2, 4-dioxotetrahydropyrimidinyl derivatives as degradation determinants in PROTAC

Abstract

The invention provides a series of cerebron combined 2, 4-dioxotetrahydropyrimidinyl derivatives and an application of the cerebron combined 2, 4-dioxotetrahydropyrimidinyl derivatives as a degradation determinant in PROTAC (Protein Reactive Therapeutic Acid). Also disclosed are androgen receptors (PROTACs) containing a 2, 4-dioxotetrahydropyrimidinyl degradation determinant, and the medical use of these PROTACs. # imgabs0 #

Description

Technical Field

[0001] The present invention provides a series of cereblon-binding 2,4-dioxotetrahydropyrimidinyl derivatives and their use as degrons in PROTACs. Also disclosed are androgen receptor PROTACs containing 2,4-dioxotetrahydropyrimidinyl degrons and the medical uses of these PROTACs. Background Art

[0002] The ubiquitin-proteasome pathway (UPS) is a pathway that degrades regulatory proteins, as well as misfolded or abnormal proteins. It achieves this through post-translational modification of substrate proteins via the covalent attachment of ubiquitin. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases. There are over 500 known E3 ubiquitin ligases. 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 cullins 1 (ROC1). This complex recognizes naturally occurring protein substrates and catalyzes the addition of ubiquitin, thereby targeting the substrate for destruction.

[0003] The PROTAC (Proteolysis Targeting Chimera) approach hijacks the UPS to degrade proteins that would not normally be substrates. PROTAC compounds are compounds that typically consist of three parts: a part that is specifically designed to bind to the target protein (target binding part), a part that binds to the E3 ligase that can recruit a complex that can ubiquitinate the target protein (degradation determinant), and a linker that connects the two parts. Upon binding to the target, PROTAC generates a ternary complex of all the components required to ubiquitinate the target, resulting in ubiquitination and subsequent degradation of the target.

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

[0005] The PROTAC approach is a principle that can be applied generally, and it is reasonable to expect that PROTACs capable of degrading specific targets can be found using validated target binding moieties and linkers known in the art. Nevertheless, it is clear that not all PROTACs have the same activity in vitro or in vivo. There are several reasons for this, including differential absorption through the intestine, differential uptake into cells, differential pharmacokinetics, and differential ability of PROTAC molecules to form functional ternary complexes (a prerequisite for target ubiquitination and degradation). In addition, for reasons that are not yet fully understood, differential selectivity of PROTACs for their targets has been observed. Therefore, it is clear that while the PROTAC approach is a generally applicable approach, it is incorrect to view them as modular molecules, and optimization is possible by modifying each PROTAC component.

[0006] Androgens usually exert their biological effects by binding to androgen receptors (AR). In the absence of androgens, AR binds to heat shock protein 90 (Hsp90) in the cytoplasm, masking the nuclear localization signal (NLS) in this way. When androgens bind to AR. This induces conformational changes, causing Hsp90 to release, thereby exposing NLS. AR is then transferred to the nucleus, where it acts as a transcription factor (Endocrin Rev. 1987, 8 (1): 1-28; Mol Endocrinol. 2002, 16 (10), 2181-7).

[0007] It has long been known that androgens are relevant to prostate cancer. Evidence for this comes from multiple sources. First, androgens induce prostate cancer in rodent models (Noble, Cancer Res., 37, 1929-1933 (1977)): secondly, men who receive androgens in the form of synthetic steroids have a higher incidence of prostate cancer (Roberts and Essenhigh, Lancet, 2, 742 (1986) and prostate cancer will not develop after castration (Wilson and Roehrborn,, J Clin Endrocrin Metab, 84, 4324-4331, 1999). Finally, the most convincing thing is that the only effective treatment available for advanced prostate cancer is to stop using androgens, and is called androgen ablation therapy (ABT) or androgen deprivation therapy (ADT) or chemical castration. However, most patients will develop drug resistance and the disease will progress (Huber et al., .1987, Scan J Urol 104, 33-39).

[0008] Castration-resistant prostate cancer cells have undergone changes that allow them to survive castration-resistant levels of androgens. These mechanisms include AR overexpression, changes in androgen biosynthesis, expression of constitutively active AR splice variants, changes in androgen cofactors, and expression of mutant versions 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, which leads to increased sensitivity to steroid ligands or conversion of antiandrogens to agonists. The T878A mutation is associated with resistance to abiraterone acetate and hydroxyflutamide. The L702H mutation is associated with receptor disorder, that is, increased sensitivity of AR to glucocorticoids.

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

[0010] In addition to the effect of androgens in prostate cancer, androgens also play a role in other diseases. One example is ovarian cancer, in which elevated androgen levels are associated with an increased risk of ovarian cancer development (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 most 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] 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:

[0012]

[0013] in:

[0014] X1 is N or CR 2 , where R 2 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, -CONR 5 R 6 and-(CONR 3 R 4)m(L)p(TBM)q;

[0015] X4 for CR 7 or N, where R 7 Selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 alkoxy;

[0016] X2 and X3 are independently selected from N or CH;

[0017] X 15 and X 22 independently selected from N or C;

[0018] or R 3 and R 4 Together with the nitrogen atom to which they are attached, they are linked together to form a monocyclic or spirocyclic nitrogen-containing heterocycle, or R 3 H or C 1-4 Alkyl and R 4 -(CH2) n R 28 , where R 28 It is a monocyclic or spirocyclic nitrogen-containing heterocycle;

[0019] n is 0 or 1;

[0020] R 5 and R 6 are independently selected from hydrogen or C 1-4 alkyl;

[0021] R 1 C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or a group of formula (II), wherein * represents the position of attachment to the compound of formula (I):

[0022]

[0023] a and b are independently 0 or 1;

[0024] X 16 N or CH;

[0025] X 17 CR 34 R 35 , where R 34 and R 35 together with the carbon atoms to which they are attached to form a cyclobutyl ring, or wherein R 34 -(CHR 36 )r- or a bond to the compound of formula (I), and R 35 is hydrogen or halogen;

[0026] X 25 CR 12 R 13 or O;

[0027] r is 0, 1, or 2;

[0028] a is 0, 1 or 2, and b and j are independently 0 or 1, provided that b and j cannot both be 0;

[0029] R 36 is hydrogen or methyl;

[0030] R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 and R 15 independently selected from hydrogen or halogen;

[0031] L is a chemical linker;

[0032] TBM is the target binding moiety;

[0033] m, p, and q are independently 0 and 1;

[0034] When X 15 When N, then X 22 is C; and

[0035] When X1 is -(CONR 3 R 4 )m(L)p(TBM)q, then R 1 C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 Alkoxy.

[0036] For the avoidance of doubt, the double dashed line in the 5,6-bicyclic structure depicts the aromatic structure.

[0037] The pairing of a single dashed line and a single solid line in a 6-membered monocyclic ring can be a single bond or a double bond.

[0038] In one embodiment, the present invention provides a compound of formula (I), a tautomer of a compound of formula (I), or a salt thereof:

[0039]

[0040] in:

[0041] X1 is N or CR 2 , where R 2Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, -CONR 5 R 6 and-CONR 3 R 4 (L)p(TBM)q;

[0042] X4 for CR 7 or N, where R 7 Selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 alkoxy;

[0043] X2 and X3 are independently selected from N or CH;

[0044] X 15 and X 22 independently selected from N or C;

[0045] or R 3 and R 4 Together with the nitrogen atom to which they are attached, they are linked together to form a monocyclic or spirocyclic nitrogen-containing heterocycle, or R 3 H or C 1-4 Alkyl and R 4 -(CH2) n R 28 , where R 28 It is a monocyclic or spirocyclic nitrogen-containing heterocycle;

[0046] n is 0 or 1;

[0047] R 5 and R 6 Independently selected from H or C 1-4 alkyl;

[0048] R 1 C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or a group of formula (II), wherein * represents the position of attachment to the compound of formula (I):

[0049]

[0050] a and b are independently 0 or 1;

[0051] X 16 N or CH;

[0052] X 17 CR 34 R 35 , where R34 and R 35 together with the carbon atoms to which they are attached to form a cyclobutyl ring, or wherein R 34 -(CHR 36 )- or a bond to a compound of formula (I), and R 35 is H or halogen;

[0053] R 36 is hydrogen or methyl;

[0054] R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 and R 15 independently selected from H or halogen;

[0055] L is a chemical linker;

[0056] TBM is the target binding moiety;

[0057] p and q are independently 0 and 1;

[0058] When X 15 When N, X 22 is C; and

[0059] When X1 is -CONR 3 R 4 (L)p(TBM)q, then R 1 C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 Alkoxy.

