2,4-Dioxotetrahydropyrimidinyl Derivatives as Degrons in PROTACs

Abstract

The present invention provides a series of 2,4-dioxotetrahydropyrimidinyl derivatives that bind to cereblon and their application as degrons in PROTACs. Androgen receptor PROTACs containing 2,4-dioxotetrahydropyrimidinyl-containing degrons and medical uses of these PROTACs are also disclosed. [Formula 1] JPEG2025510074000390.jpg90162

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention provides a series of 2,4-dioxotetrahydropyrimidinyl derivatives that bind to cereblon and their application as degrons in PROTACs. Androgen receptor PROTACs containing 2,4-dioxotetrahydropyrimidinyl-containing degrons and medical uses of these PROTACs are also disclosed. [Background technology]

[0002] Background of the Invention The ubiquitin proteosome pathway (UPS) is a pathway for the degradation of regulatory proteins as well as misfolded or abnormal proteins. This is achieved by post-translational modification of substrate proteins with the covalent attachment of ubiquitin. The covalent attachment of ubiquitin to specific protein substrates is achieved by the action of E3 ubiquitin ligases. Over 500 E3 ubiquitin ligases are known. One such E3 ubiquitin ligase is cereblon. Cereblon (CRBN) forms a complex with damaged DNA-binding protein 1 (DDB1), cullin-4A (CUL4A), and regulator of cullin 1 (ROC1). This complex recognizes natural protein substrates, catalyzes the addition of ubiquitin, and targets the substrate for destruction.

[0003] The PROteolysis Targeting Chimeric (PROTAC) approach hijacks the UPS to degrade proteins that are not normally substrates. PROTAC compounds typically consist of three parts: a target-binding moiety designed to bind to a target protein, an E3 ligase-binding moiety capable of recruiting a degron complex capable of ubiquitinating the target protein, and a linker connecting these two parts. Upon binding to the target, the PROTAC generates a ternary complex containing all the components necessary to ubiquitinate the target, leading to its ubiquitination and subsequent degradation.

[0004] Cereblon is the molecular target of immunomodulatory drugs such as thalidomide, lenalidomide, and pomalidomide. These drugs have been widely used as E3 ligase binding moieties in PROTAC compounds. WO2022069520 discloses compounds that are said to be cereblon binding moieties.

[0005] The PROTAC approach is a generally applicable principle, and it is reasonable to expect that PROTACs capable of degrading specific targets can be found using effective target-binding moieties and linkers known in the art. Nevertheless, it has become clear that not all PROTACs have equivalent activity in vitro or in vivo. This is due to several reasons, including differences in intestinal absorption, intracellular absorption, pharmacokinetics, and the ability of PROTAC molecules to form functional ternary complexes (a prerequisite for target ubiquitination and degradation). Furthermore, for reasons that are not entirely clear, differences in target selectivity have been observed among PROTACs. Thus, while the PROTAC approach is one of general applicability, it is not appropriate to view them as modular molecules, and it is clear that optimization is possible through modification of each PROTAC component.

[0006] Androgens normally exert their biological effects by binding to the androgen receptor (AR). In the absence of androgen, the AR is bound to heat shock protein 90 (Hsp90) in the cytoplasm, covering a nuclear localization signal (NLS). When androgen binds to the AR, it induces a conformational change that leads to the release of Hsp90, exposing the NLS. The AR then translocates into the nucleus, where it acts as a transcription factor (Endocrin Rev. 1987, 8(1): 1-28; Mol Endocrinol. 2002, 16(10), 2181-7).

[0007] Androgens have long been known to be involved in prostate carcinogenesis. Evidence comes from several sources. First, androgens induce prostate cancer in rodent animal models (Noble, Cancer Res., 37, 1929-1933 (1977)). Second, men receiving androgens in the form of anabolic steroids have a high incidence of prostate cancer (Roberts and Essenhigh, Lancet, 2, 742 (1986)), and prostate cancer does not develop after castration (Wilson and Roehrborn, J Clin Endrocrin Metab, 84, 4324-4331, 1999). Finally, the most compelling and only effective treatment available for advanced prostate cancer is androgen removal, also known as androgen deprivation therapy (ABT), androgen suppression therapy (ADT), or chemical castration. However, most patients develop resistance and the disease progresses (Huber et al. 1987, Scan J Urol 104, 33-39).

[0008] Castration-resistant prostate cancer cells undergo alterations that allow them to survive under castrate levels of androgen. These mechanisms include overexpression of AR, altered androgen biosynthesis, expression of constitutively active AR splice variants, altered androgen cofactors, and expression of mutant forms of AR. For example, gain-of-function mutations in the ligand-binding domain of AR, such as L702H, W742C, W742L, H875Y, and T878A, can alter ligand-binding affinity, resulting in increased sensitivity to steroid ligands or converting antiandrogens into agonists. The T878A mutation is associated with resistance to abiraterone acetate and hydroxyflutamide. The L702H mutation is associated with receptor promiscuity, i.e., increased AR sensitivity to glucocorticoids.

[0009] Thus, AR is a critical driver of prostate cancer tumorigenesis, including castration-resistant prostate cancer, and its ablation should result in therapeutically beneficial responses.

[0010] In addition to their role in prostate cancer, androgens also play a role in other diseases. One example is ovarian cancer, where elevated androgen levels are associated with an increased risk of developing the disease (Helzlsouer et al., JAMA 274, 1926-1930 (1995), Edmondson et al., Br J Cancer 86, 879-885 (2002)). In fact, androgen receptors have been detected in the majority of ovarian cancers (Risch, J. Natl. Cancer Inst., 90, 1774-1786, 1998; Rao and Slotman, Endocr Rev., 12, 14-26, 1991; Clinton and Hua, Crit Rev Oncol., Hematol., 25, 1-9, 1997). Summary of the Invention

[0011] Summary of the Invention In a first aspect, the present invention provides a compound of formula (I), a tautomer of a compound of formula (I), or a salt thereof: [ka] [In the formula, X1 is N or CR 2 where R 2 is hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, -CONR 5 R 6 and -(CONR 3 R 4 )m(L)p(TBM)q; X4 is CR 7 or N, where R 7 is hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 selected from the group consisting of alkoxy; X2 and X3 are independently selected from N or CH; X 15 and X 22 is independently selected from N or C; R 3 and R 4 together with the nitrogen atom to which they are attached form a monocyclic or spirocyclic nitrogen-containing heterocycle, or R 3 is H or C 1-4 alkyl, and R 4 is -(CH2) n R 28 where R 28 is a monocyclic or spirocyclic nitrogen-containing heterocyclic ring; n is 0 or 1; R 5 and R 6 are independently hydrogen or C 1-4 alkyl; R 1 is C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 alkoxy or a group of formula (II), wherein * represents the point of attachment to the compound of formula (I): [ka] a and b are independently 0 or 1; X 16 is N or CH; X 17 is CR 34 R 35 where R 34 and R 35 together with the carbon atoms to which they are attached form a cyclobutyl ring, or R 34 is -(CHR 36 )r-, or a bond to the compound of formula (I), and R 35 is hydrogen or halogen; X 25 is CR 12 R 13 or O; r is 0, 1 or 2; a is 0, 1, or 2, and b and j are independently 0 or 1, provided that b and j cannot both be 0; R 36 is hydrogen or methyl; R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from hydrogen or halogen; L is a chemical linker; TBM is the target binding moiety; m, p and q are independently 0 and 1; where X 15 If N, then X 22 is C; where X1 is -(CONR 3 R 4 )m(L)p(TBM)q, then R 1 is C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 It is alkoxy. to provide.

[0012] For the avoidance of doubt, the dashed-dotted line in the 5,6-bicyclic ring structure represents an aromatic structure.

[0013] The pair of one dotted line and one solid line in the six-membered monocyclic ring may be a single bond or a double bond.

[0014] In one embodiment, the present invention provides a compound of formula (I), a tautomer of a compound of formula (I), or a salt thereof: [ka] [In the formula, X1 is N or CR 2 where R 2 is hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C1-4 Alkoxy, -CONR 5 R 6 and -CONR 3 R 4 (L)p(TBM)q; X4 is CR 7 or N, where R 7 is hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 selected from the group consisting of alkoxy; X2 and X3 are independently selected from N or CH; X 15 and X 22 is independently selected from N or C; R 3 and R 4 together with the nitrogen atom to which they are attached form a monocyclic or spirocyclic nitrogen-containing heterocyclic ring, or R 3 is H or C 1-4 alkyl, and R 4 is -(CH2) n R 28 where R 28 is a monocyclic or spirocyclic nitrogen-containing heterocyclic ring; n is 0 or 1; R 5 and R 6 are independently H or C 1-4 alkyl; R 1 is C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 alkoxy or a group of formula (II), wherein * represents the point of attachment to the compound of formula (I): [ka] a and b are independently 0 or 1; X 16 is N or CH; X 17 is CR34 R 35 where R 34 and R 35 together with the carbon atoms to which they are attached form a cyclobutyl ring, or R 34 is -(CHR 36 )- or a bond to the compound of formula (I), and R 35 is H or a halogen; R 36 is hydrogen or methyl; R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from H or halogen; L is a chemical linker; TBM is the target binding moiety; p and q are independently 0 and 1; where X 15 If N, then X 22 is C; where X1 is -CONR 3 R 4 If (L)p(TBM)q, then R 1 is C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 It is alkoxy. to provide.

[0015] The compound of formula (I), or a tautomer thereof, or a salt thereof, wherein p and q are each 0, is a degron capable of binding to cereblon. When incorporated into a PROTAC, the degron can recruit a complex that can ubiquitinate a target protein.

[0016] In certain embodiments, the present invention provides degrons or tautomers thereof of formula (Iaa), (Ibb), and (Icc), or salts thereof, wherein X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, 15 , X16 , X 22 , X 25 , R 1 , R 3 , R 4 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 35 , R 36 , a, b, m, j, k, l and r are as defined for formula (I), and X 18 is CR 35 .1. [ka]

[0017] In another embodiment, the present invention provides a PROTAC comprising a degron of formula (I), (Iaa), (Ibb), or (Icc), or a tautomer thereof. A compound of formula (I), or a tautomer thereof, or a salt thereof, wherein p is 1, is a "PROTAC."

[0018] In certain embodiments, the present invention provides PROTACs in which the target-binding moiety is an androgen receptor binding moiety. Pharmaceutical compositions and medical uses of androgen receptor PROTACs are also provided. DETAILED DESCRIPTION OF THE INVENTION

[0019] Detailed Description of the Invention definition The term "alkyl" refers to a linear or branched monovalent saturated hydrocarbon radical having the specified number of carbon atoms. For example, "C 1-4 The term "alkyl" refers to an alkyl group having 1 to 4 carbon atoms. Exemplary groups include, but are not limited to, methyl, ethyl, propyl (n-propyl and isopropyl), and butyl (n-butyl, sec-butyl, isobutyl, and tert-butyl).

[0020] The term "alkoxy" refers to an -O-alkyl group, i.e., an alkyl group attached through an oxygen linking atom, where "alkyl" is defined above. For example, "C 1-4 The term "alkoxy" refers to an alkoxy group having 1 to 4 carbon atoms. Exemplary groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, isobutoxy, and t-butoxy.

[0021] The term "cycloalkyl" refers to a non-aromatic saturated monocyclic hydrocarbon ring containing the specified number of carbon atoms. For example, C 3-6 Cycloalkyl contains 3 to 6 carbon atoms as ring members. 3-6 Examples of cycloalkyl include, but are not limited to, cyclobutyl, cyclopentyl, and cyclohexyl. The term "cycloalkylene" specifically refers to a divalent cycloalkyl ring.

[0022] The terms "halogen" and "halo" refer to a chloro, fluoro, bromo, or iodo substituent.

[0023] The term "haloalkyl" is intended to mean a radical having one or more halogen atoms, which may be the same or different, at one or more carbon atoms of the alkyl group, where "alkyl" is defined above. Exemplary groups include, but are not limited to, -CF3 (trifluoromethyl), -CCl3 (trichloromethyl), 1,1-difluoroethyl, 2,2,2-trifluoroethyl, and hexafluoroisopropyl.

[0024] The term "heteroaryl" refers to a group or moiety comprising an aromatic monovalent monocyclic or bicyclic radical containing 5 to 10 ring atoms, including at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. The term also encompasses bicyclic heterocyclic aryl compounds containing a fused aryl ring moiety and a heterocycloalkyl ring moiety, each containing 5 to 10 ring atoms, including at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. The number of ring atoms can be specified. For example, a "6-membered heteroaryl" is a heteroaryl monocycle, as defined above, consisting of 6 ring atoms. The presence of specific heteroatoms can also be specified. For example, a "6-membered nitrogen-containing heteroaryl" is a 6-membered heteroaryl, as defined above, containing at least one nitrogen atom. Examples of 6-membered nitrogen-containing heteroaryl groups include pyridinyl, pyridazinyl, pyrazinyl, and pyrimidinyl. The term "heteroarylene" specifically refers to a divalent heteroaryl group.

[0025] The term "heterocycle" refers to a saturated or unsaturated 3- to 10-membered monocyclic or bicyclic ring that must contain at least one heteroatom selected from nitrogen, oxygen, and sulfur. A heterocycle may contain one or more C(O), S(O), or SO groups. Bicyclic heterocycles may be fused, bridged, or spiro bicyclic groups. However, heterocycles are not aromatic. Heterocycles containing more than one heteroatom may contain different heteroatoms. The number of ring atoms can be specified. For example, a "6-membered heterocycle" is a heterocycle as defined above consisting of six ring atoms. The presence of a particular heteroatom can also be specified. For example, a "6-membered nitrogen-containing heterocycle" is a 6-membered heterocycle as defined above containing at least one nitrogen atom. Exemplary 6-membered nitrogen-containing heterocycles include, but are not limited to, piperidinyl, piperazinyl, morpholinyl, morpholinyl-3-one, piperidyl-2-one, and pyrimidinyl-2,4(1H,3H)-dione. The term heterocyclene specifically refers to a divalent heterocycle.

[0026] The term "target binding moiety" refers to a chemical moiety capable of binding to a target protein, particularly a protein of therapeutic importance. The nature of the target is not limited, other than that it must be an intracellular protein or a protein comprising an intracellular domain.

[0027] Description of the Invention In a first aspect, the present invention provides a compound of formula (I), a tautomer of a compound of formula (I), or a salt thereof: [ka] [In the formula, X1 is N or CR 2 where R 2 is hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, -CONR 5 R 6 and -(CONR 3 R 4 )m(L)p(TBM)q; X4 is CR 7 or N, where R 7 is hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 selected from the group consisting of alkoxy; X2 and X3 are independently selected from N or CH; X 15 and X 22 is independently selected from N or C; R 3 and R 4 together with the nitrogen atom to which they are attached form a monocyclic or spirocyclic nitrogen-containing heterocyclic ring, or R 3 is H or C 1-4 alkyl, and R 4 is -(CH2) n R 28 where R 28is a monocyclic or spirocyclic nitrogen-containing heterocyclic ring; n is 0 or 1; R 5 and R 6 are independently hydrogen or C 1-4 alkyl; R 1 is C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 alkoxy or a group of formula (II), wherein * represents the point of attachment to the compound of formula (I): [ka] a and b are independently 0 or 1; X 16 is N or CH; X 17 is CR 34 R 35 where R 34 and R 35 together with the carbon atoms to which they are attached form a cyclobutyl ring, or R 34 is -(CHR 36 )r-, or a bond to the compound of formula (I), and R 35 is hydrogen or halogen; X 25 is CR 12 R 13 or O; r is 0, 1 or 2; a is 0, 1, or 2, and b and j are independently 0 or 1, provided that b and j cannot both be 0; R 36 is hydrogen or methyl; R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from hydrogen or halogen; L is a chemical linker; TBM is the target binding moiety; m, p and q are independently 0 and 1; where X 15 If N, then X 22 is C; where X1 is -(CONR 3 R 4 )m(L)p(TBM)q, then R 1 is C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 It is alkoxy. to provide.

[0028] The compound of formula (I) or its tautomer or salt thereof may be a degron or a PROTAC depending on the values ​​of p and q. A PROTAC is a compound or salt thereof that contains a degron, a target-binding moiety, and optionally a linker. The "building blocks" of a PROTAC are further described below.

[0029] In one embodiment, q is 1 and p is 0 or 1.

[0030] In one embodiment, m is 1.

[0031] In one embodiment, X1 is N or CR 2 where R 2 is hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, and -CONR 5 R 6 is selected from the group consisting of:

[0032] Degron When p and q are both 0, the compound of formula (I) or its tautomer is a degron capable of binding to the E3 ligase cereblon.

[0033] The present invention relates to a compound of formula (Iaa), a tautomer of a compound of formula (Iaa), or a salt thereof: [ka] [In the formula, X1 is N or CR 2 where R 2 is hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and -CONR 5 R 6 selected from the group consisting of: X4 is CR 7 or N, where R 7 is hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 selected from the group consisting of alkoxy; X2 and X3 are independently selected from N or CH; X 15 and X 22 is independently selected from N or C; r is 0, 1 or 2; a is 0, 1, or 2, and b and j are independently 0 or 1, provided that b and j cannot both be 0; X 16 is N or CH; X 18 is CR 35 where R 35 is hydrogen or halogen; X 25 is CR 12 R 13 or O; R 5 and R 6 are independently hydrogen or C 1-4 alkyl; R 8 , R 9 , R 10 , R 11 , R 12 , R 13, R 14 , R 15 and R 35 are independently selected from hydrogen or halogen; R 36 is hydrogen or methyl; where X 15 If N, then X 22 is C.] Degron is provided.

[0034] In more specific embodiments, the present invention provides a compound of formula (Iaaa), a tautomer of a compound of formula (Iaaa), or a salt thereof: [ka] [In the formula, X1 is N or CR 2 where R 2 is hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and -CONR 5 R 6 selected from the group consisting of: X4 is CR 7 or N, where R 7 is hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 selected from the group consisting of alkoxy; X2 and X3 are independently selected from N or CH; X 15 and X 22 is independently selected from N or C; r is 0, 1 or 2; a is 0, 1, or 2, and b and j are independently 0 or 1, provided that b and j cannot both be 0; X 16 is N or CH; X 18 is CR 35 where R 35is hydrogen or halogen; X 25 is CR 12 R 13 or O; R 5 and R 6 are independently hydrogen or C 1-4 alkyl; R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 35 is independently selected from H or halo; R 36 is hydrogen or methyl; where X 15 If N, then X 22 is C.] Degron is provided.

[0035] In one embodiment of the compound of Formula (Iaa) or (Iaaa) or a tautomer thereof or a salt thereof, X1 is N or CR 2 where R 2 is hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, and -CONR 5 R 6 is selected from the group consisting of:

[0036] In one embodiment of the compounds of Formula (Iaa) or (Iaaa) or a tautomer thereof or a salt thereof, R 2 is selected from hydrogen and halo.

[0037] In one embodiment of the compounds of formula (Iaa) or (Iaaa) or a tautomer thereof or a salt thereof, X 22 is N. In certain embodiments, X 22 is N, and one or more of X1, X2, X3, and X4 are also N.

[0038] In one embodiment of the compounds of formula (Iaa) or (Iaaa) or a tautomer thereof or a salt thereof, X 15 is C.

[0039] In one embodiment of the compounds of Formula (Iaa) or (Iaaa) or a tautomer thereof or a salt thereof, X 1 is N or CH.

[0040] In another embodiment of the compound of Formula (Iaa) or (Iaaa) or a tautomer thereof or a salt thereof, X1 is CR 2 where R 2 is selected from the group consisting of CF, F, or Cl. In more particular embodiments, X is CR 2 where R 2 is selected from the group consisting of F or Cl.

[0041] In one embodiment of the compound of Formula (Iaa) or (Iaaa) or a tautomer thereof or a salt thereof, X4 is CR 7 In a more particular embodiment, X4 is CR 7 where R 7 is F, Cl or CF. In one embodiment, X4 is CR 7 where R 7 is F. In another embodiment, X4 is CH. In another embodiment, X4 is N.

[0042] In one embodiment of the compounds of formula (Iaa) or (Iaaa) or a tautomer thereof or a salt thereof, X 22 is N and X1 is CR 2 where R 2 is H, halogen or C 1-4 haloalkyl, X2 and X3 are both CH, and X4 is CR 7 where R 7 is hydrogen or halogen, and X 15 is C. In more particular embodiments, X 22is N, and X1, X2, X 3、 X4 is CH, and X 15 is C.

[0043] In certain embodiments, X 22 is N, X1, X2, X3, and X4 are CH, and X 15 is C; a, b, and j are not all 1, or r is 1.

[0044] X 22 is N, X1, X2, X3, and X4 are CH, and X 15 In one embodiment where is C, the compound of Formula (Iaa) or (Iaaa) is not 1-(1-(piperidin-4-yl)-1H-indol-4-yl)dihydropyrimidine-2,4-(1H,3H)-dione.

[0045] In another embodiment, X 22 and X2 is N and X1 is CR 2 where R 2 is H, halogen or C 1-4 haloalkyl, X3 is CH, and X4 is CR 7 where R 7 is hydrogen or halogen, and X 15 is C. In another embodiment, X 22 is N, X1, X3 and X4 are each CH, and X 15 is C and X2 is N. In a further embodiment, X 22 is N, X1 is N, X2, X3 and X4 are each CH, and X 15 is C. In another embodiment, X 22 is N, X1 and X2 are each N, X3 and X4 are each CH, and X 15 is C. In another embodiment, X 22 is N, X2 and X4 are each N, X1 and X3 are each CH, and X 15 is C. In one embodiment, X22 is N, X3 and X4 are N, and CR 2 where R 2 is H, halogen, X2 is CH, X 15 is C. In another embodiment, X 22 is N, X3 and X4 are each N, X1 and X2 are each CH, and X 15 is C. In another embodiment, X 22 is N, X2 and X3 are each N, X1 and X4 are each CH, and X 15 is C. In another embodiment, X 22 is N, X4 is N, X1, X2 and X3 are each CH, and X 15 is C. In another embodiment, X 22 is N, X3 is N, X1, X2 and X4 are each CH, and X 15 is C.

[0046] In another embodiment of the compounds of formula (Iaa) or (Iaaa) or tautomers thereof or salts thereof, X and X 15 is N, X1, X3 and X4 are each CH, and X 22 is C.

[0047] In one embodiment of the compounds of Formula (Iaa) or (Iaaa) or a tautomer thereof or a salt thereof, R 35 is CH.

[0048] In one embodiment of the compound of Formula (Iaa) or (Iaaa) or a tautomer thereof or a salt thereof, r is 0 or 1. In one embodiment of the compound of Formula (Iaa) or a tautomer thereof or a salt thereof, r is 0. In another embodiment, r is 1 and R 36 is H. In another embodiment, r is 1 and R 36 is methyl.

[0049] In another embodiment of the compound of Formula (Iaa) or (Iaaa) or a tautomer thereof or a salt thereof, r is 2 and each R 36 is H.

[0050] In one embodiment of the compounds of formula (Iaa) or (Iaaa) or a tautomer thereof or a salt thereof, X 16 is N.

[0051] In one embodiment of the compounds of formula (Iaa) or (Iaaa) or a tautomer thereof or a salt thereof, X 25 is CR 12 R 13 is.

[0052] In one embodiment of the compound of formula (Iaa) or (Iaaa) or a tautomer thereof or a salt thereof, j is 1 and a and b are independently 0 or 1. In a more particular embodiment, X 16 is N and X 25 is CR 12 R 13 wherein j is 1, and a and b are independently 0 or 1.

[0053] In one embodiment of the compound of Formula (Iaa) or (Iaaa) or a tautomer thereof or a salt thereof, a, b, and j are each 1; and X 16 is CH or N, and X 25 is CR 12 R 13 In more particular embodiments, a, b, and j are all 1, and X 16 is N and X 25 is CR 12 R 13 In another embodiment, a, b, and j are all 1, and X 16 is CH and X 25 is CR 12 R 13 is.

[0054] In one embodiment of the compound of Formula (Iaa) or (Iaaa) or a tautomer thereof or a salt thereof, a is 0, b and j are each 1, and X 16 is N and X 25 is CR 12 R 13 is.

[0055] In one embodiment of the compound of Formula (Iaa) or (Iaaa) or a tautomer thereof or a salt thereof, a and b are both 0, j is 1, and X 16 is CH and X 25 is CR 12 R 13 is.

[0056] In another embodiment of the compound of Formula (Iaa) or (Iaaa) or a tautomer thereof or a salt thereof, a and b are both 0, j is 1, and X 16 is N and X 25 is CR 12 R 13 is.

[0057] In one embodiment of the compound of Formula (Iaa) or (Iaaa) or a tautomer thereof or a salt thereof, a is 2, b is 0, j is 1, and X 16 is N and X 25 is CR 12 R 13 is.

[0058] In one embodiment of the compound of Formula (Iaa) or (Iaaa) or a tautomer thereof or a salt thereof, a is 2, b is 0, j is 1, and X 16 is N and X 25 is O.

[0059] In one embodiment of the compounds of Formula (Iaa) or (Iaaa) or a tautomer thereof or a salt thereof, R 8 , R 9 , R 10 , R 11 , R 12 , R13 , R 14 , R 15 and R 35 is independently selected from H or fluoro. In another embodiment, R 8 , R 9 and R 35 are independently selected from H or halo, and R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are each H. In more particular embodiments, R 8 and R 9 are independently selected from H or fluoro; R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 35 are each H. In another embodiment, R 12 , R 13 and R 35 are independently selected from H or halo, and R 8 , R 9 , R 10 , R 11 , R 14 and R 15 are each H. In more particular embodiments, R 12 and R 13 are independently selected from H or fluoro; R 8 , R 9 , R 10 , R 11 , R 14 , R 15 and R 35 are each H. In more particular embodiments, R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are H and R 35 is H or fluoro.

[0060] In certain embodiments of compounds of Formula (Iaa) or (Iaaa) or tautomers thereof or salts thereof, X 22 is N and X1 is CR 2 where R 2 is H, halogen or C 1-4 haloalkyl, X2 and X3 are both CH, and X4 is CR 7 where R 7 is hydrogen or halogen, and X 15 is C and r is 1 or 2.

[0061] In certain embodiments of compounds of Formula (Iaa) or (Iaaa) or tautomers thereof or salts thereof, X 22 is N and X1 is CR 2 where R 2 is H, halogen or C 1-4 haloalkyl, X2 and X3 are both CH, and X4 is CR 7 where R 7 teeth hydrogen or halogen, X 15 is C and a, b, and j are not 1.

[0062] In certain embodiments of compounds of Formula (Iaa) or (Iaaa) or tautomers thereof or salts thereof, X 22 is N and X1 is CR 2 where R 2 is H, halogen or C 1-4 haloalkyl, X2 and X3 are both CH, and X4 is CR 7 where R 7 is hydrogen or halogen, and X 15 is C, r is 1 or 2, and a, b, and j are not 1.

[0063] The present invention relates to a compound of formula (Ibb), a tautomer of a compound of formula (Ibb), or a salt thereof: [ka] [In the formula, R 1 is C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 Alkoxy, wherein said C 1-4 An alkyl group is one C 1-4 optionally substituted with an alkoxy group; X2 and X3 are independently selected from N or CH; X 15 and X 22 is independently selected from N or C; X4 is CR 7 or N, where R 7 is hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 selected from the group consisting of alkoxy; R 3 and R 4 together with the nitrogen atom to which they are attached form a monocyclic or spirocyclic nitrogen-containing heterocyclic ring, or R 3 is H or C 1-4 alkyl, and R 4 is -(CH2) n R 28 where R 28 is a monocyclic or spirocyclic nitrogen-containing heterocyclic ring; m is 0 or 1; n is 0 or 1; where X 15 If N, then X 22 is C.] Degron is provided.

[0064] In one embodiment, the present invention provides a compound of formula (Ibbb), a tautomer of a compound of formula (Ibbb), or a salt thereof: [ka] [In the formula, R 1 is C 1-4 Alkyl, C1-4 Haloalkyl or C 1-4 Alkoxy, wherein said C 1-4 An alkyl group is one C 1-4 optionally substituted with an alkoxy group; X2 and X3 are independently selected from N or CH; X 15 and X 22 is independently selected from N or C; X4 is CR 7 or N, where R 7 is hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 selected from the group consisting of alkoxy; R 3 and R 4 together with the nitrogen atom to which they are attached form a monocyclic or spirocyclic nitrogen-containing heterocyclic ring, or R 3 is H or C 1-4 alkyl, and R 4 is -(CH2) n R 28 where R 28 is a monocyclic or spirocyclic nitrogen-containing heterocyclic ring; m is 0 or 1; n is 0 or 1; X 15 If N, then X 22 is C.] Degron is provided.

[0065] In one embodiment of the compound of Formula (Ibb) or (Ibbb) or a tautomer thereof or a salt thereof, m is 1. In another embodiment of the compound of Formula (Ibb) or (Ibbb) or a tautomer thereof or a salt thereof, m is 0.

[0066] In one embodiment of the compound of formula (Ibb) or (Ibbb) or a tautomer thereof or a salt thereof, R 1 is one C 1-4C optionally substituted with an alkoxy group 1-4 In more particular embodiments of compounds of formula (Ibb) or (Ibbb) or tautomers thereof or salts thereof, R 1 is C 1-4 In a more particular embodiment, R 1 is methyl, ethyl, or isopropyl. In more particular embodiments, R 1 is ethyl or isopropyl. In one embodiment, R 1 is isopropyl.

[0067] In one embodiment of the compound of formula (Ibb) or (Ibbb) or a tautomer thereof or a salt thereof, X 22 is N.

[0068] In one embodiment of the compounds of Formula (Ibb) or (Ibbb) or a tautomer or a salt thereof, X2 is CH.

[0069] In one embodiment of the compounds of Formula (Ibb) or (Ibbb) or a tautomer or a salt thereof, X3 is CH.

[0070] In one embodiment of the compound of formula (Ibb) or (Ibbb) or a tautomer thereof or a salt thereof, X 15 is C.

[0071] In one embodiment of the compound of Formula (Ibb) or (Ibbb) or a tautomer thereof or a salt thereof, X4 is CR 7 where R 7 is F, Cl or CF. In one embodiment, X4 is CR 7 where R 7 is F. In another embodiment, X4 is CH. In another embodiment, X4 is N.

[0072] In one embodiment of the compound of formula (Ibb) or (Ibbb) or a tautomer thereof or a salt thereof, X 22 is N and X1 is CR 2 where R 2 is H, halogen or C 1-4 haloalkyl, X2 and X3 are both CH, and X4 is CR 7 where R 7 is hydrogen or halogen, and X 15 is C. In more particular embodiments, X 22 is N, X1, X2, X3, and X4 are CH, and X 15 is C. In another embodiment, X 22 and X2 is N and X1 is CR 2 where R 2 is H, halogen or C 1-4 haloalkyl, X3 is CH, and X4 is CR 7 where R 7 is hydrogen or halogen, and X 15 is C. In another embodiment, X 22 is N, X1, X3 and X4 are each CH, and X 15 is C and X2 is N. In a further embodiment, X 22 is N, X1 is N, X2, X3 and X4 are each CH, and X 15 is C. In another embodiment, X 22 is N, X1 and X2 are each N, X3 and X4 are each CH, and X 15 is C. In another embodiment, X 22 is N, X2 and X4 are each N, X1 and X3 are each CH, and X 15 is C. In one embodiment, X 22 is N, X3 and X4 are N, and CR 2 where R 2 is H, halogen, X2 is CH, X 15 is C. In another embodiment, X 22is N, X3 and X4 are each N, X1 and X2 are each CH, and X 15 is C. In another embodiment, X 22 is N, X2 and X3 are each N, X1 and X4 are each CH, and X 15 is C. In another embodiment, X 22 is N, X4 is N, X1, X2 and X3 are each CH, and X 15 is C. In another embodiment, X 22 is N, X3 is N, X1, X2 and X4 are each CH, and X 15 is C.

[0073] In another embodiment of the compound of formula (Ibb) or (Ibbb) or a tautomer thereof or a salt thereof, X and X 15 is N, X1, X3 and X4 are each CH, and X 22 is C.

[0074] In another embodiment of the compounds of formula (Ibb) or (Ibbb) or tautomers thereof or salts thereof, X 22 is C, X3 and X4 are each CH, and X 15 and X2 are N, respectively.

[0075] In certain embodiments of compounds of Formula (Ibb) or (Ibbb) or tautomers thereof or salts thereof, R 3 is H or C 1-4 alkyl, and R 4 (CH2) n R 28 where R 28 is a monocyclic nitrogen-containing heterocyclic ring, for example, a monocyclic 5- to 6-membered nitrogen-containing heterocyclic ring, more particularly, a monocyclic 6-membered nitrogen-containing heterocyclic ring. 3 is C 1-4 alkyl, and R 4 Ha-(CH2) n R 28 where R28 is a monocyclic nitrogen-containing heterocyclic ring, for example, a monocyclic 5- to 6-membered nitrogen-containing heterocyclic ring, more particularly, a monocyclic 6-membered nitrogen-containing heterocyclic ring. 3 is C 1-4 alkyl, and R 4 Ha-(CH2) n R 28 where R 28 is a piperidine ring (e.g., piperidin-4-yl).

[0076] In certain embodiments of compounds of Formula (Ibb) or (Ibbb) or tautomers thereof or salts thereof, R 3 and R 4 taken together with the nitrogen atom to which they are attached form a monocyclic nitrogen-containing heterocyclic ring. In one embodiment, R 3 and R 4 together with the nitrogen atom to which they are attached form a monocyclic 5- to 6-membered nitrogen-containing heterocyclic ring, more particularly a monocyclic 6-membered nitrogen-containing heterocyclic ring. 3 and R 4 taken together with the nitrogen atom to which they are attached form a piperazinyl or piperidinyl ring, more particularly a piperazinyl ring.

[0077] In certain embodiments of compounds of Formula (Ibb) or (Ibbb) or tautomers thereof or salts thereof, R 3 and R 4 taken together with the nitrogen atom to which they are attached form a spirocyclic nitrogen-containing heterocyclic ring. In one embodiment, R 3 and R 4 together with the nitrogen atom to which they are attached form a spirocyclic 10- to 11-membered nitrogen-containing heterocyclic ring.

[0078] In certain embodiments of compounds of formula (Ibb) or (Ibbb) or tautomers thereof or salts thereof, the group NR 3 R 4 has the following structure: [ka] (In the formula, the asterisk represents the bonding position to the carbonyl group, and # represents the bonding point to L.) The compound has a structure selected from:

[0079] The present invention relates to a compound of formula (Icc), a tautomer of a compound of formula (Icc), or a salt thereof: [ka] [In the formula, X1 is N or CR 2 where R 2 is hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and -CONR 5 R 6 selected from the group consisting of: X4 is CR 7 or N, where R 7 is hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 selected from the group consisting of alkoxy; X2 and X3 are independently selected from N or CH; X 15 and X 22 is independently selected from N or C; R 5 and R 6 are independently H or C 1-4 alkyl; k and l are independently selected from 0 or 1; where X 15 If N, then X 22 is C.] Degron is provided.

[0080] In one embodiment, the present invention provides a compound of formula (Iccc), a tautomer of a compound of formula (Icc), or a salt thereof: [ka] [In the formula, X1 is N or CR 2 where R 2 is hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and -CONR 5 R 6 selected from the group consisting of: X4 is CR 7 or N, where R 7 is hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 selected from the group consisting of alkoxy; X2 and X3 are independently selected from N or CH; X 15 and X 22 is independently selected from N or C; R 5 and R 6 are independently H or C 1-4 alkyl; k and l are independently selected from 0 or 1; where X 15 If N, then X 22 is C.] Degron is provided.

[0081] In one embodiment of the compound of Formula (Icc) or (Iccc) or a tautomer thereof or a salt thereof, k and l are each 1.

[0082] In another embodiment of the compound of Formula (Icc) or (Iccc) or a tautomer thereof or a salt thereof, k and l are each 0.

[0083] In one embodiment of the compound of formula (Icc) or (Iccc) or a tautomer thereof or a salt thereof, X 22is N. In certain embodiments, X 22 is N, and one or more of X1, X2, X3, and X4 are also N.

[0084] In one embodiment of the compound of formula (Icc) or (Iccc) or a tautomer thereof or a salt thereof, X 15 is C.

