573] KRAS (G12D) 1-169, N-terminal 6His-tag, C-terminal avi-tag (Xtal BioStructures, Inc.); final assay concentration 10 nM and SOS1 564-1049, N-terminal 229 GST-tag, TEV cleavage site (VivaBiotech Ltd); final assay concentration 5 nM;

[1574] KRAS(G12C)1-169, N-terminal 6His-tag for purification, cleaved, C-terminal avi-tag, biotinylated, mutations: C51S, C80L, C118S (in-house); final assay concentration 7.5 nM and SOS1 564-1049, N-terminal 229 GST-tag, TEV cleavage site (Viva Biotech Ltd); final assay concentration 5 nM;

[1575] KRAS(G12V)1-169, N-terminal 6His-tag for purification, cleaved, C-terminal avi-tag, biotinylated, TEV cleavage site, mutation: C118S, GDP loading (in-house); final assay concentration 10 nM and SOS1 564-1049, N-terminal 229 GST-tag, TEV cleavage site (Viva Biotech Ltd); final assay concentration 10 nM;

[1576] KRAS(G13D)1-169, N-terminal 6His-tag for purification, cleaved, C-terminal avi-tag, biotinylated, TEV cleavage site, mutation: C118S, GDP loading (in-house); final assay concentration 10 nM and SOS1 564-1049, N-terminal 229 GST-tag, TEV cleavage site (Viva Biotech Ltd); final assay concentration 10 nM;

[1577] KRAS (WT) 1-169, N-terminal 6His-tag for purification, cleaved, C-terminal avi-tag, biotinylated, TEV cleavage site, mutation: C118S, GDP loading (in-house); final assay concentration 10 nM and SOS1 564-1049, N-terminal 229 GST-tag, TEV cleavage site (Viva Biotech Ltd); final assay concentration 10 nM.

[1578] Test compounds dissolved in DMSO were dispensed onto assay plates (Proxiplate 384PLUS, white, PerkinElmer; 6008289) using an Access Labcyte workstation with a Labcyte Echo 55x. For the selected highest assay concentration of 100 μM, 150 nL of compound solution was transferred from a 10 mM DMSO compound stock solution. A series of 11 five-fold dilutions of each compound was transferred to the assay plate, and the compound dilutions were tested in duplicate. DMSO was added as a backfill to a total volume of 150 nL.

[1579] The assay was run on a fully automated robotic system in a dark room at less than 100 lux. 10 μl of a mixture containing the KRAS mutant protein SOS1 (final assay concentration, see above) and GDP nucleotide (Sigma G7127; final assay concentration 10 μM) in assay buffer (1× PBS, 0.1% BSA, 0.05% Tween 20) was added to columns 1-24.

[1580] After a 30 minute incubation time, 5 μl of Alpha Screen bead mix in assay buffer was added to columns 1-23. The bead mix consisted of AlphaLISA glutathione acceptor beads (PerkinElmer, catalog number AL109) and AlphaScreen streptavidin protein donor beads (PerkinElmer catalog number 6760002) in assay buffer, with a final assay concentration of 10 μg / ml each.

[1581] The plates were kept at room temperature in a dark incubator.After a further 60 minutes of incubation, the signal was measured in a PerkinElmer Envision HTS Multilabel Reader using PerkinElmer's AlphaScreen format.

[1582] Depending on the dilution procedure (plate-by-plate or serial), each plate contained up to 16 negative control wells (DMSO instead of test compound; using KRAS mutant::SOS1 GDP mixture and bead mixture; column 23) and 16 positive control wells (DMSO instead of test compound; using KRAS mutant::SOS1 GDP mixture without bead mixture; column 24).

[1583] As an internal control, known inhibitors of the KRAS mutant::SOS1 interaction can be measured on each compound plate.

[1584] IC50 values ​​were calculated and analyzed with the MEGALAB IC50 application from Boehringer Ingelheim using a 4-parameter logistic model.

[1585] The table of example compounds disclosed herein contains the IC values ​​determined using the above assays. 50 values ​​(see Table 74).