[0060] The compound of formula (I), its tautomer or salt (wherein p and q are each 0) is a degron capable of binding cereblon. When the degron is incorporated into a PROTAC, the degron is able to recruit a complex capable of ubiquitinating the target protein.

[0061] In a specific embodiment, the present invention provides a degron of formula (Iaa) and (Ibb) and (Icc), a tautomer or a salt thereof, wherein X1, X2, X3, X4, X 15 、X 16 、X 22 、X 25 、R 1 、R 3 、R 4 、R 8 、R 9 、R 10 、R11 、R 12 、R 13 、R 14 、R 15 、R 35 、R 36 , a, bm, j, k, l and r are as defined in formula (I), X 18 CR 35 .1.

[0062]

[0063] In other embodiments, 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), a tautomer, or a salt thereof, wherein p is 1, is a "PROTAC."

[0064] In a specific embodiment, the present invention provides a PROTAC wherein the target binding moiety is an androgen receptor binding moiety. Also provided are pharmaceutical compositions and medical uses of androgen receptor PROTACs. Detailed Description of the Invention

[0066] definition

[0067] The term "alkyl" refers to a monovalent saturated straight or branched hydrocarbon radical having the specified number of carbon atoms. For example, the term "C 1-4 "Alkyl" refers to an alkyl group having from 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).

[0068] The term "alkoxy" refers to an -O-alkyl group, i.e., an alkyl group attached through an oxygen linking atom, wherein "alkyl" is as defined above. For example, the term "C 1-4 "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, sec-butoxy, isobutoxy, and tert-butoxy.

[0069] 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 groups contain 3 to 6 carbon atoms as member atoms in the ring. 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclobutyl, cyclopentyl, and cyclohexyl.The term "cycloalkylene" specifically refers to a divalent cycloalkyl ring.

[0070] The terms "halogen" and "halo" represent chloro, fluoro, bromo, or iodo substituents.

[0071] The term "haloalkyl" is intended to refer to a group having one or more halogen atoms (which may be the same or different) at one or more carbon atoms of an alkyl group, wherein "alkyl" is as defined above. Exemplary groups include, but are not limited to, -CF3 (trifluoromethyl), -CCl3 (trichloromethyl), 1,1-difluoroethyl, 2,2,2-trifluoroethyl, and hexafluoroisopropyl.

[0072] The term "heteroaryl" refers to a group or moiety comprising an aromatic monovalent monocyclic or bicyclic group containing 5 to 10 ring atoms, including at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. The term also includes bicyclic heteroaryl compounds containing an aromatic ring moiety fused to a heterocycloalkyl ring moiety 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 monocyclic ring as defined above composed of six 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 pyridyl, pyridazinyl, pyrazinyl, and pyrimidinyl. The term "heteroarylene" specifically refers to a divalent heteroaryl group.

[0073] 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. The heterocycle may contain one or more C(O), S(O), or SO2 groups. Bicyclic heterocycles may be fused, bridged, or spirocyclic. However, the heterocycle is not aromatic. Heterocycles containing more than one heteroatom may contain different heteroatoms. The number of ring atoms may be specified. For example, a "6-membered heterocycle" is a heterocycle as defined above composed of six ring atoms. The presence of specific heteroatoms may also be specified. For example, a "6-membered nitrogen-containing heterocycle" is a 6-membered heterocycle as defined above that contains at least one nitrogen atom. Exemplary 6-membered nitrogen-containing heterocycles include, but are not limited to, piperidinyl, piperazinyl, morpholinyl, morpholinyl-3-one, piperidinyl-2-one, and pyrimidinyl-2,4(1H,3H)-dione. The term "heterocyclene" specifically refers to a divalent heterocycle.

[0074] The term "target binding moiety" refers to a chemical moiety that is capable of binding to a target protein, particularly a protein of therapeutic importance. The nature of the target is not limited except that it must be an intracellular protein or a protein containing an intracellular domain.

[0075] Description of the Invention

[0076] 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:

[0077]

[0078] in:

[0079] X1 is N or CR 2 , where R 2 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, -CONR 5 R 6 and-(CONR 3 R 4 )m(L)p(TBM)q;

[0080] X4 for CR 7 or N, where R 7 Selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 alkoxy;

[0081] X2 and X3 are independently selected from N or CH;

[0082] X 15 and X 22 independently selected from N or C;

[0083] or R 3 and R 4 Together with the nitrogen atom to which they are attached, they are linked together to form a monocyclic or spirocyclic nitrogen-containing heterocycle, or R 3 H or C 1-4 Alkyl and R 4 -(CH2) n R 28 , where R 28 It is a monocyclic or spirocyclic nitrogen-containing heterocycle;

[0084] n is 0 or 1;

[0085] R 5 and R 6 are independently selected from hydrogen or C 1-4 alkyl;

[0086] R 1 C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or a group of formula (II), wherein * represents the position of attachment to the compound of formula (I):

[0087]

[0088]

[0089] a and b are independently 0 or 1;

[0090] X 16 N or CH;

[0091] X 17 CR 34 R 35 , where R 34 and R 35 together with the carbon atoms to which they are attached to form a cyclobutyl ring, or wherein R 34 -(CHR 36 )r- or a bond to the compound of formula (I), and R 35 is hydrogen or halogen;

[0092] X 25 CR 12 R 13 or O;

[0093] r is 0, 1, or 2;

[0094] a is 0, 1 or 2, and b and j are independently 0 or 1, provided that b and j cannot both be 0;

[0095] R 36 is hydrogen or methyl;

[0096] R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 and R 15 independently selected from hydrogen or halogen;

[0097] L is a chemical linker;

[0098] TBM is the target binding moiety;

[0099] m, p, and q are independently 0 and 1;

[0100] When X 15 When N, then X 22 is C; and

[0101] When X1 is -(CONR 3 R 4 )m(L)p(TBM)q, then R 1 C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 Alkoxy.

[0102] Depending on the values ​​of p and q, the compound of formula (I), its tautomer or salt can be a degron or a PROTAC. A PROTAC is a compound or salt containing a degron, a target binding moiety and optionally a linker. The "components" of a PROTAC are further described below.

[0103] In one embodiment, q is 1 and p is 0 or 1.

[0104] In one embodiment, m is 1.

[0105] In one embodiment, X1 is N or CR 2 , where R 2 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl and -CONR 5 R 6 .

[0106] Degron

[0107] 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.

[0108] The present invention provides a degron, which is a compound of formula (Iaa), a tautomer of a compound of formula (Iaa), or a salt thereof:

[0109]

[0110] in:

[0111] X1 is N or CR 2 , where R 2 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and -CONR 5 R 6 ;

[0112] X4 for CR 7 or N, where R 7 Selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 alkoxy;

[0113] X2 and X3 are independently selected from N or CH;

[0114] X 15 and X 22 independently selected from N or C;

[0115] r is 0, 1, or 2;

[0116] a is 0, 1 or 2, and b and j are independently 0 or 1, provided that b and j cannot both be 0;

[0117] X 16 N or CH;

[0118] X 18 CR 35 , where R 35 is hydrogen or halogen;

[0119] X 25 CR 12 R 13 or O;

[0120] R 5 and R 6 are independently selected from hydrogen or C 1-4 alkyl;

[0121] R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 and R 35 independently selected from hydrogen or halogen;

[0122] R 36 is hydrogen or methyl; and

[0123] When X 15 When N, then X 22 For C.

[0124] In a more specific embodiment, the present invention provides a degron that is a compound of formula (Iaaa), a tautomer of a compound of formula (Iaaa), or a salt thereof:

[0125]

[0126] in:

[0127] X1 is N or CR 2 , where R 2 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and -CONR 5 R 6 ;

[0128] X4 for CR 7 or N, where R 7Selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 alkoxy;

[0129] X2 and X3 are independently selected from N or CH;

[0130] X 15 and X 22 independently selected from N or C;

[0131] r is 0, 1, or 2;

[0132] a is 0, 1 or 2, and b and j are independently 0 or 1, provided that b and j cannot both be 0;

[0133] X 16 N or CH;

[0134] X 18 CR 35 , where R 35 is hydrogen or halogen;

[0135] X 25 CR 12 R 13 or O;

[0136] R 5 and R 6 are independently selected from hydrogen or C 1-4 alkyl;

[0137] R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 and R 35 independently selected from H or halogen;

[0138] R 36 is hydrogen or methyl; and

[0139] When X 15 When N, then X 22 For C.

[0140] In one embodiment of the compound of formula (Iaa) or (Iaaa), a tautomer or a salt thereof, X1 is N or CR 2 , where R 2 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl and -CONR 5 R 6 .