[0085] In one embodiment of the compound of Formula (Icc) or (Iccc) or a tautomer thereof or a salt thereof, X 1 is N or CH.

[0086] In another embodiment of the compound of Formula (Icc) or (Iccc) or a tautomer thereof or a salt thereof, X1 is CR 2 where R 2 is selected from the group consisting of CF, F, or Cl. In more particular embodiments, X is CR 2 where R 2 is selected from the group consisting of F or Cl.

[0087] In one embodiment of the compound of Formula (Icc) or (Iccc) or a tautomer thereof or a salt thereof, X4 is CR 7 In a more particular embodiment, X4 is CR 7 where R 7 is F, Cl or CF. In one embodiment, X4 is CR 7 where R 7 is F. In another embodiment, X4 is CH. In another embodiment, X4 is N.

[0088] In one embodiment of the compound of formula (Icc) or (Iccc) or a tautomer thereof or a salt thereof, R 2 is selected from hydrogen and halo.

[0089] In one embodiment of the compound of Formula (Icc) or (Iccc) or a tautomer thereof or a salt thereof, X 1 is N or CH.

[0090] In another embodiment of the compound of Formula (Icc) or (Iccc) or a tautomer thereof or a salt thereof, X1 is CR 2 where R 2 is selected from the group consisting of CF, F, or Cl. In more particular embodiments, X is CR 2 where R 2 is selected from the group consisting of F or Cl.

[0091] In one embodiment of the compound of Formula (Icc) or (Iccc) or a tautomer thereof or a salt thereof, X4 is CR 7 In a more particular embodiment, X4 is CR 7 where R 7 is F, Cl or CF. In one embodiment, X4 is CR 7 where R 7 is F. In another embodiment, X4 is CH. In another embodiment, X4 is N.

[0092] In one embodiment of the compound of formula (Icc) or (Iccc) or a tautomer thereof or a salt thereof, X 22 is N and X1 is CR 2 where R 2 is H, halogen or C 1-4 haloalkyl, X2 and X3 are both CH, and X4 is CR 7 where R 7 is hydrogen or halogen, and X 15 is C. In more particular embodiments, X 22 is N, X1, X2, X3, and X4 are CH, and X 15 is C. In another embodiment, X 22 and X2 is N and X1 is CR 2 where R 2 is H, halogen or C 1-4 haloalkyl, X3 is CH, and X4 is CR 7 where R7 is hydrogen or halogen, and X 15 is C. In another embodiment, X 22 is N, X1, X3 and X4 are each CH, and X 15 is C and X2 is N. In a further embodiment, X 22 is N, X1 is N, and X2, X3 and X4 are each CH, and X 15 is C. In another embodiment, X 22 is N, X1 and X2 are each N, X3 and X4 are each CH, and X 15 is C. In another embodiment, X 22 is N, X2 and X4 are each N, X1 and X3 are each CH, and X 15 is C. In one embodiment, X 22 is N, X3 and X4 are N, and CR 2 where R 2 is H, halogen, X2 is CH, X 15 is C. In another embodiment, X 22 is N, X3 and X4 are each N, X1 and X2 are each CH, and X 15 is C. In another embodiment, X 22 is N, X2 and X3 are each N, X1 and X4 are each CH, and X 15 is C. In another embodiment, X 22 is N, X4 is N, X1, X2 and X3 are each CH, and X 15 is C. In another embodiment, X 22 is N, X3 is N, X1, X2 and X4 are each CH, and X 15 is C.

[0093] In another embodiment of the compound of formula (Icc) or (Iccc) or a tautomer thereof or a salt thereof, X and X 15 is N, X1, X3, and X4 are CH, and X 22 is C.

[0094] Target Binding Moiety In one embodiment, the present invention relates to PROTACs using the novel degrons of the present invention, and the nature of the target is not limited, except that the target must be an intracellular protein or at least a protein comprising an intracellular domain. Many therapeutically important proteins have been well studied, with numerous compounds known to be capable of binding to them. These compounds can be used as target-binding moieties in PROTAC compounds. Examples include compounds in which the target-binding moiety is an androgen receptor-binding moiety, a RIPK2-binding moiety, and an IRAK4-binding moiety. Degradation of each of these targets has been demonstrated. This demonstrates that the nature of the target is not limited, and that the degrons of the present invention can be used to mediate the degradation of a wide variety of targets.

[0095] In one embodiment, the target is the androgen receptor. Compounds that bind to the androgen receptor are well known in the art. In one embodiment, the androgen receptor binding moiety is represented by formula (III): [ka] [In the formula, The bond position with L is indicated by an asterisk; A is selected from the group consisting of cyclohexyl, cyclobutyl, or a 6-membered nitrogen-containing heterocyclic ring, wherein said cyclohexyl, cyclobutyl, or 6-membered nitrogen-containing heterocyclic ring contains up to four C 1-4 optionally substituted with an alkyl group; B is selected from the group consisting of phenyl, a 6-membered nitrogen-containing heteroaryl group, or a fused bicyclic nitrogen-containing heterocyclic ring, wherein B is optionally substituted with one or more halogen groups; X 23 is CH or N, R 16 is selected from the group consisting of halo or CF3. It has the following structure.

[0096] In one embodiment, X 23 is CH.

[0097] In one embodiment, X 23 is N.

[0098] In one embodiment, the androgen receptor binding moiety has the structure of Formula (III), A is selected from the group consisting of cyclohexyl or cyclobutyl, wherein said cyclohexyl or cyclobutyl is selected from the group consisting of up to four C 1-4 In one embodiment, the androgen binding moiety has the structure of formula (III), A is unsubstituted cyclohexyl. In another embodiment, the androgen binding moiety has the structure of formula (III), A is unsubstituted cyclohexyl. 1-4 In another embodiment where the androgen binding moiety has the structure of Formula (III), A is cyclobutyl substituted with four methyl groups.

[0099] In one embodiment, the androgen receptor binding moiety has the structure of Formula (III), B is selected from phenyl or a 6-membered nitrogen-containing heteroaryl group, wherein the phenyl or 6-membered nitrogen-containing heteroaryl group is optionally substituted with one or more halogen groups. In one embodiment, B is selected from phenyl or a 6-membered nitrogen-containing heteroaryl group, wherein the phenyl or 6-membered nitrogen-containing heteroaryl group is unsubstituted. In one embodiment, B is phenyl, which may be substituted with one or more halogen groups. In one embodiment, B is phenyl, which is substituted with one or more fluoro groups. In one embodiment, B is unsubstituted phenyl. In another embodiment, B is selected from 6-membered nitrogen-containing heteroaryl groups, which may be substituted with one or more halogen groups. In one embodiment, B is an unsubstituted 6-membered nitrogen-containing heteroaryl group. In a more specific embodiment, B is selected from pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl. In even more particular embodiments, B is selected from pyridazin-3-yl, pyrimidin-5-yl, pyrazin-2-yl and pyridin-3-yl, where the numbering indicates the point of attachment to the carbonyl group.

[0100] In another embodiment where the androgen receptor binding moiety has the structure of Formula (III), B is a fused bicyclic nitrogen-containing heterocyclic ring optionally substituted with one or more halogen groups. In a more particular embodiment, B is a 9-10 membered fused bicyclic nitrogen-containing heterocyclic ring optionally substituted with one or more halogen groups. In one embodiment where the androgen receptor binding moiety has the structure of Formula (III), B is an unsubstituted 9-10 membered fused bicyclic nitrogen-containing heterocyclic ring. In a particular embodiment, B has the structure shown below: [ka] (where, * represents a bond to a carbonyl group, and # represents a bond to a linker.

[0101] In one embodiment of the androgen receptor binding moiety of formula (III), R 16 is chloro or CF3.

[0102] In more particular embodiments, the androgen receptor binding moiety has the structure of formula (IIIa): [ka] [In the formula, The bond position to L is indicated by an asterisk; X7, X8 and X9 are independently CH, CF or N; R 16 is selected from the group consisting of halo or CF3; R 17 , R 18 , R 19 and R 20 are independently H or C 1-4 It is alkyl. It has.

[0103] In certain embodiments of the androgen receptor binding moiety of Formula (IIIa), R 16 is chloro or CF. In certain embodiments of the androgen receptor binding moiety of Formula (IIIa), R 16 is chloro.

[0104] In certain embodiments of the androgen receptor binding moiety of Formula (IIIa), R 17 , R 18 , R 19 and R 20 is H or methyl. In one embodiment, R 17 and R 19 is methyl and R 18 and R 20 is H. In one embodiment, R 17 , R 18 , R 19 and R 20 are H respectively.

[0105] In certain embodiments of the androgen receptor binding moiety of Formula (IIIa), X7 and X8 are N and X9 is CH; or X8 and X9 are N and X7 is CH; or X7 and X9 are N and X8 is CH; or X7 is N and X8 and X9 are CH; or X8 is N and X7 and X9 are CH; or X7 is CF and X8 and X9 are CH; or X7, X8 and X9 are each CH.

[0106] In more particular embodiments of the androgen receptor binding moiety of Formula (IIIa), X7 and X8 are N and X9 is CH. In particular embodiments, X7 and X8 are N, X9 is CH, and R 17 , R 18 , R 19 and R 20 are H respectively.

[0107] In more particular embodiments of the androgen receptor binding moiety of Formula (IIIa), X7 and X9 are N and X8 is CH. In particular embodiments, X7 and X9 are N, X8 is CH, and R 17 , R 18 , R 19 and R 20 are H respectively.

[0108] In another embodiment, the androgen receptor binding moiety has the structure of Formula (IIIb): [ka] [In the formula, The bond position to L is indicated by an asterisk; X7, X8 and X9 are independently CH, CF or N; X 23 and X 24 are independently CH or N; R 16 is selected from the group consisting of halo or CF3; R 21 , R 22 , R 23 and R 24 are independently H or C 1-4 It is alkyl. It has.

[0109] The androgen receptor binding moiety of formula (IIIb) can bind to specific mutant forms of the androgen receptor.Protacs containing the androgen receptor binding moiety of formula (IIIb) show activity in the double mutant (T878A / L702H) androgen receptor degradation assay.Such protacs are expected to be useful in the treatment of castration-resistant prostate cancer.

[0110] In one embodiment, X 23 is CH.

[0111] In one embodiment, X 23 is N.

[0112] In certain embodiments of the androgen receptor binding moiety of Formula (IIIb), R 16 is chloro or CF. In certain embodiments of the androgen receptor binding moiety of Formula (IIIb), R 16 is chloro.

[0113] In certain embodiments of the androgen receptor binding moiety of Formula (IIIb), R 21 , R 22 , R 23 and R 24 are each methyl.

[0114] In certain embodiments of the androgen receptor binding moiety of Formula (IIIb), X7 and X8 are N, and X9 and X 24 is CH; or X8 and X9 are N, and X7 and X 24 is CH; or X7 and X9 are N, and X8 and X 24is CH; or X7 is N, and X8, X9 and X 24 is CH; or X8 is N, and X7, X9 and X 24 is CH; or X7 is CF, X8, X9 and X 24 is CH; or X7, X8, X9 and X 24 are CH; or X7 and X 24 is N, and X8 and X9 are CH.

[0115] In more particular embodiments of the androgen receptor binding moiety of formula (IIIb), X 23 is N, X7 and X8 are N, and X9 and X 24 is CH; or X8 and X9 are N, and X7 and X 24 is CH; or X7 is N, and X8, X9 and X 24 is CH; or X7 and X 24 is N, and X8 and X9 are CH.

[0116] In even more particular embodiments of the androgen receptor binding moiety of formula (IIIb), X 23 is N and R 21 , R 22 , R 23 and R 24 are methyl, and R 16 is chloro or CF3, X7 and X8 are N, and X9 and X 24 is CH; or X8 and X9 are N, and X7 and X 24 is CH; or X7 is N, and X8, X9 and X 24 is CH; or X7 and X 24 is N, and X8 and X9 are CH.

[0117] In another embodiment, the androgen receptor binding moiety has the structure of formula (IIIc): [ka] [In the formula, The bond position to L is indicated by an asterisk; X7, X8 and X9 are independently CH, CF or N; R 21 , R 22 , R 23 and R 24 are independently H or C 1-4 It is alkyl. It has.

[0118] In certain embodiments of the androgen receptor binding moiety of formula (IIIc), R 21 , R 22 , R 23 and R 24 are each methyl.

[0119] In certain embodiments of the androgen receptor binding moiety of Formula (IIIc), X7 and X8 are N and X9 is CH; or X8 and X9 are N and X7 is CH; or X7 and X9 are N and X8 is CH; or X7 is N and X8 and X9 are CH; or X8 is N and X7 and X9 are CH; or X7 is CF and X8 and X9 are CH; or X7, X8 and X9 are each CH.

[0120] In more particular embodiments of the androgen receptor binding moiety of formula (IIIc), X7 and X8 are N and X9 is CH; or X7 is N and X8 and X9 are CH; or X8 is N, and X7 and X9 are CH.

[0121] In another embodiment, the androgen receptor binding moiety has the structure of formula (IV): [ka] [In the formula, The bond position to L is indicated by an asterisk; R 25 is selected from the group consisting of halo or CF3; R 26 and R 27 are independently H or C 1-4 It is alkyl. It has.

[0122] In certain embodiments of the androgen receptor binding moiety of formula (IV), R 25 is chloro or CF. In more particular embodiments, R 25 is CF3.

[0123] In certain embodiments of the androgen receptor binding moiety of formula (IV), R 26 and R 27 are each methyl.

[0124] In another embodiment, the androgen receptor binding moiety has the structure of formula (V): [ka] [In the formula, The bond position to L is indicated by an asterisk; X 13 and X 14 are independently CH or N; R 29 is selected from the group consisting of halo or CF3; R 30 , R 31 , R 32 and R 33 are independently H or C 1-4 It is alkyl. It has.

[0125] In certain embodiments of the androgen receptor binding moiety of formula (V), R 29 is chloro or CF. In more particular embodiments of the androgen receptor binding moiety of formula (VI), R 29 is chloro.

[0126] In certain embodiments of the androgen receptor binding moiety of formula (V), R 30 , R 31 , R 32 and R 33 is H or methyl. In one embodiment, R 30 and R 32 is methyl and R 31 and R 33 is H. In one embodiment, R 30 , R 31 , R 32 and R 33 are H respectively.

[0127] In certain embodiments of the androgen receptor binding moiety of formula (V), X 13 and X 14 is N; or X 13 is N and X 14 is CH.

[0128] Linker L is a chemical linker. PROTAC linkers are well known in the art and can be chemically diverse. In one embodiment, L is a chemical linker group containing a total of 1 to 50 atoms. In more specific embodiments, L contains 1 to 30 atoms, 1 to 20 atoms, or 10 to 20 atoms. In one embodiment, L is a group in which one or more carbon atoms are -O-, -NH-, -NCH3-, -CO-, phenylene, 5- to 6-membered heteroarylene, C 4-6 A hydrocarbon chain substituted with cycloalkylene and 4- to 6-membered heterocyclylene, wherein the hydrocarbon chain or the phenyl, 5- to 6-membered heteroaryl, C4-6 The carbon atoms in cycloalkyl and 4- to 6-membered heterocyclic rings are oxo, C 1-3 Alkyl, C 1-3 Alkoxy, OH, halogen, NH2, NH(C 1-3 alkyl), N(C 1-3 It may be substituted with one or more substituents selected from the group consisting of alkyl)2 or CN.

[0129] Suitable L group is well known in the art.Suitable L group includes, for example, those described in WO2017197055, WO2017007612, WO2015160845, WO2021077010, WO2018071606, WO2020211822, WO2020198711, WO2020160295 and WO2020214952.In addition, a wide range of linkers suitable for the development of PROTACs are commercially available from vendors including Selleck Chemicals, BroadPharm and MedChemExpress.com.

[0130] The PROTAC approach is a generally applicable principle, allowing for the identification of PROTACs capable of degrading specific targets using effective target-binding moieties without undue burden using linkers known in the art. However, it has become clear that not all PROTACs have equivalent activity in vitro or in vivo. This is due to several reasons, including differences in intestinal absorption, intracellular absorption, pharmacokinetics, and the ability of PROTAC molecules to form functional ternary complexes (a prerequisite for target ubiquitination and degradation). PROTACs can be optimized by selecting different target-binding moieties, E3 ligase binders, and also different linkers. While various linkers are expected to result in at least some degradation of the target, the length and chemical nature of L can be optimized for specific TBMs according to methods known in the art. In some cases, flexible linkers may be optimal, while for other TBMs, more rigid linkers that maintain the relative positions of the target-binding moiety and key functional groups within the degron are appropriate.

[0131] When the target binding moiety is an androgen receptor binding moiety of formula (III), (IIIa), (IIIb), (IIIc), (IV) or (V), L is a group of formula (VI): [ka] [In the formula, * represents a bond to an androgen receptor binding moiety, and # represents a bond to a compound of formula (I); D is a nitrogen-containing heterocyclic ring, which is optionally substituted with one or more substituents selected from the group consisting of methyl, halo, CF3, and CN; R 37 is methyl or hydrogen; s is 0 or 1; t is 0 or 1; u is 0 or 1; v is 0, 1 or 2; w is 0 or 1; x is 0, 1, 2, 3 or 4; where if v is 0 then u and w cannot both be 1; Here, if t is 0, then s and u cannot both be 1.] is.

[0132] In one embodiment, D is a 4-6 membered monocyclic nitrogen-containing heterocyclic ring, which is optionally substituted with one or more substituents selected from the group consisting of methyl, halo, CF3, and CN.

[0133] In another embodiment, D is a spirocyclic nitrogen-containing heterocyclic ring, wherein the spirocyclic nitrogen-containing heterocyclic ring is optionally substituted with one or more substituents selected from the group consisting of methyl, halo, CF3, and CN.

[0134] In another embodiment, D is a bridged or fused nitrogen-containing heterocyclic ring, which is optionally substituted with one or more substituents selected from the group consisting of methyl, halo, CF3, and CN. In one embodiment, the bridged or fused heterocyclic ring has a structure selected from the following structures: [ka]

[0135] In more particular embodiments, the bridged or fused heterocyclic ring has a structure selected from the following structures: [ka]

[0136] In one embodiment, R 37 is hydrogen.

[0137] In certain embodiments, L is a group of formula (VIa): [ka] [In the formula, * represents a bond to an androgen receptor binding moiety, and # represents a bond to a compound of formula (I); X 10 is CH or N; X 11 is CR 42 or N; c is 0 or 1; d is 0 or 1; s is 0 or 1; u is 0 or 1; v is 0, 1 or 2; w is 0 or 1; x is 0, 1 or 2; R 37 is H or methyl; R 38 , R 39 , R 40, R 41 and R 42 are independently selected from H, halo, methyl, CF3, and CN. is.

[0138] In certain embodiments of the group of formula (VIa), c and d are each 0; or c is 1 and d is 0; or c and d are each 1.

[0139] In one embodiment of the group of formula (VIa), R 37 is H. In another embodiment, R 37 is methyl.

[0140] In one embodiment of the group of formula (VIa), R 42 is hydrogen, methyl, fluoro, or CN. In more particular embodiments, R 42 is hydrogen.

[0141] In one embodiment of the group of formula (VIa), R 38 , R 39 , R 40 and R 41 is independently selected from H, CF3, and methyl. In more particular embodiments, R 38 , R 39 , R 40 and R 41 is independently selected from H and methyl. In more particular embodiments, R 38 , R 39 , R 40 and R 41 are H respectively.

[0142] In certain embodiments of Formula (VIa), X 10 is N and X 11 is CR 42 or N; c is 0 or 1; d is 0 or 1; s is 0; u is 0 or 1; v is 0, 1 or 2; w is 0 or 1; x is 0, 1 or 2; R 37 , R 38 , R 39 , R 40 , R 41 and R 42 is independently selected from H or methyl.

[0143] In a more particular embodiment of formula (VIa), X 10 is N and X 11 is CR 42 and; c is 1; d is 1; s is 0; u is 0 or 1; v is 0, 1 or 2; w is 0 or 1; x is an integer from 0 to 2; R 37 , R 38 , R 39 , R 40 , R 41 and R 42 is independently selected from H or methyl.

[0144] In a more particular embodiment of formula (VIa), X 10 is N and X 11 is CR 42 and; c is 1; d is 1; s is 0; u is 0 or 1; v is 0, 1 or 2; w is 0; x is 0; R 37 , R 38 , R 39 , R 40 , R41 and R 42 is independently selected from H or methyl.

[0145] In a more particular embodiment of formula (VIa), X 10 is N and X 11 is CR 42 where c is 1, d is 1; s is 0, u is 1, v is 0, w is 0, x is 0; R 38 , R 39 , R 40 , R 41 and R 42 is independently selected from H or methyl.

[0146] In a more particular embodiment of formula (VIa), X 10 is N and X 11 is CR 42 wherein c is 1, d is 1, s is 0, u is 0, v is an integer from 0 to 2, w is 0, x is 0, and R 37 , R 38 , R 39 , R 40 , R 41 and R 42 is independently selected from H or methyl. In one embodiment, v is 0. In another embodiment, v is 1. In a further embodiment, v is 2.

[0147] In a more particular embodiment of formula (VIa), X 10 is N and X 11 is CR 42 where c is 1, d is 1, s is 0, u is 0, v is 1, w is 0, x is 0, and R 37 , R 38 , R 39 , R 40 , R 41 and R 42 are H respectively.

[0148] In a different embodiment of formula (VIa), X 10 is CH and X11 is CR 42 or N; c is 1; d is 1; s is 0 or 1; u is 0 or 1; v is 0 or 1; w is 0; x is 0; R 37 , R 38 , R 39 , R 40 , R 41 and R 42 is independently selected from H or methyl.

[0149] In a more particular embodiment, X 10 is CH, and X 11 is N; c is 1; d is 1; s is 0 or 1; u and v are each 1; w is 0; x is 0; R 37 , R 38 , R 39 , R 40 and R 41 is independently selected from H or methyl.

[0150] In another embodiment of formula (VIa), X 10 and X 11 are each CH, c and d are each 1, s, u, v, w and x are each 0, and R 38 , R 39 , R 40 and R 41 is independently selected from H or methyl.

[0151] In another embodiment of formula (VIa), X 10 is N and X 11 is N; c is 1; d is 1; s is 0; u is 0; v is 1 or 2; w is 1; x is 1 or 2; R 37 , R 38 , R 39 , R 40 and R 41 is independently selected from H or methyl.

[0152] In more particular embodiments, X 10 is N and X 11 is N, c and d are 1, s and u are 0, v is 2, w is 1, x is 2, and R 37 , R 38 , R 39 , R 40 and R 41 is independently selected from H or methyl.

[0153] In certain embodiments, L is a group of formula (VIb): [ka] [In the formula, * represents a bond to an androgen receptor binding moiety, and # represents a bond to a compound of formula (I); X 19 is CH or O; X 20 is CR 47 and; u is 0 or 1; v is 0, 1 or 2; w is 0 or 1; x is 0, 1 or 2; R 37 is H or methyl; R 43 , R 44 , R 45 , R 46and R 47 are independently selected from H, halo, methyl, CF3, and CN. is.

[0154] In one embodiment of the group of formula (VIb), R 37 is H. In another embodiment, R 37 is methyl.

[0155] In one embodiment of the group of formula (VIb), R 47 is hydrogen, methyl, fluoro, or CN. In more particular embodiments, R 47 is hydrogen.

[0156] In one embodiment of the group of formula (VIb), R 43 , R 44 , R 45 and R 46 is independently selected from H, CF3, and methyl. In more particular embodiments, R 43 , R 44 , R 45 and R 46 is independently selected from H and methyl. In more particular embodiments, R 43 , R 44 , R 45 and R 46 are H respectively.

[0157] In certain embodiments of Formula (VIb), X 19 is CH or O; X 20 is CH; u is 0; v is 0, 1 or 2; w is 0; x is 0; R 43 , R 44 , R 45 and R 46 is independently selected from H and methyl.

[0158] In certain embodiments, L is a group of formula (VIc): [ka] [In the formula, * represents a bond to an androgen receptor binding moiety, and # represents a bond to a compound of formula (I); X 21 is CH2 or O; e is 0 or 1; f is 0 or 1; g is 0 or 1; h is 0 or 1; u is 0 or 1; v is 0, 1 or 2; w is 0 or 1; x is 0, 1 or 2; y is 0 or 1; R 37 is H or methyl; where at least one of g, h, and y is 1.] is.

[0159] In one embodiment of the group of formula (VIc), R 37 is H. In another embodiment, R 37 is methyl.

[0160] In one embodiment of the group of formula (VIc), X 21 is CH2.

[0161] In certain embodiments of the group of formula (VIc), e, f, g, h and y are each 1; or e and f are 0 and g, h and y are 1; or e, f, g and h are 0 and y is e, g, and h are 0 and f and y are 1; or e, f, g and y are 0, and h is 1.

[0162] In one embodiment of the group of formula (VIc), u, w, and x are each 0; and v is 0 or 1.

[0163] In certain embodiments, L is a group of formula (VId): [ka] [In the formula, * represents a bond to an androgen receptor binding moiety, and # represents a bond to a compound of formula (I); s is 0 or 1; u is 0 or 1; v is 0, 1 or 2; x is 0, 1, 2, 3 or 4; R 37 is H or methyl; where if u is 1, then u is 0; Here, if v is 0, then u and w cannot both be 1.] is.

[0164] In certain embodiments of Formula (VId), s and w are both 0 and u is 1. In even more particular embodiments, the sum of v and x is 1 to 4, and thus L is * CO(CH2) 1-4 In a more particular embodiment, L is * CO(CH2)#.

[0165] In particular embodiments of Formula (VId), s is 1 and u and w are both 0. In even more particular embodiments, the sum of v and x is 3 or 4, and thus L is * O(CH2)3# or * O(CH2)4#.

[0166] In certain embodiments of Formula (VId), s, u, and w are each 0. In even more particular embodiments, the sum of v and x is 1 to 6, and thus L is * (CH2) 1-6In more particular embodiments, L is (CH2)4, (CH2)5, or (CH2)6.

[0167] In certain embodiments, the linker of formula (VId) as described herein is R 3 and R 4 can be used in compounds of formula (Ib) where, together with the nitrogen atom to which they are attached, they form a spirocyclic nitrogen-containing heterocyclic ring. More particularly, a linker of formula (VId) as described herein can be used in compounds of formula (Ib) where R 3 and R 4 together with the nitrogen atom to which they are attached, [ka] (In the formula, the asterisk represents the bonding position to the carbonyl group, and # represents the bonding point to L.) Compounds of formula (Ib) can be used that form a spirocyclic nitrogen-containing heterocyclic ring having a structure selected from the group consisting of:

[0168] In certain embodiments, a linker of formula (VId) as described herein can be used in compounds of formula (I), (Ia), and (Ib) in which the androgen bond has the structure of formula (III) and B is a fused bicyclic nitrogen-containing heterocyclyl ring. In certain embodiments, B has the structure shown below, where: * represents a bond to a carbonyl group, and # represents a bond to a linker. [ka]

[0169] When the target binding moiety is an androgen receptor binding moiety of formula (III), (IIIa), (IIIb), (IV) or (V), L is a group of formula * (CH2)zN(CH3)#, where * represents a bond to an androgen receptor binding moiety, and # represents a bond to a compound of formula (I), where z is 1, 2, 3, 4, or 5.

[0170] PROTAC Compounds of Formula (I), (Ia), and (Ib) where q is 1 are "PROTACs." The nature of the linker present in a PROTAC is determined by p. When p is 0, the linker is absent (alternatively, the linker can be considered to be a bond). When p is 1, the linker is as defined herein for L. Compounds where p is 1 but q is 0 are compounds comprising a degron and a linker. Such compounds are useful as intermediates in the production of PROTACs.

[0171] While it is convenient to mentally divide the PROTAC compounds of the present invention as consisting of a target-binding moiety, a linker, and a cereblon-binding moiety or degron, these are not individual moieties and will influence each other depending on the conformation adopted by the compound as a whole. For example, a portion of a compound falling within the definition of L may actually bind to either the target-binding moiety or cereblon, depending on the conformation of the compound as a whole. Conversely, a portion of the cereblon-binding moiety may not actually participate in binding to cereblon, depending on the conformation of the compound as a whole. Those skilled in the art will appreciate that the designation of portions of a molecule as a linker, cereblon-binding agent, or target-binding agent (androgen-binding moiety) is merely for convenience and is not intended to limit the function of these portions of the compound.

[0172] A compound of Formula (I) or a tautomer thereof or a salt thereof, wherein q is 1 and the target binding moiety is an androgen binding moiety of Formula (III), (IIIa), (IIIb), (IV), or (V), is an androgen receptor PROTAC (or a salt thereof). In certain embodiments, the compound is a compound of Formula (Ia) or a tautomer thereof or a salt thereof. In more certain embodiments, the compound is a compound of Formula (Ia) or a tautomer thereof or a salt thereof, and has an androgen binding moiety of Formula (IIIa).

[0173] In certain embodiments of the androgen receptor binding moiety of Formula (IIIa), R 16 is chloro or CF3.

[0174] In certain embodiments of the androgen receptor binding moiety of Formula (IIIa), R 17 , R 18 , R 19 and R 20 is H or methyl. In one embodiment, R 17 and R 19 is methyl and R 18 and R 20 is H. In one embodiment, R 17 , R 18 , R 19 and R 20 are H respectively.

[0175] In certain embodiments of the androgen receptor binding moiety of Formula (IIIa), X7 and X8 are N and X9 is CH; or X8 and X9 are N and X7 is CH; or X7 and X9 are N and X8 is CH; or X7 is N and X8 and X9 are CH; or X8 is N and X7 and X9 are CH; or X7 is CF and X8 and X9 are CH; or X7, X8 and X9 are each CH.

[0176] In more particular embodiments of the androgen receptor binding moiety of Formula (IIIa), X7 and X8 are N and X9 is CH. In particular embodiments where X7 and X8 are N and X9 is CH, R 17 , R 18 , R 19 and R 20 are H respectively.

[0177] In certain embodiments, the present invention provides a compound of formula (VII), a tautomer of a compound of formula (VII), or a salt thereof: [ka] [In the formula, X1 is N or CR 2 where R 2 is hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and -CONR 5 R 6 selected from the group consisting of: X4 is CR 7 or N, where R 7 is hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 selected from the group consisting of alkoxy; X2 and X3 are independently selected from N or CH; X 15 and X 22 is independently selected from N or C; X 16 is N or CH; X 18 is CR 35 where R 35 is H or halo; a and b are independently 0 or 1; r is 0 or 1; R 5 and R 6 are independently H or C 1-4 alkyl; R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 35 is independently selected from H or halo; R 36is hydrogen or methyl; X 10 is CH or N; X 11 is CR 34 or N, where R 34 is hydrogen or halo; c is 0 or 1; d is 0 or 1; R 37 is H or methyl; R 38 , R 39 , R 40 , R 41 and R 42 is independently selected from H, halo, methyl, CF3, and CN; s is 0 or 1; u is 0 or 1; v is 0, 1 or 2; X7, X8 and X9 are independently CH, CF or N; R 16 is selected from the group consisting of halo or CF3; R 17 , R 18 , R 19 and R 20 are independently H or C 1-4 is alkyl; where X 15 If N, then X 22 is CH.] to provide.

[0178] In one embodiment of the compound of formula (VII) or a tautomer thereof or a salt thereof, R 2 is selected from hydrogen and halo.

[0179] In one embodiment of the compound of formula (VII) or a tautomer or a salt thereof, X 1 is N or CH.

[0180] In another embodiment of the compound of formula (VII) or a tautomer thereof or a salt thereof, X1 is CR 2where R 2 is selected from the group consisting of CF, F, or Cl. In more particular embodiments, X is CR 2 where R 2 is selected from the group consisting of F or Cl.

[0181] In one embodiment of the compound of formula (VII) or a tautomer or a salt thereof, X4 is CR 7 In a more particular embodiment, X4 is CR 7 where R 7 is F, Cl or CF. In one embodiment, X4 is CR 7 where R 7 is F. In another embodiment, X4 is CH. In another embodiment, X4 is N.

[0182] In one embodiment of the compound of formula (VII) or a tautomer thereof or a salt thereof, X 22 is N.

[0183] In one embodiment of the compound of formula (VII) or a tautomer thereof or a salt thereof, X 15 is C.

[0184] In certain embodiments, X 22 is N, X1, X2, X3, and X4 are CH, and X 15 is C. In another embodiment, X 22 is N, X1, X3 and X4 are each CH, and X 15 is C and X2 is N. In a further embodiment, X 22 is N, X1 is N, X2, X3 and X4 are each CH, and X 15 is C. In another embodiment, X 22 is N, X1 and X2 are each N, X3 and X4 are each CH, and X 15 is C. In another embodiment, X 22is N, X2 and X4 are each N, X1 and X3 are each CH, and X 15 is C.

[0185] In another embodiment, X and X 15 is N, X1, X3 and X4 are each CH, and X 22 is C.

[0186] In one embodiment of the compound of formula (VII) or a tautomer thereof or a salt thereof, R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 35 is independently selected from H or fluoro. In another embodiment, R 8 , R 9 and R 35 are independently selected from H or halo, and R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are each H. In more particular embodiments, R 8 and R 9 are independently selected from H or fluoro; R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 35 are each H. In more particular embodiments, R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are H and R 35 is H or fluoro.

[0187] In one embodiment of the compound of formula (VII) or a tautomer thereof or a salt thereof, r is 0. In another embodiment, r is 1 and R 36 is H. In another embodiment, r is 1 and R 36 is methyl.

[0188] In one embodiment of the compound of formula (VII) or a tautomer thereof or a salt thereof, a and b are both 1 and X 16 is CH or N. In more particular embodiments, a and b are both 1 and X 16 is N. In another embodiment, a and b are both 1 and X 16 is CH.

[0189] In one embodiment of the compound of formula (VII) or a tautomer thereof or a salt thereof, a is 0, b is 1, and X 16 is N.

[0190] In one embodiment of the compound of formula (VII) or a tautomer or a salt thereof, a and b are both 0, and X 16 is CH.

[0191] In one embodiment of the compound of formula (VII) or a tautomer thereof or a salt thereof, R 34 is hydrogen or fluoro. In more particular embodiments, R 34 is hydrogen.

[0192] In one embodiment of the compound of formula (VII) or a tautomer thereof or a salt thereof, c and d are each 0; or c is 1 and d is 0; or c and d are each 1.

[0193] In one embodiment of the compound of formula (VII) or a tautomer thereof or a salt thereof, R 37 is H. In another embodiment, R 37is methyl.

[0194] In one embodiment of the compound of formula (VII) or a tautomer thereof or a salt thereof, R 42 is hydrogen, methyl, fluoro, or CN. In more particular embodiments, R 42 is hydrogen.

[0195] In one embodiment of the compound of formula (VII) or a tautomer thereof or a salt thereof, R 38 , R 39 , R 40 and R 41 is independently selected from H, CF3, and methyl. In more particular embodiments, R 38 , R 39 , R 40 and R 41 is independently selected from H and methyl. In more particular embodiments, R 38 , R 39 , R 40 and R 41 are H respectively.

[0196] In certain embodiments of compounds of formula (VII) or tautomers thereof or salts thereof, X 10 is N and X 11 is CR 34 and; s is 0; u is 0 or 1; v is 0, 1, or 2; R 34 is hydrogen or halo.

[0197] In more particular embodiments of the compound of formula (VII) or a tautomer thereof or a salt thereof, X 10 is N and X 11 is CR 34 , s is 0, u is 1, v is 0, and R 34 is hydrogen or halo. In certain embodiments, R 34 is H.

[0198] In more particular embodiments of the compound of formula (VII) or a tautomer thereof or a salt thereof, X 10 is N and X 11 is CR 34 where s is 0, u is 0, v is an integer from 0 to 2, and R 34 is hydrogen or halo. In one embodiment, v is 0. In another embodiment, v is 1. In a further embodiment, v is 2. In certain embodiments, R 34 is H.

[0199] In different embodiments of the compound of formula (VII) or a tautomer thereof or a salt thereof, X 10 is CH and X 11 is CH or N; s is 0 or 1; u is 0 or 1; v is 0 or 1.

[0200] In a more particular embodiment, X 10 is CH and X 11 is N; s is 0 or 1; u and v are each 1.