[1586] Table 74

[1587]

[1588]

[1589]

[1590]

[1591]

[1592]

[1593]

[1594]

[1595] Generation of Ba / F3 cell model and proliferation analysis

[1596] The Ba / F3 cell line was ordered from DSMZ (ACC300, Lot 17) and grown at 37°C in RPMI-1640 (ATCC 30-2001) + 10% FCS + 10 ng / mL IL-3 in a 5% CO2 atmosphere. Plasmids containing KRASG12 mutants (i.e., G12D, G12C, G12V) were obtained from GeneScript. To generate the KRASG12-dependent Ba / F3 model, Ba / F3 cells were transduced with retrovirus containing a vector carrying KRASG12 isoforms. Platinum-E cells (Cell Biolabs) were used for retroviral packaging. Retrovirus was added to Ba / F3 cells. To ensure infection, 4 μg / mL polybrene was added and the infected cells were spun down. Infection efficiency was confirmed by measuring GFP-positive cells using a cell analyzer. Cells with an infection efficiency of 10% to 20% were further cultured and selection was initiated with 1 μg / mL puromycin. As a control, parental Ba / F3 cells were used to demonstrate the selection status. Selection was considered successful when the parental Ba / F3 cell culture died. To assess the transforming potential of the KRASG12 mutation, the growth medium was no longer supplemented with IL-3. Ba / F3 cells harboring an empty vector were used as a control. Approximately ten days before conducting the experiment, the puromycin was removed.

[1597] For proliferation analysis, Ba / F3 cells were cultured in growth medium (RPMI-1640 + 10% FCS) at a concentration of 1.5 × 10 3 Cells / 60 μl were seeded into 384-well plates. Compounds were added using an AccessLabcyte workstation with a Labcyte Echo 550 or 555 acoustic dispenser. All treatments were performed in technical replicates. Treated cells were incubated at 37°C and 5% CO2 for 72 h. AlamarBlue was added. TM (ThermoFisher), a viability stain, and fluorescence was measured in a PerkinElmer Envision HTS Multilabel Reader. Raw data were imported into and analyzed using Boehringer Ingelheim proprietary software MegaLab (curve fitting based on the program PRISM, GraphPad Inc.).

[1598] IC of representative compounds according to the invention measured using this assay 50 The values ​​are presented in Table 75.

[1599] Table 75

[1600]

[1601]

[1602]

[1603]

[1604]

[1605]

[1606]

[1607]

[1608] Additional proliferation analysis using mutant cancer cell lines

[1609] NCI-H358 CTG proliferation assay (120 hours) (NSCLC, G12C)

[1610] NCI-H358 cells (ATCC No. CRL-5807) were plated at a density of 2000 cells / well in 100 μL RPMI-1640 ATCC-formulation (Gibco No. A10491) + 10% FCS (fetal calf serum) in a white opaque 96-well plate (Perkin Elmer Catalog No. 5680) (Assay 1) or at a density of 200 cells / well in 60 μL RPMI-1640 ATCC-formulation (Gibco No. A10491) + 10% FCS (fetal calf serum) in a flat and clear bottom black 384-well plate (Greiner, PNr. 781091) (Assay 2). The cells were incubated overnight at 37° C. in a humidified tissue culture incubator under 5% CO 2 . Compounds (10 mM stock in DMSO) were added in a logarithmic dose series using an HP Digital Dispenser D300 (Tecan) (Assay 1) or an ECHO Acoustic Liquid Handling System (Beckman Coulter) (Assay 2), normalized to the added DMSO and including a DMSO control. For T0 time point measurements, untreated cells were analyzed at the time of compound addition. The plates were incubated for 120 hours and cell viability was measured using the CellTiter-Glo Luminescent Cell Viability Reagent (Promega product code G7570). Viability (stated as a percentage of the control) was defined as the relative luminescence units (RLU) of each well divided by the RLU of the cells in the DMSO control. IC was determined from viability measurements by nonlinear regression using a four-parameter model. 50 value.