[0141] In one embodiment of the compound of Formula (Iaa) or (Iaaa), a tautomer or a salt thereof, R 2 is selected from hydrogen and halogen.

[0142] In one embodiment of the compound of Formula (Iaa) or (Iaaa), a tautomer or a salt thereof, X 22 is N. In which X 22 In certain embodiments where X1, X2, X3, or X4 is N, one or more of X1, X2, X3, or X4 is additionally N.

[0143] In one embodiment of the compound of Formula (Iaa) or (Iaaa), a tautomer or a salt thereof, X 15 For C.

[0144] In one embodiment of the compound of Formula (Iaa) or (Iaaa), a tautomer or a salt thereof, X1 is N or CH.

[0145] In another embodiment of Formula (Iaa) or (Iaaa), a tautomer or a salt thereof, X1 is CR 2 , where R 2 is selected from CF3, F or Cl. In a more specific embodiment, X1 is CR 2 , where R 2 Selected from F or Cl.

[0146] In one embodiment of the compound of formula (Iaa) or (Iaaa), a tautomer or a salt thereof, X4 is CR 7 In a more specific embodiment, X4 is CR 7 , where R 7 In one embodiment, X4 is CR 7 , where R 7 In another embodiment, X4 is CH. In an alternative embodiment, X4 is N.

[0147] In one embodiment of the compound of Formula (Iaa) or (Iaaa), a tautomer or a salt thereof, wherein X 22 is N, X1 is CR 2 (where R 2 is H, halogen or C 1-4 haloalkyl), X2 and X3 are both CH, X4 is CR 7 (where R 7 is hydrogen or halogen), and X 15 is C. In a more specific embodiment, X 22 is N, X1, X2, X3, X4 are each CH, and X 15For C.

[0148] In which X 22 In certain embodiments, X1, X2, X3, and X4 are each CH and X 15 is C, or:

[0149] a, b, and j are not independently 1, or

[0150] r is 1.

[0151] In which X 22 is N, X1, X2, X3, X4 are each CH and X 15 In one embodiment of 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.

[0152] In which X 22 In another embodiment where X2 is N, X1 is CR 2 (where R 2 is H, halogen or C 1-4 haloalkyl), X3 is CH, X4 is CR 7 (where R 7 is hydrogen or halogen), and X 15 is C. In which X 22 In another embodiment where X1, X3 and X4 are each CH, X 15 is C, and X2 is N. 22 In a further embodiment wherein X1 is N, X2, X3 and X4 are each CH, and X 15 is C. In which X 22 In alternative embodiments where X1 and X2 are each N, and X3 and X4 are each CH, and X 15 is C. In which X 22 In alternative embodiments where X2 and X4 are each N, and X1 and X3 are each CH, and X 15 is C. In which X 22 In one embodiment where X3 and X4 are each N, CR 2 (where R 2 is H, halogen), X2 is CH and X 15 is C. In which X 22 In alternative embodiments where X3 and X4 are each N, X1 and X2 are each CH and X 15 is C. In which X 22 In alternative embodiments where X2 and X3 are each N, X1 and X4 are each CH and X 15is C. In which X 22 In an alternative embodiment where X4 is N, X1, X2 and X3 are each CH and X 15 is C. In which X 22 In an alternative embodiment where X3 is N, X1, X2 and X4 are each CH and X 15 For C.

[0153] In an alternative embodiment of the compound of formula (Iaa) or (Iaaa), a tautomer or a salt thereof, wherein X2 and X 15 is N, X1, X3, X4 are each CH and X 22 For C.

[0154] In one embodiment of the compound of Formula (Iaa) or (Iaaa), a tautomer or a salt thereof, R 35 For CH.

[0155] In one embodiment of the compound of Formula (Iaa) or (Iaaa), a tautomer or a salt thereof, r is 0 or 1. In one embodiment of the compound of Formula (Iaa), a tautomer or a salt thereof, r is 0. In an alternative embodiment, r is 1 and R 36 is H. In an alternative embodiment, r is 1 and R 36 It is a methyl group.

[0156] In an alternative embodiment of a compound of Formula (Iaa) or (Iaaa), a tautomer or a salt thereof, r is 2 and each R 36 For H.

[0157] In one embodiment of the compound of Formula (Iaa) or (Iaaa), a tautomer or a salt thereof, X 16 is N.

[0158] In one embodiment of the compound of Formula (Iaa) or (Iaaa), a tautomer or a salt thereof, X 25 CR 12 R 13 .

[0159] In one embodiment of the compound of Formula (Iaa) or (Iaaa), a tautomer or a salt thereof, j is 1 and a and b are independently 0 or 1. In a more specific embodiment, X 16 N, X 25 CR 12 R 13 , j is 1 and a and b are independently 0 or 1.

[0160] In one embodiment of the compound of Formula (Iaa) or (Iaaa), a tautomer or a salt thereof, a, b and j are each 1, X 16is CH or N and X 25 CR 12 R 13 In a more specific embodiment, a, b and j are all 1, X 16 is N and X 25 CR 12 R 13 In an alternative embodiment, a, b, and j are all 1, X 16 is CH and X 25 CR 12 R 13 .

[0161] In one embodiment of the compound of Formula (Iaa) or (Iaaa), a tautomer or a salt thereof, a is 0 and b and j are each 1, X 16 is N and X 25 CR 12 R 13 .

[0162] In one embodiment of the compound of Formula (Iaa) or (Iaaa), a tautomer or a salt thereof, a and b are both 0, j is 1, X 16 is CH and X 25 CR 12 R 13 .

[0163] In an alternative embodiment of the compound of Formula (Iaa) or (Iaaa), a tautomer or a salt thereof, a and b are both 0, j is 1, X 16 is N and X 25 CR 12 R 13 .

[0164] In one embodiment of the compound of Formula (Iaa) or (Iaaa), a tautomer or a salt thereof, a is 2, b is 0, j is 1, X 16 is N and X 25 CR 12 R 13 .

[0165] In one embodiment of the compound of Formula (Iaa) or (Iaaa), a tautomer or a salt thereof, a is 2, b is 0, j is 1, X 16 is N and X 25 It is O.

[0166] In one embodiment of the compound of Formula (Iaa) or (Iaaa), a tautomer or a salt thereof, R 8 、R 9 、R 10 、R 11 、R 12 、R13 、R 14 、R 15 and R 35 In another embodiment, R 8 、R 9 and R 35 are independently selected from H or halogen, and R 10 、R 11 、R 12 、R 13 、R 14 and R 15 Each is H. In a more specific embodiment, R 8 and R 9 are independently selected from H or fluorine, and R 10 、R 11 、R 12 、R 13 、R 14 、R 15 and R 35 Each is H. In another embodiment, R 12 、R 13 and R 35 are independently selected from H or halogen, and R 8 、R 9 、R 10 、R 11 、R 14 and R 15 Each is H. In a more specific embodiment, R 12 and R 13 are independently selected from H or fluorine, and R 8 、R 9 、R 10 、R 11 、R 14 、R 15 and R 35 Each is H. In a more specific embodiment, R 8 、R 9 R 10 、R 11 、R 12 、R 13 、R 14 and R 15 Each is H and R 35 is H or fluorine.

[0167] In particular embodiments of the compound of Formula (Iaa) or (Iaaa), a tautomer or a salt thereof, wherein X 22 is N, X1 is CR 2 (where R 2 is H, halogen or C 1-4haloalkyl), X2 and X3 are both CH, X4 is CR 7 (where R 7 is hydrogen or halogen), and X 15 is C, r is 1 or 2.

[0168] In particular embodiments of the compound of Formula (Iaa) or (Iaaa), a tautomer or a salt thereof, wherein X 22 is N, X1 is CR 2 (where R 2 is H, halogen or C 1-4 haloalkyl), X2 and X3 are both CH, X4 is CR 7 (where R 7 is hydrogen or halogen), and X 15 For C, a, b, and j are not each 1.

[0169] In particular embodiments of the compound of Formula (Iaa) or (Iaaa), a tautomer or a salt thereof, wherein X 22 is N, X1 is CR 2 (where R 2 is H, halogen or C 1-4 haloalkyl), X2 and X3 are both CH, 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 each 1.