[0201] In another embodiment of the compound of formula (VII) or a tautomer thereof or a salt thereof, X 10 and X 11 are CH, and s, u, and v are each 0.

[0202] In certain embodiments of compounds of Formula (VII) or tautomers thereof or salts thereof, R 16 is chloro or CF3.

[0203] In certain embodiments of compounds of Formula (VII) or tautomers thereof or salts thereof, R 17 , R 18 , R 19 and R 20is H or methyl. In one embodiment, R 17 and R 19 is methyl and R 18 and R 20 is H. In one embodiment, R 17 , R 18 , R 19 and R 20 are H respectively.

[0204] In certain embodiments of compounds of formula (VII) or tautomers thereof or salts thereof, X7 and X8 are N and X9 is CH; or X8 and X9 are N and X7 is CH; or X7 and X9 are N and X8 is CH; or X7 is N and X8 and X9 are CH; or X8 is N and X7 and X9 are CH; or X7 is CF and X8 and X9 are CH; or X7, X8 and X9 are each CH.

[0205] In more particular embodiments of the compound of formula (VII) or a tautomer thereof or a salt thereof, X7 and X8 are N and X9 is CH. In particular embodiments, X7 and X8 are N, X9 is CH, and R 17 , R 18 , R 19 and R 20 are H respectively.

[0206] In more particular embodiments of the compound of formula (VII) or a tautomer thereof or a salt thereof, X7 and X9 are N and X8 is CH. In particular embodiments, X7 and X9 are N, X8 is CH, and R 17 , R 18 , R 19 and R 20 are H respectively.

[0207] In certain embodiments, the present invention provides a compound of formula (XXXXV), a tautomer of a compound of formula (XXXXV), or a salt thereof: [ka] [In the formula, X1 is N or CR 2 where R 2 is hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and -CONR 5 R 6 selected from the group consisting of: X4 is CR 7 or N, where R 7 is hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 selected from the group consisting of alkoxy; X2 and X3 are independently selected from N or CH; X 15 and X 22 is independently selected from N or C, where X 15 If N, then X 22 is C; r is 0, 1 or 2; a is 0, 1, or 2, and b and j are independently 0 or 1, provided that b and j cannot both be 0; X 16 is N or CH; X 18 is CR 35 where R 35 is hydrogen or halogen; X 25 is CR 12 R 13 or O; R 5 and R 6 are independently hydrogen or C 1-4 alkyl; R 8 , R 9, R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from hydrogen or halogen; R 36 and R 37 are independently hydrogen or methyl; v is 0, 1 or 2; X7, X8 and X9 are independently CH, CF or N; X 24 is CH or N; R 16 is a halogen or CF3; R 21 , R 22 , R 23 and R 24 are independently H or C 1-4 It is alkyl. to provide.

[0208] The compound of formula (XXXXV) or its tautomer or salt thereof comprises an androgen receptor binding moiety of formula (IIIb). The androgen receptor binding moiety of formula (IIIb) can bind to certain mutant forms of the androgen receptor, including the double mutant (T878A / L702H) androgen receptor. The compound of formula (XXXXV) or its tautomer or salt thereof is expected to be useful in the treatment of castration-resistant prostate cancer.

[0209] In one embodiment of the compound of formula (XXXXV) or a tautomer thereof or a salt thereof, X 22 is N. In certain embodiments, X 22 is N, and one or more of X1, X2, X3, and X4 are also N.

[0210] In one embodiment of the compound of formula (XXXXV) or a tautomer thereof or a salt thereof, X 15 is C.

[0211] In one embodiment of the compound of Formula (XXXXV) or a tautomer or salt thereof, X 1 is N or CH.

[0212] In another embodiment of the compound of formula (XXXXV) or a tautomer or a salt thereof, X1 is CR 2 where R 2 is selected from the group consisting of CF, F, or Cl. In more particular embodiments, X is CR 2 where R 2 is selected from the group consisting of F or Cl.

[0213] In one embodiment of the compound of formula (XXXXV) or a tautomer thereof or a salt thereof, X4 is CR 7 In a more particular embodiment, X4 is CR 7 where R 7 is F, Cl or CF. In one embodiment, X4 is CR 7 where R 7 is F. In another embodiment, X4 is CH. In another embodiment, X4 is N.

[0214] In one embodiment of the compound of formula (XXXXV) or a tautomer thereof or a salt thereof, X 22 and X2 is N, X1, X3 and X4 are CH, and X 15 is C; or X 22 and X3 is N, X1, X2 and X4 are CH, and X 15 is C; or X 22 and X4 is N, X1, X2 and X3 are CH, and X 15 is C; or X 22 , X2 and X3 are N, X and X4 are CH, and X 15 is C; or X 22 , X3 and X4 are N, X1 and X2 are CH, and X15 is C; or X 22 , X2 and X4 are N, X1 and X3 are CH, and X 15 is C.

[0215] In one embodiment of the compound of formula (XXXXV) or a tautomer thereof or a salt thereof, X 18 is CH.

[0216] In one embodiment of the compound of Formula (XXXXV) or a tautomer thereof or a salt thereof, r is 0 or 1. In one embodiment of the compound of Formula (XXXXV) or a tautomer thereof or a salt thereof, r is 0. In another embodiment, r is 1 and R 36 is H. In another embodiment, r is 1 and R 36 is methyl.

[0217] In another embodiment of the compound of Formula (XXXXV) or a tautomer or salt thereof, r is 2 and each R 36 is H.

[0218] In one embodiment of the compound of formula (XXXXV) or a tautomer thereof or a salt thereof, R 35 is H.

[0219] In one embodiment of the compound of formula (XXXXV) or a tautomer thereof or a salt thereof, X 16 is N.

[0220] In one embodiment of the compound of formula (XXXXV) or a tautomer thereof or a salt thereof, X 25 is CR 12 R 13 is.

[0221] In one embodiment of the compound of formula (XXXXV) or a tautomer thereof or a salt thereof, j is 1 and a and b are independently 0 or 1. In a more particular embodiment, X 16 is N and X25 is CR 12 R 13 wherein j is 1 and a and b are independently 0 or 1. In a more particular embodiment, X 16 is N and X 25 is CR 12 R 13 where a, b, and j are each 1.

[0222] In one embodiment of the compound of Formula (XXXXV) or a tautomer thereof or a salt thereof, a is 0, b and j are each 1, and X 16 is N and X 25 is CR 12 R 13 is.

[0223] In one embodiment of the compound of formula (XXXXV) or a tautomer thereof or a salt thereof, R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 is independently selected from H or fluoro. In another embodiment, R 8 and R 9 are independently selected from H or halo, and R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are each H. In more particular embodiments, R 8 and R 9 are independently selected from H or fluoro; R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are each H. In another embodiment, R 12 and R 13 are independently selected from H or halo, and R 8 , R 9 , R 10 , R11 , R 14 and R 15 are each H. In more particular embodiments, R 12 and R 13 are independently selected from H or fluoro; R 8 , R 9 , R 10 , R 11 , R 14 and R 15 are each H. In more particular embodiments, R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are H respectively.

[0224] In certain embodiments of compounds of Formula (XXXXV) or tautomers or salts thereof, v is 1.

[0225] In certain embodiments of compounds of Formula (XXXXV) or tautomers thereof or salts thereof, R 37 is hydrogen.

[0226] In certain embodiments of compounds of Formula (XXXXV) or tautomers thereof or salts thereof, R 16 is chloro or CF. In certain embodiments of compounds of formula (XXXXV) or tautomers thereof or salts thereof, R 16 is chloro.

[0227] In certain embodiments of compounds of Formula (XXXXV) or tautomers thereof or salts thereof, R 21 , R 22 , R 23 and R 24 are each methyl.

[0228] In more particular embodiments of the compound of formula (XXXXV) or a tautomer thereof or a salt thereof, X7 and X8 are N, and X9 and X24 is CH; or X8 and X9 are N, and X7 and X 24 is CH; or X7 is N, and X8, X9 and X 24 is CH; or X7 and X 24 is N, and X8 and X9 are CH.

[0229] In certain embodiments, the present invention provides a compound of formula (XXXXVI), a tautomer of a compound of formula (XXXXVI), or a salt thereof: [ka] [In the formula, X1 is N or CR 2 where R 2 is hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and -CONR 5 R 6 selected from the group consisting of: X4 is CR 7 or N, where R 7 is hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 selected from the group consisting of alkoxy; X2 and X3 are independently selected from N or CH; X 15 and X 22 is independently selected from N or C, where X 15 If N, then X 22 is C; r is 0, 1 or 2; a is 0, 1, or 2, and b and j are independently 0 or 1, provided that b and j cannot both be 0; X 16 is N or CH; X 18 is CR 35where R 35 is hydrogen or halogen; X 25 is CR 12 R 13 or O; R 5 and R 6 are independently hydrogen or C 1-4 alkyl; R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from hydrogen or halogen; R 36 and R 37 are independently hydrogen or methyl; v is 0, 1 or 2; X7, X8 and X9 are independently CH, CF or N; R 21 , R 22 , R 23 and R 24 are independently H or C 1-4 It is alkyl. to provide.

[0230] In one embodiment of the compound of formula (XXXXVI) or a tautomer thereof or a salt thereof, X 22 is N. In certain embodiments, X 22 is N, and one or more of X1, X2, X3, and X4 are also N.

[0231] In one embodiment of the compound of formula (XXXXVI) or a tautomer thereof or a salt thereof, X 15 is C.

[0232] In one embodiment of the compound of formula (XXXXVI) or a tautomer or a salt thereof, X 1 is N or CH.

[0233] In another embodiment of the compound of formula (XXXXVI) or a tautomer or salt thereof, X1 is CR 2 where R 2 is selected from the group consisting of CF, F, or Cl. In more particular embodiments, X is CR 2 where R 2 is selected from the group consisting of F or Cl.

[0234] In one embodiment of the compound of formula (XXXXVI) or a tautomer or salt thereof, X4 is CR 7 In a more particular embodiment, X4 is CR 7 where R 7 is F, Cl or CF. In one embodiment, X4 is CR 7 where R 7 is F. In another embodiment, X4 is CH. In another embodiment, X4 is N.

[0235] In one embodiment of the compound of formula (XXXXVI) or a tautomer thereof or a salt thereof, X 22 and X2 is N, X1, X3 and X4 are CH, and X 15 is C; or X 22 and X3 is N, X1, X2 and X4 are CH, and X 15 is C; or X 22 and X4 is N, X1, X2 and X3 are CH, and X 15 is C; or X 22 , X2 and X3 are N, X and X4 are CH, and X 15 is C; or X 22 , X3 and X4 are N, X1 and X2 are CH, and X 15 is C; or X 22 , X2 and X4 are N, X1 and X3 are CH, and X 15 is C.

[0236] In one embodiment of the compound of formula (XXXXVI) or a tautomer thereof or a salt thereof, X 18 is CH.

[0237] In one embodiment of the compound of formula (XXXXVI) or a tautomer thereof or a salt thereof, r is 0 or 1. In one embodiment of the compound of formula (XXXXVI) or a tautomer thereof or a salt thereof, r is 0. In another embodiment, r is 1 and R 36 is H. In another embodiment, r is 1 and R 36 is methyl.

[0238] In another embodiment of the compound of Formula (XXXXVI) or a tautomer or salt thereof, r is 2 and each R 36 is H.

[0239] In one embodiment of the compound of formula (XXXXVI) or a tautomer thereof or a salt thereof, X 16 is N.

[0240] In one embodiment of the compound of formula (XXXXV) or a tautomer thereof or a salt thereof, X 25 is CR 12 R 13 is.

[0241] In one embodiment of the compound of formula (XXXXVI) or a tautomer thereof or a salt thereof, j is 1 and a and b are independently 0 or 1. In a more particular embodiment, X 16 is N and X 25 is CR 12 R 13 wherein j is 1 and a and b are independently 0 or 1. In a more particular embodiment, X 16 is N and X 25 is CR 12 R 13 where a, b, and j are each 1.

[0242] In one embodiment of the compound of Formula (XXXXVI) or a tautomer thereof or a salt thereof, a is 0, b and j are each 1, and X 16 is N and X 25 is CR 12 R 13 is.

[0243] In one embodiment of the compound of formula (XXXXVI) or a tautomer thereof or a salt thereof, R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 is independently selected from H or fluoro. In another embodiment, R 8 and R 9 are independently selected from H or halo, and R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are each H. In more particular embodiments, R 8 and R 9 are independently selected from H or fluoro; R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are each H. In another embodiment, R 12 and R 13 are independently selected from H or halo, and R 8 , R 9 , R 10 , R 11 , R 14 and R 15 are each H. In more particular embodiments, R 12 and R 13 are independently selected from H or fluoro; R 8 , R 9 , R 10 , R 11 , R 14and R 15 are each H. In more particular embodiments, R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are H respectively.

[0244] In certain embodiments of compounds of Formula (XXXXVI) or tautomers or salts thereof, v is 1.

[0245] In certain embodiments of compounds of Formula (XXXXVI) or tautomers thereof or salts thereof, R 37 is hydrogen.

[0246] In certain embodiments of compounds of Formula (XXXXVI) or tautomers thereof or salts thereof, R 21 , R 22 , R 23 and R 24 are each methyl.

[0247] In certain embodiments of compounds of formula (XXXXVI) or tautomers thereof or salts thereof, X7 and X8 are N and X9 is CH; or X8 and X9 are N and X7 is CH; or X7 and X9 are N and X8 is CH; or X7 is N and X8 and X9 are CH; or X8 is N and X7 and X9 are CH; or X7 is CF and X8 and X9 are CH; or X7, X8 and X9 are each CH.

[0248] In more particular embodiments of the compound of formula (XXXXVI) or a tautomer thereof or a salt thereof, X7 and X8 are N and X9 is CH; or X7 is N and X8 and X9 are CH; or X8 is N, and X7 and X9 are CH.

[0249] The compounds of formula (I), (Iaa), (Iaaa), (Ibb), (Ibbb), (Ia), (Ib), (VII), (XXXXV), and (XXXXVI) exist in tautomeric forms. The predominant form of these compounds is the lactam form (depicted in the structures). It should be understood that reference to a named or structurally depicted compound is intended to encompass all tautomeric forms of such compound.

[0250] In one embodiment, the present invention provides a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof, selected from ECB1-53 or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0251] In one embodiment, the present invention provides a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt thereof, selected from EAR1-273 or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0252] In one embodiment, the present invention provides N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide or a tautomer thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the invention provides N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide free base, or a tautomer thereof. In another embodiment, the present invention provides N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide hydrochloride, or a tautomer thereof.

[0253] In one embodiment, the present invention provides N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-indazol-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0254] In one embodiment, the present invention provides N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0255] In one embodiment, the present invention provides N-((1r,3r)-3-((5-chloro-6-cyanopyridin-3-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-indazol-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0256] In one embodiment, the present invention provides N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0257] In one embodiment, the present invention provides N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0258] In one embodiment, the present invention provides N-((1r,3r)-3-((5-chloro-6-cyanopyridin-3-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-indol-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)pyrimidine-5-carboxamide or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0259] In one embodiment, the present invention provides N-((1r,3r)-3-((5-chloro-6-cyanopyridin-3-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-indazol-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)pyrimidine-5-carboxamide or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0260] In one embodiment, the present invention provides N-((1r,3r)-3-((5-chloro-6-cyanopyridin-3-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-indazol-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)nicotinamide or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0261] In one embodiment, the present invention provides N-((1r,3r)-3-((5-chloro-6-cyanopyridin-3-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)nicotinamide or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0262] In one embodiment, the present invention provides N-((1r,3r)-3-((5-chloro-6-cyanopyridin-3-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)nicotinamide or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0263] In one embodiment, the present invention provides N-((1r,3r)-3-((5-chloro-6-cyanopyridin-3-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)nicotinamide or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0264] In one embodiment, the present invention provides N-((1r,3r)-3-((5-chloro-6-cyanopyridin-3-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidin-1-yl)methyl)piperidin-1-yl)nicotinamide or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0265] In one embodiment, the present invention provides N-((1r,3r)-3-((5-chloro-6-cyanopyridin-3-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)nicotinamide or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0266] In one embodiment, the present invention provides N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)picolinamide, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0267] In one embodiment, the present invention provides N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-indazol-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)nicotinamide or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0268] In one embodiment, the present invention provides N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0269] In one embodiment, the present invention provides N-((1r,3r)-3-((5-chloro-6-cyanopyridin-3-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0270] In one embodiment, the present invention provides N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)nicotinamide or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0271] In one embodiment, the present invention provides N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)nicotinamide or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0272] In one embodiment, the present invention provides N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)nicotinamide or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0273] In one embodiment, the present invention provides N-((1r,3r)-3-((8-cyanoquinolin-5-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)nicotinamide or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0274] In one embodiment, the present invention provides N-((1r,3r)-3-((5-chloro-6-cyanopyridin-3-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-indazol-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)pyrimidine-2-carboxamide or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0275] In one embodiment, the present invention provides N-((1r,3r)-3-((5-chloro-6-cyanopyridin-3-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)pyrimidine-2-carboxamide or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0276] In one embodiment, the present invention provides N-((1r,3r)-3-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-indazol-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)pyrimidine-2-carboxamide or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0277] In one embodiment, the present invention provides N-((1r,3r)-3-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)pyrimidine-2-carboxamide or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0278] In one embodiment, the present invention provides N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)pyrimidine-2-carboxamide or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0279] In one embodiment, the present invention provides N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)pyrimidine-2-carboxamide or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0280] In one embodiment, the invention provides a tautomer or a pharmaceutically acceptable salt.

[0281] For use in medicine, salts of PROTACs, including PROTACs of formula (VII), (XXXXV) and (XXXXVI), are preferably pharmaceutically acceptable.

[0282] Pharmaceutically acceptable salts include, in particular, those described in Berge, J. Pharm. Sci., 1977, 66, 1-19, or in P.H. Stahl and C.G. Wermuth (eds.), Handbook of Pharmaceutical Salts; Properties, Selection and Use, 2nd ed. Stahl / Wermuth: Wiley- VCH / VHCA, 2011 (see http: / / www.wiley.com / WileyCDA / WileyTitle / productCd-3906390519.html).

[0283] Suitable pharmaceutically acceptable salts include acid addition salts, which can be formed by reacting a compound of Formula (I), (Ia), (Ib), (Ic), (VII), (XXXXV) or (XXXXVI) (e.g., containing a basic amine or other basic functional group) with the appropriate acid, optionally in a suitable solvent such as an organic solvent, to provide a salt that can be isolated by various methods, including crystallization and filtration.

[0284] Salts can be prepared in situ during the final isolation and purification of a compound of Formula (I), (Ia), (Ib), (Ic), (VII), (XXXXV), or (XXXXVI). When a basic compound of Formula (I), (Ia), (Ib), (Ic), (VII), (XXXXV), or (XXXXVI) is isolated as a salt, the corresponding free base form of the compound can be prepared by any suitable method known in the art, such as treating the salt with an inorganic or organic base. Similarly, when a compound of Formula (I) containing a carboxylic acid or other acidic functional group is isolated as a salt, the corresponding free acid form of the compound can be prepared by any suitable method known in the art, such as treating the salt with an inorganic or organic acid.

[0285] Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate, disuccinate, dodecyl sulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane-1,2-disulfonate (edisylate), ), ethanesulfonate (esylate), formate, fumarate, galactarate (mucate), gentisate (2,5-dihydroxybenzoate), glucoheptonate (gluceptate), gluconate, glucuronate, glutamate, glutarate, glycerophosphorate, glycolate, hexylresorcinate, hippurate, hydrabamine (N,N'-di(dehydroabietyl)-ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methylsulfate, mucate, naphthalene-1,5-disulfonate (napadisylate), naphthalene-2-sulfonate (napsylate), nicotinate, nitrate, oleate, palmitate, p-aminobenzenesulfonate, p-aminosalicyclate, pamoate (embonate), pantothenate, pectinate, persulfate, phenylacetate, phenylethylbarbiturate, phosphate, polygalacturonate, propionate, p-toluenesulfonate (tosylate), pyroglutamate, pyruvate, salicylate, sebacate, stearate, subacetate, succinate, sulfamate, sulfate, tannate, tartrate, teoclate (8-chlorotheophylline), thiocyanate, triethiodide, undecanoate, undecylenate, and valerate salts. It will be understood that when a compound of Formula (I), (Ia), (Ib), (Ic), (VII), (XXXXV) or (XXXXVI) contains more than one basic moiety, the salt formation stoichiometry may include one, two or more equivalents of acid. Such salts may contain one, two or more acid counterions, e.g., dihydrochloride.

[0286] Also included within the scope of the present invention are stoichiometric and non-stoichiometric forms of pharmaceutically acceptable salts of compounds of formula (I), (Ia), (Ib), (Ic), (VII), (XXXXV) or (XXXXVI), including, for example, substoichiometric salts where the counterion contains more than one acidic proton.

[0287] Compound preparation process The processes utilized in preparing the compounds described herein will vary depending upon the compound desired. Factors such as the selection of specific substituents and the various possible locations of specific substituents will all play a role in the path to be followed in preparing a particular compound of this invention. These factors will be readily recognized by one of ordinary skill in the art.

[0288] In general, the compounds of the present invention can be prepared by standard techniques known in the art and known processes analogous thereto. General methods for preparing compounds of formula (Iaa), (Ibb), (III), (IV) and (V) are shown below. All starting materials and reagents described in the following general experimental schemes are commercially available or can be prepared by methods known to those skilled in the art. For completeness, it should be noted that the group L is not usually synthesized as a separate intermediate. Instead, L can be synthesized by standard techniques in the art by binding either to a compound of formula (Iaa) or (Ibb) or to a target-binding moiety, or by synthesizing one portion of L by binding to formula (Iaa) or (Ibb) and another portion of L by binding to a target-binding moiety.

[0289] Those skilled in the art will understand that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group can be removed at an appropriate point in the reaction sequence to provide a desired intermediate or target compound. Suitable protecting groups and methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art, and examples can be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd Edition), John Wiley & Sons, NY (1999). In some cases, a substituent may be specifically selected to be reactive under the reaction conditions used. In such situations, the reaction conditions convert the selected substituent into another substituent that is useful as an intermediate compound or is a desired substituent in a target compound.

[0290] General Scheme 1 shows X 16 Exemplary synthetic steps for preparing compounds of formula (Iaa) where X is N are shown in General Scheme 1. 15 , X 18 , X 22 , X 25 , R8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 36 , a, b and r are as defined for formula (Iaa), PG1 and PG2 are suitable protecting groups, L is a suitable leaving group, and Hal is Br or I. Compounds of formula (XXXXI) can be prepared by the method described in Chemistry - A European Journal (2011), 17(49), 13698-13705. It should be noted that if the amine form of compound (XVIII) is not readily available, it can be prepared by reducing the nitro form of compound (XIX) with iron in the presence of ammonium chloride. Those skilled in the art will recognize that the compound of formula (XXXXI) can be prepared by the method described in Chemistry - A European Journal (2011), 17(49), 13698-13705. 16 It will also be appreciated that compounds of formula (Iaa) where is CH may be prepared by an analogous process without the need to protect the nitrogen. Compounds of formula (Icc) may also be prepared in an analogous manner.

[0291] General Scheme 1 [ka] JPEG2025510074000036.jpg74170

[0292] When L is bromo or methylsulfonyloxy, steps (i) and (vii) may comprise treatment with sodium hydride followed by reaction of a compound of formula (IX). When L is methylsulfonyloxy, steps (i) and (vii) may alternatively comprise reaction with a compound of formula (IX) in the presence of a base such as cesium carbonate.

[0293] Step (ii) is a reductive amination reaction using acetic acid and a suitable reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride, and is carried out at a suitable temperature such as 0° C. to room temperature.

[0294] Step (iii) is a dehydrogenation reaction using a suitable oxidizing agent such as DDQ. Step (ii) is carried out in the presence of a suitable solvent such as THF at a suitable temperature such as 0° C. to room temperature.

[0295] Steps (iv) and (xiii) are amination reactions. This reaction can be catalyzed by a palladium catalyst / ligand system, such as BrettPhos Pd G3 precatalyst and BrettPhos ligand, in the presence of a suitable base, such as potassium phosphate tribasic. Alternatively, it can be catalyzed by copper(I) iodide in the presence of trans-N,N'-dimethylcyclohexane-1,2-diamine and a suitable base, such as potassium carbonate.

[0296] Steps (v) and (x) are deprotection reactions. When PG2 is a trimethylsilylethoxymethyl group, deprotection can be achieved by treatment with trifluoroacetic acid.

[0297] Steps (vi) and (ix) are also deprotection reactions. When PG1 is benzyl carboxylate, deprotection can be achieved by hydrogenation catalyzed by Pd—C10% / carbon. When PG1 is tert-butoxycarbonyl, deprotection can be achieved by treatment with trifluoroacetic acid.

[0298] Step (viii) comprises treating the compound of formula (IX) with acrylic acid followed by urea.

[0299] Step (xi) is the formation of an amide by reacting HATU with an amine in the presence of a suitable base such as DIPEA or triethylamine.

[0300] Step (xii) is a two-part reaction in which a compound of formula (XXXIII) is treated with phosphorus oxychloride followed by di-tert-butyl dicarbonate in the presence of a suitable base such as triethylamine.

[0301] General Scheme 2 is X 15 is C and X 22In General Scheme 2, X2, X3, X4, R are each independently substituted or unsubstituted, and R is substituted or unsubstituted. 3 and R 4 is as defined for formula (Ibbb), and PG3 is a suitable protecting group. X 15 is N and X 22 Compounds of formula (Ibbb) and compounds of formula (Ibb) where is C can be prepared according to processes known to those skilled in the art.

[0302] General Scheme 2 [ka]

[0303] Step (i) comprises reaction with 2-iodopropane in the presence of a suitable base such as cesium carbonate.

[0304] Step (ii) comprises the reaction of BINAP, Pd2(dba)3 with benzophenone imine in the presence of a suitable base such as cesium carbonate.

[0305] Step (iii) is a deprotection reaction when PG3 is a methyl group, which may comprise treatment with sodium hydroxide.

[0306] Step (iv) comprises treating the compound of formula (XXIII) with acrylic acid followed by urea.

[0307] Step (v) is an amide formation step by reacting HATU with an amine in the presence of a suitable base such as triethylamine or DIPEA.

[0308] General Scheme 3 shows exemplary synthetic steps for preparing compounds of formula (III). In General Scheme 3, A, B, X 23 and R 16 is as defined for formula (III), and PG4 and PG5 are suitable protecting groups.

[0309] General Scheme 3 [ka]

[0310] Step (i) is treatment with sodium hydride followed by reaction with a compound of formula (XXVI).

[0311] Step (ii) is a deprotection reaction. When PG4 is tert-butoxycarbonyl, deprotection can be achieved by treatment with an acid such as HCl or TFA.

[0312] Step (iii) is also a deprotection reaction. When PG5 is methyl or ethyl, deprotection can be achieved by treatment with an alkali such as sodium hydroxide.

[0313] Step (iv) is the formation of an amide by reacting HATU with an amine in the presence of a suitable base such as DIPEA or triethylamine. Alternatively, PyBOP may be used as a reagent in the presence of ethyl (E)-2-cyano-2-(hydroxyimino)acetate and N-methylmorpholine or OxymaPure and DIPEA.

[0314] General Scheme 4 shows exemplary synthetic steps for preparing compounds of formula (IV). In General Scheme 4, R 25 , R 26 and R 27 is as defined for formula (IV).

[0315] General Scheme 4 [ka]

[0316] Step (i) is a hydrogenation reaction. When the reaction is carried out under a hydrogen atmosphere, palladium on carbon (10% by weight) can be used as a catalyst. Alternatively, the reaction can comprise a reaction with ammonium chloride and iron.

[0317] Step (ii) is an alkylation reaction. 26 and R 27 When is methyl, this comprises reaction with methyl 2-bromo-2-methylpropanoate in the presence of a suitable base such as DIPEA.

[0318] Step (iii) is a cyclisation reaction which comprises reaction with a compound of formula (XXXIV) in the presence of a suitable solvent such as a mixture of isopropyl acetate and DMSO.

[0319] General Scheme 5 shows exemplary synthetic steps for preparing compounds of formula (V). In General Scheme 5, R 29 , R 30 , R 31 , R 32 and R 33 is as defined for formula (V).

[0320] General Scheme 5 [ka]

[0321] Step (i) is generally carried out in the presence of a suitable base, such as potassium carbonate.

[0322] Step (ii) is a deprotection reaction. When PG7 is tert-butyl carboxylate, deprotection can be achieved by treatment with an acid such as hydrochloric acid.

[0323] Step (iii) comprises reaction with phenyl carbonochloridate in the presence of a suitable base such as DIPEA.

[0324] Step (iv) is carried out in a suitable solvent such as MeCN.

[0325] Pharmaceutical Composition The PROTAC or its pharmaceutically acceptable salt of the present invention may be administered by any convenient route. In certain embodiments, the PROTAC or its pharmaceutically acceptable salt may be administered orally, parenterally, nasally, or by inhalation. In one embodiment, the PROTAC or its pharmaceutically acceptable salt is administered in a pharmaceutical composition. In one embodiment, the PROTAC or its pharmaceutically acceptable salt is formulated into a pharmaceutical composition suitable for oral or parenteral administration, or for nasal or inhalation administration. The appropriate dosage will be readily recognized by those skilled in the art.

[0326] In one aspect, the present invention provides a pharmaceutical composition comprising a PROTAC or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In another aspect, the present invention provides a process for preparing the pharmaceutical composition, comprising mixing a PROTAC or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable excipient.

[0327] Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water or water-in-oil liquid emulsions.

[0328] Pharmaceutical formulations adapted for nasal administration may consist of a coarse powder, for example having a particle size in the range of 20 to 500 microns, administered in the manner of taking snuff, i.e., by rapid inhalation through the nasal passages from a container of the powder held close to the nose. Formulations wherein the carrier is a liquid and suitable for administration as a nasal spray or nasal drops include aqueous or oil solutions of the PROTAC or a pharmaceutically acceptable salt thereof.

[0329] Pharmaceutical formulations adapted for administration by inhalation include particle dusts or mists that may be generated by means of various types of metered dose pressurized aerosols, nebulizers or insufflators.

[0330] Pharmaceutical preparations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes that render the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents. The preparations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition, requiring only the addition of a sterile liquid carrier, for example, water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may also be prepared from sterile powders, granules, and tablets.

[0331] It will be understood that the formulations described herein may include, in addition to the ingredients particularly mentioned above, other agents conventional in the art having regard to the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0332] The present invention also provides a unit pharmaceutical composition in which a PROTAC or a pharmaceutically acceptable salt thereof can be administered together with one or more other therapeutic agents. When a PROTAC or a pharmaceutically acceptable salt thereof is used in combination with a second therapeutic agent, the dose of each therapeutic agent may differ from the dose of that therapeutic agent when used alone.

[0333] medical use The compounds of formula (I), (Ia), (Ib), (Ic) or their tautomers or pharmaceutically acceptable salts thereof, in which q is 1, are capable of degrading proteins targeted by TBM. When this protein is a potential therapeutic target, the compounds of formula (I), (Ia), (Ib), (Ic) or their tautomers or pharmaceutically acceptable salts thereof, in which q is 1, are useful in medicine.

[0334] Thus, in one aspect, the present invention provides a compound of formula (I), (Ia), (Ib), (Ic) or a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein q is 1, for use in therapy.

[0335] When TBM is an androgen receptor binding moiety as described herein, the compounds of Formula (I), (Ia), (Ib) or (Ic) or their tautomers or pharmaceutically acceptable salts wherein q is 1 are useful in the treatment of cancer, benign prostatic hyperplasia, ovarian cysts, polycystic ovary syndrome or Kennedy's disease.

[0336] Thus, in one aspect, the present invention provides a compound of Formula (I), (Ia), (Ib), (Ic) or a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein q is 1 and TBM is an androgen receptor binding moiety, for use in the treatment of cancer, benign prostatic hyperplasia, ovarian cysts, polycystic ovary syndrome or Kennedy's disease.

[0337] In another embodiment, the invention provides the use of a compound of Formula (I), (Ia), (Ib), or (Ic) or a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein q is 1 and TBM is an androgen receptor binding moiety, in the manufacture of a medicament for the treatment of cancer, benign prostatic hyperplasia, ovarian cysts, polycystic ovary syndrome, or Kennedy's disease.

[0338] In another embodiment, the present invention provides a method of treating cancer, benign prostatic hyperplasia, ovarian cyst, polycystic ovary syndrome, or Kennedy's disease, comprising administering to the subject a compound of Formula (I), (Ia), (Ib), or (Ic) or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein q is 1 and TBM is an androgen receptor binding moiety.

[0339] Suitably, the subject is a mammal, hi certain embodiments, the subject is a human.

[0340] In one embodiment, the cancer is selected from prostate cancer, ovarian cancer, breast cancer, endometrial cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, and salivary gland cancer. In a more particular embodiment, the cancer is selected from prostate cancer or breast cancer.

[0341] In one embodiment, the prostate cancer is androgen-dependent prostate cancer. In another embodiment, the treatment is performed following androgen deprivation therapy. In one embodiment, the treatment is performed following abiraterone acetate or hydroxyflutamide treatment.

[0342] In more particular embodiments, prostate cancer is castration-resistant prostate cancer. In one embodiment, prostate cancer is metastatic castration-resistant prostate cancer. In another embodiment, prostate cancer is non-metastatic castration-resistant prostate cancer. In one embodiment, prostate cancer is locally advanced prostate cancer.

[0343] In one embodiment, the breast cancer is triple-negative breast cancer.

[0344] In one particular embodiment, the disorder being treated is Kennedy's disease.

[0345] When a compound of Formula (I), (Ia), (Ib) or (Ic) or a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein q is 1 and TBM is an androgen receptor binding moiety, is intended for use in the treatment of cancer, it can be used in combination with one or more additional anti-cancer agents, such as a PARP inhibitor. Thus, in one embodiment, the present invention provides a combination of a compound of Formula (I), (Ia), (Ib) or (Ic) or a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein q is 1 and TBM is an androgen receptor binding moiety, and an active pharmaceutical ingredient which is an anti-cancer agent, such as a PARP inhibitor.

[0346] Numbered Embodiments: Set 1 Embodiment 1. A compound of formula (I) or a tautomer thereof or a salt thereof: [ka] [In the formula, X1 is N or CR 2 where R 2 is hydrogen, halogen, C 1-4 Alkyl, C1-4 Haloalkyl, C 1-4 Alkoxy, -CONR 5 R 6 and -CONR 3 R 4 (L)p(TBM)q; X4 is CR 7 or N, where R 7 is hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 selected from the group consisting of alkoxy; X2 and X3 are independently selected from N or CH; X 15 and X 22 is independently selected from N or C; R 3 and R 4 together with the nitrogen atom to which they are attached form a monocyclic or spirocyclic nitrogen-containing heterocyclic ring, or R 3 is H or C 1-4 alkyl, and R 4 is -(CH2) n R 28 where R 28 is a monocyclic or spirocyclic nitrogen-containing heterocyclic ring; n is 0 or 1; R 5 and R 6 are independently H or C 1-4 alkyl; R 1 is C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 alkoxy or a group of formula (II), wherein * represents the point of attachment to the compound of formula (I): [ka] a and b are independently 0 or 1; X 16 is N or CH; X17 is CR 34 R 35 where R 34 and R 35 together with the carbon atom to which they are attached form a cyclobutyl ring, or R 34 is -(CHR 36 )- or a bond to the compound of formula (I), and R 35 is H or a halogen; R 36 is hydrogen or methyl; R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from H or halogen; L is a chemical linker; TBM is the target binding moiety; p and q are independently 0 and 1; where X 15 If N, then X 22 is CH; where X1 is -CONR 3 R 4 If (L)p(TBM)q, then R 1 is C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 It is alkoxy.