[1611] NCI-H2122 CTG proliferation assay (120h) (NSCLC, G12C)

[1612] The CTG assay was designed to quantitatively measure the proliferation of NCI-H2122 cells (ATCC CRL-5985) using the CellTiter Glow assay kit (Promega G7571). Cells were grown in RPMI medium (ATCC) supplemented with fetal bovine serum (Life Technologies, Gibco BRL, catalog number 10270-106). On "Day 0," 200 NCI-H2122 cells were seeded in 60 μL of RPMI ATCC + 10% FCS + Penstrep in a flat, clear-bottomed black 384-well plate (Greiner, PNr. 781091). The cells were then incubated in the plates overnight at 37°C in a CO2 incubator. On Day 1, compounds (10 mM stock in DMSO) were added using an ECHO Acoustic Liquid Handling System (Beckman Coulter), including a DMSO control. The plates were incubated for 120 hours and cell viability was measured using the CellTiter-Glo Luminescent Cell Viability Reagent (Promega product code G7570). Viability (stated as a percentage of the control) was defined as the relative luminescence units (RLU) of each well divided by the RLU of cells in the DMSO control. IC was determined from viability measurements by nonlinear regression using a four-parameter model. 50 value.

[1613] AsPC-1 CTG analysis (120h) (pancreatic cancer, G12D)

[1614] The CTG assay was designed to quantitatively measure the proliferation of AsPC-1 cells (ATCC CRL-5985) using the CellTiter Glow assay kit (Promega G7571). Cells were grown in RPMI medium (ATCC) supplemented with fetal bovine serum (Life Technologies, Gibco BRL, catalog number 10270-106). On "Day 0," 2,000 AsPC-1 cells were seeded in 60 μL of RPMI ATCC + 10% FCS + Penstrep in a flat, clear-bottomed 384-well plate (Greiner, PNr. 781091). The cells were then incubated in the plates overnight at 37°C in a CO2 incubator. On Day 1, compounds (10 mM stock in DMSO) were added using an ECHO Acoustic Liquid Handling System (Beckman Coulter), including a DMSO control. The plates were incubated for 120 hours and cell viability was measured using the CellTiter-Glo Luminescent Cell Viability Reagent (Promega product code G7570). Viability (stated as a percentage of the control) was defined as the relative luminescence units (RLU) of each well divided by the RLU of cells in the DMSO control. IC was determined from viability measurements by nonlinear regression using a four-parameter model. 50 value.

[1615] GP2D proliferation assay (120h) (colorectal cancer, G12D)

[1616] GP2D cells (ATCC No. CRL-5807) were plated at a density of 500 cells / well into flat, white-bottomed, white 384-well plates (Perkin Elmer, 6007680) in 40 μl of DMEM (Sigma, D6429) + 1× GlutaMAX (Gibco, 35050038) + 10% FCS (fetal calf serum). Cells were incubated overnight at 37°C in a humidified tissue culture incubator under 5% CO2. Compounds (10 mM stock in DMSO) were added in a logarithmic dose series using an HP Digital Dispenser D300 (Tecan), including a DMSO control and normalized to added DMSO. For T0 time point measurements, untreated cells were analyzed at the time of compound addition. Plates were incubated for 120 hours, and cell viability was measured using the CellTiter-Glo Luminescent Cell Viability Reagent (Promega product code G7570). Viability (stated as a percentage of control) was defined as the relative luminescence units (RLU) of each well divided by the RLU of cells in the DMSO control. IC was determined from viability measurements by nonlinear regression using a four-parameter model. 50 value.

[1617] SAS CTG proliferation assay (120 hours) (HNSCC, wt expansion)

[1618] SAS cells (JCRB0260) were plated at a density of 300 cells / well in 60 μL of DMEM:F12 (Gibco 31330-038) + 10% fetal bovine serum (HyClone, PNr.: SH30084.03) in a flat, clear-bottomed 384-well plate (Greiner, PNr. 781091) and incubated overnight at 37°C in a CO2 incubator. The following day, compounds (10 mM stock in DMSO), including a DMSO control, were added using an ECHO acoustic liquid handling system (Beckman Coulter). The plates were incubated for 120 hours, and cell viability was measured using the CellTiter-Glo Luminescent Cell Viability Reagent (Promega product code G7570). Viability (stated as a percentage of the control) was defined as the relative luminescence units (RLU) of each well divided by the RLU of cells in the DMSO control. IC values ​​were determined from viability measurements using a four-parameter model by nonlinear regression. 50 value.