[0170] The present invention provides a degron, which is a compound of formula (Ibb), a tautomer of a compound of formula (Ibb), or a salt thereof:

[0171]

[0172] in:

[0173] R 1 C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 Alkoxy, wherein the C 1-4 The alkyl group is optionally replaced by a C 1-4 Alkoxy group substitution;

[0174] X2 and X3 are independently selected from N or CH;

[0175] X 15 and X 22 independently selected from N or C;

[0176] X4 for CR 7 or N, where R 7 Selected from hydrogen, halogen, C1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 alkoxy;

[0177] or R 3 and R 4 Together with the nitrogen atom to which they are attached, they are linked together to form a monocyclic or spirocyclic nitrogen-containing heterocycle, or R 3 H or C 1-4 Alkyl and R 4 -(CH2) n R 28 , where R 28 It is a monocyclic or spirocyclic nitrogen-containing heterocycle;

[0178] m is 0 or 1;

[0179] n is 0 or 1; and

[0180] When X 15 When N, then X 22 For C.

[0181] In one embodiment, the present invention provides a degron which is a compound of formula (Ibbb), a tautomer of a compound of formula (Ibbb), or a salt thereof:

[0182]

[0183] in:

[0184] R 1 C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 Alkoxy, wherein the C 1-4 The alkyl group is optionally replaced by a C 1-4 Alkoxy group substitution;

[0185] X2 and X3 are independently selected from N or CH;

[0186] X 15 and X 22 independently selected from N or C;

[0187] X4 for CR 7 or N, where R 7 Selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 alkoxy;

[0188] or R 3 and R 4 Together with the nitrogen atom to which they are attached, they are linked together to form a monocyclic or spirocyclic nitrogen-containing heterocycle, or R3 H or C 1-4 Alkyl and R 4 -(CH2) n R 28 , where R 28 It is a monocyclic or spirocyclic nitrogen-containing heterocycle;

[0189] m is 0 or 1;

[0190] n is 0 or 1; and

[0191] When X 15 When N, then X 22 For C.

[0192] In one embodiment of the compound of formula (Ibb) or (Ibbb), a tautomer or a salt thereof, m is 1. In an alternative embodiment of the compound of formula (Ibb) or (Ibbb), a tautomer or a salt thereof, m is 0.

[0193] In one embodiment of the compound of formula (Ibb) or (Ibbb), a tautomer or a salt thereof, R 1 For optionally a C 1-4 Alkoxy-substituted C 1-4 In a more specific embodiment of the compound of formula (Ibb) or (Ibbb), its tautomer or salt, R 1 C 1-4 In a more specific embodiment, R 1 is methyl, ethyl or isopropyl. In a more specific embodiment, R 1 In one embodiment, R 1 It is isopropyl.

[0194] In one embodiment of the compound of formula (Ibb) or (Ibbb), a tautomer or a salt thereof, X 22 is N.

[0195] In one embodiment of the compound of formula (Ibb) or (Ibbb), a tautomer or a salt thereof, X2 is CH.

[0196] In one embodiment of the compound of formula (Ibb) or (Ibbb), a tautomer or a salt thereof, X3 is CH.

[0197] In one embodiment of the compound of formula (Ibb) or (Ibbb), a tautomer or a salt thereof, X 15 For C.

[0198] In one embodiment of the compound of formula (Ibb) or (Ibbb), a tautomer or a salt thereof, X4 is CR 7, where R 7 In one embodiment, X4 is CR 7 , where R 7 In another embodiment, X4 is CH. In an alternative embodiment, X4 is N.

[0199] In one embodiment of the compound of formula (Ibb) or (Ibbb), a tautomer or a salt thereof, wherein X 22 is N, X1 is CR 2 (where R 2 is H, halogen or C 1-4 haloalkyl), X2 and X3 are both CH, X4 is CR 7 (where R 7 is hydrogen or halogen), and X 15 is C. In a more specific embodiment, X 22 is N, X1, X2, X3, X4 are each CH, and X 15 is C. In which X 22 In another embodiment where X2 is N, X1 is CR 2 (where R 2 is H, halogen or C 1-4 haloalkyl), X3 is CH, X4 is CR 7 (where R 7 is hydrogen or halogen), and X 15 is C. In which X 22 In another embodiment where X1, X3 and X4 are each CH, X 15 is C, and X2 is N. 22 In a further embodiment wherein X1 is N, X2, X3 and X4 are each CH, and X 15 is C. In which X 22 In alternative embodiments where X1 and X2 are each N, and X3 and X4 are each CH, and X 15 is C. In which X 22 In alternative embodiments where X2 and X4 are each N, and X1 and X3 are each CH, and X 15 is C. In which X 22 In one embodiment where X3 and X4 are each N, CR 2 (where R 2 is H, halogen), X2 is CH, and X 15 is C. Where X 22 In alternative embodiments, X3 and X4 are each N, X1 and X2 are each CH, and X 15 is C. In which X 22In alternative embodiments where X2 and X3 are each N, X1 and X4 are each CH, and X 15 is C. In which X 22 In an alternative embodiment where X4 is N, X1, X2 and X3 are each CH, and X 15 is C. In which X 22 In an alternative embodiment where X3 is N, X1, X2 and X4 are each CH and X 15 For C.

[0200] In alternative embodiments of the compounds of formula (Ibb) or (Ibbb), tautomers or salts thereof, X2 and X 15 is N, X1, X3, X4 are each CH and X 22 For C.

[0201] In alternative embodiments of the compound of Formula (Ibb) or (Ibbb), a tautomer or a salt thereof, X 22 is C, X3 and X4 are each CH, and X 15 and X2 are each N.

[0202] In certain embodiments of the compound of Formula (Ibb) or (Ibbb), a tautomer or a salt thereof, R 3 H or C 1-4 Alkyl, and R 4 (CH2) n R 28 , where R 28 is a monocyclic nitrogen-containing heterocycle, such as a monocyclic 5-6-membered nitrogen-containing heterocycle, more specifically a monocyclic 6-membered nitrogen-containing heterocycle. In a more specific embodiment, R 3 C 1-4 Alkyl, and R 4 -(CH2) n R 28 , where R 28 is a monocyclic nitrogen-containing heterocycle, for example a monocyclic 5-6-membered nitrogen-containing heterocycle, more specifically a monocyclic 6-membered nitrogen-containing heterocycle. In even more specific embodiments, R 3 C 1-4 Alkyl and R 4 -(CH2) n R 28 , where R 28 is a piperidine ring (eg, piperidin-4-yl).

[0203] In certain embodiments of the compound of Formula (Ibb) or (Ibbb), a tautomer or a salt thereof, R 3 and R 4 Together with the nitrogen atom to which they are attached, they are linked together to form a monocyclic nitrogen-containing heterocycle.3 and R 4 Together with the nitrogen atom to which they are attached, they are joined to form a monocyclic 5-6 membered nitrogen-containing heterocycle, more specifically a monocyclic 6 membered nitrogen-containing heterocycle. In even more specific embodiments, R 3 and R 4 Together with the nitrogen atom to which they are attached, they are joined together to form a piperazinyl or piperidinyl ring, more particularly a piperazinyl ring.

[0204] In certain embodiments of the compound of Formula (Ibb) or (Ibbb), a tautomer or a salt thereof, R 3 and R 4 Together with the nitrogen atom to which they are attached, they are linked together to form a spirocyclic nitrogen-containing heterocycle. 3 and R 4 Together with the nitrogen atom to which they are attached, they are linked together to form a spirocyclic 10-11 membered nitrogen-containing heterocycle.

[0205] In certain embodiments of the compound of Formula (Ibb) or (Ibbb), a tautomer or a salt thereof, the group NR 3 R 4 Having a structure selected from the following:

[0206]

[0207] Where the asterisk represents the position of attachment to the carbonyl group, and # represents the point of attachment to L.

[0208] The present invention provides a degron, which is a compound of formula (Icc), a tautomer of a compound of formula (Icc), or a salt thereof:

[0209]

[0210] in:

[0211] X1 is N or CR 2 , where R 2 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and -CONR 5 R 6 ;

[0212] X4 for CR 7 or N, where R 7 Selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 alkoxy;

[0213] X2 and X3 are independently selected from N or CH;

[0214] X 15 and X 22 independently selected from N or C;

[0215] R 5 and R 6 Independently selected from H or C 1-4 alkyl; and

[0216] k and l are independently selected from 0 or 1;

[0217] When X 15 When N, then X 22 For C.

[0218] In one embodiment, the present invention provides a degron, which is a compound of formula (Iccc), a tautomer of a compound of formula (Icc), or a salt thereof:

[0219]

[0220] in:

[0221] X1 is N or CR 2 , where R 2 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and -CONR 5 R 6 ;

[0222] X4 for CR 7 or N, where R 7 Selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 alkoxy;

[0223] X2 and X3 are independently selected from N or CH;

[0224] X 15 and X 22 independently selected from N or C;

[0225] R 5 and R 6 Independently selected from H or C 1-4 alkyl; and

[0226] k and l are independently selected from 0 or 1;

[0227] When X 15 When N, X 22 For C.