[0347] Embodiment 2. Formula (Ia): [ka] [In the formula, X1 is N or CR 2 where R 2 is hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and -CONR 5 R 6selected from the group consisting of: X4 is CR 7 or N, where R 7 is hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 selected from the group consisting of alkoxy; X2 and X3 are independently selected from N or CH; X 15 and X 22 is independently selected from N or C; X 16 is N or CH; X 18 is CR 35 where R 35 is H or halo; r is 0 or 1; R 5 and R 6 are independently H or C 1-4 alkyl; R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 35 is independently selected from H or halo; R 36 is hydrogen or methyl; L is a chemical linker; TBM is the target binding moiety; p and q are independently 0 and 1; where X 15 If N, then X 22 is CH.] or a tautomer thereof or a salt thereof, as defined in embodiment 1, wherein:

[0348] Embodiment 3. The compound of formula (Ia) or a tautomer thereof or a salt thereof as defined in embodiment 2, wherein X1 is N or CH.

[0349] Embodiment 4. X4 is CR 7 or a tautomer or a salt thereof, according to embodiment 2 or 3.

[0350] Embodiment 5. The compound of formula (Ia) or a tautomer thereof or a salt thereof as defined in embodiment 2 or 3, wherein X4 is N.

[0351] Embodiment 6. The compound of formula (Ia) or a tautomer thereof or a salt thereof according to any one of embodiments 2 to 5, wherein X2 is CH.

[0352] Embodiment 7. The compound of formula (Ia) or a tautomer thereof or a salt thereof according to any one of embodiments 2 to 6, wherein X3 is CH.

[0353] Embodiment 8. X 15 The compound of (Ia) according to any one of embodiments 2 to 7, wherein is C, or a tautomer thereof, or a salt thereof.

[0354] Embodiment 9. X 22 The compound of formula (Ia) according to any one of embodiments 2 to 8, wherein is N, or a tautomer thereof, or a salt thereof.

[0355] Embodiment 10. a and b are both 1, and X 16 The compound of formula (Ia) according to any one of embodiments 2 to 9, wherein is N, or a tautomer thereof, or a salt thereof.

[0356] Embodiment 11. 11. Compounds of formula (Ia) or tautomers or salts thereof according to any one of embodiments 2 to 10, wherein r is 0.

[0357] Embodiment 12. R 8 , R 9 and R 35 are independently selected from H or halo; R 10 , R 11 , R 12 , R 13 , R 14 and R 15 12. The compound of formula (Ia) according to any one of embodiments 2 to 11, or a tautomer thereof, or a salt thereof, wherein each is H.

[0358] Embodiment 13. Formula (Ib): [ka] [In the formula, R 1 is C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 is alkoxy; X2 and X3 are independently selected from N or CH; X 15 and X 22 is independently selected from N or C; X4 is CR 7 or N, where R 7 is hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 selected from the group consisting of alkoxy; R 3 and R 4 together with the nitrogen atom to which they are attached form a monocyclic or spirocyclic nitrogen-containing heterocyclic ring, or R 3 is H or C 1-4 alkyl, and R 4 is -(CH2) n R28 where R 28 is a monocyclic or spirocyclic nitrogen-containing heterocyclic ring; n is 0 or 1; L is a chemical linker; TBM is the target binding moiety; p and q are independently 0 and 1; where X 15 is N and X 22 is CH.] or a tautomer thereof or a salt thereof, as defined in embodiment 1, wherein:

[0359] Embodiment 14. The compound of Formula (Ib) or a tautomer thereof or a salt thereof as defined in embodiment 13, wherein X4 is N or CH.

[0360] Embodiment 15. The compound of Formula (Ib) or a tautomer thereof or a salt thereof as defined in embodiment 14, wherein X4 is CH.

[0361] Embodiment 16. 16. The compound of formula (Ib) according to any one of embodiments 13 to 15, wherein X2 is CH, or a tautomer thereof, or a salt thereof.

[0362] Embodiment 17. 17. Compounds of formula (Ib) according to any one of embodiments 13 to 16, or tautomers thereof, or salts thereof, wherein X3 is CH.

[0363] Embodiment 18. X 15 17. The compound of formula (Ib) according to any one of embodiments 13 to 16, wherein is C, or a tautomer thereof, or a salt thereof.

[0364] Embodiment 19. X 22 is N; or a tautomer or a salt thereof, of formula (Ib) according to any one of embodiments 13 to 18.

[0365] Embodiment 20. R 3 is H or C 1-4 alkyl, and R 4 -(CH2) n R 28 where R 28 Embodiment 20. The compound of Formula (Ib) according to any one of embodiments 13 to 19, wherein is a monocyclic nitrogen-containing heterocyclic ring, or a tautomer thereof, or a salt thereof.

[0366] Embodiment 21. base NR 3 R 4 But the following: [ka] (In the formula, the asterisk represents the bonding position to the carbonyl group, and # represents the bonding point to L.) or a tautomer thereof, or a salt thereof, according to any one of embodiments 13 to 19, having a structure selected from:

[0367] Embodiment 22. R 1 C 1-4 22. The compound of formula (Ib) or a tautomer or a salt thereof according to any one of embodiments 13 to 21, wherein: R is alkyl.

[0368] Embodiment 23. R 1 23. The compound of Formula (Ib) or a tautomer or a salt thereof as defined in embodiment 22, wherein is isopropyl.

[0369] Embodiment 24. 24. The compound of Formula (I), (Ia), (Ib) or a tautomer thereof or a salt thereof according to any one of embodiments 1 to 23, wherein q is 1 and TBM is an androgen receptor binding moiety.

[0370] Embodiment 25. The androgen receptor binding moiety has the structure of formula (III): [ka] [In the formula, The bond position with L is indicated by an asterisk; A is selected from the group consisting of cyclohexyl, cyclobutyl, or a 6-membered nitrogen-containing heterocyclic ring, wherein said cyclohexyl, cyclobutyl, or 6-membered nitrogen-containing heterocyclyl ring contains up to four C 1-4 optionally substituted with an alkyl group; B is selected from the group consisting of phenyl, a 6-membered nitrogen-containing heteroaryl group, or a fused bicyclic nitrogen-containing heterocyclic ring, wherein B is optionally substituted with one or more halogen groups; R 16 is selected from the group consisting of halo or CF3. 25. The compound of Formula (I), (Ia), (Ib) or a tautomer thereof or a salt thereof as defined in embodiment 24, wherein:

[0371] Embodiment 26. The androgen receptor binding moiety has the structure of formula (IIIa): [ka] [In the formula, The bond position to L is indicated by an asterisk; X7, X8 and X9 are independently CH, CF or N; R 16 is selected from the group consisting of halo or CF3; R 17 , R 18 , R 19 and R 20 are independently H or C 1-4 It is alkyl. 26. The compound of Formula (I), (Ia), (Ib) or a tautomer thereof or a salt thereof as defined in embodiment 25, having the formula:

[0372] Embodiment 27. 27. A compound of Formula (I), (Ia), (Ib) or a tautomer thereof or a salt thereof as defined in embodiment 26, wherein X7 and X8 are N and X9 is CH.

[0373] Embodiment 28. R 17 , R 18 , R 19 and R 20 28. A compound of Formula (I), (Ia), (Ib) or a tautomer or a salt thereof, as defined in embodiment 26 or 27, wherein each is H.

[0374] Embodiment 29. The androgen receptor binding moiety has the structure of formula (IIIb): [ka] [In the formula, The bond position with L is indicated by an asterisk; X7, X8 and X9 are independently CH or N; R 16 is selected from the group consisting of halo or CF3; R 21 , R 22 , R 23 and R 24 are independently H or C 1-4 It is alkyl. 26. The compound of Formula (I), (Ia), (Ib) or a tautomer thereof or a salt thereof as defined in embodiment 25, having the formula:

[0375] Embodiment 30. R 21 , R 22 , R 23 and R 24 30. A compound of Formula (I), (Ia), (Ib) or a tautomer or a salt thereof as defined in embodiment 29, wherein each is methyl.

[0376] Embodiment 31. The androgen receptor binding moiety has the structure of formula (IV): [ka] [In the formula, The bond position with L is indicated by an asterisk; R 25 is selected from the group consisting of halo or CF3; R 26 and R 27 are independently H or C 1-4 It is alkyl. 25. The compound of Formula (I), (Ia), (Ib) or a tautomer thereof or a salt thereof as defined in embodiment 24, wherein:

[0377] Embodiment 32. R 26 and R 27 A compound of Formula (I), (Ia), (Ib) or a tautomer or a salt thereof as described in embodiment 31, wherein each is methyl.

[0378] Embodiment 33. p is 1 and L is a group of formula (VI): [ka] [In the formula, * represents a bond to an androgen receptor binding moiety, and # represents a bond to a compound of formula (I); D is a nitrogen-containing heterocyclic ring, which is optionally substituted with one or more substituents selected from the group consisting of methyl, halo, CF3, and CN; R 37 is methyl or hydrogen; s is 0 or 1; t is 0 or 1; u is 0 or 1; v is 0, 1 or 2; w is 0 or 1; x is 0, 1, 2, 3 or 4; where if v is 0 then u and w cannot both be 1; Here, if t is 0, then s and u cannot both be 1.] 33. The compound of Formula (I), (Ia), (Ib) or a tautomer or salt thereof according to any one of embodiments 24 to 32, wherein:

[0379] Embodiment 34. L is a group of formula (VIa): [ka] [In the formula, * represents a bond to an androgen receptor binding moiety, and # represents a bond to a compound of formula (I); X 10 is CH or N; X 11 is CR 42 or N; c is 0 or 1; d is 0 or 1; s is 0 or 1; u is 0 or 1; v is 0, 1 or 2; w is 0 or 1; x is 0, 1 or 2; R 37 is H or methyl; R 38 , R 39 , R 40 , R 41 and R 42 are independently selected from H, halo, methyl, CF3, and CN. or a tautomer or a salt thereof, as defined in embodiment 33.

[0380] Embodiment 35. X 10 is N and X 11 is CR 42 or N; c is 0 or 1; d is 0 or 1; s is 0; u is 0 or 1; v is 0, 1, or 2; w is 0 or 1; x is 0, 1 or 2; R 37 , R 38 , R 39 , R 40 , R 41 and R 42 is independently selected from H or methyl. 35. A compound of Formula (I), (Ia), (Ib) or a tautomer or a salt thereof as defined in embodiment 34.

[0381] Embodiment 36. A pharmaceutical composition comprising a compound according to any one of embodiments 24 to 35, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0382] Embodiment 37. A compound of Formula (I), (Ia), (Ib) or a tautomer thereof or a pharmaceutically acceptable salt thereof, as defined in any one of embodiments 24 to 35, for use in the treatment of cancer, benign prostatic hyperplasia, ovarian cysts, polycystic ovary syndrome or Kennedy's disease.

[0383] Embodiment 38. The use of a compound as defined in any one of embodiments 24 to 35, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of cancer, benign prostatic hyperplasia, ovarian cysts, polycystic ovary syndrome, or Kennedy's disease.

[0384] Embodiment 39. A method of treating a disorder selected from the group consisting of cancer, benign prostatic hyperplasia, ovarian cyst, polycystic ovary syndrome, or Kennedy's disease, comprising administering to a human being in need thereof a therapeutically effective amount of a compound as defined in any one of embodiments 24 to 35, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in embodiment 36.

[0385] Embodiment 40. 24. The compound of Formula (I), (Ia), (Ib) or a tautomer thereof or a salt thereof according to any one of embodiments 1 to 23, which is not 1-(1-(piperidin-4-yl)-1H-indol-4-yl)dihydropyrimidine-2,4-(1H,3H)-dione or 1-(1-(1-methylpiperidin-4-yl)-1H-indol-4-yl)dihydropyrimidine-2,4-(1H,3H)-dione.

[0386] Embodiment 41. The compound of formula (Ia) or a tautomer thereof or a salt thereof as defined in embodiment 9, which is not 1-(1-(piperidin-4-yl)-1H-indol-4-yl)dihydropyrimidine-2,4-(1H,3H)-dione.

[0387] Numbered Embodiments: Set 2 Embodiment 1. A compound of formula (I) or a tautomer thereof or a salt thereof: [ka] [In the formula, X1 is N or CR 2 where R 2 is hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, -CONR 5 R 6 and -(CONR 3 R 4 )m(L)p(TBM)q; X4 is CR 7 or N, where R 7 is hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 selected from the group consisting of alkoxy; X2 and X3 are independently selected from N or CH; X 15 and X22 is independently selected from N or C; R 3 and R 4 together with the nitrogen atom to which they are attached form a monocyclic or spirocyclic nitrogen-containing heterocyclic ring, or R 3 is H or C 1-4 alkyl, and R 4 is -(CH2) n R 28 where R 28 is a monocyclic or spirocyclic nitrogen-containing heterocyclic ring; n is 0 or 1; R 5 and R 6 are independently H or C 1-4 alkyl; R 1 is C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 alkoxy or a group of formula (II), wherein * represents the point of attachment to the compound of formula (I): [ka] a and b are independently 0 or 1; X 16 is N or CH; X 17 is CR 34 R 35 where R 34 and R 35 together with the carbon atoms to which they are attached form a cyclobutyl ring, or R 34 is -(CHR 36 )r-, or a bond to the compound of formula (I), and R 35 is H or a halogen; r is 0, 1 or 2; a is 0, 1, or 2, and b and j are independently 0 or 1, provided that b and j cannot both be 0; R 36is hydrogen or methyl; R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from H or halogen; L is a chemical linker; TBM is the target binding moiety; m, p and q are independently 0 and 1; where X 15 If N, then X 22 is C; where X1 is -(CONR 3 R 4 )m(L)p(TBM)q, then R 1 is C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 It is alkoxy.

[0388] Embodiment 2. Formula (Ia): [ka] [In the formula, X1 is N or CR 2 where R 2 is hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and -CONR 5 R 6 selected from the group consisting of: X4 is CR 7 or N, where R 7 is hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 selected from the group consisting of alkoxy; X2 and X3 are independently selected from N or CH; X 15 and X22 is independently selected from N or C; r is 0, 1 or 2; a is 0, 1, or 2, and b and j are independently 0 or 1, provided that b and j cannot both be 0; X 16 is N or CH; X 18 is R 35 where R 35 is H or halo; R 5 and R 6 are independently H or C 1-4 alkyl; R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 35 is independently selected from H or halo; R 36 is hydrogen or methyl; L is a chemical linker; TBM is the target binding moiety; p and q are independently 0 and 1; where X 15 If N, then X 22 is CH.] or a tautomer thereof or a salt thereof, as defined in embodiment 1, wherein:

[0389] Embodiment 3. The compound of formula (Ia) or a tautomer thereof or a salt thereof as defined in embodiment 2, wherein X1 is N or CH.

[0390] Embodiment 4. X4 is CR 7 or a tautomer or a salt thereof, according to embodiment 2 or 3.

[0391] Embodiment 5. The compound of formula (Ia) or a tautomer thereof or a salt thereof as defined in embodiment 2 or 3, wherein X4 is N.

[0392] Embodiment 6. The compound of formula (Ia) or a tautomer thereof or a salt thereof according to any one of embodiments 2 to 5, wherein X2 is CH.

[0393] Embodiment 7. The compound of formula (Ia) or a tautomer thereof or a salt thereof according to any one of embodiments 2 to 6, wherein X3 is CH.

[0394] Embodiment 8. X 15 The compound of formula (Ia) according to any one of embodiments 2 to 7, wherein is C, or a tautomer thereof, or a salt thereof.

[0395] Embodiment 9. X 22 The compound of formula (Ia) according to any one of embodiments 2 to 8, wherein is N, or a tautomer thereof, or a salt thereof.

[0396] Embodiment 10. X 16 A compound of formula (Ia) or a tautomer thereof or a salt thereof according to any one of embodiments 2 to 9, wherein is N, j is 1, and a and b are independently 0 or 1.

[0397] Embodiment 11. 11. Compounds of formula (Ia) or tautomers or salts thereof according to any one of embodiments 2 to 10, wherein r is 0.

[0398] Embodiment 12. R 8 , R 9 and R 35 are independently selected from H or halo; R 10 , R 11 , R12 , R 13 , R 14 and R 15 12. The compound of formula (Ia) according to any one of embodiments 2 to 11, or a tautomer thereof, or a salt thereof, wherein each is H.

[0399] Embodiment 13. Formula (Iaaaa): [ka] or a tautomer or a salt thereof, according to any one of embodiments 2 to 12, wherein:

[0400] Embodiment 14. Formula (Ib): [ka] [In the formula, R 1 is C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 Alkoxy, wherein said C 1-4 Alkyl is one C 1-4 optionally substituted with an alkoxy group; X2 and X3 are independently selected from N or CH; X 15 and X 22 is independently selected from N or C; X4 is CR 7 or N, where R 7 is hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 selected from the group consisting of alkoxy; R 3 and R 4 together with the nitrogen atom to which they are attached form a monocyclic or spirocyclic nitrogen-containing heterocyclic ring, or R 3 is H or C 1-4 alkyl, and R 4is -(CH2) n R 28 where R 28 is a monocyclic or spirocyclic nitrogen-containing heterocyclic ring; m is 1 or 1; n is 0 or 1; L is a chemical linker; TBM is the target binding moiety; p and q are independently 0 and 1; where X 15 If N, then X 22 is CH.] or a tautomer thereof or a salt thereof, as defined in embodiment 1, wherein:

[0401] Embodiment 15. The compound of Formula (Ib) or a tautomer thereof or a salt thereof as defined in embodiment 14, wherein X4 is N or CH.

[0402] Embodiment 16. The compound of Formula (Ib) or a tautomer thereof or a salt thereof as defined in embodiment 15, wherein X4 is CH.

[0403] Embodiment 17. 17. Compounds of formula (Ib) according to any one of embodiments 14 to 16, or tautomers thereof, or salts thereof, wherein X2 is CH.

[0404] Embodiment 18. 18. Compounds of formula (Ib) according to any one of embodiments 14 to 17, or tautomers thereof, or salts thereof, wherein X3 is CH.

[0405] Embodiment 19. X 15

[0037] 19. The compound of formula (Ib) according to any one of embodiments 14 to 18, wherein is C, or a tautomer or salt thereof.

[0406] Embodiment 20. X 2220. The compound of formula (Ib) according to any one of embodiments 14 to 19, wherein is N, or a tautomer or salt thereof.

[0407] Embodiment 21. 21. Compounds of formula (Ib) or tautomers or salts thereof according to any one of embodiments 14 to 20, wherein m is 1.

[0408] Embodiment 22. R 3 is H or C 1-4 alkyl, and R 4 -(CH2) n R 28 where R 28 22. The compound of Formula (Ib) according to any one of embodiments 14 to 21, wherein is a monocyclic nitrogen-containing heterocyclic ring, or a tautomer thereof, or a salt thereof.

[0409] Embodiment 23. base NR 3 R 4 But the following: [ka] (In the formula, the asterisk represents the bonding position to the carbonyl group, and # represents the bonding point to L.) or a tautomer or salt thereof, according to any one of embodiments 14 to 21, having a structure selected from:

[0410] Embodiment 24. R 1 C 1-4 The compound of formula (Ib) or a tautomer or a salt thereof according to any one of embodiments 14 to 23, wherein R is alkyl.

[0411] Embodiment 25. R 1 The compound of Formula (Ib) or a tautomer or a salt thereof as defined in embodiment 24, wherein is isopropyl.

[0412] Embodiment 26. Formula (Ibbbb): [ka] or a tautomer or a salt thereof, of formula (Ib) according to any one of embodiments 2 to 12, wherein:

[0413] Embodiment 27. 27. The compound of Formula (I), (Ia), (Iaaaa), (Ib), (Ibbbb) or a tautomer thereof or a salt thereof according to any one of embodiments 1 to 26, wherein q is 1 and TBM is an androgen receptor binding moiety.

[0414] Embodiment 28. The androgen receptor binding moiety has the structure of formula (III): [ka] [In the formula, The bond position to L is indicated by an asterisk; A is selected from the group consisting of cyclohexyl, cyclobutyl, or a 6-membered nitrogen-containing heterocyclic ring, wherein said cyclohexyl, cyclobutyl, or 6-membered nitrogen-containing heterocyclyl ring contains up to four C 1-4 optionally substituted with an alkyl group; B is selected from the group consisting of phenyl, a 6-membered nitrogen-containing heteroaryl group, or a fused bicyclic nitrogen-containing heterocyclic ring, wherein B is optionally substituted with one or more halogen groups; R 16 is selected from the group consisting of halo or CF3. 28. The compound of formula (I), (Ia), (Iaaaa), (Ib), (Ibbbb) or a tautomer thereof or a salt thereof as defined in embodiment 27, wherein:

[0415] Embodiment 29. The androgen receptor binding moiety has the structure of formula (IIIa): [ka] [In the formula, The bond position to L is indicated by an asterisk; X7, X8 and X9 are independently CH, CF or N; R 16 is selected from the group consisting of halo or CF3; R 17 , R 18 , R 19 and R 20 are independently H or C 1-4 It is alkyl. 29. The compound of Formula (I) (Ia), (Iaaaa), (Ib), (Ibbbb) or a tautomer thereof or a salt thereof as defined in embodiment 28, wherein:

[0416] Embodiment 30. A compound of Formula (I), (Ia), (Iaaaa), (Ib), (Ibbbb) or a tautomer thereof or a salt thereof as described in embodiment 29, wherein X7 and X8 are N and X9 is CH.

[0417] Embodiment 31. R 17 , R 18 , R 19 and R 20 A compound of Formula (I), (Ia), (Iaaaa), (Ib), (Ibbbb) or a tautomer or a salt thereof, as defined in embodiment 29 or 30, wherein each is H.

[0418] Embodiment 32. The androgen receptor binding moiety has the structure of formula (IIIb): [ka] [In the formula, The bond position to L is indicated by an asterisk; X7, X8 and X9 are independently CH or N; R 16 is selected from the group consisting of halo or CF3; R 21 , R 22 , R 23and R 24 are independently H or C 1-4 It is alkyl. 29. The compound of formula (I), (Ia), (Iaaaa), (Ib), (Ibbbb) or a tautomer thereof or a salt thereof as defined in embodiment 28, wherein:

[0419] Embodiment 33. R 21 , R 22 , R 23 and R 24 A compound of Formula (I), (Ia), (Iaaaa), (Ib), (Ibbbb) or a tautomer or a salt thereof as described in embodiment 32, wherein each is methyl.

[0420] Embodiment 34. The androgen receptor binding moiety has the structure of formula (IV): [ka] [In the formula, The bond position to L is indicated by an asterisk; R 25 is selected from the group consisting of halo or CF3; R 26 and R 27 are independently H or C 1-4 It is alkyl. 28. The compound of formula (I), (Ia), (Iaaaa), (Ib), (Ibbbb) or a tautomer thereof or a salt thereof as defined in embodiment 27, wherein:

[0421] Embodiment 35. R 26 and R 27 A compound of Formula (I), (Ia), (Iaaaa), (Ib), (Ibbbb) or a tautomer or a salt thereof as described in embodiment 34, wherein each is methyl.

[0422] Embodiment 36. p is 1 and L is a group of formula (VI): [ka] [In the formula, * represents a bond to an androgen receptor binding moiety, and # represents a bond to a compound of formula (I); D is a nitrogen-containing heterocyclic ring, which is optionally substituted with one or more substituents selected from the group consisting of methyl, halo, CF3, and CN; R 37 is methyl or hydrogen; s is 0 or 1; t is 0 or 1; u is 0 or 1; v is 0, 1 or 2; w is 0 or 1; x is 0, 1, 2, 3 or 4; If v is 0, then u and w cannot both be 1; If t is 0, then s and u cannot both be 1.] or a tautomer or a salt thereof, according to any one of embodiments 27 to 35, wherein:

[0423] Embodiment 37. L is a group of formula (VIa): [ka] [In the formula, * represents a bond to an androgen receptor binding moiety, and # represents a bond to a compound of formula (I); X 10 is CH or N; X 11 is CR 42 or N; c is 0 or 1; d is 0 or 1; s is 0 or 1; u is 0 or 1; v is 0, 1 or 2; w is 0 or 1; x is 0, 1 or 2; R 37 is H or methyl; R 38 , R 39 , R 40 , R 41 and R 42 are independently selected from H, halo, methyl, CF3, and CN. 37. The compound of Formula (I), (Ia), (Ib) or a tautomer or a salt thereof as defined in embodiment 36, wherein:

[0424] Embodiment 38. X 10 is N and X 11 is CR 42 or N; c is 0 or 1; d is 0 or 1; s is 0; u is 0 or 1; v is 0, 1, or 2; w is 0 or 1; x is 0, 1 or 2; R 37 , R 38 , R 39 , R 40 , R 41 and R 42 A compound of Formula (I), (Ia), (Ib) or a tautomer or a salt thereof as defined in embodiment 37, wherein is independently selected from H or methyl.

[0425] Embodiment 39. N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide or a tautomer thereof, or a salt thereof.

[0426] Embodiment 40. A pharmaceutical composition comprising a compound according to any one of embodiments 27 to 39 or a tautomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0427] Embodiment 41. A compound of Formula (I), (Ia), (Ib) or a tautomer thereof or a pharmaceutically acceptable salt thereof, as defined in any one of embodiments 27 to 39, for use in the treatment of cancer, benign prostatic hyperplasia, ovarian cysts, polycystic ovary syndrome or Kennedy's disease.

[0428] Embodiment 42. A compound or a tautomer thereof, or a pharmaceutically acceptable salt thereof, as defined in any one of embodiments 27-39, in the manufacture of a medicament for use in the treatment of cancer, benign prostatic hyperplasia, ovarian cysts, polycystic ovary syndrome, or Kennedy's disease.

[0429] Embodiment 43. 41. A method for treating a disorder selected from the group consisting of cancer, benign prostatic hyperplasia, ovarian cyst, polycystic ovary syndrome, or Kennedy's disease, comprising administering to a human being in need thereof a therapeutically effective amount of a compound as defined in any one of embodiments 27 to 39, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in embodiment 40. [Example]

[0430] Abbreviation aq aqueous solution BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene Boc tert-butoxycarbonyl BrettPhos 2-Dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl DavePhos 2-Dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl DCE 1,2-dichloroethane DCM dichloromethane DIAD Diisopropyl azodicarboxylate DIBAL-H Diisobutylaluminum hydride DIPEA N,N-Diisopropylethylamine DDQ 2,3-dichloro-5,6-dicyano-p-benzoquinone DMA N,N-dimethylacetamide DMP Dess-Martin Periodinane DMAP 4-(dimethylamino)pyridine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EtOAc ethyl acetate EtOH ethanol FHT fixed retention time GCMS Gas Chromatography Mass Spectrometry h time HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate LCMS Liquid Chromatography Mass Spectrometry MDAP mass spectrometry automated preparative HPLC MeCN acetonitrile MeOH Methanol min MsCl methanesulfonyl chloride MTBE tert-butyl methyl ether NMP N-methyl-2-pyrrolidone NMR nuclear magnetic resonance OxymaPure 2-cyano-2-(hydroxyimino)ethyl acetate PCC Pyridinium Chloroformate Pd2(dba)3 tris(dibenzylideneacetone)dipalladium PPh3 Triphenylphosphine PyBOP (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate Pd-PEPPSI-IPent Dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) Rt retention time RT room temperature TBDMS tert-butyldimethylsilyl TBME tert-butyl methyl ether TEA Trimethylamine TFA trifluoroacetic acid THF tetrahydrofuran TMU Tetramethylurea Tosyl-Cl 4-Toluenesulfonyl chloride XantPhos Bis(diphenylphosphino)-9,9-dimethylxanthene

[0431] Purification method GCMS was performed using an Agilent 5977B MS detector on a 30 mm x 0.32 mm, 0.25 μm HP5 column.

[0432] LCMS was performed using one of the following methods. Formic Acid Method A ("Formic Acid A") LC conditions Column: 30mm x 2.1mm x 1.7μm or 50mm x 2.1mm, 1.7μm CSH C18 Temperature: 40℃ Injection volume: 0.2 or 0.3 μL Mobile phase: A = 0.1% v / v formic acid solution in water and B = 0.1% v / v formic acid solution in MeCN Flow rate=1mL / min gradient:

[0433] [Table 1]

[0434] UV detection was the sum of signals from wavelengths between 210 nm and 350 nm.

[0435] MS conditions MS: Waters QDA Ionization mode: Alternating scan positive-negative electrospray Scan range: 100~1000AMU Scanning frequency: 5Hz

[0436] Formic Acid Method B ("Formic Acid B") LC conditions Column: 30mm x 2.1mm x 3.5μm Sunfire C18 Injection volume: 0.4μL Mobile phase: A = 0.1% formic acid in water and B = 0.1% formic acid in MeCN gradient:

[0437] [Table 2]

[0438] High pH method A (“High pH A”) LC conditions Column: 30mm x 2.1mm x 1.7μm or 50mm x 2.1mm, 1.7μm CSH C18 Temperature: 40℃ Injection volume: 0.3μL Mobile phase: A = 10 mM ammonium bicarbonate in water adjusted to pH 10 with ammonia solution and B = MeCN Flow rate=1mL / min gradient:

[0439] [Table 3]

[0440] UV detection was the sum of signals from wavelengths between 210 nm and 350 nm.

[0441] MS conditions MS: Waters QDA Ionization mode: Alternating scan positive-negative electrospray Scan range: 100~1000AMU Scanning frequency: 5Hz

[0442] High pH method A (“High pH B”) LC conditions Column: 50mm x 4.6mm x 3.5μm Xbridge C8 Injection volume: 0.2μL Mobile phase: A = 10 mM ammonium bicarbonate in water and B = MeCN Flow rate=1.2mL / min gradient:

[0443] [Table 4]

[0444] TFA Act A ("TFA A") Column: 30mm x 2.1mm, 1.7μm CSH C18 Temperature: 45℃ Injection volume: 0.5μL Mobile phase: A = 0.1% v / v TFA solution in water and B = 0.1% v / v TFA solution in MeCN Flow rate=1.3mL / min gradient:

[0445] [Table 5]

[0446] UV detection was performed by averaging signals from wavelengths of 210 nm to 350 nm.

[0447] MS conditions (Waters SQD or QDa) QDa Settings: MS: Waters Acquity QDa Mass Detector Ionization mode: Alternating scan positive-negative electrospray Scan range: 100~1000AMU Target sampling frequency: 8Hz SQD Settings: MS: Waters Acquity SQD Ionization mode: Alternating scan positive-negative electrospray Scan range: 100~1000AMU Scan time: 0.1 seconds

[0448] TFA Act B (“TFA B”) Column: 50mm x 4.6mm, 5.0μm Atlantis C18 Injection volume: 2.0μL Mobile phase: A = 0.1% v / v TFA solution in water and B = MeOH Flow rate=1.0mL / min gradient:

[0449] [Table 6]

[0450] Mass spectrometric automated purification (MDAP) was performed using either of these methods. MDAP formic acid Column: 150mm x 30mm, 5μm or 75mm x 30mm, 5μm XSelect CSH C18 Mobile phase A: 0.1% v / v formic acid solution in water Mobile phase B: 0.1% v / v formic acid solution in MeCN Total flow rate: 40mL / min Temperature: Ambient temperature Injection volume: variable Instrument name: Waters MDAP UV detection parameters: 210~350nm gradient: Gradient ranging from 100% A and 0% B to 0% A and 100% B for various times up to 32 min.

[0451] MDAP High pH Column: 150mm x 30mm, 5μm or 100mm x 19mm, 5μm or 75mm x 30mm, 5μm XSelect CSH C18 Mobile phase A: 10 mM ammonium bicarbonate in water adjusted to pH 10 with ammonia solution Mobile phase B: MeCN Total flow rate: 40mL / min Temperature: Ambient temperature Injection volume: variable Instrument name: Waters MDAP UV detection parameters: 210-350 nm (resolution 1.2 nm; 1 Hz) gradient: Gradient ranging from 100% A and 0% B to 0% A and 100% B for various times up to 32 min.

[0452] MDAP TFA Column: 150mm x 30mm, 5μm Sunfire C18 Mobile phase A: 0.1% TFA in water Mobile phase B: MeOH Total flow rate: 40mL / min Temperature: Ambient temperature Injection volume: Variable, typically 300-350 μL Instrument name: Waters MDAP UV detection parameters: 210-350 nm (resolution 1.2 nm; 1 Hz) MS detection parameters: Waters QDa; ESI + / -; 100-1000 AMU; 0.3 sec / scan; 0.1 sec interscan delay Collection mode: fractionation by UV (DAD) and MS (+ / -)

[0453] The gradient was delivered by two pumps to allow for column dilution during sample injection. The gradient program used for purification was outlined below:

[0454] [Table 7]

[0455] SFC1 Column: 150mm x 30mm, 5μm, Reprospher PEI Mobile phase A: CO2 Mobile phase B: 0.5% v / v isopropylamine in MeOH Total flow rate: 120mL / min Temperature: 55℃ Injection volume: 2000 μL every 6.5 minutes Equipment: PIC Solutions 'Sapphire (PIC-1)' Preparative SFC Outlet pressure: 130 bar UV detection parameter: 220nm MS detection parameters: None Collection mode: fractionation by time and UV (DAD)

[0456] [Table 8]

[0457] SFC2 Column: 150mm x 30mm, 5μm, Reprospher PEI Mobile phase A: CO2 Mobile phase B: 0.5% v / v isopropylamine in MeOH Total flow rate: 120mL / min Temperature: 55℃ Injection volume: 400 μL every 6.5 minutes Equipment: PIC Solutions 'Sapphire (PIC-1)' Preparative SFC Outlet pressure: 130 bar UV detection parameter: 220nm MS detection parameters: None Collection mode: fractionation by time and UV (DAD)

[0458] [Table 9]

[0459] The appropriate fractions were combined and evaporated to dryness using a rotary evaporator. The dried sample was then transferred to a small amount of MeOH in a final vial. The sample was then dried under a stream of nitrogen at 25°C to give the title compound.

[0460] Intermediates Explanation 1 3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (D1) Dihydropyrimidine-2,4(1H,3H)-dione (50 g × 2, 438 mmol) was suspended in DMF (500 mL) and heated to 140 °C until the solution became clear. The reaction mixture was cooled to room temperature, and Cs2CO3 (214 g, 657 mmol) was added in small portions over 30 minutes. The reaction mixture was further cooled to 10 °C, and (2-(chloromethoxy)ethyl)trimethylsilane (29.2 g, 175 mmol) was added dropwise, and the reaction was then stirred at room temperature for 48 hours. The reaction mixture was filtered under vacuum. The filtrate was diluted with water (2 L) and extracted with EtOAc (2 × 1 L). The combined organic layers were evaporated under reduced pressure to give the crude compound. The crude material was purified in small portions by dissolving in DCM (200 mL) and purifying on a 330 g silica column eluting with 50-100% EtOAc:petroleum ether. The desired fractions were combined and concentrated in vacuo to give the title compound as a colorless gummy solid (47 g, 187 mmol, 21% yield). GCMS: Rt=4.94 min, MH - =243.1

[0461] Explanation 2 Benzyl 4-(4-bromoindolin-1-yl)piperidine-1-carboxylate (D2) Benzyl 4-oxopiperidine-1-carboxylate (8 g, 34.3 mmol) and 4-bromoindoline (6 g, 30.3 mmol) were dissolved in acetic acid (100 mL), stirred for 1 hour, then cooled in an ice bath, and sodium triacetoxyborohydride (12.84 g, 60.6 mmol) was added. The mixture was stirred for 18 hours, then evaporated to approximately half of its original volume, diluted with water (200 mL), and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with water and sodium bicarbonate solution (200 mL each), then dried and evaporated in vacuo to give the title compound as a pale yellow gum (16.0 g), which was used in the next step without purification. LCMS (high pH A): Rt = 1.52 min, MH + =415.1, 417.1

[0462] Explanation 3 Benzyl 4-(4-bromo-1H-indol-1-yl)piperidine-1-carboxylate (D3) Benzyl 4-(4-bromoindolin-1-yl)piperidine-1-carboxylate (can be prepared as described in Description 2; 20 g, 38.5 mmol) (crude, estimated to be approximately 80% pure) was dissolved in THF (60 mL) and cooled in an ice bath. DDQ (8.74 g, 38.5 mmol) was then added, and the mixture was stirred for 10 min and then allowed to warm to room temperature. The mixture was diluted with EtOAc (200 mL) and washed with sodium bicarbonate solution (200 mL) followed by 1 M NaOH (200 mL). The organic layer was dried and evaporated in vacuo to give a dark brown gum. The crude product was dissolved in DCM and loaded onto a 330 g silica column, then eluted with 0–50% MTBE / cyclohexane. The product-containing fractions were evaporated in vacuo to give the title compound (15.7 g, 38.0 mmol, 99% yield) as a pale yellow gum. LCMS (high pH A): Rt=1.52 min, MH + =413.1, 415.1.