[1619] MKN1 CTG proliferation assay (120 hours) (gastric cancer, wt amplification)

[1620] MKN1 cells (JCRB0252) were plated at a density of 400 cells / well in 50 μL RPMI 1640 (PAN-Biotech, PNr.: P04-18047) + 10% FCS (HyClone, PNr.: SH30084.03) in a flat and white bottom 384-well plate (Corning Costar, PNr.: 3570) (Assay 1) or at a density of 500 cells / well in 40 μL RPMI (Gibco, PNr.: 21875034) + 10% FCS (HyClone, PNr.: SH30084.03) in a flat and white bottom 384-well plate (Perkin Elmer, 6007680). Cells were plated at a density of 200 cells / well in 60 μl of RPMI-1640 (Gibco No. A10491) + 10% FCS (HyClone, PNr.: SH30084.03) + PenStrep (Gibco, PNr. 15140-122) in a flat, clear-bottomed black 384-well plate (Greiner, PNr. 781091) (Assay 3). Cells were incubated overnight at 37°C in a humidified tissue culture incubator under 5% CO2. Compounds (10 mM stock in DMSO) were added in a logarithmic dose series using an HP Digital Dispenser D300 (Tecan) (Assays 1+2) or an ECHO Acoustic Liquid Handling System (Beckman Coulter) (Assay 3). A DMSO control was included and normalized to the added DMSO. The plates were incubated for 120 hours and cell viability was measured using the CellTiter-Glo Luminescent Cell Viability Reagent (Promega product code G7570). Viability (stated as a percentage of the control) was defined as the relative luminescence units (RLU) of each well divided by the RLU of cells in the DMSO control. IC was determined from viability measurements by nonlinear regression using a four-parameter model. 50 value.

[1621] SK-CO-1CTG proliferation assay (120h) (CRC, G12V)

[1622] SK-CO-1 cells (ATCC HTB-39) were plated at a density of 500 cells / well in 60 μL EMEM (Sigma M5650) + 10% fetal bovine serum (HyClone, PNr.: SH30084.03) in a flat, clear-bottomed 384-well plate (Greiner, PNr. 781091) and incubated overnight at 37°C in a CO2 incubator. The following day, compounds (10 mM stock in DMSO), including a DMSO control, were added using an ECHO acoustic liquid handling system (Beckman Coulter). The plates were incubated for 120 hours, and cell viability was measured using the CellTiter-Glo Luminescent Cell Viability Reagent (Promega product code G7570). Viability (stated as a percentage of the control) was defined as the relative luminescence units (RLU) of each well divided by the RLU of cells in the DMSO control. IC values ​​were determined from viability measurements using a four-parameter model by nonlinear regression. 50 value.

[1623] LOVO CTG proliferation assay (120h) (CRC, G13D)

[1624] LOVO cells (ATCC CCL-229) were plated at a density of 1000 cells / well in 60 μL of DMEM (Sigma D6429) + 10% fetal bovine serum (HyClone, PNr.: SH30084.03) in a flat, clear-bottomed 384-well plate (Greiner, PNr. 781091) and incubated overnight at 37°C in a CO2 incubator. The following day, compounds (10 mM stock solution in DMSO), including a DMSO control, were added using an ECHO acoustic liquid handling system (Beckman Coulter). The plates were incubated for 120 hours, and cell viability was measured using the CellTiter-Glo Luminescent Cell Viability Reagent (Promega product code G7570). Viability (stated as a percentage of the control) was defined as the relative luminescence units (RLU) of each well divided by the RLU of cells in the DMSO control. IC values ​​were determined from viability measurements using a four-parameter model by nonlinear regression. 50 value.