[0228] In one embodiment of the compound of Formula (Icc) or (Iccc), a tautomer or a salt thereof, k and 1 are each 1.

[0229] In another embodiment of the compound of Formula (Icc) or (Iccc), a tautomer or a salt thereof, k and l are each 0.

[0230] In one embodiment of the compound of Formula (Icc) or (Iccc), a tautomer or a salt thereof, X 22 is N. In which X 22 In certain embodiments where X1, X2, X3, or X4 is N, one or more of X1, X2, X3, or X4 is additionally N.

[0231] In one embodiment of the compound of Formula (Icc) or (Iccc), a tautomer or a salt thereof, X 15 For C.

[0232] In one embodiment of the compound of formula (Icc) or (Iccc), a tautomer or a salt thereof, X1 is N or CH.

[0233] In another embodiment of Formula (Icc) or (Iccc), a tautomer or a salt thereof, X1 is CR 2 , where R 2 is selected from CF3, F or Cl. In a more specific embodiment, X1 is CR 2 , where R 2 Selected from F or Cl.

[0234] In one embodiment of the compound of formula (Icc) or (Iccc), a tautomer or a salt thereof, X4 is CR 7 In a more specific embodiment, X4 is CR 7 , where R 7 In one embodiment, X4 is CR 7 , where R 7 In another embodiment, X4 is CH. In an alternative embodiment, X4 is N.

[0235] In one embodiment of the compound of formula (Icc) or (Iccc), a tautomer or a salt thereof, R 2 is selected from hydrogen and halogen.

[0236] In one embodiment of the compound of formula (Icc) or (Iccc), a tautomer or a salt thereof, X1 is N or CH.

[0237] In another embodiment of Formula (Icc) or (Iccc), a tautomer or a salt thereof, X1 is CR 2 , where R2 is selected from CF3, F or Cl. In a more specific embodiment, X1 is CR 2 , where R 2 Selected from F or Cl.

[0238] In one embodiment of the compound of formula (Icc) or (Iccc), a tautomer or a salt thereof, X4 is CR 7 In a more specific embodiment, X4 is CR 7 , where R 7 In one embodiment, X4 is CR 7 , where R 7 In another embodiment, X4 is CH. In an alternative embodiment, X4 is N.

[0239] In one embodiment of the compound of Formula (Icc) or (Iccc), a tautomer or a salt thereof, X 22 is N, X1 is CR 2 (where R 2 is H, halogen or C 1-4 haloalkyl), X2 and X3 are both CH, X4 is CR 7 (where R 7 is hydrogen or halogen), and X 15 is C. In a more specific embodiment, X 22 is N, X1, X2, X3, X4 are each CH, and X 15 is C. In which X 22 In another embodiment where X2 is N, X1 is CR 2 (where R 2 is H, halogen or C 1-4 haloalkyl), X3 is CH, X4 is CR 7 (where R 7 is hydrogen or halogen), and X 15 is C. In which X 22 In another embodiment where X1, X3 and X4 are each CH, X 15 is C, and X2 is N. 22 In a further embodiment wherein X1 is N, X2, X3 and X4 are each CH, and X 15 is C. In which X 22 In alternative embodiments where X1 and X2 are each N, and X3 and X4 are each CH, and X 15 is C. In which X 22 In alternative embodiments where X2 and X4 are each N, and X1 and X3 are each CH, and X 15 is C. In which X22 In one embodiment where X3 and X4 are each N, CR 2 (where R 2 is H, halogen), X2 is CH and X 15 is C. In which X 22 In the alternative embodiment, X3 and X4 are each N, X1 and X2 are each CH, and X 15 is C. In which X 22 In alternative embodiments where X2 and X3 are each N, X1 and X4 are each CH and X 15 is C. In which X 22 In an alternative embodiment where X4 is N, X1, X2 and X3 are each CH and X 15 is C. In which X 22 In an alternative embodiment where X3 is N, X1, X2 and X4 are each CH and X 15 For C.

[0240] In alternative embodiments of the compound of formula (Icc) or (Iccc), a tautomer or a salt thereof, X2 and X 15 is N, X1, X3, X4 are each CH and X 22 For C.

[0241] Target binding moiety

[0242] In one embodiment, the present invention relates to PROTACs using the novel degron of the present invention, and the nature of the target is not limited, except that it must be an intracellular protein or at least a protein containing an intracellular domain. Many proteins of therapeutic importance have been well studied, and a large number of compounds are known to bind to these proteins. These compounds can be used as the target binding portion in PROTAC compounds. Examples include compounds in which the target binding portion is an androgen receptor binding portion, a RIPK2 binding portion, and an IRAK4 binding portion. Degradation of each of these targets has been demonstrated. This demonstrates that the nature of the target is not limited, and the degron of the present invention can be used to mediate degradation of a wide variety of targets.

[0243] 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 has the structure of formula (III)

[0244]

[0245] The connection position with L is indicated by an asterisk;

[0246] A is selected from: cyclohexyl, cyclobutyl or 6-membered nitrogen-containing heterocyclic ring, wherein the cyclohexyl, cyclobutyl or 6-membered nitrogen-containing heterocyclic ring may be optionally replaced by up to 4 C 1-4 Alkyl group substitution;

[0247] B is selected from phenyl, a 6-membered nitrogen-containing heteroaryl group or a fused bicyclic nitrogen-containing heterocycle, wherein B is optionally substituted with one or more halogen groups;

[0248] X 23 is CH or N, and

[0249] R 16 Selected from halogen or CF3.

[0250] In one embodiment, X 23 It is CH.

[0251] In one embodiment, X 23 It's N.

[0252] In one embodiment of the androgen receptor binding moiety having the structure of formula (III), A is selected from: cyclohexyl or cyclobutyl, wherein the cyclohexyl or cyclobutyl group may be optionally substituted with up to 4 C 1-4 In one embodiment of the androgen binding moiety having the structure of formula (III), A is an unsubstituted cyclohexyl group. In another embodiment of the androgen binding moiety having the structure of formula (III), A is substituted with 4 C 1-4 Cyclobutyl substituted with alkyl groups. In another embodiment wherein the androgen binding moiety has the structure of formula (III), A is cyclobutyl substituted with 4 methyl groups.

[0253] In one embodiment of the androgen receptor binding portion having 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 is optionally 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 an alternative embodiment, B is selected from a 6-membered nitrogen-containing heteroaryl group, which is optionally 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 pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl. In an even more specific embodiment, B is selected from pyridazin-3-yl, pyrimidin-5-yl, pyrazin-2-yl and pyridin-3-yl, wherein the number represents the position connected to the carbonyl group.

[0254] In an alternative embodiment of the androgen receptor binding portion having the structure of formula (III), B is a fused bicyclic nitrogen-containing heterocycle, which is optionally substituted with one or more halogen groups. In a more specific embodiment, B is a 9-10 membered fused bicyclic nitrogen-containing heterocycle, which is optionally substituted with one or more halogen groups. In one embodiment of the androgen receptor binding portion having the structure of formula (III), B is an unsubstituted 9-10 membered fused bicyclic nitrogen-containing heterocycle. In a specific embodiment, B has the structure shown below (wherein * represents a connection to a carbonyl group, and # represents a connection to a linker):

[0255]

[0256] In one embodiment of the androgen receptor binding portion of formula (III), R 16 It is chlorine or CF3.

[0257] In a more specific embodiment, the androgen receptor binding moiety has the structure of Formula (IIIa)

[0258]

[0259] The connection position with L is indicated by an asterisk;

[0260] X7, X8 and X9 are independently CH, CF or N;

[0261] R 16 Selected from halogen or CF3;

[0262] R 17 、R 18 、R 19 and R 20 are independently H or C 1-4 alkyl.

[0263] In specific embodiments of the androgen receptor binding portion of Formula (IIIa), R 16 is chlorine or CF3. In a specific embodiment of the androgen receptor binding portion of formula (IIIa), R 16 For chlorine.

[0264] In specific embodiments of the androgen receptor binding portion of Formula (IIIa), R 17 、R 18 、R 19 and R 20 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 Each is H.

[0265] In specific embodiments of the androgen receptor binding portion of Formula (IIIa), either:

[0266] X7 and X8 are N and X9 is CH; or

[0267] X8 and X9 are N and X7 is CH; or

[0268] X7 and X9 are N and X8 is CH; or

[0269] X7 is N and X8 and X9 are CH; or

[0270] X8 is N and X7 and X9 are CH; or

[0271] X7 is CF and X8 and X9 are CH; or

[0272] X7, X8 and X9 are each CH.