[0463] Explanation 4 Benzyl 4-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)-1H-indol-1-yl)piperidine-1-carboxylate (D4) To BrettPhos Pd G3 (1.162 g, 1.282 mmol), BrettPhos (0.688 g, 1.282 mmol), 3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (can be prepared as described in Description 1; 4 g, 16.37 mmol), and potassium phosphate tribasic (6.80 g, 32.1 mmol) was added a solution of benzyl 4-(4-bromo-1H-indol-1-yl)piperidine-1-carboxylate (can be prepared as described in Description 3; 5.3 g, 12.82 mmol) in 1,4-dioxane (100 mL). The reaction mixture was degassed (vacuum / nitrogen × 3) and then heated at 100 °C under nitrogen for 18 h. The reaction mixture was allowed to cool. The mixture was diluted with EtOAc and filtered through a pad of Celite. The pad was washed with EtOAc. The combined filtrate and washings were evaporated in vacuo. The residue was dissolved in DCM and applied to a 330 g silica cartridge. This was eluted with a gradient of 0-60% EtOAc in cyclohexane over 30 min. The required fractions were combined and evaporated in vacuo to give the title compound (5.61 g, 9.73 mmol, 76% yield). LCMS (high pH A): Rt = 1.44 min, MH + =577.1

[0464] Explanation 5 Benzyl 4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-indol-1-yl)piperidine-1-carboxylate (D5) Benzyl 4-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)-1H-indol-1-yl)piperidine-1-carboxylate (can be prepared as described in Description 4; 7.6 g, 13.18 mmol) was dissolved in DCM (30 mL) and cooled to 0° C. in an ice bath, then TFA (10 mL, 130 mmol) was added, and the mixture was stirred for 2 h and then evaporated in vacuo to give a brown oil. This was suspended in MeOH (30 mL), treated with SG 0.88 ammonium hydroxide (20 mL), stirred for 10 min, then diluted with DCM (100 mL) and washed with saturated sodium bicarbonate solution. The organic layer was dried and evaporated in vacuo to give a beige solid. This crude material was dissolved in DCM and loaded onto a 120 g silica column, then eluted with 0-100% EtOAc / cyclohexane, and the product-containing fractions were evaporated in vacuo to give the title compound as a colorless solid (5.23 g, 11.71 mmol, 89% yield). LCMS (high pH A): Rt=1.07 min, MH + =447.2.

[0465] Explanation 6 tert-Butyl 4-((4-bromo-1H-indol-1-yl)methyl)piperidine-1-carboxylate (D6) To a solution of 4-bromo-1H-indole (0.3 mL, 2.392 mmol) in DMF (13 mL) stirred at 0° C. under nitrogen, 60% sodium hydride (0.124 g, 3.11 mmol) was added portionwise. The reaction mixture was stirred at 0° C. for 5 minutes. To the reaction mixture was added tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (0.8 g, 2.88 mmol) and potassium iodide (0.476 g, 2.87 mmol). The reaction mixture was stirred at 60° C. for 1.5 hours and then cooled to room temperature. The reaction was quenched by the addition of saturated aqueous ammonium chloride (50 mL), and the mixture was extracted with EtOAc (3×50 mL). The organic layers were combined, washed with 5% aqueous LiCl (4×25 mL), brine (40 mL), dried through a hydrophobic frit, and the solvent was removed in vacuo. The residue was dissolved in DCM (1 mL) and loaded onto an 80 g Redisep silica column pretreated with cyclohexane. The crude material on the silica was eluted by Combiflash with 100% EtOAc (user error). The crude product-containing fractions were collected and the solvent removed in vacuo. The resulting crude gum was dissolved in DCM (1 mL) and loaded onto an 80 g Redisep silica column pretreated with cyclohexane. The crude silica material was purified by Combiflash using a gradient of 0–20% TBME in cyclohexane over 12 column volumes, followed by 20–30% TBME in cyclohexane over 3 column volumes. The desired product-containing fractions were collected and the solvent removed in vacuo to yield a pale yellow gum (containing 5% cyclohexane and 8% TBME by NMR). The sample was further dried in a vacuum oven to give the title compound as a pale yellow solid (560 mg, 1.424 mmol, 60% yield). LCMS (high pH A): Rt=1.52 min, MH + =337, 339.

[0466] Explanation 7 tert-Butyl 4-((4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)-1H-indol-1-yl)methyl)piperidine-1-carboxylate (D7) A solution of 3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (can be prepared as described in Description 1; 383 mg, 1.566 mmol), potassium carbonate (394 mg, 2.85 mmol), copper(I) iodide (40.7 mg, 0.214 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (0.067 mL, 0.427 mmol), and tert-butyl 4-((4-bromo-1H-indol-1-yl)methyl)piperidine-1-carboxylate (can be prepared as described in Description 6; 560 mg, 1.424 mmol) in anhydrous 1,4-dioxane (16.4 mL) was mixed in a microwave vial, flushed with nitrogen, sealed, and heated at 140°C for 16 h. The reaction mixture was evaporated in vacuo and diluted with DCM (25 mL) and water (25 mL). The layers were separated and the aqueous layer was extracted with DCM (25 mL). The organic layers were combined, dried through a hydrophobic frit, and concentrated in vacuo. The crude material was dissolved in a minimal amount of DCM, loaded onto a 40 g Redisep silica column pre-conditioned with cyclohexane, and purified by Combiflash using a gradient of 0-60% EtOAc in cyclohexane over 15 column volumes. Fractions containing the desired product were collected and the solvent removed under high vacuum to give the title compound as a pale brown foam (528 mg, 0.948 mmol, 67% yield). LCMS (high pH A): Rt = 1.47 min, MNH4 + =574.

[0467] Explanation 8 tert-Butyl 4-(4-bromo-1H-indol-1-yl)-3,3-difluoropiperidine-1-carboxylate (D8) 4-Bromoindoline (1 g, 5.05 mmol) and tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (1.425 g, 6.06 mmol) were heated at 140 °C for 40 minutes and then cooled to room temperature. Acetic acid (10 mL) and sodium cyanoborohydride (0.952 g, 15.15 mmol) were added, and the reaction was stirred for 5 hours and then overnight. The reaction was diluted with ether and 1 M NaOH solution. The organic phase was washed with brine (twice), dried (MgSO), filtered, and evaporated in vacuo. The residue was taken up in THF (10.00 mL), cooled to 0 °C, treated with DDQ (1.719 g, 7.57 mmol), and allowed to warm to room temperature. After 1 hour, the reaction mixture was diluted with EtOAc, washed with NaOH solution, sodium bicarbonate solution, and brine, dried (MgSO), filtered, and evaporated in vacuo to give a brown oil. This material was purified by flash chromatography (silica, 120 g, 0-30% EtOAc / cyclohexane) to give the title compound as a pale yellow, collapsing foam (1.35 g, 3.09 mmol, 61% yield). LCMS (high pH A): Rt=1.41 min, MH + =415, 417.

[0468] Explanation 9 Benzyl 4-(4-bromo-6-fluoro-1H-indol-1-yl)piperidine-1-carboxylate (D9) A mixture of 4-bromo-6-fluoro-1H-indole (917 mg, 4.28 mmol), benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (2014 mg, 6.43 mmol), and cesium carbonate (2094 mg, 6.43 mmol) in anhydrous DMF (11 mL) was stirred at 100 °C for 16 h. The reaction mixture was allowed to cool to room temperature and diluted with EtOAc (50 mL). The solution was washed sequentially with water (50 mL), 5% LiCl(aq) (50 mL), and brine (50 mL). The organic layer was passed through a hydrophobic frit, and the filtrate was evaporated in vacuo. The oil (approximately 1.8 g) was purified by reverse-phase flash chromatography on a 100 g C18 cartridge eluting with a 30–95% gradient of MeCN and 10 mM ammonium carbonate in water adjusted to pH 10 with ammonia solution over 22 min at a flow rate of 60 mL / min. The appropriate fractions were combined and the solvent removed by rotary evaporation to give the title compound as a dark brown gum (267 mg, 0.619 mmol, 14% yield). LCMS (high pH A): Rt=1.47 min, MH + =431, 433.

[0469] Explanation 10 Benzyl 4-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)-6-fluoro-1H-indol-1-yl)piperidine-1-carboxylate (D10) A mixture of copper(I) iodide (12 mg, 0.063 mmol), potassium carbonate (170 mg, 1.228 mmol), and 3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (prepared as described in Description 1; 150 mg, 0.614 mmol) was diluted with a solution of benzyl 4-(4-bromo-6-fluoro-1H-indol-1-yl)piperidine-1-carboxylate (prepared as described in Description 9; 264 mg, 0.612 mmol) in anhydrous 1,4-dioxane (3.0 mL). trans-N,N'-dimethylcyclohexane-1,2-diamine (0.019 mL, 0.123 mmol) was added, and the vessel was sealed, degassed, and purged with nitrogen (three times). The mixture was stirred at 140 °C for 4 h. The reaction was allowed to cool to room temperature, the cap was removed, and additional copper(I) iodide (24 mg) and trans-N,N'-dimethylcyclohexane-1,2-diamine (0.019 mL, 0.123 mmol) were added. The vial was sealed, degassed, and purged with nitrogen (three times). The mixture was stirred at 140 °C for 16 h. The reaction was allowed to cool to room temperature, and the suspension was diluted with DCM (5 mL) and passed through a hydrophobic frit. The filtrate was evaporated in vacuo, and the residue was loaded in DCM (3 mL) and purified on a 24 g silica cartridge using a gradient of 0 to 75% EtOAc in cyclohexane over 14 column volumes. Appropriate fractions were combined, and the solvent was evaporated in vacuo to give the title compound as a light brown gum (270 mg, 0.454 mmol, 74% yield). LCMS (high pH A): Rt = 1.42 min, M-C2H6 + 567.

[0470] Explanation 11 1-(6-Fluoro-1-(piperidin-4-yl)-1H-indol-4-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (D11) A flask containing 10 wt% palladium on carbon (22 mg, 0.021 mmol) was degassed and purged with nitrogen (3 times), and a solution of benzyl 4-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)-6-fluoro-1H-indol-1-yl)piperidine-1-carboxylate (can be prepared as described in Description 10; 235 mg, 0.395 mmol) in ethanol (20 mL) was added. The mixture was degassed and purged with nitrogen (3 times), and stirred at room temperature under atmospheric pressure of hydrogen for 16 hours. The mixture was degassed and purged with nitrogen (3 times), and 10 wt% palladium on carbon (22 mg, 0.021 mmol) was added. The mixture was degassed and purged with nitrogen (3 times), and stirred at room temperature under atmospheric pressure of hydrogen for 24 hours. The reaction mixture was filtered through Celite and the pad was washed with ethanol (20 mL). The filtrate was evaporated in vacuo and the gum was dried under high vacuum to give the title compound as a pale green gum (155 mg, 0.336 mmol). LCMS (high pH A): Rt = 1.22 min, MH + =461.

[0471] Explanation 12 tert-Butyl 4-(4-bromo-1H-indazol-1-yl)piperidine-1-carboxylate (D12) 4-Bromo-1H-indazole (38 g, 193 mmol) was dissolved in DMF (400 mL). CsCO (126 g, 386 mmol) and tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (81 g, 289 mmol) were added, and the reaction mixture was heated at 60 °C for 16 h. The reaction mixture was quenched by the addition of water (500 mL) and extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with water (250 mL), dried over anhydrous sodium sulfate (3 g), and concentrated under reduced pressure. The crude material was purified on a 330 g silica cartridge using EtOAc in hexane as the eluent to give the title compound as an orange gummy solid (29 g, 76 mmol, 40% yield). LCMS (formic acid A): Rt = 1.33 min, M- t Bu + =324.

[0472] Explanation 13 tert-Butyl 4-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)-1H-indazol-1-yl)piperidine-1-carboxylate (D13) A solution of tert-butyl 4-(4-bromo-1H-indazol-1-yl)piperidine-1-carboxylate (prepared as described in Description 12; 1 g, 2.63 mmol), 3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (prepared as described in Description 1; 0.643 g, 2.63 mmol), (1R,2R)-N,N-dimethylcyclohexane-1,2-diamine (0.224 g, 1.578 mmol), and KCO (0.909 g, 6.57 mmol) in 1,4-dioxane (20 mL) was purged with nitrogen gas for 5 minutes. Copper(I) iodide (0.100 g, 0.526 mmol) was added, and the mixture was purged with nitrogen gas for 5 minutes. The reaction was stirred in a microwave at 120° C. for 3 hours. This reaction procedure was repeated five more batches. Six reaction mixtures were filtered through Celite, and the filtrate was concentrated under reduced pressure. The material was washed with water (100 mL) and dried under vacuum. The material was dissolved in DCM (20 mL), loaded onto a 120 g silica cartridge, and purified using 40% EtOAc in hexanes to give the title compound as an orange gummy liquid (4.7 g, 8.46 mmol, 54% yield). LCMS (formic acid A): Rt=1.31 min, M-C6H 11 + =460.

[0473] Explanation 14 tert-Butyl 4-(6-chloro-4-iodo-1H-indazol-1-yl)piperidine-1-carboxylate (D14) A mixture of 6-chloro-4-iodo-1H-indazole (216 mg, 0.776 mmol), tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (260 mg, 0.931 mmol), and cesium carbonate (379 mg, 1.163 mmol) in anhydrous DMF (6.0 mL) was stirred at 60° C. for 5 hours. Additional tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (390 mg) was added, and the mixture was stirred at 60° C. for 18 hours. The reaction mixture was allowed to cool to room temperature and diluted with EtOAc (20 mL). The solution was washed sequentially with water (20 mL), 5% LiCl (aq) (20 mL), and brine (20 mL). The organic layer was passed through a hydrophobic frit, and the filtrate was evaporated in vacuo. The resulting oil was loaded in DCM (3 mL) and purified on a 24 g silica cartridge using a gradient of 0-40% EtOAc in cyclohexane over 12 column volumes. Appropriate fractions were combined and the solvent evaporated in vacuo to give the title compound as a pale yellow solid (172 mg, 0.373 mmol). LCMS (formic acid A): Rt = 1.59 min, M- t Bu + =406, 408.

[0474] Explanation 15 tert-Butyl 4-(6-chloro-4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)-1H-indazol-1-yl)piperidine-1-carboxylate (D15) A mixture of copper(I) iodide (10 mg, 0.053 mmol), potassium carbonate (96 mg, 0.697 mmol), and 3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (can be prepared as described in Description 1; 102 mg, 0.418 mmol) was suspended in a solution of tert-butyl 4-(6-chloro-4-iodo-1H-indazol-1-yl)piperidine-1-carboxylate (can be prepared as described in Description 14; 161 mg, 0.349 mmol) in anhydrous 1,4-dioxane (3.5 mL). trans-N,N'-dimethylcyclohexane-1,2-diamine (0.016 mL, 0.105 mmol) was added, and the vessel was sealed, degassed, and purged with nitrogen (three times). The mixture was stirred in a sealed vessel at 120°C for 6 hours. The reaction was allowed to cool to room temperature and the suspension was filtered through Celite, which was washed with EtOAc (10 mL). The filtrate was evaporated in vacuo and the residue was loaded in DCM (3 mL) and purified on a 24 g silica cartridge using a gradient of 0-80% EtOAc in cyclohexane over 12 column volumes. Appropriate fractions were combined and the solvent evaporated in vacuo to give the title compound as a white solid (136 mg, 0.235 mmol, 68% yield). LCMS (high pH A): Rt = 1.47 min, MH - =576, 578.

[0475] Explanation 16 4-Bromo-N,N-dimethyl-1H-indole-6-carboxamide (D16) A mixture of 4-bromo-1H-indole-6-carboxylic acid (900 mg, 3.75 mmol) and HATU (2138 mg, 5.62 mmol) in anhydrous DMF (15 mL) was treated with DIPEA (1.310 mL, 7.50 mmol). The solution was allowed to stand at room temperature in a stoppered vessel for 20 minutes, then treated with 2 M dimethylamine solution in THF (12 mL, 24.00 mmol) and allowed to stand for 16 hours. The reaction mixture was evaporated in vacuo (do not dry), and the remaining solution was diluted with EtOAc (30 mL). This solution was washed sequentially with water (30 mL), 1 M HCl (aq) (30 mL), saturated NaHCO3 (aq) (30 mL), and brine (30 mL) and passed through a hydrophobic frit. The solid was collected on the frit, suspended in water (10 mL), filtered, and washed with water (30 mL). The solid was added to the EtOAc filtrate from the hydrophobic frit and evaporated in vacuo. The solid was dissolved in MeOH (30 mL) and preabsorbed onto Florisil. This material was purified on a 40 g silica cartridge using a gradient of 0-90% EtOAc:ethanol (3:1) in TBME over 14 column volumes. Appropriate fractions were combined and the solvent evaporated in vacuo. The solid was dried under high vacuum for 16 hours to give the title compound as an off-white solid (586 mg, 2.194 mmol, 59% yield). LCMS (high pH A): Rt = 0.90 min, MH + =267, 269.

[0476] Explanation 17 Benzyl 4-(4-bromo-6-(dimethylcarbamoyl)-1H-indol-1-yl)piperidine-1-carboxylate (D17) A mixture of 4-bromo-N,N-dimethyl-1H-indole-6-carboxamide (can be prepared as described in Description 16; 584 mg, 2.186 mmol), benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1400 mg, 4.47 mmol), and cesium carbonate (1400 mg, 4.30 mmol) in anhydrous DMF (12 mL) was degassed and purged with nitrogen (three times). The reaction was stirred under nitrogen at 100° C. for 74 h. The reaction mixture was allowed to cool to room temperature and diluted with EtOAc (25 mL). The organic solution was washed successively with water (30 mL), 5% LiCl(aq) (30 mL), and brine (30 mL) and passed through a hydrophobic frit. The filtrate was evaporated in vacuo. The residue was loaded in DCM (10 mL) and purified on an 80 g silica cartridge using a gradient of 0-4% MeOH in DCM over 12 column volumes. Appropriate fractions were combined and the solvent evaporated in vacuo to give the title compound as a yellow gum (465 mg, 0.960 mmol, 44% yield). LCMS (high pH A): Rt = 1.28 min, MH + =484, 486.

[0477] Explanation 18 Benzyl 4-(6-(dimethylcarbamoyl)-4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)-1H-indol-1-yl)piperidine-1-carboxylate (D18) A mixture of copper(I) iodide (12 mg, 0.063 mmol), potassium carbonate (170 mg, 1.228 mmol), and 3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (can be prepared as described in Description 1; 150 mg, 0.614 mmol) was diluted with a solution of benzyl 4-(4-bromo-6-(dimethylcarbamoyl)-1H-indol-1-yl)piperidine-1-carboxylate (can be prepared as described in Description 17; 315 mg, 0.650 mmol) in anhydrous 1,4-dioxane (4 mL). trans-N,N'-dimethylcyclohexane-1,2-diamine (0.019 mL, 0.123 mmol) was added, and the vessel was sealed, degassed, and purged with nitrogen (three times). The mixture was stirred at 140 °C for 21 h and allowed to cool to room temperature. The cap was removed, and copper(I) iodide (12 mg, 0.063 mmol) and trans-N,N'-dimethylcyclohexane-1,2-diamine (0.019 mL, 0.123 mmol) were added. The vessel was sealed, evacuated, and purged with nitrogen (three times). The mixture was stirred at 140 °C for 16 h. The reaction was allowed to cool to room temperature, and the suspension was filtered through Celite, which was washed with 1:1 MeOH:MeCN (10 mL). The filtrate was evaporated in vacuo, and the residue was loaded in DCM (3 mL) and purified on a 40 g silica cartridge using a gradient of 0–5% MeOH in DCM over 14 column volumes. Appropriate fractions were combined, and the solvent was evaporated in vacuo to give the title compound as an off-white gum (190 mg, 0.293 mmol, 48% yield). LCMS (high pH A): Rt=1.31 min, MH + =648.

[0478] Explanation 19 4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)-N,N-dimethyl-1-(piperidin-4-yl)-1H-indole-6-carboxamide (D19) A flask containing 10 wt% palladium on carbon (20 mg, 0.019 mmol) was degassed and purged with nitrogen (3 times), and a solution of benzyl 4-(6-(dimethylcarbamoyl)-4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)-1H-indol-1-yl)piperidine-1-carboxylate (can be prepared as described in Description 18; 148 mg, 0.228 mmol) in ethanol (12 mL) was added. The mixture was degassed and purged with nitrogen (3 times), and stirred under atmospheric pressure of hydrogen at room temperature for 3 days. The reaction mixture was filtered, and the filtrate was evaporated in vacuo. The resulting gum was dissolved in MeOH (4 mL) and the solution was hydrogenated using a flow hydrogenator (settings: 60° C., 60 bar pressure, 1 mL / min) and a 10% Pd / C CatCart 30 as catalyst. The eluent was evaporated in vacuo to give the title compound as a pale yellow gum (91 mg, 0.177 mmol). LCMS (formic acid A): Rt=0.71 min; MH + =514.

[0479] Explanation 20 tert-Butyl 4-(4-bromo-1H-pyrrolo[2,3-c]pyridin-1-yl)piperidine-1-carboxylate (D20) A mixture of 4-bromo-1H-pyrrolo[2,3-c]pyridine (10 g, 50.8 mmol), tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (28.4 g, 102 mmol), and cesium carbonate (33.1 g, 102 mmol) in DMF (100 mL) was heated at 100° C. for 16 hours and then allowed to stand at room temperature for 2 days. This was then treated with tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (28.4 g, 102 mmol) and cesium carbonate (33.1 g, 102 mmol) and stirred at 100° C. for 4 hours. The reaction mixture was evaporated in vacuo, then partitioned between water and EtOAc, washed with water and brine, dried (MgSO), filtered, and evaporated to give a brown oil. Flash chromatography on 330 g silica eluting with 50-100% EtOAc in cyclohexane gave, after evaporation of the relevant fractions, the title compound as a colorless oil that solidified on standing to a hard white solid (15 g, 35.5 mmol, 70% yield). LCMS (high pH A): Rt=1.24 min, MH + =380, 382.

[0480] Explanation 21 Benzyl 4-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate (D21) 4-Bromo-1H-pyrazolo[4,3-c]pyridine (2.16 g, 10.91 mmol) and DMF (30 mL) were mixed, stirred at room temperature, and treated with 60% NaH (0.873 g, 21.82 mmol). The mixture was stirred for 15 minutes, treated with benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (3.14 g, 10.9 mmol), and heated to 80 °C. After approximately 1 hour, benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (3.14 g, 10.9 mmol) was added. After an additional hour, benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (3.14 g, 10.9 mmol) was added, and the reaction mixture was stirred at 80 °C for 3 hours. The reaction mixture was diluted with EtOAc and NH4Cl, washed with brine (2x), dried (MgSO4), filtered, and evaporated in vacuo. Purification by flash column chromatography (120 g, silica, 0-70% EtOAc / cyclohexane) afforded, after evaporation of the relevant fractions, a mixture of N1 and N2 alkylated regioisomers as a brown oil (4.3 g). This was mixed with 3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (prepared as described in Description 1; 2.78 g, 11.39 mmol), potassium carbonate (2.86 g, 20.71 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (0.490 mL, 3.11 mmol), copper(I) iodide (0.296 g, 1.553 mmol), and anhydrous 1,4-dioxane (45 mL), degassed several times with vacuum / nitrogen, and then heated at 135 °C for 36 h. The reaction mixture was diluted with water and EtOAc, washed with brine (twice), dried (MgSO), filtered, and evaporated in vacuo to give a brown oil. Purification by flash column chromatography (silica, 120 g, 50-100% EtOAc / cyclohexane) followed by further chromatography (C18-silica, 150 g 40-90% (10 mM pH 10 NH4CO2H / water-MeCN) gave the title compound as a fine white powder (600 mg, 0.985 mmol, 10% yield). LCMS (high pH A): Rt = 1.35 min, MH + =579.4.

[0481] Explanation 22 tert-Butyl 4-(4-bromo-1H-pyrazolo[3,4-c]pyridin-1-yl)piperidine-1-carboxylate (D22) 4-Bromo-1H-pyrazolo[3,4-c]pyridine (7.17 g, 36.2 mmol) and DMF (100 mL) were mixed, stirred at room temperature, treated with 60% NaH (2.90 g, 72.4 mmol), stirred for 15 minutes, then treated with one-third of tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (30.3 g, 109 mmol), heated to 80 °C, and then the remaining two-thirds were added at approximately one-hour intervals. After one hour, the reaction mixture was diluted with EtOAc and NH4Cl, and the layers were separated. The organic layer was washed with brine, dried, filtered, evaporated in vacuo, and purified using a 330 g silica column eluting with 0-100% EtOAc:cyclohexane. The product-containing fractions were combined and concentrated in vacuo. The resulting yellow oil was divided into five portions, diluted with DMSO-MeOH (1:1, ca. 20 mL), and each batch was further purified using a 150 g C18 column eluted with 30-85% MeCN:10 mM aqueous ammonium bicarbonate. The desired fractions were combined and concentrated in vacuo to give the title compound (6.1 g, 15.20 mmol, 42% yield). LCMS (high pH A): Rt = 1.26 min, MH + =381, 383.

[0482] Explanation 23 tert-Butyl 4-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)piperidine-1-carboxylate (D23) 3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (can be prepared as described in Description 1; 3.91 g, 16.00 mmol), potassium carbonate (4.42 g, 32.0 mmol), tert-butyl 4-(4-bromo-1H-pyrazolo[3,4-c]pyridin-1-yl)piperidine-1-carboxylate (can be prepared as described in Description 22; 6.1 g, 16.00 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (0.757 mL, 4.80 mmol), copper(I) iodide (0.457 g, 2.400 mmol), and anhydrous 1,4-dioxane (150 mL) were mixed and degassed with N for 10 min, then heated at 120 °C (heating block temperature) for 36 h. The resulting mixture was filtered through Celite, evaporated in vacuo, taken up in EtOAc, washed with water and brine, dried (MgSO), filtered, and evaporated in vacuo to give a green oil. The crude product was purified using an 80 g silica column eluting with 0-8% 4M NH-MeOH:DCM; the desired fractions were combined and concentrated in vacuo to give the title compound as a pale yellow sticky gum (4.5 g, 7.43 mmol, 47% yield). CMS (high pH A): Rt = 1.27 min, MH + =545.

[0483] Explanation 24 Benzyl 4-(6-chloro-4-nitro-1H-indol-1-yl)piperidine-1-carboxylate (D24) A mixture of 6-chloro-4-nitro-1H-indole (900 mg, 4.58 mmol), benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (2.15 g, 6.86 mmol), and cesium carbonate (2.25 g, 6.91 mmol) in anhydrous DMF (10 mL) was degassed and purged with nitrogen (three times). The reaction was stirred under nitrogen at 85° C. for 40 hours. Additional benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (2.15 g, 6.86 mmol) and cesium carbonate (2.25 g, 6.91 mmol) were added, and the reaction was stirred under nitrogen at 100° C. for 3 days. The reaction mixture was diluted with EtOAc (50 mL) and washed sequentially with water (50 mL) and brine (25 mL). The organic phase was dried (MgSO), filtered, and evaporated to dryness. The resulting residue was dissolved in DCM and purified by flash column chromatography (silica, 80 g, eluting with a gradient of 0-80% cyclohexane / EtOAc over 14 column volumes). Appropriate fractions were combined and evaporated to dryness to give the title compound as a brown solid (1.15 g, 2.78 mmol), which was used directly in the next step. LCMS (high pH A): Rt=1.44 min, MH + =414.

[0484] Explanation 25 Benzyl 4-(4-amino-6-chloro-1H-indol-1-yl)piperidine-1-carboxylate (D25) A solution of benzyl 4-(6-chloro-4-nitro-1H-indol-1-yl)piperidine-1-carboxylate (can be prepared as described in Description 24; 1.15 g, 2.78 mmol), iron (0.776 g, 13.89 mmol), and ammonium chloride (1.189 g, 22.23 mmol) in ethanol (12 mL) and water (6.00 mL) was stirred at 90 °C for 2 h. The reaction mixture was allowed to cool to room temperature and filtered through a 10 g Celite cartridge, washing with ethanol. The filtrate was evaporated, diluted with EtOAc (100 mL), and washed sequentially with water (100 mL) and brine (100 mL). The organic layer was then evaporated to dryness to give the title compound (268 mg, 0.698 mmol) as a dark brown gum, which was used directly in the next step. LCMS (high pH A): Rt = 1.26 min, MH + =384.

[0485] Explanation 26 Benzyl 4-(6-chloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-indol-1-yl)piperidine-1-carboxylate (D26) Benzyl 4-(4-amino-6-chloro-1H-indol-1-yl)piperidine-1-carboxylate (prepared as described in Description 25; 268 mg, 0.698 mmol) was dissolved in toluene (1 mL) and treated with acrylic acid (0.144 mL, 2.094 mmol). The mixture was stirred at 50°C for 2.5 hours, then at 70°C for 4 hours, and then at 40°C for 24 hours. Additional acrylic acid (0.048 mL) was added, and the mixture was stirred at 70°C for 5 hours. The reaction mixture was evaporated, taken up in acetic acid (2.5 mL), treated with urea (189 mg, 3.14 mmol), and heated at 140°C for 24 hours. The reaction mixture was evaporated in vacuo and partitioned between saturated sodium bicarbonate (10 mL) and EtOAc (50 mL). The organic phase was washed successively with water (50 mL) and brine (40 mL) and evaporated to dryness to give a dark brown gum. This was dissolved in DCM (3 mL) and purified by flash column chromatography (silica, 40 g, eluting with a gradient of 0-80% 3:1 EtOAc:ethanol in TBME over 14 column volumes). Appropriate fractions were combined and evaporated to dryness to give the title compound as an orange solid (98 mg, 0.137 mmol, 20% yield). LCMS (high pH A): Rt = 1.14 min, MH + =481.

[0486] Explanation 27 Benzyl 4-(4-amino-6-fluoro-1H-indazol-1-yl)piperidine-1-carboxylate (D27) 6-Fluoro-1H-indazol-4-amine (3 g, 19.85 mmol) and DMF (30 mL) were combined, stirred at room temperature, treated with NaH (1.588 g, 39.7 mmol), stirred for 15 minutes, then treated with benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (6.22 g, 19.8 mmol) and heated to 80° C. After approximately 1 hour, benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (6.22 g, 19.8 mmol) was added. After an additional hour, benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (6.22 g, 19.8 mmol) was added, and the reaction mixture was heated to 80° C. for 3 hours. The reaction mixture was diluted with EtOAc and NH4Cl, washed with brine (2x), dried (MgSO4), filtered, evaporated in vacuo and purified by flash column chromatography (120 g, silica, 0-70% EtOAc / cyclohexane) to give, after evaporation of the relevant fractions, the title compound as a colorless gum (2.1 g, 5.70 mmol, 29% yield). LCMS (high pH A): Rt = 1.11 min, MH + =369.2.

[0487] Explanation 28 tert-Butyl 4-fluoro-4-formylpiperidine-1-carboxylate (D28) To a stirred solution of tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (available from Porse Fine Chemical Co. Ltd.; 233 mg, 0.999 mmol) in DCM (5 mL) was added Dess-Martin periodinane (635 mg, 1.498 mmol) in small portions. After the addition was complete, the reaction mixture was stirred at room temperature for 1.5 h. Saturated sodium bicarbonate solution (10 mL) was added, and the mixture was stirred for 10 min. The organic phase was separated. The aqueous phase was extracted with DCM (2 × 5 mL). The combined organic layers were dried and evaporated to give the title compound as a colorless solid (231 mg, 0.999 mmol, 100% yield).