[1625] A375 CTG proliferation assay (120 hours) (melanoma, wt, B-Raf mutant, negative control)

[1626] A375 cells (ATCC CRL-1619) were plated at a density of 300 cells / well in 60 μL of DMEM (Sigma D6429) + 10% fetal bovine serum (HyClone, PNr.: SH30084.03) in a flat, clear-bottomed 384-well plate (Greiner, PNr. 781091) and incubated overnight at 37°C in a CO2 incubator. The following day, compounds (10 mM stock in DMSO) were added in a logarithmic dose series using an HP Digital Dispenser D300 (Tecan), including a DMSO control. Plates were incubated for 120 hours, and cell viability was measured using the CellTiter-Glo Luminescent Cell Viability Reagent (Promega product code G7570). Viability (stated as a percentage of the control) was defined as the relative luminescence units (RLU) of each well divided by the RLU of cells in the DMSO control. The IC was determined from the viability measurements by nonlinear regression using a four-parameter model. 50 value. ...

Claims

1. A compound of formula (I) in R 1a and R 1b are independently selected from the group consisting of: hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, halogen, -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, C 3-5 Cycloalkyl and 3-5 membered heterocyclic group; R 2a and R 2b are independently selected from the group consisting of: hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, halogen, -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, C 3-5 Cycloalkyl and 3-5 membered heterocyclic group; and / or optionally R 1a or R 1b One of them and R 2a or R 2b One of them, together with the carbon atom to which it is attached, forms a cyclopropane ring; Z is -(CR 6a R 6b ) n -; Each R 6a and R 6b are independently selected from the group consisting of: hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, halogen, -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, C 3-5 Cycloalkyl and 3-5 membered heterocyclic group; or R 6a and R 6b Together with the carbon atom to which it is attached, it forms a cyclopropane ring; n is selected from the group consisting of 0, 1 and 2; R 3 Selected from the group consisting of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -N3, C 3-10 Cycloalkyl, 3-11 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic group, C 6-10 All aryl and 5-10 membered heteroaryl groups are optionally and independently substituted with one or more identical or different R 7 and / or R 8 replace; Each R 7 Independently selected from the group consisting of: -OR 8 、-NR 8 R 8 , halogen, -CN, -C(=O)R 8 、-C(=O)OR 8 、-C(=O)NR 8 R 8 、-NHC(=O)OR 8 and a divalent substituent =O; Each R 8 are independently selected from the group consisting of: hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic group, C 6-10 All aryl and 5-10 membered heteroaryl groups are optionally substituted with one or more identical or different R 9 and / or R 10 replace; Each R 9 Independently selected from the group consisting of: -OR 10 、-NR 10 R 10 and -C(O)NR 10 R 10 ; Each R 10 are independently selected from the group consisting of: hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl and 5-10 membered heteroaryl, wherein the C 1-6 The alkyl group is optionally substituted with a substituent selected from the group consisting of: 1-6 Alkoxy, C 3-10 Cycloalkyl and optionally C 1-6 an alkyl-substituted 3-11-membered heterocyclic group; W is nitrogen (-N=) or -CH=; V is nitrogen (-N=) or -CH=; U is nitrogen (-N=) or -C (R 11 )=; R 11 is selected from hydrogen, halogen and C 1-4 Alkoxy; Ring A is a ring selected from the group consisting of pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole and triazole; If present, each R 4 Independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, cyano-C 1-6 Alkyl, halogen, -OH, -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, -CN, C 3-5 Cycloalkyl and 3-5 membered heterocyclic group; p is selected from the group consisting of 0, 1, 2 and 3; R 5 is optionally substituted by one or more identical or different C 1-6 Alkyl, C 1-6 alkoxy or 5-6 membered heterocyclic substituted 3-11 membered heterocyclic group, wherein C 1-6 The alkyl group is optionally substituted with a cyclopropyl group; or R 5 -OC substituted by a 3-11 membered heterocyclic group 1-6 Alkyl, wherein the 3-11 membered heterocyclic group is optionally substituted by one or more identical or different R 12 replace, Each R 12 Choose from C 1-6 Alkyl, C 1-6 The group consisting of alkoxy, halogen and 3-11 membered heterocyclic group; or a salt thereof.