[0273] In a more specific embodiment of the androgen receptor binding portion of formula (IIIa), X7 and X8 are N, and X9 is C H In the embodiment where X7 and X8 are N and X9 is CH, R 17 、R 18 、R 19 and R 20 Each is H.

[0274] In a more specific embodiment of the androgen receptor binding portion of formula (IIIa), X7 and X9 are N, and X8 is CH. In a specific embodiment wherein X7 and X9 are N and X8 is CH, R 17 、R 18 、R 19 and R 20 Each is H.

[0275] In an alternative embodiment, the androgen receptor binding moiety has the structure of Formula (IIIb):

[0276]

[0277] The connection position with L is indicated by an asterisk;

[0278] X7, X8 and X9 are independently CH, CF or N;

[0279] X 23 and X 24 are independently CH or N;

[0280] R16 is selected from halogen or CF3; and

[0281] R 21 、R 22 、R 23 and R 24 are independently H or C 1-4 alkyl.

[0282] The androgen receptor binding portion of formula (IIIb) can bind to certain mutant versions of the androgen receptor. Protac containing the androgen receptor binding portion of formula (IIIb) exhibits activity in a double mutant (T878A / L702H) androgen receptor degradation assay. Such proteins are expected to be used to treat castration-resistant prostate cancer.

[0283] In one embodiment, X 23 For CH.

[0284] In one embodiment, X 23 is N.

[0285] In specific embodiments of the androgen receptor binding portion of Formula (IIIb), R 16 Chlorine or CF 3。 In specific embodiments of the androgen receptor binding portion of Formula (IIIb), R 16 For chlorine.

[0286] In specific embodiments of the androgen receptor binding portion of Formula (IIIb), R 21 、R 22 、R 23 and R 24 Each is a methyl group.

[0287] In specific embodiments of the androgen receptor binding portion of Formula (IIIb),

[0288] X7 and X8 are N and X9 and X 24 is CH; or

[0289] X8 and X9 are N and X7 and X 24 is CH; or

[0290] X7 and X9 are N and X8 and X 24 is CH; or

[0291] X7 is N and X8, X9 and X 24 is CH; or

[0292] X8 is N and X7, X9 and X 24 is CH; or

[0293] X7 is CF and X8, X9 and X24 is CH; or

[0294] X7, X8, X9 and X 24 each CH; or

[0295] X7 and X 24 is N, and X8 and X9 are CH.

[0296] In more specific embodiments of the androgen receptor binding portion of Formula (IIIb), X 23 is N, and:

[0297] X7 and X8 are N and X9 and X 24 is CH; or

[0298] X8 and X9 are N and X7 and X 24 is CH; or

[0299] X7 is N and X8, X9 and X 24 is CH; or

[0300] X7 and X 24 is N, and X8 and X9 are CH.

[0301] In an even more specific embodiment of the androgen receptor binding portion of Formula (IIIb), X 23 N, R 21 、R 22 、R 23 and R 24 Each is a methyl group, R 16 is chlorine or CF3 and:

[0302] X7 and X8 are N and X9 and X 24 is CH; or

[0303] X8 and X9 are N and X7 and X 24 is CH; or

[0304] X7 is N and X8, X9 and X 24 is CH; or

[0305] X7 and X 24 is N, and X8 and X9 are CH.

[0306] In an alternative embodiment, the androgen receptor binding moiety has the structure of Formula (IIIc):

[0307]

[0308] The connection position with L is indicated by an asterisk;

[0309] X7, X8 and X9 are independently CH, CF or N;

[0310] R 21 、R 22 、R 23 and R 24 are independently H or C 1-4 alkyl.

[0311] In specific embodiments of the androgen receptor binding portion of Formula (IIIc), R 21 、R 22 、R 23 and R 24 Each is a methyl group.

[0312] In specific embodiments of the androgen receptor binding portion of Formula (IIIc),

[0313] X7 and X8 are N and X9 is CH; or

[0314] X8 and X9 are N and X7 is CH; or

[0315] X7 and X9 are N and X8 is CH; or

[0316] X7 is N and X8 and X9 are CH; or

[0317] X8 is N and X7 and X9 are CH; or

[0318] X7 is CF and X8 and X9 are CH; or

[0319] X7, X8 and X9 are each CH.

[0320] In more specific embodiments of the androgen receptor binding portion of Formula (IIIc),

[0321] X7 and X8 are N and X9 is CH; or

[0322] X7 is N and X8 and X9 are CH; or

[0323] X8 is N and X7 and X9 are CH.

[0324] In an alternative embodiment, the androgen receptor binding moiety has the structure of Formula (IV):

[0325]

[0326] The connection position with L is indicated by an asterisk;

[0327] R 25 is selected from halogen or CF3; and

[0328] R 26 and R 27 are independently H or C 1-4alkyl.

[0329] In specific embodiments of the androgen receptor binding portion of Formula (IV), R 25 is chlorine or CF3. In a more specific embodiment, R 25 It is CF3.

[0330] In specific embodiments of the androgen receptor binding portion of Formula (IV), R 26 and R 27 Each is a methyl group.

[0331] In an alternative embodiment, the androgen receptor binding moiety has the structure of Formula (V):

[0332]

[0333] The connection position with L is indicated by an asterisk;

[0334] X 13 and X 14 are independently CH or N;

[0335] R 29 Selected from halogen or CF3;

[0336] R 30 、R 31 、R 32 and R 33 are independently H or C 1-4 alkyl.

[0337] In specific embodiments of the androgen receptor binding portion of Formula (V), R 29 is chlorine or CF3. In more specific embodiments of the androgen receptor binding portion of formula (VI), R 29 For chlorine.

[0338] In specific embodiments of the androgen receptor binding portion of Formula (V), R 30 、R 31 、R 32 and R 33 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 Each is H.

[0339] In specific embodiments of the androgen receptor binding portion of Formula (V),

[0340] X13 and X 14 is N; or

[0341] X 13 N and X 14 For CH.

[0342] Connector

[0343] L is a chemical linker. The linkers of PROTAC are well known in the art and can be chemically different. In one embodiment, L is a chemical linker group containing 1-50 atoms in total. In more specific embodiments, L contains 1 to 30 atoms, 1-20 atoms, and 10 to 20 atoms. In one embodiment, L is a hydrocarbon chain in which one or more carbon atoms are replaced by -O-, -NH-, -NCH3-, -CO-, phenylene, 5-6 membered heteroarylene, C 4-6 Cycloalkylene and -4-6 membered heterocyclylene are substituted, wherein the hydrocarbon chain or the phenyl, 5-6 membered heteroaryl, C 4-6 The carbon atoms in the cycloalkyl and -4-6 membered heterocyclic ring are optionally selected from oxo, C 1-3 Alkyl, C 1-3 Alkoxy, OH, halogen, NH2, NH(C 1-3 alkyl), N(C 1-3 alkyl)2 or one or more substituents in CN.

[0344] Suitable L groups are well known in the art. Suitable L groups include those described in, for example, WO2017197055, WO2017007612, WO2015160845, WO2021077010, WO2018071606, WO2020211822, WO2020198711, WO2020160295, and WO2020214952. In addition, a variety of linkers suitable for PROTAC development are available from suppliers including Selleck Chemicals, BroadPharm, and MedChemExpress.com.

[0345] While the PROTAC approach is a generally applicable principle that allows for finding PROTACs that can degrade a specific target using a validated target binding moiety without undue burden using linkers known in the art, it is clear that not all PROTACs have the same activity in vitro or in vivo. There are several reasons for this, including differential absorption through the intestine, differential uptake into cells, differential pharmacokinetics, and differential 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 different linkers. While various linkers are expected to result in at least some degradation of the target, the length and chemical properties of L can be optimized for specific TBMs according to methods known in the art. In some cases, a flexible linker may be optimal, while for other TBMs, a more rigid linker (which maintains the relative positions of key functional groups within the target binding moiety and the degron) is appropriate.

[0346] 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):

[0347]

[0348] wherein * represents a connection to the androgen receptor binding moiety, and # represents a connection to the compound of formula (I);

[0349] D is a nitrogen-containing heterocycle, which is optionally substituted with one or more substituents selected from methyl, halogen, CF3 and CN;

[0350] R 37 is methyl or hydrogen;

[0351] s is 0 or 1;

[0352] t is 0 or 1;

[0353] u is 0 or 1;

[0354] v is 0, 1, or 2;

[0355] w is 0 or 1;

[0356] x is 0, 1, 2, 3, or 4

[0357] When v is 0, u and w are not both 1;

[0358] When t is 0, s and u are not both 1.

[0359] In one embodiment, D is a 4-6 membered monocyclic nitrogen-containing heterocycle optionally substituted with one or more substituents selected from methyl, halogen, CF3 and CN.