[0488] Explanation 29 tert-Butyl 4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)piperidin-1-yl)methyl)-4-fluoropiperidine-1-carboxylate (D29) A mixture of 1-(1-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione (prepared as described in Example CB6; 100 mg, 0.319 mmol) and tert-butyl 4-fluoro-4-formylpiperidine-1-carboxylate (prepared as described in Description 28; 148 mg, 0.638 mmol) in DCM (5 mL) was stirred at room temperature for 1 hour. Triethylamine (65 mg, 0.09 mL, 0.642 mmol) was added, followed by sodium triacetoxyborohydride (203 mg, 0.957 mmol). The reaction mixture was stirred at room temperature for 1 hour and then allowed to stand for 16 hours. Saturated sodium bicarbonate solution (10 mL) was added. The mixture was stirred for 10 minutes. The organic phase was separated. The aqueous phase was extracted with DCM (5 mL). The combined organic layers were dried and evaporated. The residue was chromatographed [0-20% ethanol / EtOAc] to give the title compound as a colorless solid (90 mg, 0.170 mmol, 53% yield). LCMS (high pH A): Rt=1.04 min, MH + =529

[0489] Explanation 30 tert-Butyl 2-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-indol-1-yl)piperidin-1-yl)acetate (D30) A mixture of 1-(1-(piperidin-4-yl)-1H-indol-4-yl)dihydropyrimidine-2,4(1H,3H)-dione (can be prepared as described in Example CB1; 500 mg, 1.601 mmol), tert-butyl 2-bromoacetate (0.25 mL, 1.693 mmol), and triethylamine (0.45 mL, 3.23 mmol) was dissolved in anhydrous DMF (9 mL). The reaction vessel was then sealed, degassed, and purged with nitrogen (3 times), then stirred at room temperature for 4 hours. The mixture was diluted with EtOAc (30 mL) and washed with brine (2×20 mL). The solid that formed between the partitions was isolated and dried to give the title compound as a white powder (433 mg, 1.015 mmol, 63% yield). LCMS (high pH A): Rt=1.04 min, MH + =427

[0490] Explanation 31 tert-Butyl 4-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-indol-1-yl)piperidin-1-yl)benzoate (D31) A mixture of 1-(1-(piperidin-4-yl)-1H-indol-4-yl)dihydropyrimidine-2,4(1H,3H)-dione (prepared as described in Example ECB1; 150 mg, 0.480 mmol) and tert-butyl 4-fluorobenzoate (119 mg, 0.606 mmol) in anhydrous N-methyl-2-pyrrolidone (NMP) (3500 μL) was treated with DIPEA (210 μL, 1.200 mmol) in a 2.0-5.0 mL vial. The vial was sealed, stirred, and heated at 140°C for 88 h using conventional methods. The reaction mixture was then diluted with water (10 mL) and extracted with EtOAc (50 mL) and washed with brine (30 mL). The organic layer was then passed through a hydrophobic frit, and the filtrate was evaporated using rotary evaporation. The resulting sample was loaded in DCM (5 mL) and purified on a 40 g silica cartridge using a gradient of 0-100% EtOAc in cyclohexane over 14 column volumes. Appropriate fractions were combined and the solvent removed by rotary evaporation to give the title compound as a white solid (60.8 mg, 0.124 mmol, 26% yield). LCMS (high pH A): Rt = 1.27 min, MH + =489

[0491] Explanation 32 4-Bromo-1-isopropyl-1H-indole-6-carboxylic acid methyl ester (D32) A mixture of methyl 4-bromo-1H-indole-6-carboxylate (30 g, 118 mmol) and cesium carbonate (115 g, 354 mmol) in CH3CN (500 mL) was treated with 2-iodopropane (23.61 mL, 236 mmol) and stirred at 80 °C for 16 h. The reaction mixture was filtered and concentrated. The brown residue was partitioned between saturated NaHCO3 (aq) and EtOAc. The organic layer was washed with brine, dried over MgSO4, and the brown residue was concentrated. This was purified on a 300 g silica column using a gradient of 5-50% EtOAc in hexanes to give the title compound as a yellow solid (29.22 g, 99 mmol, 84% yield). LCMS (TFA A): Rt = 1.27 min, MH + =296, 298

[0492] Explanation 33 4-Amino-1-isopropyl-1H-indole-6-carboxylic acid methyl ester (D33) Methyl 4-bromo-1-isopropyl-1H-indole-6-carboxylate (prepared as described in Description 32; 15.3 g, 51.7 mmol), cesium carbonate (42.1 g, 129 mmol), BINAP (6.43 g, 10.33 mmol), and Pd(dba) (4.73 g, 5.17 mmol) were mixed in toluene (250 mL), and benzophenone imine (10.40 mL, 62.0 mmol) was added. The mixture was stirred at 110 °C for 16 h. The mixture was cooled to room temperature and filtered. The filtrate was partitioned between saturated NaHCO (aq) and EtOAc. The organic layer was washed with brine, dried over MgSO, and concentrated to give a brown residue. The residue was dissolved in THF (300 mL), and 3 N HCl (aq) (34.4 mL, 103 mmol) was added. The mixture was stirred at room temperature for 2 h. To the mixture was added Na2CO3 in small portions until the pH was approximately 9. The mixture was then partitioned between saturated NaHCO3 (aq) and EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated to give a brown residue. The residue was purified on a 330 g silica column using a gradient of 5-50% 3:1 EtOAc:ethanol in hexanes to give the title compound as a yellow oil, which solidified under high vacuum to give a yellow foam (7.48 g, 32.2 mmol, 62% yield). LCMS (formic acid A): Rt = 0.68 min, MH + =233

[0493] Explanation 34 4-Amino-1-isopropyl-1H-indole-6-carboxylic acid (D34) Methyl 4-amino-1-isopropyl-1H-indole-6-carboxylate (can be prepared as described in Description 33; 7.48 g, 32.2 mmol) was dissolved in THF (50 mL), then NaOH (2.5 M in HO) (38.6 mL, 97 mmol) was added and heated at 70 °C for 16 h. The mixture was cooled to room temperature and partitioned between water (100 mL) and EtOAc (100 mL). The organic layer was impure and discarded. To the aqueous layer was added concentrated HCl (aq) (40 mL) dropwise until pH ∼5. The resulting black oil was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO and concentrated to give the title compound as a brown residue (6.23 g, 28.5 mmol, 89% yield). LCMS (TFA A): Rt = 0.43 min, MH + =219

[0494] Explanation 35 4-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)-1-isopropyl-1H-indole-6-carboxylic acid (D35) 4-Amino-1-isopropyl-1H-indole-6-carboxylic acid (7.23 g, 33.1 mmol) was suspended in toluene (100 mL). Acrylic acid (6.82 mL, 99 mmol) was added and heated at 40°C for 16 hours. Additional acrylic acid (6.82 mL, 99 mmol) was added and heated at 60°C for 48 hours. The mixture was concentrated to give a mixture of 4-((2-carboxyethyl)amino)-1-isopropyl-1H-indole-6-carboxylic acid and 3,3'-((6-carboxy-1-isopropyl-1H-indol-4-yl)azanediyl)dipropionic acid (9.62 g) as a black oil. The mixture was dissolved in acetic acid (50 mL), urea (9.95 g, 166 mmol) was added, and the mixture was heated at 130°C for 16 hours. The mixture was cooled to room temperature and added to rapidly stirred water (250 mL). The resulting off-white precipitate was filtered and dried under vacuum to give the title compound as a light brown solid (8.07 g, 25.6 mmol, 77% yield). LCMS (formic acid A): Rt = 0.63 min, MH + =316

[0495] Explanation 36 tert-Butyl 4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-isopropyl-1H-indole-6-carbonyl)piperazine-1-carboxylate (D36) A mixture of 4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-isopropyl-1H-indole-6-carboxylic acid (prepared as described in Description 35; 3.5 g, 11.10 mmol), tert-butyl piperazine-1-carboxylate (2.89 g, 15.54 mmol), and triethylamine (7.74 mL, 55.5 mmol) in DMF (20 mL) was treated with HATU (5.91 g, 15.54 mmol) and stirred at ambient temperature for 2 h. The mixture was partitioned between EtOAc (120 mL) and brine (50 mL). The organic phase was washed with additional brine (3 × 50 mL), dried (MgSO), filtered, and evaporated to dryness. The product was purified by chromatography on silica using a gradient elution of 0% to 10% MeOH in DCM to give the title compound (4.3 g, 8.89 mmol, 80% yield). LCMS (Formic Acid A): Rt = 0.96 min, M- t Bu + =428

[0496] Explanation 37 tert-Butyl 4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-isopropyl-N-methyl-1H-indole-6-carboxamido)piperidine-1-carboxylate (D37) A mixture of 4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-isopropyl-1H-indole-6-carboxylic acid (can be prepared as described in Description 35; 2 g, 6.34 mmol), tert-butyl 4-(methylamino)piperidine-1-carboxylate (1.903 g, 8.88 mmol) and triethylamine (4.42 mL, 31.7 mmol) in DMF (10 mL) was treated with HATU (3.38 g, 8.88 mmol). mol and stirred at ambient temperature for 2 hours. The mixture was partitioned between EtOAc (120 mL) and brine (50 mL). The organic phase was washed with more brine (3 x 50 mL), dried, filtered, and evaporated to dryness. The product was purified by chromatography on C18 silica using a gradient elution of 30% to 70% MeCN in 10 mM aqueous ammonium bicarbonate (pH 10) to give the title compound (2.6 g, 5.08 mmol, 80% yield). LCMS (high pH A): Rt = 0.98 min, M+Na + =534 M-Boc+H + =412.

[0497] Explanation 38 tert-Butyl 4-((4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-isopropyl-N-methyl-1H-indole-6-carboxamido)methyl)piperidine-1-carboxylate (D38) A mixture of 4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-isopropyl-1H-indole-6-carboxylic acid (can be prepared as described in Description 35; 2 g, 6.34 mmol), tert-butyl 4-((methylamino)methyl)piperidine-1-carboxylate (2.028 g, 8.88 mmol), and triethylamine (4.42 mL, 31.7 mmol) in DMF (10 mL) was treated with HATU (3.38 g, 8.88 mmol) and stirred at ambient temperature for 2 h. The mixture was partitioned between EtOAc (120 mL) and brine (50 mL). The organic phase was washed with additional brine (3 × 50 mL), dried, filtered, and evaporated to dryness. The product was purified by chromatography on silica using a gradient elution of 0% to 10% MeOH in DCM to give the title compound (2.72 g, 5.17 mmol, 82% yield). LCMS (Formic Acid A): Rt = 1.02 min, M-Boc + H + =426.

[0498] Explanation 39 tert-Butyl 9-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-isopropyl-1H-indole-6-carbonyl)-2,9-diazaspiro[5.5]undecane-2-carboxylate (D39) To a mixture of DIPEA (0.170 mL, 0.980 mmol), 4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-isopropyl-1H-indole-6-carboxylic acid (prepared as described in Description 35; 103 mg, 0.327 mmol), and tert-butyl 2,9-diazaspiro[5.5]undecane-2-carboxylate (100 mg, 0.392 mmol) in DMF (5 mL) was carefully added HATU (149 mg, 0.392 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted in EtOAc (20 mL) and quenched with sodium bicarbonate solution (15 mL). The organic layer was separated and washed with 1 M hydrochloric acid (15 mL) followed by brine (15 mL). The organic layer was dried and evaporated to give the title compound as a brown gum (204 mg, 0.370 mmol). LCMS (high pH A): Rt=1.11 min, M- t Bu + =496

[0499] Explanation 40 9-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-isopropyl-1H-indole-6-carbonyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl chloride hydrochloride (D40) To a mixture of DIPEA (0.165 mL, 0.951 mmol), 4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-isopropyl-1H-indole-6-carboxylic acid (prepared as described in Description 35; 100 mg, 0.317 mmol), and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (97 mg, 0.381 mmol) in DMF (5 mL) was carefully added HATU (145 mg, 0.381 mmol). The reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture was diluted in EtOAc (20 mL) and quenched with sodium bicarbonate solution (15 mL). The organic layer was separated and washed with 1 M hydrochloric acid (15 mL) followed by brine (15 mL). The organic layer was dried and evaporated to give the title compound as a brown gum (191 mg, 0.346 mmol). LCMS (high pH A): Rt=0.68 min, MH + =452

[0500] Explanation 41 tert-Butyl 2-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-isopropyl-1H-indole-6-carbonyl)-2,8-diazaspiro[4.5]decane-8-carboxylate (D41) To a mixture of DIPEA (0.165 mL, 0.951 mmol), 4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-isopropyl-1H-indole-6-carboxylic acid (prepared as described in Description 35; 100 mg, 0.317 mmol), and tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (91 mg, 0.381 mmol) in DMF (5 mL) was carefully added HATU (145 mg, 0.381 mmol). The reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture was diluted in EtOAc (20 mL) and quenched with sodium bicarbonate solution (15 mL). The organic layer was separated and washed with 1 M hydrochloric acid (15 mL) and then brine (15 mL). The organic layer was dried and evaporated. The residue was chromatographed [0-100% EtOAc / cyclohexane, 0-10% ethanol / EtOAc] to give the title compound as a brown solid (60 mg, 0.112 mmol, 35% yield). LCMS (high pH A): Rt = 1.05 min, M- t Bu + =482

[0501] Explanation 42 tert-Butyl ((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamate (D42) To a stirred solution of tert-butyl ((1r,4r)-4-hydroxycyclohexyl)carbamate (15.3 g, 71.1 mmol) in DMF (100 mL) cooled in an ice-water bath was added 60% NaH in mineral oil (3.70 g, 92 mmol), the reaction mixture was stirred for 20 min, then 2-chloro-4-fluorobenzonitrile (12.16 g, 78 mmol) was added in small portions (effervescence), and the mixture was stirred for 2 h, allowing it to warm to room temperature. The mixture was quenched with water (100 mL), the resulting suspension was stirred for 30 min, and the product was then collected by filtration and washed with water to give a pale yellow solid. The crude material was dissolved in DCM (100 mL) and washed with water (100 mL), then the organic layer was dried and evaporated in vacuo to give the title compound as a colorless solid (28.6 g, 82 mmol). The material was carried on to the next step without purification. LCMS (formic acid A): Rt = 1.33 min, M-t Bu + =295, 297.

[0502] Explanation 43 tert-Butyl ((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)carbamate (D43) To a stirred solution of 4-fluoro-2-(trifluoromethyl)benzonitrile (5.27 g, 27.9 mmol) and tert-butyl ((1r,4r)-4-hydroxycyclohexyl)carbamate (5 g, 34.8 mmol) in DMF (100 mL) in an ice bath, 60% NaH in mineral oil (1.393 g, 34.8 mmol) was added, and the reaction mixture was stirred under a nitrogen atmosphere for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 200 mL). The organic layers were combined, passed through a hydrophobic frit, and the solvent was removed in vacuo. The residue was split into two batches, both of which were purified by normal phase column chromatography (0–30% EtOAc in cyclohexane, 330 g silica, 10 column volumes) and then combined to give the title compound as a white solid (7.32 g, 19.04 mmol, 82% yield). LCMS (high pH A): Rt=1.34 min, M-Boc+285.

[0503] Description 44 tert-Butyl ((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamate (D44) To a stirred solution of tert-butyl ((1r,3r)-3-hydroxy-2,2,4,4-tetramethylcyclobutyl)carbamate (1 g, 4.11 mmol) in DMF (100 mL) cooled in an ice-water bath was added 60% NaH in mineral oil (0.214 g, 5.34 mmol), the reaction mixture was stirred for 20 min, then 2-chloro-4-fluorobenzonitrile (0.703 g, 4.52 mmol) was added portionwise (effervescently), and the mixture was stirred for 2 h, allowing it to warm to room temperature. The mixture was quenched with water (100 mL), and the resulting suspension was stirred for 30 min, then the product was collected by filtration and washed with water to give a pale yellow solid. The crude material was dissolved in DCM and loaded onto a 40 g silica column, then eluted with 0-50% EtOAc / cyclohexane. Product-containing fractions were evaporated in vacuo to give the title compound as a colorless gum (1.58 g, 4.17 mmol, 101% yield). LCMS (formic acid A): Rt = 1.49 min, M- t Bu + =323, 325.

[0504] Explanation 45 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile hydrochloride (D45) To tert-butyl ((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamate (can be prepared as described in Description 42; 7.1204 g, 20.30 mmol) was added 4 M HCl in dioxane (25.4 mL, 101 mmol) and the reaction mixture was stirred at room temperature for 35 min. The solvent was removed in vacuo to give the title compound as a white solid (6.59 g, 20.42 mmol, 101% yield). LCMS (high pH A): Rt = 0.93 min, MH + =251, 253.

[0505] Explanation 46 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile (D46) tert-Butyl ((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamate (can be prepared as described in Description 42; 24 g, 68.4 mmol) was dissolved in DCM (100 mL), TFA (26.4 mL, 342 mmol) was added, and the mixture was stirred at room temperature for 2 h. The solvent was evaporated in vacuo, and the residue was partitioned between 1 M HCl and MTBE (200 mL each). The aqueous layer was made basic with potassium carbonate and extracted with DCM (2 x 200 mL), and the organic layer was dried and evaporated in vacuo to give the title compound as a colorless liquid (16.8 g, 67.0 mmol, 98% yield). LCMS (high pH A): Rt = 0.91 min, MH + =251, 253

[0506] Explanation 47 2,2,2-Trifluoroacetic acid 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile (D47) A solution of tert-butyl ((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamate (can be prepared as described in Description 42; 20.0 g, 57.0 mmol) in DCM (80 mL) was cooled to 0° C. A solution of TFA (20 mL) in DCM (20 mL) was added slowly. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 18 h. TFA (20 mL) was added slowly, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with diethyl ether (200 mL) and stirred for 30 min. The precipitate was collected by filtration, washed with diethyl ether, and dried to give the title compound as an off-white solid (18.02 g, 49.4 mmol, 87% yield). LCMS (high pH A): Rt=0.91 min, MH + =251, 253.

[0507] Explanation 48 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-(trifluoromethyl)benzonitrile hydrochloride (D48) To tert-butyl ((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)carbamate (can be prepared as described in Description 43; 7.32 g, 19.04 mmol) was added 4 M HCl in dioxane (23.80 mL, 95 mmol) and the reaction mixture was stirred at room temperature for 10 min. The solvent was removed in vacuo to give the title compound (6.67 g, 19.34 mmol, 102% yield) as a white solid. Carried on to the next step without purification. LCMS (high pH A): Rt=0.99 min, MH + =285.

[0508] Explanation 49 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile (D49) To a solution of tert-butyl ((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamate (can be prepared as described in Description 44; 1.58 g, 4.17 mmol) in DCM (10 mL) was added TFA (3 mL, 38.9 mmol), and the mixture was stirred at room temperature for 2 h, then evaporated in vacuo. The gummy residue was stirred in water and 1 M HCl (20 mL each) to give a thick suspension. The mixture was basified with solid potassium carbonate and extracted with DCM (3 x 20 mL), and the organic layer was dried and evaporated in vacuo to give the title compound as a colorless solid (1.05 g, 3.77 mmol, 90% yield). Carried on to the next step without purification. LCMS (formic acid A): Rt = 0.64 min, MH + =279, 281.

[0509] Explanation 50 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-(trifluoromethyl)benzonitrile hydrochloride (D50) A solution of tert-butyl ((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamate (can be prepared as described in Description 186; 1 g, 2.425 mmol) in 1,4-dioxane (6 mL) was treated with hydrogen chloride (4 M in 1,4-dioxane) (6 mL, 24.00 mmol) and stirred at ambient temperature for 6 hours. The mixture was blown to dryness with a stream of nitrogen to give the title compound. LCMS (formic acid A): Rt = 0.69 min, MH + =313.

[0510] Explanation 51 Methyl 5-(4-(hydroxymethyl)piperidin-1-yl)pyrazine-2-carboxylate (D51) Methyl 5-chloropyrazine-2-carboxylate (5 g, 29.0 mmol) and piperidin-4-ylmethanol (4.00 g, 34.8 mmol) in DCM (40 mL) The solution was treated with triethylamine (8.08 mL, 57.9 mmol) and stirred at 60° C. for 4 h. The mixture was partitioned between DCM (50 mL) and water (20 mL) and the organic phase was evaporated to dryness to give the title compound (6.6 g, 26.3 mmol, 91% yield). LCMS (formic acid A): Rt=0.62 min, MH + =252

[0511] Explanation 52 Methyl 6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxylate (D52) A solution of methyl 6-chloropyridazine-3-carboxylate (6 g, 34.8 mmol) and piperidin-4-ylmethanol (5 g, 43.4 mmol) in MeCN (100 mL) was treated with triethylamine (5 mL, 35.9 mmol) and stirred at ambient temperature for 18 hours. The mixture was evaporated in vacuo, and the residue was dissolved in DCM and washed with water. The solvent was dried and evaporated in vacuo to give the title compound as a grey solid (5.4 g, 21.49 mmol, 62% yield). LCMS (formic acid A): Rt = 0.50 min, MH + =252.

[0512] Explanation 53 Ethyl 2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidine-5-carboxylate (D53) A solution of ethyl 2-chloropyrimidine-5-carboxylate (5 g, 26.8 mmol) and piperidin-4-ylmethanol (3.70 g, 32.2 mmol) in DCM (40 mL) was treated with triethylamine (7.47 mL, 53.6 mmol) and stirred at 60° C. for 4 h. The mixture was partitioned between DCM (50 mL) and water (20 mL) and the organic phase was evaporated to dryness to give the title compound (6.8 g, 25.6 mmol, 96% yield). LCMS (formic acid A): Rt=0.86 min, MH + =266.

[0513] Description 54 Methyl 6-(4-(hydroxymethyl)piperidin-1-yl)nicotinate (D54) A solution of methyl 6-chloronicotinate (5.5 g, 32.1 mmol) and piperidin-4-ylmethanol (4.43 g, 38.5 mmol) in chloroform (60 mL) was treated with DIPEA (11.20 mL, 64.1 mmol) and stirred at 60 °C for 4 h. The mixture was partitioned between DCM (50 mL) and water (20 mL), and the organic phase was evaporated to dryness to give a pale yellow solid. The crude material was dissolved in DCM and loaded onto a 120 g silica column, which was then eluted with 0-100% EtOAc / cyclohexane. The product-containing fractions were evaporated in vacuo to give the title compound as a colorless solid (5.2 g, 20.78 mmol, 65% yield). LCMS (high pH A): Rt = 0.80 min, MH + =251.

[0514] Explanation 55 Methyl 6-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyridazine-3-carboxylate (D55) A mixture of methyl 6-chloropyridazine-3-carboxylate (1.7 g, 9.85 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (1.25 mL, 9.75 mmol), and DIPEA (3.5 mL, 20.04 mmol) was dissolved in DMSO (13 mL). The reaction mixture was then sealed in a microwave vessel and heated at 90° C. for 45 minutes in a Biotage Initiator microwave using the high absorption setting. The reaction mixture was allowed to cool to room temperature before being diluted with water (50 mL), extracted with EtOAc (100 mL), and then washed with brine (30 mL). The organic layer was then passed through a hydrophobic frit, and the filtrate was evaporated to dryness to give the title compound as an off-white powder (2.2 g, 7.88 mmol). LCMS (formic acid A): Rt=1.66 min, MH + =280.

[0515] Explanation 56 Methyl 6-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-1-yl)pyridazine-3-carboxylate (D56) To a mixture of crude 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine (2.54 g, 10.43 mmol) and methyl 6-chloropyridazine-3-carboxylate (1.5 g, 8.69 mmol) in DMSO (11 mL) was added DIPEA (3.34 mL, 19.12 mmol). The mixture was stirred at 90° C. for 45 min in a Biotage microwave (cool-off; FHT-on; absorbance-high). A precipitate formed which was diluted with water (20 mL) and filtered. The solid was washed with water (200 mL), filtered, and dried in a vacuum oven for 16 h to give the title compound as tan crystals (2.74 g, 7.22 mmol, 83% yield). LCMS (formic acid A): Rt=1.45 min, MH + =380.

[0516] Explanation 57 Methyl 4-(3-hydroxypropyl)benzoate (D57) To a stirred mixture of methyl 4-iodobenzoate (2.62 g, 10.0 mmol), allyl alcohol (1.162 g, 1.36 mL, 20 mmol), sodium bicarbonate (2.52 g, 30.0 mmol), and benzyltriethylammonium chloride (2.278 g, 10 mmol) in dry MeCN (40 mL) under nitrogen, palladium(II) acetate (112 mg, 5 mol%) was added. The reaction mixture was stirred at 40° C. for 18 hours. The reaction mixture was cooled to 0° C. Sodium borohydride (1.135 g, 30 mmol) was added in small portions over 10 minutes. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. Saturated ammonium chloride solution (50 mL) was added slowly. The mixture was stirred at room temperature for 10 minutes. The mixture was extracted with EtOAc (3×25 mL). The combined extracts were washed with brine (30 mL), dried, and evaporated. The residue was chromatographed [0-60% EtOAc / cyclohexane] to give the title compound as a yellow oil (1.36 g, 7.00 mmol, 70% yield). LCMS (formic acid A): Rt = 0.80 min, MH + =195.

[0517] Explanation 58 Methyl 4-(5-hydroxypentyl)benzoate (D58) To a stirred mixture of methyl 4-iodobenzoate (2.62 g, 10.0 mmol), pent-4-en-1-ol (1.723 g, 2.039 mL, 20 mmol), sodium bicarbonate (2.52 g, 30.0 mmol), and benzyltriethylammonium chloride (2.278 g, 10 mmol) in dry MeCN (40 mL) under nitrogen, palladium(II) acetate (112 mg, 5 mol%) was added. The reaction mixture was stirred at 40° C. for 18 hours. The reaction mixture was cooled to 0° C. Sodium borohydride (1.135 g, 30 mmol) was added in small portions over 10 minutes. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. Saturated ammonium chloride solution (50 mL) was added slowly. The mixture was stirred at room temperature for 10 minutes. The mixture was extracted with EtOAc (3×25 mL). The combined extracts were washed with brine (30 mL), dried, and evaporated. The residue was chromatographed [0-60% EtOAc / cyclohexane] to give the title compound as a colorless oil (1.69 g, 7.60 mmol, 76% yield). LCMS (high pH A): Rt = 1.01 min, low ionization.

[0518] Description 59 Methyl 4-(6-hydroxyhex-1-yn-1-yl)benzoate (D59) A solution of methyl 4-iodobenzoate (3 g, 11.45 mmol), hex-5-yn-1-ol (1.515 mL, 13.74 mmol), and triethylamine (4.79 mL, 34.3 mmol) in anhydrous THF (20 mL) was degassed by alternating nitrogen and vacuum four times and then placed under a nitrogen atmosphere. The mixture was treated with bis(triphenylphosphine)palladium(II) chloride (0.241 g, 0.343 mmol) and copper(I) iodide (0.131 g, 0.687 mmol). It was then stirred at ambient temperature for an additional 2 hours. The mixture was treated with aqueous ammonium chloride (10%, 50 mL) and extracted with methyl tert-butyl ether (3 × 40 mL). The combined organic layers were washed with brine (40 mL), then dried (MgSO), filtered, and evaporated to dryness. The product was purified by chromatography on silica using a gradient elution of 0% to 50% EtOAc in DCM to give the title compound (2.43 g, 10.46 mmol, 91% yield). LCMS (Formic Acid A): Rt=0.99 min, MH + =233.

[0519] Explanation 60 Methyl 4-(6-hydroxyhexyl)benzoate (D60) A solution of methyl 4-(6-hydroxyhex-1-yn-1-yl)benzoate (can be prepared as described in Description 59; 2.5 g, 10.76 mmol) in MeOH (20 mL) was added to palladium on carbon (10% Degussa type) (100 mg, 0.940 mmol) under a nitrogen atmosphere and then stirred under a hydrogen atmosphere for 6 h. The mixture was filtered through a bed of Florisil, and the filtrate was evaporated to dryness to give the title compound (2.1 g, 8.89 mmol, 83% yield). LCMS (formic acid A): Rt = 1.04 min, MH + =237(weak), M-CH3 + =223.

[0520] Description 61 6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxylic acid (D61) A solution of methyl 6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxylate (can be prepared as described in Description 52; 17 g, 67.7 mmol) in MeOH (50 mL) was treated with 2 M aqueous sodium hydroxide (80 mL, 160 mmol) and stirred at 60° C. for 2 h. The mixture was evaporated to dryness and treated with water (50 mL). The pH of the mixture was adjusted to 4 by adding concentrated aqueous HCl, and the mixture was then allowed to stand at room temperature over the weekend to give a thick suspension. The solid was collected by filtration, washed with water, and then dried in vacuo to give the title compound as a beige solid (14.4 g, 60.7 mmol, 90% yield). LCMS (formic acid A): Rt=0.33 min, MH + =238.

[0521] Description 62 5-(4-(hydroxymethyl)piperidin-1-yl)pyrazine-2-carboxylic acid (D62) A solution of methyl 5-(4-(hydroxymethyl)piperidin-1-yl)pyrazine-2-carboxylate (can be prepared as described in Description 51; 7.2 g, 28.7 mmol) in MeOH (50 mL) was treated with 2 M aqueous sodium hydroxide (28.7 mL, 57.3 mmol) and stirred at 60° C. for 2 h. The mixture was evaporated to dryness and treated with water (50 mL). The pH of the mixture was adjusted to 4 by adding 6 M aqueous HCl, then cooled in an ice-water bath. The precipitated product was collected by filtration, washed with a minimum of ice / water, then a minimum of diethyl ether, and dried under vacuum to give the title compound (3.9 g, 16.44 mmol, 57% yield). LCMS (formic acid A): Rt=0.51 min, MH + =238.

[0522] Explanation 63 2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidine-5-carboxylic acid (D63) A solution of ethyl 2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidine-5-carboxylate (can be prepared as described in Description 53; 7.1 g, 26.8 mmol) in MeOH (50 mL) was treated with 2 M aqueous sodium hydroxide (26.8 mL, 53.5 mmol) and stirred at 60° C. for 2 h. The mixture was evaporated to dryness and treated with water (30 mL). The pH of the mixture was adjusted to 4 by adding 6 M aqueous HCl, then cooled in an ice-water bath. The precipitated product was collected by filtration, washed with a minimum of ice / water, then a minimum of diethyl ether, and dried under vacuum to give the title compound (2.95 g, 12.43 mmol, 46% yield). LCMS (formic acid A): Rt=0.59 min, MH + =238.

[0523] Description 64 6-(4-(hydroxymethyl)piperidin-1-yl)nicotinic acid (D64) A solution of methyl 6-(4-(hydroxymethyl)piperidin-1-yl)nicotinate (can be prepared as described in Description 54; 5.2 g, 20.78 mmol) in MeOH (50 mL) was treated with 2 M aqueous sodium hydroxide (20.78 mL, 41.6 mmol) and stirred at 60° C. for 2 h. The mixture was evaporated to dryness and treated with water (50 mL). The pH of the mixture was adjusted to 4 by adding 6 M aqueous HCl, then cooled in an ice-water bath. The precipitated product was collected by filtration, washed with a minimum of ice / water, then a minimum of diethyl ether, and dried under vacuum to give the title compound (4.2 g, 17.78 mmol, 86% yield). LCMS (high pH A): Rt=0.40 min, MH + =237

[0524] Explanation 65 6-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-1-yl)pyridazine-3-carboxylic acid (D65) A suspension of methyl 6-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-1-yl)pyridazine-3-carboxylate (can be prepared as described in Description 56; 2.45 g, 6.45 mmol) in MeOH (20 mL) was treated with 2 M aqueous sodium hydroxide (4.84 mL, 9.68 mmol) and stirred in a stoppered vessel at room temperature for 22 h. The reaction mixture was evaporated in vacuo and water (5 mL) was added. The mixture was carefully acidified with 2 M HCl (aq) to pH 6-7. The aqueous solution was extracted with EtOAc (2 x 25 mL) and the extracts combined and passed through a hydrophobic frit. The filtrate was evaporated in vacuo to give the title compound as an off-white solid (1.92 g, 5.25 mmol). LCMS (high pH A): Rt = 0.95 min, MH + =366.

[0525] Explanation 66 Sodium 6-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyridazine-3-carboxylate (D66) A mixture of methyl 6-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyridazine-3-carboxylate (prepared as described in Description 55; 2.2 g, 7.88 mmol) and 2 M aqueous sodium hydroxide (11.82 mL, 23.63 mmol) was diluted in MeOH (15 mL) and THF (15 mL) and stirred in a stoppered vessel at 45 °C for 2 h. The reaction mixture was then evaporated using a rotary evaporator, and the resulting gum was acidified to pH 5 with 2 M aqueous HCl. This solution was then extracted with DCM (150 mL), and the organic layer was then passed through a hydrophobic frit. The filtrate was then evaporated to dryness using a rotary evaporator to give 6-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyridazine-3-carboxylic acid as a pale yellow powder (450 mg, 1.696 mmol). The aqueous layer was then evaporated to dryness using a rotary evaporator to give the title compound as an off-white powder (2.0 g, 6.94 mmol), which was used in the next step without purification. LCMS (Formic Acid A): Rt=0.43 min, MH + =266.

[0526] Explanation 67 4-(3-hydroxypropyl)benzoic acid (D67) To a stirred solution of methyl 4-(3-hydroxypropyl)benzoate (can be prepared as described in Description 57; 1.36 g, 7.00 mmol) in ethanol (5 mL) was added 2 M sodium hydroxide (5 mL, 10 mmol). The reaction mixture was stirred at room temperature for 18 h. The ethanol was evaporated. The residue was diluted with water (20 mL). The mixture was acidified by the dropwise addition of 5 M hydrochloric acid. The mixture was extracted with EtOAc (3 x 25 mL). The combined extracts were dried and evaporated to give the title compound as a yellow solid (1.20 g, 6.66 mmol, 95% yield). LCMS (formic acid A): Rt = 0.60 min, weak ionization.

[0527] Description 68 4-(5-hydroxypentyl)benzoic acid (D68) To a stirred solution of methyl 4-(5-hydroxypentyl)benzoate (can be prepared as described in Description 58; 1.60 g, 7.20 mmol) in ethanol (10 mL) was added 2 M sodium hydroxide (10 mL, 20 mmol). The reaction mixture was stirred at room temperature for 2 h and then allowed to stand for 18 h. The ethanol was evaporated. The residue was diluted with water (15 mL). The mixture was acidified by the dropwise addition of 5 M hydrochloric acid. The mixture was extracted with EtOAc (3 x 10 mL). The combined extracts were dried and evaporated to give the title compound as a colorless solid (1.31 g, 6.29 mmol, 87% yield). LCMS (formic acid A): Rt = 0.78 min, MH + =209.

[0528] Description 69 4-(6-hydroxyhexyl)benzoic acid (D69) A solution of methyl 4-(6-hydroxyhexyl)benzoate (can be prepared as described in Description 60; 2 g, 8.46 mmol) in ethanol (10 mL) was treated with aqueous sodium hydroxide (2 M) (6.35 mL, 12.70 mmol), and the mixture was stirred at 50° C. for 2 h. The mixture was reduced to half its volume and then treated with water (10 mL). The solution was treated dropwise with aqueous hydrochloric acid (2 M) until a pH of 4 was reached, resulting in a white suspension. The suspension was filtered, washed with water, and dried under vacuum to give the title compound as a white solid (1.52 g, 6.84 mmol, 81% yield). LCMS (formic acid A): Rt=0.88 min, low ionization.

[0529] Explanation 70 N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxamide (D70) 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile (can be prepared as described in Description 46; 2.8 g, 11.17 mmol), 6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxylic acid (can be prepared as described in Description 61; 2.8 g, 11.80 mmol), HATU (5.52 g, 14.52 mmol) and DIPEA (5.85 mL, 33.5 mmol) were stirred in DCM (30 mL) at room temperature for 4 hours, then the mixture was washed with water (40 mL) and the organic layer was dried and evaporated in vacuo to give a brown gum. The crude material was dissolved in DCM and loaded onto a 40 g silica column, then eluted with 0-100% (25% ethanol / EtOAc 1% NH4OH / cyclohexane) and the product-containing fractions evaporated in vacuo to give the title compound as a colorless solid (3.8 g, 8.09 mmol, 72% yield). LCMS (formic acid A): Rt = 1.08 min, MH + =470, 472

[0530] Explanation 71 N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-1-yl)nicotinamide (D71) 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile (can be prepared as described in Description 46; 1 g, 3.99 mmol), 6-(4-(hydroxymethyl)piperidin-1-yl)nicotinic acid (can be prepared as described in Description 64; 0.942 g, 3.99 mmol), HATU (1.971 g, 5.18 mmol) and DIPEA (2.090 mL, 11.97 mmol) were stirred in DCM (30 mL) at room temperature for 4 hours, then the mixture was washed with water (40 mL) and the organic layer was dried and evaporated in vacuo to give the title compound as a pale yellow gum (3.4 g) with residual DCM and TMU. Used in the next step without purification. LCMS (high pH A): Rt=1.07 min, MH + =469, 471.

[0531] Description 72 N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxamide (D72) 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile (can be prepared as described in Description 49; 1.02 g, 3.66 mmol), 6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxylic acid (can be prepared as described in Description 61; 0.868 g, 3.66 mmol), HATU (1.809 g, 4.76 mmol) and DIPEA (1.917 mL, 10.98 mmol) were stirred in DCM (30 mL) at room temperature for 4 hours, then the mixture was washed with water (40 mL) and the organic layer was dried and evaporated in vacuo to give a brown gum. The crude material was dissolved in DCM and loaded onto a 40 g silica column, then eluted with 0-100% (25% ethanol / EtOAc 1% NH4OH / cyclohexane) and the product-containing fractions evaporated in vacuo to give the title compound (1.42 g, 2.85 mmol, 78% yield) as a colorless solid. LCMS (formic acid A): Rt = 1.23 min, MH + =498,500.

[0532] Explanation 73 N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-(hydroxymethyl)piperidin-1-yl)pyrazine-2-carboxamide (D73) 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile (can be prepared as described in Description 49; 0.59 g, 2.116 mmol), 5-(4-(hydroxymethyl)piperidin-1-yl)pyrazine-2-carboxylic acid (can be prepared as described in Description 62; 0.502 g, 2.116 mmol), HATU (1.046 g, 2.75 mmol) and DIPEA (1.109 mL, 6.35 mmol) were stirred in DCM (30 mL) at room temperature for 4 hours, then the mixture was washed with water (40 mL) and the organic layer was dried and evaporated in vacuo to give the title compound as a brown gum. This compound was carried on to the next step without purification. LCMS (high pH A): Rt=1.29 min, MH +=496, 498.

[0533] Description 74 N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidine-5-carboxamide (D74) A mixture of 2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidine-5-carboxylic acid (prepared as described in Description 63; 400 mg, 1.686 mmol) and HATU (800 mg, 2.104 mmol) in anhydrous DMF (4 mL) was treated with DIPEA (0.73 mL, 4.18 mmol), and the suspension was stirred in a stoppered vessel at room temperature for 20 minutes (a solution formed during this time). 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile (prepared as described in Description 49; 470 mg, 1.686 mmol) was added, and the mixture was stirred in a stoppered vessel at room temperature for 1 hour (a suspension formed during this time). The reaction mixture was diluted with water (25 mL) and filtered. The solid was washed successively with water (100 mL) and diethyl ether (25 mL) and dried in a vacuum oven to give the title compound as an off-white solid (648 mg, 1.301 mmol). This compound was carried on to the next step without purification. LCMS (high pH A): Rt=1.24 min, MH + =498,500.

[0534] Explanation 75 N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(hydroxymethyl)piperidin-1-yl)nicotinamide (D75) 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile (can be prepared as in Description 49; 0.5 g, 1.794 mmol), 6-(4-(hydroxymethyl)piperidin-1-yl)nicotinic acid (can be prepared as in Description 64; 0.424 g, 1.794 mmol), HATU (0.887 g, 2.332 mmol), and DIPEA (0.940 mL, 5.38 mmol) were stirred in DCM (30 mL) at room temperature for 4 hours to give a thick suspension. This was filtered, and the solid was washed with DCM (10 mL) and dried to give the title compound as a colorless solid (0.72 g, 1.449 mmol, 81% yield). This compound was carried on to the next step without purification. LCMS (formic acid A): Rt = 1.02 min, MH + =497, 499.