2. A compound of formula (Ia) or a salt thereof in A, V, U, W, R 3 and R 5 As defined in claim 1.

3. A compound of formula (Ib) or a salt thereof in A, V, U, W, R 3 and R 5 As defined in claim 1.

4. The compound or salt thereof according to any one of claims 1 to 3, wherein Ring A is selected from and 5. The compound or salt thereof according to any one of claims 1 to 4, wherein R 3 Selected from the group consisting of: 3-11 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein 3-11 membered heterocyclic group, C 6-10 All aryl and 5-10 membered heteroaryl groups are optionally and independently substituted with one or more identical or different R 7 and / or R 8 replace; Each R 7 Independently selected from the group consisting of: -OH, C 1-6 Alkoxy, -NR 8 R 8 , halogen, -CN, -C(=O)R 8 、-C(=O)OR 8 、-C(=O)NR 8 R 8 、-NHC(=O)OR 8 and a divalent substituent =O; Each R 8 are independently selected from the group consisting of: hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic group, C 6-10 All aryl and 5-10 membered heteroaryl groups are optionally substituted with one or more identical or different R 9 and / or R 10 replace; Each R 9 Independently selected from the group consisting of: -OR 10 、-NR 10 R 10 and -C(O)NR 10 R 10 ; Each R 10 are independently selected from the group consisting of: hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclyl and 5-10 membered heteroaryl, wherein the C 1-6 The alkyl group is optionally substituted with a substituent selected from the group consisting of: 1-6 Alkoxy, C 3-10 Cycloalkyl and optionally C 1-6 Alkyl-substituted 3- to 11-membered heterocyclic group.

6. The compound or salt thereof according to any one of claims 1 to 5, wherein R 3 Selected from the group consisting of 3-11 membered heterocyclyl and 5-10 membered heteroaryl, wherein the 3-11 membered heterocyclyl and 5-10 membered heteroaryl are all optionally and independently substituted with one or more identical or different R 7 and / or R 8 replace; Each R 7 Independently selected from the group consisting of: -OR 8 、-NR 8 R 8 , halogen, -CN, -C(=O)R 8 、-C(=O)OR 8 、-C(=O)NR 8 R 8 、-NHC(=O)OR 8 and a divalent substituent =O; Each R 8 are independently selected from the group consisting of: hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic group, C 6-10 All aryl and 5-10 membered heteroaryl groups are optionally substituted with one or more identical or different R 9 and / or R 10 replace; Each R 9 -OH or C 1-6 Alkoxy; Each R 10 Independently selected from the group consisting of: C 1-6 alkyl, 3-11 membered heterocyclyl and 5-10 membered heteroaryl.

7. The compound or salt thereof according to any one of claims 1 to 6, wherein R 5 Selected from the group consisting of: and 8. The compound according to claim 7 or a salt thereof, wherein R 5 Selected from the group consisting of: and 9. The compound or salt thereof according to any one of claims 1 to 8, wherein W is nitrogen (-N=); V is nitrogen (-N=) U = C(R 11 )-; R 11 is selected from hydrogen, halogen and C 1-4 Alkoxy.

10. The compound or salt thereof according to any one of claims 1 to 9, wherein R 3 Selected from the group consisting of: and Each of the groups is bonded to formula (I) at any ring position by removing a hydrogen atom and is optionally and independently connected via one or more identical or different R 7 and / or R 8 Replace, where Each R 7 Independently selected from the group consisting of: -OR 8 、-NR 8 R 8 , halogen, -CN, -C(=O)R 8 、-C(=O)OR 8 、-C(=O)NR 8 R 8 、-NHC(=O)OR 8 and a divalent substituent =O; Each R 8 are independently selected from the group consisting of: hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-11 membered heterocyclic group, C 6-10 All aryl and 5-10 membered heteroaryl groups are optionally substituted with one or more identical or different R 9 and / or R 10 replace; Each R 9 -OH or C 1-6 Alkoxy; Each R 10 Independently selected from the group consisting of: C 1-6 alkyl, 3-11 membered heterocyclyl and 5-10 membered heteroaryl.

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