[0360] In an alternative embodiment, D is a spirocyclic nitrogen-containing heterocycle optionally substituted with one or more substituents selected from methyl, halogen, CF3 and CN.

[0361] In alternative embodiments, D is a bridged or fused nitrogen-containing heterocycle optionally substituted with one or more substituents selected from methyl, halogen, CF and CN. In one embodiment, the bridged or fused heterocycle has a structure selected from the group consisting of:

[0362]

[0363] In more specific embodiments, the bridged or fused heterocycle has a structure selected from the group consisting of:

[0364]

[0365] In one embodiment, R 37 For hydrogen.

[0366] In a specific embodiment, L is a group of formula (VIa):

[0367]

[0368] wherein * represents a connection to the androgen receptor binding moiety, and # represents a connection to the compound of formula (I);

[0369] X 10 is CH or N;

[0370] X 11 CR 42 or N;

[0371] c is 0 or 1;

[0372] d is 0 or 1;

[0373] s is 0 or 1;

[0374] u is 0 or 1;

[0375] v is 0, 1, or 2;

[0376] w is 0 or 1;

[0377] x is 0, 1, or 2;

[0378] R 37 is H or methyl; and

[0379] R38 、R 39 、R 40 、R 41 and R 42 Independently selected from H, halogen, methyl, CF3 and CN.

[0380] In a specific embodiment of the group of formula (VIa):

[0381] c and d are each 0; or

[0382] c is 1 and d is 0; or

[0383] c and d are each 1.

[0384] In one embodiment of the group of formula (VIa), R 37 is H. In an alternative embodiment, R 37 It is a methyl group.

[0385] In one embodiment of the group of formula (VIa), R 42 is hydrogen, methyl, fluorine or CN. In a more specific embodiment, R 42 For hydrogen.

[0386] In one embodiment of the group of formula (VIa), R 38 、R 39 、R 40 and R 41 In a more specific embodiment, R 38 、R 39 、R 40 and R 41 In a more specific embodiment, R 38 、R 39 、R 40 and R 41 Each is H.

[0387] In a specific embodiment of Formula (VIa):

[0388] X 10 is N and X 11 CR 42 or N;

[0389] c is 0 or 1;

[0390] d is 0 or 1;

[0391] s is 0;

[0392] u is 0 or 1; and

[0393] v is 0, 1, or 2;

[0394] w is 0 or 1;

[0395] x is 0, 1, or 2; and

[0396] R 37 、R 38 、R 39 、R 40 、R 41 and R 42 Independently selected from H or methyl.

[0397] In a more specific embodiment of Formula (VIa):

[0398] X 10 is N and X 11 CR 42 ;

[0399] c is 1;

[0400] d is 1;

[0401] s is 0;

[0402] u is 0 or 1; and

[0403] v is 0, 1, or 2;

[0404] w is 0 or 1;

[0405] x is an integer between 0 and 2; and

[0406] R 37 、R 38 、R 39 、R 40 、R 41 and R 42 Independently selected from H or methyl.

[0407] In a more specific embodiment of Formula (VIa):

[0408] X 10 is N and X 11 CR 42 ;

[0409] c is 1;

[0410] d is 1;

[0411] s is 0;

[0412] u is 0 or 1; and

[0413] v is 0, 1, or 2;

[0414] w is 0;

[0415] x is 0; and

[0416] R 37 、R 38 、R 39 、R 40 、R 41 and R 42 Independently selected from H or methyl.

[0417] In which X 10 is N and X 11 CR 42 In a more specific embodiment of formula (VIa), c is 1, d is 1; s is 0, u is 1, v is 0, w is 0, x is 0; and R 38 、R 39 、R 40 、R 41 and R 42 Independently selected from H or methyl.

[0418] In which X 10 is N and X 11 CR 42 In a more specific embodiment of Formula (VIa), c is 1, d is 1, s is 0, u is 0, v is an integer between 0 and 2, w is 0, x is 0, and R 37 、R 38 、R 39 、R 40 、R 41 and R 42 In one embodiment, v is 0. In another embodiment, v is 1. In a further embodiment, v is 2.

[0419] In a more specific embodiment of Formula (VIa), X 10 is N and X 11 CR 42 , 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 Each is H.

[0420] In various embodiments of Formula (VIa):

[0421] X 10 is CH and X 11 CR 42 or N;

[0422] c is 1;

[0423] d is 1;

[0424] s is 0 or 1;

[0425] u is 0 or 1;

[0426] v is 0 or 1;

[0427] w is 0;

[0428] x is 0; and

[0429] R 37 、R 38 、R 39 、R 40 、R 41 and R 42 Independently selected from H or methyl.

[0430] In a more specific embodiment:

[0431] X 10 is CH and X 11 is N;

[0432] c is 1;

[0433] d is 1;

[0434] s is 0 or 1; and

[0435] u and v are each 1;

[0436] w is 0;

[0437] x is 0; and

[0438] R 37 、R 38 、R 39 、R 40 and R 41 Independently selected from H or methyl.

[0439] In an alternative 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 Independently selected from H or methyl.

[0440] In an alternative embodiment of Formula (VIa):

[0441] X 10 is N and X 11 is N;

[0442] c is 1;

[0443] d is 1;

[0444] s is 0;

[0445] u is 0; and

[0446] v is 1 or 2;

[0447] w is 1; and

[0448] x is 1 or 2; and

[0449] R 37 、R 38 、R 39 、R 40 and R 41 Independently selected from H or methyl.

[0450] In which X 10 is N and X 11 In a more specific embodiment where N is present, 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 Independently selected from H or methyl.

[0451] In a specific embodiment, L is a group of formula (VIb):

[0452]

[0453] wherein * represents a connection to the androgen receptor binding moiety, and # represents a connection to the compound of formula (I);

[0454] X 19 is CH or O;

[0455] X 20 CR 47 ;

[0456] u is 0 or 1;

[0457] v is 0, 1, or 2;

[0458] w is 0 or 1;

[0459] x is 0, 1, or 2;

[0460] R 37 is H or methyl; and

[0461] R 43 、R 44 、R 45 、R 46 and R 47 Independently selected from H, halogen, methyl, CF3 and CN.

[0462] In one embodiment of the group of formula (VIb), R 37 is H. In an alternative embodiment, R 37 It is a methyl group.

[0463] In one embodiment of the group of formula (VIb), R 47 is hydrogen, methyl, fluorine or CN. In a more specific embodiment, R 47 For hydrogen.

[0464] In one embodiment of the group of formula (VIb), R 43 、R 44 、R 45 and R 46 In a more specific embodiment, R 43 、R 44 、R 45 and R 46 In a more specific embodiment, R 43 、R 44 、R 45 and R 46 Each is H.

[0465] In a specific embodiment of Formula (VIb):

[0466] X 19 is CH or O;

[0467] X 20 for CH;

[0468] u is 0; and

[0469] v is 0, 1, or 2;

[0470] w is 0;

[0471] x is 0; and

[0472] R 43 、R 44 、R 45 and R 46 Independently selected from H and methyl.

[0473] In a specific embodiment, L is a group of formula (VIc):

[0474]

[0475] wherein * represents a connection to the androgen receptor binding moiety, and # represents a connection to the compound of formula (I);

[0476] X 21is CH2 or O;

[0477] e is 0 or 1;

[0478] f is 0 or 1;

[0479] g is 0 or 1;

[0480] h is 0 or 1;

[0481] u is 0 or 1;

[0482] v is 0, 1, or 2;

[0483] w is 0 or 1;

[0484] x is 0, 1, or 2;

[0485] y is 0 or 1; and

[0486] R 37 is H or methyl; and

[0487] At least one of gh and y is 1.

[0488] In one embodiment of the group of formula (VIc), R 37 is H. In an alternative embodiment, R 37 It is a methyl group.

[0489] In one embodiment of the group of formula (VIc), X 21 For CH2.

[0490] In a specific embodiment of the group of formula (VIc):

[0491] e, f, g, h, and y are each 1; or

[0492] e and f are 0 and g, h, and y are 1; or

[0493] e, f, g and h are 0, and y is; or

[0494] e, g, and h are 0 and f and y are 1; or

[0495] e, f, g, and y are 0 and h is 1.

[0496] In one embodiment of the radical of formula (VIc), u, w and x are each 0 and v is 0 or 1.

[0497] In a specific embodiment, L is a group of formula (VId):

[0498]

[0499] wherein * represents a connection to the androgen receptor binding moiety, and # represents a connection to the compound of formula (I);

[0500] s is 0 or 1;

[0501] u is 0 or 1;

[0502] v is 0, 1, or 2;

[0503] x is 0, 1, 2, 3, or 4; and

[0504] R 37 is H or methyl;

[0505] When u is 1, s is 0; and

[0506] When v is 0, u and w are not both 1.