[0535] Description 76 N-((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxamide (D76) To a suspension of 6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxylic acid (can be prepared as described in Description 61; 0.814 g, 3.43 mmol), 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-(trifluoromethyl)benzonitrile hydrochloride (can be prepared as described in Description 48; 1 g, 3.12 mmol), PyBOP (1.947 g, 3.74 mmol) and ethyl (E)-2-cyano-2-(hydroxyimino)acetate (0.532 g, 3.74 mmol) in DMF (37.1 mL) was added N-methylmorpholine (1.028 mL, 9.35 mmol), the vessel was sealed, and the reaction mixture was stirred at room temperature for 57 h. Additional PyBOP (0.649 g, 1.25 mmol) and N-methylmorpholine (0.34 mL, 3.12 mmol) were added, and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with EtOAc (80 mL) and washed sequentially with water (70 mL), 5% LiCl (aq) (70 mL), and brine (70 mL). The aqueous layer was further extracted with EtOAc (3 x 80 mL). The organic layers were combined and washed with brine (100 mL), then the organic layer was passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by normal phase column chromatography (0-25% 3:1 EtOAc:ethanol in TBME, 120 g silica, 10 column volumes) to give the title compound as a yellow oil (1.547 g, 2.504 mmol, 77% yield). CMS (formic acid A): Rt = 1.06 min, MH + =504.

[0536] Explanation 77 N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-(hydroxymethyl)piperidin-1-yl)pyrazine-2-carboxamide (D77) 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile (can be prepared as described in Description 46; 0.5 g, 1.994 mmol), 5-(4-(hydroxymethyl)piperidin-1-yl)pyrazine-2-carboxylic acid (can be prepared as described in Description 62; 0.473 g, 1.994 mmol), HATU (0.986 g, 2.59 mmol) and DIPEA (1.045 mL, 5.98 mmol) were stirred in DCM (30 mL) at room temperature for 4 h, then the mixture was washed with water (40 mL) and the organic layer was dried and evaporated in vacuo to give the title compound as a brown gum, which contained approximately 1 equivalent of tetramethylurea. Used in the next step without purification. LCMS (high pH A): Rt=1.12 min, MH + =470, 472.

[0537] Description 78 N-((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)-2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidine-5-carboxamide (D78) A mixture of 2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidine-5-carboxylic acid (prepared as described in Description 63; 400 mg, 1.686 mmol) and HATU (800 mg, 2.104 mmol) in anhydrous DMF (4 mL) was treated with DIPEA (1.03 mL), and the suspension was stirred in a stoppered vessel at room temperature for 20 min (a solution formed during this time). 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-(trifluoromethyl)benzonitrile hydrochloride (prepared as described in Description 48; 541 mg, 1.686 mmol) was added, and the mixture was stirred in a stoppered vessel at room temperature for 1 h. The reaction mixture was diluted with EtOAc (25 mL) and washed sequentially with water (25 mL), 5% LiCl (aq) (25 mL), and brine (25 mL). The organic layer was passed through a hydrophobic frit, and the filtrate was evaporated in vacuo. The resulting solid was triturated with petroleum ether (2 x 10 mL) and dried in a vacuum oven to give the title compound as a light brown solid (922 mg, 1.831 mmol). LCMS (high pH A): Rt = 1.12 min, MH + =504.

[0538] Description 79 N-((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)-5-(4-(hydroxymethyl)piperidin-1-yl)pyrazine-2-carboxamide (D79) 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-(trifluoromethyl)benzonitrile hydrochloride (can be prepared as described in Description 48; 0.52 g, 1.621 mmol), 5-(4-(hydroxymethyl)piperidin-1-yl)pyrazine-2-carboxylic acid (can be prepared as described in Description 62; 0.385 g, 1.621 mmol), HATU (0.801 g, 2.108 mmol) and DIPEA (0.849 mL, 4.86 mmol) were stirred in DCM (30 mL) at room temperature for 4 hours, then the mixture was washed with water (40 mL) and the organic layer was dried and evaporated in vacuo to give the title compound as a brown gum. Carried on to the next step without further purification. LCMS (high pH A): Rt=1.15 min, MH + =504.

[0539] Description 80 N-((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-1-yl)nicotinamide (D80) 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-(trifluoromethyl)benzonitrile hydrochloride (can be prepared as described in Description 48; 0.52 g, 1.621 mmol), 6-(4-(hydroxymethyl)piperidin-1-yl)nicotinic acid (can be prepared as described in Description 64; 0.383 g, 1.621 mmol), HATU (0.801 g, 2.108 mmol) and DIPEA (0.849 mL, 4.86 mmol) were stirred in DCM (30 mL) at room temperature for 4 hours, then the mixture was washed with water (40 mL) and the organic layer was dried and evaporated in vacuo to give a brown gum. The crude material was dissolved in DCM and loaded onto a 40 g silica column, then eluted with 0-100% EtOAc / cyclohexane, and the product-containing fractions were evaporated in vacuo to give the title compound (750 mg, 1.492 mmol, 92% yield) as a colorless foam. LCMS (high pH A): Rt=1.10 min, MH + =503.

[0540] Description 81 N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidine-5-carboxamide (D81) A mixture of 2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidine-5-carboxylic acid (can be prepared as described in Description 63; 400 mg, 1.686 mmol) and HATU (800 mg, 2.104 mmol) in anhydrous DMF (4 mL) was treated with DIPEA (0.73 mL, 4.18 mmol), and the suspension was stirred in a stoppered vessel at room temperature for 20 min (a solution formed during this time). 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile (can be prepared as described in Description 46; 423 mg, 1.686 mmol) was added, and the mixture was stirred in a stoppered vessel at room temperature for 1 h. The reaction mixture was diluted with EtOAc (25 mL) and washed sequentially with water (25 mL), 5% LiCl (aq) (25 mL), and brine (25 mL). The organic layer was passed through a hydrophobic frit, and the filtrate was evaporated in vacuo. The resulting solid was triturated with diethyl ether (2 x 10 mL) and dried in a vacuum oven to give the title compound as a light brown solid (879 mg, 1.870 mmol). LCMS (high pH A): Rt = 1.08 min, MH + =470, 472

[0541] Description 82 N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(hydroxymethyl)benzamide (D82) A mixture of 4-(hydroxymethyl)benzoic acid (2 g, 13.15 mmol), 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile (can be prepared as described in Description 46; 3.30 g, 13.15 mmol), DIPEA (6.89 mL, 39.4 mmol), and HATU (6.00 g, 15.77 mmol) in DCM (50 mL) was stirred at room temperature for 1.5 h. The mixture was washed with water, dried, and evaporated in vacuo. The crude material was dissolved in EtOAc (50 mL, reflux), then allowed to cool to room temperature, and the resulting solid was collected by filtration to give the title compound as a colorless solid (4.5 g, 11.69 mmol, 89% yield). LCMS (high pH A): Rt=1.04 min, MH + =385, 387.

[0542] Explanation 83 N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(3-hydroxypropyl)benzamide (D83) A mixture of 4-(3-hydroxypropyl)benzoic acid (can be prepared as described in Description 67; 500 mg, 2.77 mmol), 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile (can be prepared as described in Description 46; 835 mg, 3.33 mmol), DIPEA (717 mg, 0.969 mL, 5.55 mmol) and HATU (1266 mg, 3.33 mmol) in DMF (5 mL) was stirred at room temperature for 1.5 h. The reaction mixture was partitioned between EtOAc (25 mL) and saturated sodium bicarbonate solution (25 mL). The aqueous phase was separated. The organic phase was washed with 2 M hydrochloric acid (10 mL), water (10 mL) and brine (10 mL). The organic phase was dried and evaporated. The residue was chromatographed [0-10% ethanol / DCM] to give the title compound as an off-white solid (895 mg, 2.168 mmol, 78% yield). LCMS (high pH A): Rt = 1.07 min, MH + =413, 415.

[0543] Description 84 N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(5-hydroxypentyl)benzamide (D84) A mixture of 4-(5-hydroxypentyl)benzoic acid (can be prepared as described in Description 68; 500 mg, 2.401 mmol), 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile (can be prepared as described in Description 46; 722 mg, 2.88 mmol), DIPEA (621 mg, 0.839 mL, 4.80 mmol) and HATU (1095 mg, 2.88 mmol) in DMF (5 mL) was stirred at room temperature for 1.5 h. The reaction mixture was partitioned between EtOAc (25 mL) and saturated sodium bicarbonate solution (20 mL). The aqueous phase was separated. The organic phase was washed with 2 M hydrochloric acid (10 mL), water (10 mL) and brine (10 mL). The organic phase was dried and evaporated. The residue was chromatographed [0-10% ethanol / DCM] to give the title compound as an off-white solid (0.97 g, 2.200 mmol, 92% yield). LCMS (Formic Acid A): Rt = 1.17 min, MH + =441, 443.

[0544] Explanation 85 N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(6-hydroxyhexyl)benzamide (D85) A mixture of 4-(6-hydroxyhexyl)benzoic acid (500 mg, 2.249 mmol), 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile hydrochloride (prepared as described in Description 45; 775 mg, 2.70 mmol), HATU (1026 mg, 2.70 mmol), and DIPEA (1.179 mL, 6.75 mmol) in DMF (7 mL) was stirred at room temperature for 2 h. The reaction mixture was partitioned between EtOAc (15 mL) and saturated sodium bicarbonate solution (15 mL). The aqueous phase was separated. The organic phase was washed with 2 M hydrochloric acid (10 mL), water (10 mL), and brine (10 mL). The organic phase was dried and evaporated. The residue was purified by normal phase column chromatography (30-70% EtOAc in cyclohexane, 80 g silica, 12 column volumes) to give the title compound as a white solid (863 mg, 1.897 mmol, 84% yield). LCMS (formic acid A): Rt = 1.22 min, MH + =455.

[0545] Description 86 N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(2-hydroxyethyl)piperidin-1-yl)pyridazine-3-carboxamide (D86) A suspension of 6-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-1-yl)pyridazine-3-carboxylic acid (can be prepared as described in Description 65; 969 mg, 2.65 mmol), ethyl (hydroxyimino)cyanoacetate (436 mg, 3.07 mmol), 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile hydrochloride (can be prepared as described in Description 45; 720 mg, 2.507 mmol), and PyBOP (1610 mg, 3.09 mmol) in anhydrous DMF (15 mL) was treated with N-methylmorpholine (0.83 mL, 7.55 mmol), and the mixture was stirred at room temperature in a stoppered vessel for 22 h. The mixture was diluted with EtOAc (30 mL) and washed sequentially with water (25 mL), 5% LiCl (aq) (25 mL), and brine (25 mL). The organic layer was passed through a hydrophobic frit, and the filtrate was evaporated in vacuo. The resulting gum was dissolved in MeOH (15 mL) and treated with 2 M HCl(aq) (5.0 mL, 10.00 mmol). The solution was allowed to stand at room temperature in a stoppered vessel for 2 h. The mixture was basified with 2 M NaOH(aq) to approximately pH = 10 and partially evaporated in vacuo. The remaining aqueous solution was extracted with EtOAc (25 mL), and the organic layer was washed sequentially with saturated NaHCO3(aq) (25 mL) and brine (25 mL). The organic layer was passed through a hydrophobic frit, and the filtrate was evaporated in vacuo. The residue was loaded in DCM (5 mL) and purified on an 80 g silica cartridge using a gradient of 0 to 75% EtOAc:ethanol (3:1) in TBME over 12 column volumes. Appropriate fractions were combined, and the solvent was evaporated in vacuo. The solid was dried under high vacuum for 16 hours to give the title compound as an off-white solid (835 mg, 1.725 mmol). LCMS (Formic Acid A): Rt = 1.03 min, MH + =484, 486.

[0546] Explanation 87 N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(3-hydroxypiperidin-1-yl)benzamide (D87) A mixture of 4-(3-hydroxypiperidin-1-yl)benzoic acid (100 mg, 0.452 mmol), 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile trifluoroacetate (prepared as described in Description 47; 198 mg, 0.542 mmol), DIPEA (117 mg, 0.158 mL, 0.904 mmol) and HATU (206 mg, 0.542 mmol) in DMF (3 mL) was stirred at room temperature for 1.5 h. The reaction mixture was partitioned between EtOAc (15 mL) and saturated sodium bicarbonate solution (15 mL). The aqueous phase was separated. The organic phase was washed with water (10 mL) and brine (10 mL). The organic phase was dried and evaporated. The residue was chromatographed [0-10% ethanol / EtOAc] to give the title compound as an off-white solid (155 mg, 0.341 mmol, 76% yield). LCMS (high pH A): Rt = 1.10 min, MH + =454, 456.

[0547] Description 88 N-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(6-hydroxyhexyl)benzamide (D88) A mixture of 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-(trifluoromethyl)benzonitrile hydrochloride (can be prepared as described in Description 50; 300 mg, 0.860 mmol), 4-(6-hydroxyhexyl)benzoic acid (191 mg, 0.860 mmol), and triethylamine (0.480 mL, 3.44 mmol) in DCM (10 mL) was treated with HATU (425 mg, 1.118 mmol) and stirred at ambient temperature for 30 min. The mixture was treated with DCM (10 mL) and saturated aqueous sodium bicarbonate solution (20 mL). The aqueous phase was extracted with additional DCM (10 mL), and the combined organic layers were evaporated to dryness. The product was purified by chromatography on silica using a gradient elution of 0% to 100% EtOAc in cyclohexane to give the title compound (390 mg, 0.755 mmol, 88% yield). LCMS (formic acid A): Rt=1.38 min, MH + =517.

[0548] Description 89 N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyridazine-3-carboxamide (D89) A mixture of sodium 6-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyridazine-3-carboxylate (prepared as described in Description 66; 1.45 g, 5.05 mmol), PyBop (3.15 g, 6.06 mmol), OxymaPure (0.85 g, 5.98 mmol), and DIPEA (3.10 mL, 17.75 mmol) was suspended in DMF (35 mL) and stirred at room temperature for 30 min. Next, 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile (prepared as described in Description 46; 1.75 g, 6.09 mmol) was added to the mixture, followed by stirring at room temperature for 16 h. The mixture was diluted with water (30 mL), extracted with EtOAc (100 mL), and washed with 5% aqueous LiCl (20 mL). The organic layer was then passed through a hydrophobic frit and the filtrate evaporated to dryness. The resulting residue was then loaded in DCM (10 mL) and purified on a 40 g silica cartridge using a gradient of 0-60% EtOAc:ethanol (3:1) in TBME over 14 column volumes. Appropriate fractions were combined and the solvent removed by rotary evaporation to give the title compound as an orange solid (700 mg, 1.406 mmol). LCMS (formic acid A): Rt = 1.17 min, MH + =498,500.

[0549] Explanation 90 6-chloro-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide (D90) A mixture of 6-chloropyridazine-3-carboxylic acid (0.5 g, 3.15 mmol), 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile trifluoroacetate (prepared as described in Description 47; 1.380 g, 3.78 mmol), DIPEA (815 mg, 1.102 mL, 6.31 mmol) and HATU (1.439 g, 3.78 mmol) in DMF (10 mL) was stirred at room temperature for 1.5 h. The reaction mixture was partitioned between EtOAc (50 mL) and saturated sodium bicarbonate solution (50 mL). The mixture was filtered through Celite. The aqueous phase was separated. The organic phase was washed with water (10 mL) and brine (10 mL). The organic phase was dried and evaporated. The residue was chromatographed [30-75% EtOAc / cyclohexane] to give the title compound (640 mg, 1.636 mmol, 52% yield) as an off-white solid. LCMS (high pH A): Rt = 1.17 min, MH + =389, 391.

[0550] Description 91 N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(3-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxamide (D91) 6-Chloro-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide (can be prepared as described in Description 90; 200 mg, 0.511 mmol), piperidin-3-ylmethanol (70.6 mg, 0.613 mmol), and DIPEA (0.107 mL, 0.613 mmol) were placed in a microwave vial, to which DMSO (1 mL) was added and the mixture was heated at 70° C. for 2 h. The mixture was then diluted with water and extracted with EtOAc. The organic layer was washed with water, dried, and evaporated in vacuo to give a pale yellow gum. This was dissolved in DCM and loaded onto a 24 g silica column, then eluted with 0-100% (25% ethanol / EtOAc 1% NHOH / cyclohexane). The product-containing fractions were evaporated in vacuo to give the title compound (232 mg, 0.494 mmol, 97% yield) as a pale yellow gum. LCMS (high pH A): Rt = 1.10 min, MH + =470, 472.

[0551] Description 92 N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-formylpiperidin-1-yl)pyrazine-2-carboxamide (D92) N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-(hydroxymethyl)piperidin-1-yl)pyrazine-2-carboxamide (can be prepared as described in Description 73; 1.52 g, 2.136 mmol) was dissolved in DCM (20 mL), cooled in an ice bath, Dess-Martin periodinane (1.2 g, 2.83 mmol) was added, and the mixture was stirred at room temperature for 2 h and then evaporated in vacuo to give a yellow gum. The crude material was suspended in DCM, filtered, and the filtrate was purified by chromatography on a 12 g silica column eluting with 0–100% EtOAc / cyclohexane. The product-containing fractions were evaporated in vacuo to give the title compound as a pale yellow solid (0.76 g, 1.532 mmol, 72% yield). LCMS (Formic Acid A): Rt=1.35 min, M+MeOH+ 528, 530

[0552] Description 93 N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-formylpiperidin-1-yl)pyrimidine-5-carboxamide (D93) N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidine-5-carboxamide (can be prepared as described in Description 74; 648 mg, 1.301 mmol) was dissolved in DCM (8 mL) and Dess-Martin periodinane (1.2 g, 2.83 mmol) was added. The mixture was then stirred at room temperature for 4 h, suspended in DCM (10 mL), and filtered through Celite. The filtrate was purified on a 40 g silica cartridge using a gradient of 0 to 100% EtOAc in cyclohexane over 12 column volumes. Appropriate fractions were combined and the solvent was evaporated in vacuo. The residue was suspended in 10% MeOH in DCM (20 mL) and washed with 0.5 M NaOH (aq) (2 x 10 mL) (4 mL of brine was added to aid separation). The organic layer was passed through a hydrophobic frit, evaporated under a stream of nitrogen, and dried in a vacuum oven to give the title compound as an off-white solid (132 mg, 0.266 mmol). LCMS (formic acid A): Rt = 1.33 min, MH + =496, 498.

[0553] Description 94 N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-formylpiperidin-1-yl)nicotinamide (D94) N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-1-yl)nicotinamide (can be prepared as described in Description 71; 3.4 g, 4.35 mmol) was dissolved in DCM (20 mL), cooled in an ice bath, Dess-Martin iodinane (2.398 g, 5.65 mmol) was added, and the mixture was stirred at room temperature for 2 h and then evaporated in vacuo to give a colorless gum / solid. The crude material was suspended in DCM, filtered, and the filtrate purified by chromatography on a 40 g silica column eluting with 0-100% EtOAc / cyclohexane. Product-containing fractions were evaporated in vacuo to give the title compound (1.72 g, 3.68 mmol, 85% yield), containing approximately 0.5 equivalents of TMU from the initial HATU step. LCMS (high pH A): Rt = 1.11 min, MH + =467, 469.

[0554] Explanation 95 N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-formylpiperidin-1-yl)pyridazine-3-carboxamide (D95) N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxamide (can be prepared as described in Description 70; 3.8 g, 8.09 mmol) was dissolved in DCM (20 mL), cooled in an ice bath, Dess-Martin periodinane (5.14 g, 12.13 mmol) was added, and the mixture was stirred at room temperature for 2 h and then evaporated in vacuo to give a gummy solid. The crude material was suspended in DCM and loaded onto a 24 g silica column, then eluted with 0–100% EtOAc / cyclohexane. The product-containing fractions were evaporated in vacuo to give the title compound (3.01 g, 6.43 mmol, 80% yield) as a colorless foam. LCMS (formic acid A): Rt = 1.11 min, MH + =468, 470.

[0555] Description 96 N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-formylpiperidin-1-yl)nicotinamide (D96) N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(hydroxymethyl)piperidin-1-yl)nicotinamide (can be prepared as described in Description 75; 720 mg, 1.449 mmol) was dissolved in DCM (20 mL), cooled in an ice bath, Dess-Martin periodinane (799 mg, 1.883 mmol) was added, and the mixture was stirred at room temperature for 2 hours before being evaporated in vacuo to give a colorless gum / solid. The crude material was suspended in DCM, filtered, and the filtrate purified by chromatography on a 12 g silica column eluting with 0-100% EtOAc / cyclohexane. Product-containing fractions were evaporated in vacuo to give the title compound as a beige solid (410 mg, 0.828 mmol, 57% yield). LCMS (high pH A): Rt=1.35 min, MH + =495, 497.

[0556] Explanation 97 N-((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)-6-(4-formylpiperidin-1-yl)pyridazine-3-carboxamide (D97) N-((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxamide (can be prepared as described in Description 76; 700 mg, 1.112 mmol) was dissolved in DCM (11.5 mL) and cooled in an ice bath. Dess-Martin periodinane (708 mg, 1.668 mmol) was added, and the mixture was stirred at room temperature for 4.5 h. The reaction mixture was concentrated in vacuo. The resulting yellow gum was diluted with DCM, filtered, and the filtrate was partially concentrated and then loaded onto a 12 g Redisep silica column pre-conditioned with cyclohexane and purified by Combiflash using a gradient of 0–100% EtOAc in cyclohexane over 15 column volumes. Fractions containing the desired product were collected and the solvent removed in vacuo to give the title compound as a yellow gum (495 mg, 0.592 mmol, 53% yield). LCMS (high pH A): Rt=1.20 min, MH + =502

[0557] Explanation 98 N-((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)-5-(4-formylpiperidin-1-yl)pyrazine-2-carboxamide (D98) N-((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)-5-(4-(hydroxymethyl)piperidin-1-yl)pyrazine-2-carboxamide (can be prepared as described in Description 79; 1.35 g, 1.877 mmol) was dissolved in DCM (20 mL), cooled in an ice bath, Dess-Martin periodinane (1.2 g, 2.83 mmol) was added, and the mixture was stirred at room temperature for 2 h and then evaporated in vacuo to give a yellow gum. The crude material was suspended in DCM, filtered, and the filtrate was purified by chromatography on a 12 g silica column eluting with 0-100% EtOAc / cyclohexane. Product-containing fractions were evaporated in vacuo to give the title compound as a pale yellow gum (0.68 g, 1.356 mmol, 72% yield). LCMS (high pH A): Rt=1.20 min, MH+ =502.

[0558] Description 99 N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-formylpiperidin-1-yl)pyrazine-2-carboxamide (D99) N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-(hydroxymethyl)piperidin-1-yl)pyrazine-2-carboxamide (can be prepared as described in Description 77; 1.3 g, 1.936 mmol) was dissolved in DCM (20 mL), cooled in an ice bath, Dess-Martin periodinane (1.2 g, 2.83 mmol) was added, and the mixture was stirred at room temperature for 2 h and then evaporated in vacuo to give a colorless gum / solid. The crude material was suspended in DCM, filtered, and the filtrate purified by chromatography on a 12 g silica column eluting with 0-100% EtOAc / cyclohexane. Product-containing fractions were evaporated in vacuo to give the title compound (0.72 g, 1.54 mmol, 79% yield). LCMS (high pH A): Rt=1.15 min, MH + =468, 470.

[0559] Explanation 100 N-((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)-2-(4-formylpiperidin-1-yl)pyrimidine-5-carboxamide (D100) N-((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)-2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidine-5-carboxamide (can be prepared as described in Description 78; 922 mg, 1.831 mmol) was dissolved in DCM (12 mL), Dess-Martin periodinane (1100 mg, 2.59 mmol) was added, and the mixture was stirred at room temperature for 4 h and then evaporated in vacuo. The crude material was suspended in DCM (10 mL), filtered, and the filtrate was purified by chromatography on a 40 g silica column eluting with 0–100% EtOAc / cyclohexane. The product-containing fractions were evaporated in vacuo. The residue was suspended in 10% MeOH in DCM (20 mL) and washed with 0.5 M NaOH (aq) (2 × 10 mL) (4 mL of brine was added to aid separation). The organic layer was passed through a hydrophobic frit, evaporated under a stream of nitrogen and dried in vacuo to give the title compound (142 mg, 0.283 mmol). LCMS (Formic Acid A): Rt = 1.19 min, MH + =502.

[0560] Explanation 101 N-((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)-6-(4-formylpiperidin-1-yl)nicotinamide (D101) N-((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-1-yl)nicotinamide (can be prepared as described in Description 80; 750 mg, 1.492 mmol) was dissolved in DCM (20 mL), cooled in an ice bath, Dess-Martin periodinane (760 mg, 1.791 mmol) was added, and the mixture was stirred at room temperature for 2 hours before being evaporated in vacuo to give a colorless gum / solid. The crude material was suspended in DCM, filtered, and the filtrate purified by chromatography on a 24 g silica column eluting with 0-100% EtOAc / cyclohexane. Product-containing fractions were evaporated in vacuo to give the title compound as a beige solid (680 mg, 1.359 mmol, 91% yield). LCMS (high pH A): Rt=1.15 min, MH + =501.

[0561] Explanation 102 N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(3-formylpiperidin-1-yl)pyridazine-3-carboxamide (D102) To a solution of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(3-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxamide (can be prepared as described in Description 91; 200 mg, 0.426 mmol) in DCM (20 mL) at room temperature was added Dess-Martin periodinane (180 mg, 0.426 mmol), the mixture was stirred for 2 h, then quenched with saturated sodium bicarbonate solution, the organic layer was separated, dried, and evaporated in vacuo to give a white gummy solid. This was triturated with DCM (10 mL), filtered, and the filtrate was evaporated in vacuo to give the title compound as a pale yellow gum (183 mg, 0.391 mmol, 92% yield). LCMS (high pH A): Rt = 1.18 min, MH + =468, 470.

[0562] Explanation 103 N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-2-(4-formylpiperidin-1-yl)pyrimidine-5-carboxamide (D103) N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidine-5-carboxamide (can be prepared as described in Description 81; 875 mg, 1.862 mmol) was dissolved in DCM (12 mL), Dess-Martin periodinane (1100 mg, 2.59 mmol) was added, and the mixture was stirred at room temperature for 4 h and then evaporated in vacuo. The crude material was suspended in DCM (10 mL), filtered, and the filtrate was purified by chromatography on a 40 g silica column eluting with 0–100% EtOAc / cyclohexane. Product-containing fractions were evaporated in vacuo. The residue was suspended in 10% MeOH in DCM (20 mL) and washed with 0.5 M NaOH (aq) (2 × 10 mL) (4 mL of brine was added to aid separation). The organic layer was passed through a hydrophobic frit, evaporated under a stream of nitrogen, and dried in a vacuum oven to give the title compound (80 mg, 1.16 mmol, 9% yield). LCMS (formic acid A): Rt=1.09 min, MH + =468, 470.

[0563] Explanation 104 N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-formylpiperidin-1-yl)pyridazine-3-carboxamide (D104) N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxamide (can be prepared as described in Description 72; 90 mg, 0.181 mmol) was dissolved in DCM (20 mL), cooled in an ice bath, Dess-Martin periodinane (115 mg, 0.271 mmol) was added, and the mixture was stirred at room temperature for 2 hours before being evaporated in vacuo to give a colorless gum / solid. The crude material was suspended in DCM, filtered, and the filtrate purified by chromatography on a 12 g silica column eluting with 0-100% EtOAc / cyclohexane. Product-containing fractions were evaporated in vacuo to give the title compound (55 mg, 0.111 mmol, 61% yield). LCMS (high pH A): Rt=1.09 min, MH + =496, 498.

[0564] Explanation 105 N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-formylbenzamide (D105) To N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(hydroxymethyl)benzamide (2.0 g, 5.20 mmol, can be prepared as described in Description 82) in DCM (40 mL) was added Dess-Martin periodinane (2.64 g, 6.24 mmol) and stirred at room temperature for 2 h. The mixture was quenched with aqueous sodium thiosulfate (5% aqueous solution, 40 mL), stirred for 30 min, then diluted with sodium bicarbonate solution and stirred for 20 min. The organic layer was separated, dried, and evaporated in vacuo to give the title compound as a colorless solid (1.85 g, 4.83 mmol, 93% yield). LCMS (high pH A): Rt = 1.16 min, MH + =383.

[0565] Explanation 106 N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(3-oxopropyl)benzamide (D106) To N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(3-hydroxypropyl)benzamide (50 mg, 0.121 mmol, prepared as described in Description 83) in DCM (2 mL) was added Dess-Martin periodinane (61.6 mg, 0.145 mmol) and stirred at room temperature for 2 h. Additional Dess-Martin periodinane (61.6 mg, 0.145 mmol) was added, and stirring was continued at room temperature for an additional 3 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (3 × 10 mL), then dried and evaporated. The residue was chromatographed [0–10% EtOAc / ethanol] to give the title compound as an off-white solid (47 mg, 0.114 mmol, 94% yield). LCMS (high pH A): Rt=1.16 min, MH + =411, 413.

[0566] Explanation 107 N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(5-oxopentyl)benzamide (D107) To N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(5-hydroxypentyl)benzamide (prepared as described in Description 84; 50 mg, 0.113 mmol) in DCM (2 mL) was added Dess-Martin periodinane (57.7 mg, 0.136 mmol) and stirred at room temperature for 5 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 mL). The organic layer was separated and the aqueous layer was extracted with DCM (3 × 10 mL). The combined organic extracts were dried and evaporated. The residue was chromatographed [0–50% EtOAc / cyclohexane] to give the title compound as an off-white solid (17 mg, 0.039 mmol, 34% yield). LCMS (high pH A): Rt = 1.25 min, MH + =439.

[0567] Explanation 108 N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(6-oxohexyl)benzamide (D108) To N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(6-hydroxyhexyl)benzamide (prepared as described in Description 85; 120 mg, 0.264 mmol) in DCM (4 mL) was added Dess-Martin periodinane (134 mg, 0.316 mmol) and stirred at room temperature for 2 h. Additional Dess-Martin periodinane (134 mg, 0.316 mmol) was added and stirring continued for 30 min. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 mL). The organic layer was separated and the aqueous layer was extracted with DCM (3 × 10 mL). The combined organic extracts were dried and evaporated to give the crude title compound as an off-white solid (126 mg, 0.278 mmol), which was used in further experiments without purification. LCMS (high pH A): Rt = 1.28 min, MH + =452.

[0568] Explanation 109 N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-oxopiperidin-1-yl)pyridazine-3-carboxamide (D109) A mixture of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyridazine-3-carboxamide (can be prepared as described in Description 89; 700 mg, 1.406 mmol) and 2 M aqueous HCl (10 mL, 20.00 mmol) was stirred in a stoppered vessel at 60° C. for 3 h. The mixture was then allowed to cool to room temperature before being neutralized with 2 M aqueous NaOH. The mixture was then extracted with EtOAc (75 mL) and the organic layer was passed through a hydrophobic frit. The filtrate was then evaporated to dryness to give the title compound as a yellow powder (480 mg, 1.057 mmol). LCMS (formic acid A): Rt=1.07 min, MH + =454, 456.

[0569] Description 110 (1-(6-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)pyridazin-3-yl)piperidin-4-yl)methyl methanesulfonate (D110) To a solution of N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxamide (can be prepared as described in Description 72; 220 mg, 0.442 mmol) and DIPEA (0.154 mL, 0.883 mmol) in DCM (20 mL) at 0° C., Ms-Cl (0.052 mL, 0.663 mmol) was added, the mixture was stirred for 2 h, allowed to warm to room temperature, then washed with water (20 mL), the organic layer was dried and evaporated in vacuo. The residue was dissolved in DCM and loaded onto a 24 g silica column, then eluted with 0-100% EtOAc / cyclohexane. The product-containing fractions were evaporated in vacuo to give the title compound (125 mg, 0.217 mmol, 49% yield) as a colorless solid. LCMS (high pH A): Rt = 1.35 min, MH + =576, 578.

[0570] Description 111 6-(4-(((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)hexyl 4-methylbenzenesulfonate (D111) A mixture of N-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(6-hydroxyhexyl)benzamide (can be prepared as described in Description 88; 390 mg, 0.755 mmol), tosyl-Cl (216 mg, 1.132 mmol), DMAP (9.22 mg, 0.075 mmol), and triethylamine (0.316 mL, 2.265 mmol) in DCM (10 mL) was stirred at ambient temperature for 20 h. The mixture was treated with 5% aqueous ammonium chloride solution (10 mL) and separated. The aqueous phase was extracted with additional DCM (10 mL), and the combined organic layers were evaporated to dryness. The product was purified by chromatography on silica using a gradient elution of 0% to 100% methyl tert-butyl ether in cyclohexane to give the title compound (354 mg, 0.528 mmol, 70% yield). LCMS (formic acid A): Rt=1.59 min, MH + =671.

[0571] Description 112 6-(4-(2-bromoethyl)piperidin-1-yl)-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide (D112) A solution of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(2-hydroxyethyl)piperidin-1-yl)pyridazine-3-carboxamide (prepared as described in Description 86; 200 mg, 0.413 mmol) in anhydrous DCM (4 mL) was added to tetrabromomethane (206 mg, 0.620 mmol) and triphenylphosphine (163 mg, 0.620 mmol), and the mixture was stirred at room temperature in a stoppered vessel for 2 h. This solution was purified on a 12 g silica cartridge using a gradient of 0 to 100% EtOAc:ethanol (3:1) in TBME over 18 column volumes. Appropriate fractions were combined, and the solvent was evaporated in vacuo. The solid was dried under high vacuum for 16 h to give the title compound as a light brown solid (113 mg, 0.207 mmol). LCMS (formic acid A): Rt = 1.39 min, M +=546, 548, 550.

[0572] Description 113 N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-hydroxypicolinamide (D113) A mixture of 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile (can be prepared as described in Description 46; 1 g, 3.99 mmol), 5-hydroxypicolinic acid (0.694 g, 4.99 mmol), and triethylamine (2.78 mL, 19.94 mmol) in DMF (10 mL) was treated with HATU (2.123 g, 5.58 mmol) and stirred at ambient temperature for 2 h. The mixture was partitioned between EtOAc (120 mL) and brine (50 mL). The organic phase was washed with additional brine (3 × 50 mL), dried (MgSO), filtered, and evaporated to dryness. The product was purified by chromatography on C18 silica using a gradient elution of 20% to 80% MeCN in water (0.1% formic acid) to give the title compound (1.12 g, 3.01 mmol, 76% yield). LCMS (formic acid A): Rt = 1.04 min, MH + =372, 374.

[0573] Description 114 5-(3-Bromopropoxy)-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)picolinamide (D114) A mixture of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-hydroxypicolinamide (can be prepared as described in Description 113; 150 mg, 0.403 mmol), 1,3-dibromopropane (0.123 mL, 1.210 mmol), and potassium carbonate (112 mg, 0.807 mmol) in MeCN (10 mL) was stirred at 80 °C for 2 h. The product was directly subjected to purification by MDAP (formic acid) to give the title compound (105 mg, 0.213 mmol, 53% yield) as a white solid. LCMS (formic acid A): Rt = 1.32 min, MH + =492, 494, 496.

[0574] Description 115 5-(4-Bromobutoxy)-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)picolinamide (D115) A mixture of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-hydroxypicolinamide (can be prepared as described in Description 113; 150 mg, 0.403 mmol) and potassium carbonate (112 mg, 0.807 mmol) in MeCN (10 mL) was treated with 1,3-dibromopropane (0.145 mL, 1.210 mmol) and the mixture was heated at 70 °C for 18 h. The mixture was cooled, evaporated to dryness, and partitioned between DCM (40 mL) and water (20 mL). The organic phase was evaporated to dryness and the product purified by MDAP (formic acid) to give the title compound (117 mg, 0.231 mmol, 57% yield). LCMS (high pH A): Rt = 1.37 min, MH + =506, 508, 510.

[0575] Description 116 1-(4-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)phenyl)piperidin-3-yl 4-methylbenzenesulfonate (D116) A mixture of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(3-hydroxypiperidin-1-yl)benzamide (can be prepared as described in Description 87; 73.1 mg, 0.161 mmol) and sodium hydride, 60 wt% (26 mg, 0.650 mmol) was stirred in THF (5 mL) at 60 °C for 15 min. Next, 4-methylbenzenesulfonyl chloride (125 mg, 0.656 mmol) was added, and the mixture was stirred at 60 °C for 4 h. An additional 60 wt% sodium hydride (37.1 mg, 0.928 mmol) was added, and the reaction mixture was stirred at 60 °C for 5 min. Next, 4-methylbenzenesulfonyl chloride (168 mg, 0.881 mmol) was added, and the mixture was stirred at 60 °C for 1 h. Sodium hydride (37.1 mg, 0.928 mmol) was added again at 60°C, and the reaction mixture was stirred at 60°C for 5 minutes. 4-Methylbenzenesulfonyl chloride (165 mg, 0.866 mmol) was then added, and the mixture was stirred at 60°C for 1.5 hours. The reaction mixture was allowed to cool for 16 hours. The reaction mixture was partitioned between EtOAc (15 mL) and water (15 mL). The aqueous phase was separated. The organic phase was washed with water (10 mL) and brine (10 mL). The organic phase was dried and evaporated. The residue was chromatographed [0-50% cyclohexane / EtOAc] to give the title compound as a clear gum (22 mg, 0.036 mmol, 22% yield). LCMS (formic acid A): Rt = 1.38 min, MH + =608, 610.

[0576] Description 117 1-(5-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyrimidin-2-yl)piperidine-4-carboxylic acid (D117) N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidine-5-carboxamide (can be prepared as described in Description 81; 875 mg, 1.862 mmol) was dissolved in DCM (12 mL), Dess-Martin periodinane (1100 mg, 2.59 mmol) was added, and the mixture was stirred at room temperature for 4 h and then evaporated in vacuo. The crude material was suspended in DCM (10 mL), filtered, and the filtrate was purified by chromatography on a 40 g silica column eluting with 0–100% EtOAc / cyclohexane. Appropriate fractions were combined, and the solvent was evaporated in vacuo. The residue was suspended in 10% MeOH in DCM (20 mL) and washed with 0.5 M NaOH (aq) (2 × 10 mL) (4 mL of brine was added to aid separation). The basic washings were acidified to pH=2 with 2M HCl (aq) and extracted with DCM (2×10 mL). The organic extracts were combined and passed through a hydrophobic frit to give the title compound as an off-white solid (37 mg, 0.076 mmol, 4% yield). LCMS (formic acid A): Rt=1.09 min, MH + =484, 486.

[0577] Description 118 1-(5-(((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)carbamoyl)pyrimidin-2-yl)piperidine-4-carboxylic acid (D118) N-((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)-2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidine-5-carboxamide (can be prepared as described in Description 78; 922 mg, 1.831 mmol) was dissolved in DCM (12 mL), Dess-Martin periodinane (1100 mg, 2.59 mmol) was added, and the mixture was stirred at room temperature for 4 h and then evaporated in vacuo. The crude material was suspended in DCM (10 mL), filtered, and the filtrate was purified by chromatography on a 40 g silica column eluting with 0–100% EtOAc / cyclohexane. Appropriate fractions were combined, and the solvent was evaporated in vacuo. The residue was suspended in 10% MeOH in DCM (20 mL) and washed with 0.5 M NaOH (aq) (2 × 10 mL) (4 mL of brine was added to aid separation). The basic washings were acidified to pH=2 with 2M HCl (aq) and extracted with DCM (2×10 mL). The organic extracts were combined and passed through a hydrophobic frit to give the title compound as an off-white solid (37 mg, 0.076 mmol, 4% yield). LCMS (formic acid A): Rt=1.13 min, MH + =518.

[0578] Description 119 1-(5-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)pyrimidin-2-yl)piperidine-4-carboxylic acid (D119) N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidine-5-carboxamide (can be prepared as described in Description 74; 648 mg, 1.301 mmol) was dissolved in DCM (8 mL) and Dess-Martin periodinane (1.2 g, 2.83 mmol) was added. The mixture was then stirred at room temperature for 4 h, suspended in DCM (10 mL), and filtered through Celite. The filtrate was purified on a 40 g silica cartridge using a gradient of 0 to 100% EtOAc in cyclohexane over 12 column volumes. Appropriate fractions were combined and the solvent was evaporated in vacuo. The residue was suspended in 10% MeOH in DCM (20 mL) and washed with 0.5 M NaOH (aq) (2 x 10 mL) (4 mL of brine was added to aid separation). The basic washings were acidified to pH = 2 with 2 M HCl (aq) and extracted with DCM (2 x 10 mL). The organic extracts were combined and passed through a hydrophobic frit to give the title compound as an off-white solid (25 mg, 0.049 mmol, 3% yield). LCMS (formic acid A): Rt = 1.09 min, MH + =512, 514.

[0579] Description 120 tert-Butyl 4-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperazine-1-carboxylate (D120) A mixture of 6-chloro-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide (can be prepared as described in Description 90; 750 mg, 1.917 mmol), tert-butyl piperazine-1-carboxylate (714 mg, 3.83 mmol), and DIPEA (743 mg, 1.004 mL, 5.75 mmol) in DMSO (10 mL) was stirred at 60° C. for 3 hours. The reaction mixture was allowed to stand at room temperature overnight. The reaction mixture was diluted with water (25 mL) and stirred for 30 minutes. The precipitate was collected by filtration, washed with water, and dried. The solid was suspended in diethyl ether (25 mL). The suspension was stirred for 10 minutes. The solid was collected by filtration and dried to give the title compound as a colorless solid (600 mg, 1.109 mmol, 58% yield). LCMS (high pH A): Rt=1.29 min, MH + =541.

[0580] Description 121 2,2,2-Trifluoroacetic acid N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(piperazin-1-yl)pyridazine-3-carboxamide (D121) To a stirred solution of tert-butyl 4-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperazine-1-carboxylate (can be prepared as described in Description 120; 580 mg, 1.072 mmol) in DCM (4 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with diethyl ether (25 mL) and stirred for 30 min. The supernatant liquid was removed by decantation. The residue was triturated with diethyl ether to give the title compound as a colorless solid (521 mg, 0.939 mmol, 88% yield). LCMS (high pH A): Rt=1.01 min, MH + =441.

[0581] Description 122 tert-Butyl (2-(2-(4-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperazin-1-yl)ethoxy)ethyl)carbamate (D122) A mixture of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(piperazin-1-yl)pyridazine-3-carboxamide trifluoroacetate (can be prepared as described in Description 121; 60 mg, 0.108 mmol), tert-butyl (2-(2-bromoethoxy)ethyl)carbamate (31.9 mg, 0.119 mmol), and sodium bicarbonate (45.4 mg, 0.541 mmol) in DMF (3 mL) was heated at 60 °C for 2 h. The cooled mixture was treated with DCM (20 mL) and washed with water (10 mL). The organic phase was evaporated to dryness, and the product was directly subjected to purification by MDAP (formic acid) to give the title compound (45 mg, 0.072 mmol, 66% yield). LCMS (formic acid A): Rt = 0.85 min, MH + =628.

[0582] Description 123 2,2,2-Trifluoroacetic acid 6-(4-(2-(2-aminoethoxy)ethyl)piperazin-1-yl)-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide (D123) A solution of tert-butyl (2-(2-(4-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperazin-1-yl)ethoxy)ethyl)carbamate (can be prepared as described in Description 122; 54 mg, 0.086 mmol) in DCM (5 mL) was treated with TFA (5 mL) and stirred at ambient temperature for 1 h. The mixture was evaporated to dryness to give the title compound (36 mg, 0.056 mmol, 65% yield), which was used without further purification. LCMS (high pH A): Rt=1.02 min, MH + =528, 530.

[0583] Description 124 1-(4-Nitrophenyl)piperidin-4-ol (D124) A stirred solution of 1-fluoro-4-nitrobenzene (1.4 g, 1.053 mL, 9.92 mmol), triethylamine (1.004 g, 1.383 mL, 9.92 mmol), and piperidin-4-ol (1.004 g, 9.92 mmol) in DMSO (20 mL) was heated to 80° C. for 3 h, then cooled to room temperature. The yellow solution was diluted with EtOAc (100 mL) and water (100 mL). The layers were separated and the organic layer was washed with water (100 mL), filtered through a hydrophobic frit, and concentrated in vacuo to give the title compound as a yellow solid (2.08 g, 9.36 mmol, 94% yield). LCMS (high pH A): Rt=0.81 min, MH + =223.

[0584] Description 125 (1-(4-nitrophenyl)piperidin-4-yl)methanol (D125) A stirred solution of 1-fluoro-4-nitrobenzene (1.4 g, 1.053 mL, 9.92 mmol) and piperidin-4-ylmethanol (2.5 g, 21.71 mmol) in DMSO (20 mL) was heated to 80° C. for 45 min, then cooled to room temperature. The yellow solution was poured into 200 mL of water, causing a precipitate to form. The mixture was filtered, washed with water (30 mL), and the solid (washed into a new flask with MeOH) was concentrated in vacuo to give the title compound as a light yellow solid (2.14 g, 9.06 mmol, 91% yield). LCMS (high pH A): Rt=0.90 min, MH + =237.

[0585] Description 126 2-(1-(4-nitrophenyl)piperidin-4-yl)ethan-1-ol (D126) A stirred solution of 1-fluoro-4-nitrobenzene (1.4 g, 1.053 mL, 9.92 mmol), triethylamine (1.004 g, 1.383 mL, 9.92 mmol), and 2-(piperidin-4-yl)ethan-1-ol (1.282 g, 9.92 mmol) in DMSO (20 mL) was heated to 80° C. for 16 h. The orange solution was cooled to room temperature and diluted with EtOAc (100 mL) and water (100 mL). The layers were separated and the organic layer was washed with water (100 mL), filtered through a hydrophobic frit, and concentrated in vacuo to give the title compound as a yellow solid (2.60 g, 10.39 mmol, 105% yield). LCMS (high pH A): Rt=0.97 min, MH + =251.

[0586] Description 127 1-(4-aminophenyl)piperidin-4-ol (D127) A solution of 1-(4-nitrophenyl)piperidin-4-ol (can be prepared as described in Description 124; 2.08 g, 9.36 mmol) in ethanol (100 mL) was added under nitrogen to a flask containing palladium on carbon (10% by weight) (0.996 g, 0.936 mmol), the flask was charged with hydrogen gas, and stirred under hydrogen for 22 hours. The black mixture was filtered through Celite, the filter was washed with ethanol (200 mL), and the filtrate was concentrated in vacuo to give the title compound as a very pale pink solid (1.73 g, 9.00 mmol, 96% yield). LCMS (high pH A): Rt = 0.48 min, MH + =193.

[0587] Description 128 (1-(4-aminophenyl)piperidin-4-yl)methanol (D128) A stirred mixture of (1-(4-nitrophenyl)piperidin-4-yl)methanol (prepared as described in Description 125; 2.14 g, 9.06 mmol), ammonium chloride (1.453 g, 27.2 mmol), and iron (1.517 g, 27.2 mmol) in water (15.10 mL) and ethanol (75 mL) was heated under reflux for 24 hours. The mixture was filtered through Celite and washed with ethanol (100 mL). After removing the ethanol in vacuo, the residue was diluted with EtOAc (200 mL) and water (200 mL), the layers were separated, and the organic layer was discarded. The aqueous layer was diluted with saturated aqueous sodium bicarbonate (100 mL) and then extracted with EtOAc (2 × 200 mL) followed by DCM (2 × 200 mL). The combined organic fractions were dried, filtered, and concentrated in vacuo to give the title compound as a black solid (981 mg, 4.76 mmol, 53% yield). LCMS (high pH A): Rt=0.56 min, MH + =207.

[0588] Description 129 2-(1-(4-aminophenyl)piperidin-4-yl)ethan-1-ol (D129) Under nitrogen, a solution of 2-(1-(4-nitrophenyl)piperidin-4-yl)ethan-1-ol (can be prepared as described in Description 126; 2.6 g, 10.39 mmol) in ethanol (100 mL) was added to a flask containing palladium on carbon (10% by weight) (1.105 g, 1.039 mmol), the flask was charged with hydrogen gas, and stirred for 24 h. The black mixture was filtered through Celite, the filter was washed with ethanol (200 mL), and the filtrate was concentrated in vacuo to give the title compound as a pale pink solid (2.01 g, 9.12 mmol, 88% yield). LCMS (high pH A): Rt = 0.62 min, MH + =221.

[0589] Description 130 Methyl 2-((4-(4-hydroxypiperidin-1-yl)phenyl)amino)-2-methylpropanoate (D130) To 1-(4-aminophenyl)piperidin-4-ol (prepared as described in Description 127; 1.37 g, 7.13 mmol) and methyl 2-bromo-2-methylpropanoate (2.305 mL, 17.81 mmol) was added DIPEA (3.68 g, 4.98 mL, 28.5 mmol), and the mixture was stirred at 120 °C for 1 h before being cooled to room temperature. The mixture was dissolved in MeOH (5 mL), EtOAc (120 mL), and water (120 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (120 mL), and the combined organic layers were dried, filtered through a hydrophobic frit, and concentrated in vacuo. The residue was purified using an 80 g silica column eluting with 0–100% EtOAc:cyclohexane, and the desired fractions were combined and concentrated in vacuo to give the title compound as a brown oil (1.83 g, 6.26 mmol, 88% yield). LCMS (high pH A): Rt=0.77 min, MH + =293.

[0590] Description 131 Methyl 2-((4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)amino)-2-methylpropanoate (D131) To (1-(4-aminophenyl)piperidin-4-yl)methanol (prepared as described in Description 128; 747 mg, 3.62 mmol) and methyl 2-bromo-2-methylpropanoate (1.639 g, 1171 μL, 9.05 mmol) was added DIPEA (1.872 g, 2530 μL, 14.48 mmol), and the mixture was stirred at 120 °C for 1 h before being cooled to room temperature. The mixture was dissolved in MeOH (5 mL), EtOAc (75 mL), and water (75 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (75 mL), and the combined organic layers were filtered through a hydrophobic frit and concentrated in vacuo. The residue was purified using a 40 g silica column eluting with 0–100% EtOAc:cyclohexane. The desired fractions were combined and concentrated in vacuo to give the title compound as a brown oil (683 mg, 2.229 mmol, 62% yield). LCMS (high pH A): Rt=0.82 min, MH + =307.

[0591] Description 132 Methyl 2-((4-(4-(2-hydroxyethyl)piperidin-1-yl)phenyl)amino)-2-methylpropanoate (D132) To 2-(1-(4-aminophenyl)piperidin-4-yl)ethan-1-ol (can be prepared as described in Description 129; 1.77 g, 8.03 mmol) and methyl 2-bromo-2-methylpropanoate (3.64 g, 2.60 mL, 20.08 mmol) was added DIPEA (4.15 g, 5.61 mL, 32.1 mmol), and the mixture was stirred at 120 °C for 1 h before being cooled to room temperature. The mixture was dissolved in MeOH (10 mL), EtOAc (120 mL), and water (120 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (120 mL), and the combined organic layers were filtered through a hydrophobic frit and concentrated in vacuo. The residue was purified using an 80 g silica column eluting with 0-100% EtOAc:cyclohexane, and the desired fractions were combined and concentrated in vacuo to give the title compound as a brown oil that solidified upon standing (2.58 g, 8.05 mmol, 100% yield). LCMS (high pH A): Rt=0.89 min, MH + =321.

[0592] Description 133 4-(3-(4-(4-hydroxypiperidin-1-yl)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (D133) A stirred solution of methyl 2-((4-(4-hydroxypiperidin-1-yl)phenyl)amino)-2-methylpropanoate (can be prepared as described in Description 130; 0.819 g, 2.80 mmol) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (0.639 g, 2.80 mmol) in isopropyl acetate (10.00 mL) and DMSO (5 mL) was heated to 80 °C for 2 h, then cooled to room temperature. The golden solution was diluted with EtOAc (50 mL) and water (50 mL) and the layers were separated. The organic layer was filtered through a hydrophobic frit and concentrated in vacuo. The residue was purified using a 40 g silica column eluting with 0-100% EtOAc:cyclohexane. The desired fractions were combined and concentrated in vacuo to give the title compound as a yellow gum (1.33 g, 2.72 mmol, 97% yield). LCMS (high pH A): Rt = 1.15 min, MH + =489.

[0593] Description 134 4-(3-(4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (D134) A stirred solution of methyl 2-((4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)amino)-2-methylpropanoate (can be prepared as described in Description 131; 584 mg, 1.906 mmol) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (435 mg, 1.906 mmol) in isopropyl acetate (10.00 mL) and DMSO (5 mL) was heated to 80 °C for 2 h and then cooled to room temperature. The golden solution was diluted with EtOAc (40 mL) and water (40 mL) and the layers were separated. The organic layer was filtered through a hydrophobic frit and concentrated in vacuo. The residue was purified using a 40 g silica column eluting with 0–100% EtOAc:cyclohexane; the desired fractions were combined and concentrated in vacuo to give the title compound as a yellow gum (906 mg, 1.803 mmol, 95% yield). LCMS (high pH A): Rt=1.20 min, MH + =503.

[0594] Description 135 4-(3-(4-(4-(2-hydroxyethyl)piperidin-1-yl)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (D135) A stirred solution of methyl 2-((4-(4-(2-hydroxyethyl)piperidin-1-yl)phenyl)amino)-2-methylpropanoate (can be prepared as described in Description 132; 0.974 g, 3.04 mmol) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (0.694 g, 3.04 mmol) in isopropyl acetate (10.00 mL) and DMSO (5 mL) was heated to 80 °C for 2 h, then cooled to room temperature. The golden solution was diluted with EtOAc (40 mL) and water (40 mL), and the layers were separated. The organic layer was filtered through a hydrophobic frit and concentrated in vacuo. The residue was purified using a 40 g silica column eluting with 0–100% EtOAc:cyclohexane; the desired fractions were combined and concentrated in vacuo to give the title compound as a yellow solid foam (1.20 g, 2.323 mmol, 76% yield). LCMS (high pH A): Rt=1.26 min, MH + =517.

[0595] Description 136 4-Methylbenzenesulfonic acid 1-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenyl)piperidin-4-yl ester (D136) To a stirred solution of 4-(3-(4-(4-hydroxypiperidin-1-yl)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (can be prepared as described in Description 133; 1.33 g, 2.72 mmol) and 4-methylbenzenesulfonyl chloride (1.557 g, 8.17 mmol) in DCM (20 mL) was added triethylamine (1.102 g, 1.518 mL, 10.89 mmol) and then stirred for 18 h. The pale yellow mixture was diluted with EtOAc (100 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified using a 40 g silica column eluting with 0-100% EtOAc:cyclohexane, and the desired fractions were combined and concentrated in vacuo to give the title compound as an orange gum that solidified on standing (750 mg, 1.167 mmol, 43% yield). LCMS (high pH A): Rt=1.43 min, MH + =643.

[0596] Description 137 4-Methylbenzenesulfonic acid (1-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenyl)piperidin-4-yl)methyl ester (D137) To a stirred solution of 4-(3-(4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (can be prepared as described in Description 134; 906 mg, 1.803 mmol) and 4-methylbenzenesulfonyl chloride (1031 mg, 5.41 mmol) in DCM (20 mL) was added triethylamine (730 mg, 1.005 mL, 7.21 mmol) and then stirred for 16 h. The light brown solution was diluted with EtOAc (70 mL) and water (70 mL), and brine (30 mL). The layers were separated and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were dried, filtered through a hydrophobic frit, and concentrated in vacuo. The crude product was purified using a 40 g silica column eluting with 0-70% EtOAc:cyclohexane, and the desired fractions were combined and concentrated in vacuo to give the title compound as a yellow gum (904 mg, 1.376 mmol, 76% yield). LCMS (high pH A): Rt = 1.46 min, MH + =657.

[0597] Description 138 2-(1-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenyl)piperidin-4-yl)ethyl 4-methylbenzenesulfonate (D138) To a stirred solution of 4-(3-(4-(4-(2-hydroxyethyl)piperidin-1-yl)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (can be prepared as described in Description 135; 1.20 g, 2.323 mmol) and 4-methylbenzenesulfonyl chloride (1.329 g, 6.97 mmol) in DCM (20 mL) was added triethylamine (0.94 g, 1.295 mL, 9.29 mmol) and then stirred for 18 h. The pale yellow mixture was diluted with EtOAc (100 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified using a 40 g silica column eluting with 0-70% EtOAc:cyclohexane, and the desired fractions were combined and concentrated in vacuo to give the title compound as a pale yellow solid foam (1.39 g, 2.072 mmol, 89% yield). LCMS (high pH A): Rt = 1.49 min, MH + =671.

[0598] Description 139 4-(3-(4-(3-hydroxypropoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (D139) To a stirred suspension of 4-(3-(4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (commercially available, for example, from Ambeed; 200 mg, 0.493 mmol) and potassium carbonate (170 mg, 1.233 mmol) in DMF (5 mL) was added 3-bromopropan-1-ol (137 mg, 0.089 mL, 0.987 mmol) and then stirred for 64 h. The mixture was diluted with EtOAc (20 mL) and water (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (30 mL). The combined organic layers were filtered through a hydrophobic frit and concentrated in vacuo. The crude product was loaded onto a 24 g silica column and eluted with 0-100% EtOAc:cyclohexane. The desired fractions were combined and concentrated in vacuo to give the title compound as a colorless oil (262 mg, 0.565 mmol, 115% yield). LCMS (high pH A): Rt = 1.16 min, MH + =464.

[0599] Description 140 4-(3-(4-(4-hydroxybutoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (D140) To a stirred suspension of 4-(3-(4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (commercially available, for example, from Ambeed; 200 mg, 0.493 mmol) and potassium carbonate (170 mg, 1.233 mmol) in DMF (5 mL) was added 4-bromobutan-1-ol (0.104 mL, 0.987 mmol) and then stirred for 64 h. Additional 4-bromobutan-1-ol (0.104 mL, 0.987 mmol) was added, followed by additional potassium carbonate (170 mg, 1.233 mmol) and stirred for 24 h. The pale yellow mixture was heated to 60° C. for 5 h and then cooled to room temperature. The final addition of potassium carbonate (170 mg, 1.233 mmol) and 4-bromobutan-1-ol (0.104 mL, 0.987 mmol) was followed by stirring for 16 h. The pale yellow solution was diluted with EtOAc (20 mL) and water (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were filtered through a hydrophobic frit and concentrated in vacuo. The crude product was loaded onto a 24 g silica column with minimal DCM and eluted with 0-100% EtOAc:cyclohexane. The desired fractions were combined and concentrated in vacuo to give the title compound as a colorless oil (151 mg, 0.316 mmol, 64% yield). LCMS (high pH A): Rt=1.20 min, MH + =478.

[0600] Description 141 4-Methylbenzenesulfonate 3-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenoxy)propyl (D141) To a stirred solution of 4-(3-(4-(3-hydroxypropoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (can be prepared as described in Description 139; 210 mg, 0.453 mmol) and 4-methylbenzenesulfonyl chloride (259 mg, 1.359 mmol) in DCM (5 mL) was added triethylamine (183 mg, 0.253 mL, 1.812 mmol) followed by stirring for 5 h. The pale yellow mixture was diluted with EtOAc (15 mL) and water (15 mL). The layers were separated and the aqueous layer was extracted with EtOAc (15 mL). The combined organic layers were filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified using a 12 g silica column eluting with 0-70% EtOAc:cyclohexane, and the desired fractions were combined and concentrated in vacuo to give the title compound as a colorless gum (238 mg, 0.385 mmol, 85% yield). LCMS (high pH A): Rt = 1.43 min, MH + =618.

[0601] Description 142 4-Methylbenzenesulfonate 4-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenoxy)butyl ester (D142) To a stirred solution of 4-(3-(4-(4-hydroxybutoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (can be prepared as described in Description 140; 151 mg, 0.316 mmol) and 4-methylbenzenesulfonyl chloride (181 mg, 0.949 mmol) in DCM (3 mL) was added triethylamine (128 mg, 0.176 mL, 1.265 mmol) followed by stirring for 5 h. The pale yellow mixture was diluted with EtOAc (15 mL) and water (15 mL). The layers were separated and the aqueous layer was extracted with EtOAc (15 mL). The combined organic layers were filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified using a 12 g silica column eluting with 0-70% EtOAc:cyclohexane, and the desired fractions were combined and concentrated in vacuo to give the title compound as a colorless gum (154 mg, 0.244 mmol, 77% yield). LCMS (high pH A): Rt = 1.46 min, MH + =632.

[0602] Description 143 (2R,5S)-tert-butyl 4-(3-chloro-4-cyanophenyl)-2,5-dimethylpiperazine-1-carboxylate (D143) A mixture of 2-chloro-4-fluorobenzonitrile (5 g, 32.1 mmol), potassium carbonate (8.88 g, 64.3 mmol), and tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (6 g, 28.0 mmol) in DMSO (40 mL) and water (4 mL) was stirred at 60 °C for 46 h. The mixture was allowed to cool to room temperature, diluted with water (40 mL), and then extracted with EtOAc (2 × 40 mL). The organic extracts were combined, washed with brine (50 mL), and passed through a hydrophobic frit. The filtrate was concentrated in vacuo, and the gum was loaded in CHCl (10 mL) and purified on a 120 g silica cartridge using a gradient of 0 to 50% EtOAc in cyclohexane over 10 column volumes. Appropriate fractions were combined, and the solvent was evaporated in vacuo to give the title compound as a pale yellow solid (7.2 g, 20.58 mmol, 64% yield). This material was used in the next step without further purification. LCMS (high pH A): Rt=1.36 min, M- t Bu + 294.0, 296.0.

[0603] Description 142 2-Chloro-4-((2S,5R)-2,5-dimethylpiperazin-1-yl)benzonitrile (D142) To a solution of tert-butyl (2R,5S)-4-(3-chloro-4-cyanophenyl)-2,5-dimethylpiperazine-1-carboxylate (7.2 g, 20.58 mmol, can be prepared as described in Description 143) in DCM (40 mL) was added 4 M HCl in dioxane (20 mL, 80 mmol), and the mixture was stirred overnight at room temperature. The resulting suspension was diluted with MTBE (50 mL) and filtered to give a hygroscopic solid. This solid was dissolved in water (50 mL), basified with solid potassium carbonate (10 g), and then extracted with EtOAc (2 × 50 mL). The organic layer was dried and evaporated in vacuo to give the title compound as a pale yellow gum (4.7 g, 18.82 mmol, 91% yield). LCMS (high pH A): Rt = 0.95 min, MH + =250, 252.

[0604] Description 143 2-Chloro-4-((2R,5S)-2,5-dimethylpiperazin-1-yl)benzonitrile (D143) The material was prepared in a similar manner to D142 from tert-butyl (2S,5R)-2,5-dimethylpiperazine-1-carboxylate (6.89 g) to give the title compound as a yellow gum (3.5 g). LCMS (high pH A): Rt=0.96 min, MH + =250.0, 252.0.

[0605] Description 144 4-((5-nitropyridin-2-yl)oxy)butan-1-ol (D144) To a solution of butane-1,4-diol (1.137 g, 12.62 mmol) in THF (10 mL) was added sodium hydride (0.631 g, 15.77 mmol), and the mixture was stirred for 10 minutes. Then, 2-chloro-5-nitropyridine (1 g, 6.31 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was quenched with water and extracted with EtOAc. The organic layer was dried and evaporated in vacuo to give a pale yellow liquid. This was dissolved in DCM and loaded onto a 40 g silica column, then eluted with 0-100% EtOAc / cyclohexane. The product-containi...

Claims

1. Compounds of formula (I) or their tautomers or salts thereof: 【Chemistry 1】 [In the formula, X １ is N or C-R ２ where R ２ is selected from the group consisting of hydrogen, halogen, C １－４ alkyl, C １－４ haloalkyl, C １－４ alkoxy, -CONR ５ R ６ and -(CONR ３ R ４ ), m (L) p (TBM) q; X ４ , C-R ７ Or N, where R ７ is hydrogen, halogen, C １－３ Alkyl, C １－３ Haloalkyl and CC １－３ Selected from the group consisting of alkoxys; X ２ and X ３ It is independently selected from N or CH; X １５ and X ２２ It is independently selected from N or C; R ３ and R ４ These, together with the nitrogen atoms to which they are bonded, form monocyclic or spirocyclic nitrogen-containing heterocyclic rings, or R ３ is H or C １－４ It is alkyl, R ４ is, -(CH ２ ) ｎ R ２８ And here, R ２８ It is a monocyclic or spirocyclic nitrogen-containing heterocyclic ring; n is either 0 or 1; R ５ and R ６ These are, independently, hydrogen or C １－４ Selected from alkyl groups; R １ C １－４ Alkyl, C １－４ Haloalkyl, C １－４ It is an alkoxy or a base of formula (II), where, ＊ represents the bonding position with the compound of formula (I): 【Chemistry 2】 a and b are independently either 0 or 1; X １６ is N or CH; X １７ CR ３４ R ３５ And here, R ３４ and R ３５ They, together with the carbon atoms to which they are bonded, form a cyclobutyl ring, or R ３４ is, -(CHR ３６ )r-, or a bond with a compound of formula (I), R ３５ is either hydrogen or a halogen; X ２５ CR １２ R １３ or O; r is 0, 1, or 2; a is 0, 1, or 2, and b and j are independently 0 or 1, provided that b and j cannot both be 0; R ３６ is hydrogen or methyl; R ８ , R ９ , R １０ , R １１ , R １２ , R １３ , R １４ and R １５ These are independently selected from hydrogen or halogen; L is a chemical linker; The TBM is the target binding site; m, p, and q are independently 0 and 1; Here, X １５ If X is N, ２２ is C; Here, X １ ga- (CONR ３ R ４ If )m(L)p(TBM)q, then R １ is C １－４ Alkyl, C １－４ Haloalkyl or C １－４ It is an alkoxy.

2. Equation (Ia): 【Transformation 3】 [In the formula, X １ is N or C-R ２ And here, R ２ is hydrogen, halogen, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy and -CONR ５ R ６ Selected from the group consisting of; X ４ , C-R ７ Or N, where R ７ is hydrogen, halogen, C １－３ Alkyl, C １－３ Haloalkyl and CC １－３ Selected from the group consisting of alkoxys; X ２ and X ３ It is independently selected from N or CH; X １５ and X ２２ It is independently selected from N or C; r is 0, 1, or 2; a is 0, 1, or 2, and b and j are independently 0 or 1, provided that b and j cannot both be 0; X １６ is N or CH; X １８ CR ３５ And here, R ３５ is hydrogen or halogen; X ２５ is either CR １２ R １３ or O; R ５ and R ６ These are, independently, hydrogen or C １－４ Selected from alkyl groups; R ８ 、 R ９ 、 R １０ 、 R １１ 、 R １２ 、 R １３ 、 R １４ 、 R １５ 以及 R ３５ 各自独立地选自氢或卤素; R ３６ is hydrogen or methyl; L is a chemical linker; The TBM is the target binding site; p and q are independently 0 and 1; Here, X １５ If X is N, ２２ It is CH. A compound of formula (I) according to claim 1, or a tautomer thereof, or a salt thereof, having the above characteristics.

3. X １ A compound of formula (Ia) according to claim 2, or a tautomer thereof, or a salt thereof, wherein is N or CH.

4. X ４ CR ７ The compound of formula (Ia) according to claim 2, or a tautomer thereof, or a salt thereof.

5. X ４ A compound of formula (Ia) according to claim 2, or a tautomer thereof, or a salt thereof, wherein is N.

6. X ２ A compound of formula (Ia) according to claim 2, or a tautomer thereof, or a salt thereof, wherein CH is present.

7. X ３ A compound of formula (Ia) according to claim 2, or a tautomer thereof, or a salt thereof, wherein CH is present.

8. X １５ A compound of formula (Ia) according to claim 2, or a tautomer thereof, or a salt thereof, wherein C is C.

9. X ２２ A compound of formula (Ia) according to claim 2, or a tautomer thereof, or a salt thereof, wherein is N.

10. X １６ N is X ２５ CR １２ R １３ A compound of formula (Ia) according to claim 2, or a tautomer thereof, or a salt thereof, wherein j is 1 and a and b are independently 0 or 1.

11. A compound of formula (Ia) according to claim 2, or a tautomer thereof, or a salt thereof, wherein r is 0.

12. R ８ , R ９ and R ３５ These are independently selected from hydrogen or halogen; R １０ , R １１ , R １２ , R １３ , R １４ and R １５ A compound of formula (Ia) according to claim 2, or a tautomer thereof, or a salt thereof, wherein each of the atoms is hydrogen.

13. Formula (Iaaaa): 【Chemistry 4】 A compound of formula (Ia) according to claim 2, or a tautomer thereof, or a salt thereof, having the above.

14. Formula (Ib): 【Transformation 5】 [In the formula, R １ C １－４ Alkyl, C １－４ Haloalkyl or C １－４ It is an alkoxy, where the C １－４ Alkyl is a single C １－４ They may also be substituted with alkoxy groups; X ２ and X ３ It is independently selected from N or CH; X １５ and X ２２ It is independently selected from N or C; X ４ , C-R ７ Or N, where R ７ is hydrogen, halogen, C １－３ Alkyl, C １－３ Haloalkyl and CC １－３ Selected from the group consisting of alkoxys; R ３ and R ４ These, together with the nitrogen atoms to which they are bonded, form monocyclic or spirocyclic nitrogen-containing heterocyclic rings, or R ３ is H or C １－４ It is alkyl, R ４ is, -(CH ２ ) ｎ R ２８ And here, R ２８ It is a monocyclic or spirocyclic nitrogen-containing heterocyclic ring; m is either 0 or 1; n is either 0 or 1; L is a chemical linker; The TBM is the target binding site; p and q are independently 0 and 1; Here, X １５ If X is N, ２２ It is CH. A compound of formula (I) according to claim 1, or a tautomer thereof, or a salt thereof, having the above characteristics.

15. X ４ A compound of formula (Ib) according to claim 14, or a tautomer thereof, or a salt thereof, wherein is N or CH.

16. X ４ A compound of formula (Ib) according to claim 15, or a tautomer thereof, or a salt thereof, wherein CH is present.

17. X ２ A compound of formula (Ib) according to claim 14, or a tautomer thereof, or a salt thereof, wherein CH is present.

18. X ３ A compound of formula (Ib) according to claim 14, or a tautomer thereof, or a salt thereof, wherein CH is present.

19. X １５ A compound of formula (Ib) according to claim 14, or a tautomer thereof, or a salt thereof, wherein C is C.

20. X ２２ A compound of formula (Ib) according to claim 14, or a tautomer thereof, or a salt thereof, wherein is N.

21. A compound of formula (Ib) according to claim 14, or a tautomer thereof, or a salt thereof, wherein m is 1.

22. R ３ is H or C １－４ It is alkyl, R ４ ga- (CH ２ ) ｎ R ２８ And here, R ２８ The compound of formula (Ib) according to claim 14, or a tautomer thereof, or a salt thereof, wherein the compound is a monocyclic nitrogen-containing heterocyclic ring.

23. Group NR ３ R ４ The structure is as follows: 【Transformation 6】 (In the formula, an asterisk indicates the bond position with the carbonyl group, and # indicates the bond point with L.) A compound of formula (Ib) according to claim 14, or a tautomer thereof, or a salt thereof, having a structure selected from the above.

24. R １ C １－４ A compound of formula (Ib) according to claim 14, or a tautomer thereof, or a salt thereof, which is alkyl.

25. R １ A compound of formula (Ib) according to claim 24, or a tautomer thereof, or a salt thereof, wherein isopropyl.

26. Formula (Ibbbb): 【Transformation 7】 A compound of formula (Ib) according to claim 14, or a tautomer thereof, or a salt thereof, having the above.

27. A compound of formula (I), (Ia), (Iaaaa), (Ib), (Ibbbb) according to any one of claims 1 to 26, or a tautomer thereof, or a salt thereof, wherein q is 1.

28. A compound of formula (I), (Ia), (Iaaaa), (Ib), (Ibbbb) according to claim 27, or a tautomer thereof, or a salt thereof, wherein TBM is the androgen receptor binding moiety.

29. A pharmaceutical composition comprising the compound described in claim 27 or a tautomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

30. The pharmaceutical composition according to claim 29, wherein TBM is an androgen receptor binding portion.

31. A pharmaceutical composition for use in the treatment of cancer, benign prostatic hyperplasia, ovarian cyst, polycystic ovary syndrome, or Kennedy disease, comprising the compound described in claim 28, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

32. Use of the compound according to claim 28, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a drug for use in the treatment of cancer, benign prostatic hyperplasia, ovarian cyst, polycystic ovary syndrome, or Kennedy disease.

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