[0507] In a specific embodiment of formula (VId), s and w are both 0, and u is 1. In a more specific embodiment, the sum of v and x is between 1 and 4, such that L is *CO(CH2) 1-4 #。 In a more specific embodiment, L is *CO(CH2)#.

[0508] In a specific embodiment of formula (VId), s is 1 and u and w are both 0. In a more specific embodiment, the sum of v and x is 3 or 4, such that L is *O(CH2)3# or *O(CH2)4#.

[0509] In a specific embodiment of formula (VId), s, u and w are each 0. In a more specific embodiment, the sum of v and x is between 1 and 6, such that L is *(CH2) 1-6 #。 In more specific embodiments, L is (CH2)4, (CH2)5 or (CH2)6.

[0510] In certain embodiments, the linkers of formula (VId) described herein can be used in compounds of formula (Ib) wherein R 3 and R 4 Together with the nitrogen atom to which they are attached, they are linked together to form a spirocyclic nitrogen-containing heterocycle. More specifically, the linker groups of formula (VId) described herein can be used in compounds of formula (Ib) wherein R 3 and R 4 Together with the nitrogen atom to which they are attached, they are joined together to form a spirocyclic nitrogen-containing heterocycle having a structure selected from the group consisting of:

[0511]

[0512] Where the asterisk represents the position of attachment to the carbonyl group, and # represents the point of attachment to L.

[0513] In certain embodiments, the linker of formula (VId) described herein can be used in compounds of formula (I), (Ia), and (Ib), wherein the androgen binding agent has a structure of formula (III), wherein B is a fused bicyclic nitrogen-containing heterocycle. In specific embodiments, B has the structure shown below (wherein * represents a connection to a carbonyl group, and # represents a connection to a linker):

[0514]

[0515] When the target binding moiety is an androgen receptor binding moiety of Formula (III), (IIIa), (IIIb), (IV) or (V), L can be a group of the formula *(CH2)zN(CH3)#, wherein * represents the connection to the androgen receptor binding moiety and # represents the connection to the compound of Formula (I), and wherein z is 1, 2, 3, 4 or 5.

[0516] PROTAC

[0517] Compounds of formula (I), (Ia) and (Ib) wherein q is 1 are "PROTACs". The nature of the linker present in a PROTAC is determined by p. When p is 0, there is no linker (alternatively, the linker can be considered a bond). When p is 1, the linker is as defined herein for L. Compounds wherein p is 1 but q is 0 are compounds comprising a degron and a linker. Such compounds can be used as intermediates in the manufacture of PROTACs.

[0518] While it is convenient to mentally divide the PROTAC compounds of the present invention into being composed of a target binding moiety, a linker, and a cereblon binding moiety or a degron, it will be appreciated that these are not discrete moieties and interact with each other due to the conformation adopted by the compound as a whole. For example, a portion of a compound that falls within the definition of L may actually bind to 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 cereblon due to the conformation of the compound as a whole. One skilled in the art will appreciate that designating a portion of a molecule as a linker, cereblon binder, or target binder (androgen binding moiety) is merely a matter of convenience and is not intended to limit the functionality of these portions of the compound.

[0519] The compound of formula (I), 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 a specific embodiment, the compound is a compound of formula (Ia), a tautomer thereof, or a salt thereof. In a more specific embodiment, the compound is a compound of formula (Ia), a tautomer thereof, or a salt thereof, and has an androgen binding moiety of formula (IIIa).

[0520] In specific embodiments of the androgen receptor binding portion of Formula (IIIa), R 16 It is chlorine or CF3.

[0521] In specific embodiments of the androgen receptor binding portion of Formula (IIIa), R 17 、R 18 、R 19 and R 20 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 Each is H.

[0522] In specific embodiments of the androgen receptor binding portion of Formula (IIIa),

[0523] X7 and X8 are N and X9 is CH; or

[0524] X8 and X9 are N and X7 is CH; or

[0525] X7 and X9 are N and X8 is CH; or

[0526] X7 is N and X8 and X9 are CH; or

[0527] X8 is N and X7 and X9 are CH; or

[0528] X7 is CF and X8 and X9 are CH; or

[0529] X7, X8 and X9 are each CH.

[0530] In a more specific embodiment of the androgen receptor binding portion of formula (IIIa), X7 and X8 are N, and X9 is CH. In a specific embodiment wherein X7 and X8 are N and X9 is CH, R 17 、R 18 、R 19 and R20 Each is H.

[0531] In a specific embodiment, the present invention provides a compound of formula (VII), a tautomer of a compound of formula (VII), or a salt thereof:

[0532]

[0533] in:

[0534] X1 is N or CR 2 , where R 2 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and -CONR 5 R 6 ;

[0535] X4 for CR 7 or N, where R 7 Selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 alkoxy;

[0536] X2 and X3 are independently selected from N or CH;

[0537] X 15 and X 22 independently selected from N or C;

[0538] X 16 N or CH;

[0539] X 18 CR 35 , where R 35 is H or halogen;

[0540] a and b are independently 0 or 1;

[0541] r is 0 or 1;

[0542] R 5 and R 6 Independently selected from H or C 1-4 alkyl;

[0543] R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 and R 35 independently selected from H or halogen;

[0544] R 36 is hydrogen or methyl.

[0545] X 10 is CH or N;

[0546] X 11 CR 34 or N, where R 34 is hydrogen or halogen;

[0547] c is 0 or 1;

[0548] d is 0 or 1;

[0549] R 37 is H or methyl;

[0550] R 38 、R 39 、R 40 、R 41 and R 42 independently selected from H, halogen, methyl, CF3 and CN;

[0551] s is 0 or 1;

[0552] u is 0 or 1; and

[0553] v is 0, 1, or 2;

[0554] X7, X8 and X9 are independently CH, CF or N;

[0555] R 16 Selected from halogen or CF3;

[0556] R 17 、R 18 、R 19 and R 20 are independently H or C 1-4 alkyl; and

[0557] When X 15 When N, X 22 For CH.

[0558] In one embodiment of the compound of formula (VII), a tautomer or a salt thereof, R 2 is selected from hydrogen and halogen.

[0559] In one embodiment of the compound of formula (VII), a tautomer or a salt thereof, X1 is N or CH.

[0560] In another embodiment of Formula (VII), a tautomer or a salt thereof, X1 is CR 2 , where R 2is selected from CF3, F or Cl. In a more specific embodiment, X1 is CR 2 , where R 2 Selected from F or Cl.

[0561] In one embodiment of the compound of formula (VII), its tautomer or salt, X4 is CR 7 In a more specific embodiment, X4 is CR 7 , where R 7 In one embodiment, X4 is CR 7 , where R 7 In another embodiment, X4 is CH. In an alternative embodiment, X4 is N.

[0562] In one embodiment of the compound of formula (VII), a tautomer or a salt thereof, X 22 is N.

[0563] In one embodiment of the compound of formula (VII), a tautomer or a salt thereof, X 15 For C.

[0564] In which X 22 In the embodiment where X1, X2, X3 and X4 are each CH and X 15 is C. In which X 22 In another embodiment where X1, X3 and X4 are each CH, X 15 is C and X2 is N. 22 In a further embodiment where X1 is N, X2, X3 and X4 are each CH and X 15 is C. In which X 22 In alternative embodiments where X1 and X2 are each N and X3 and X4 are each CH and X 15 is C. In which X 22 In alternative embodiments where X2 and X4 are each N and X1 and X3 are each CH and X 15 For C.

[0565] In which X2 and X 15 In alternative embodiments where X1, X3 and X4 are each CH and X 22 For C.

[0566] In one embodiment of the compound of formula (VII), a tautomer or a salt thereof, R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R14 、R 15 and R 35 In another embodiment, R 8 、R 9 and R 35 are independently selected from H or halogen, and R 10 、R 11 、R 12 、R 13 、R 14 and R 15 Each is H. In a more specific embodiment, R 8 and R 9 are independently selected from H or fluorine, and R 10 、R 11 、R 12 、R 13 、R 14 、R 15 and R 35 Each is H. In a more specific embodiment, R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 and R 15 Each is H, and R 35 is H or fluorine.

[0567] In one embodiment of the compound of formula (VII), a tautomer or a salt thereof, r is 0. In an alternative embodiment, r is 1 and R 36 is H. In an alternative embodiment, r is 1 and R 36 It is a methyl group.

[0568] In one embodiment of the compound of formula (VII), a tautomer or salt thereof, a and b are both 1 and X 16 is CH or N. In a more specific embodiment, a and b are both 1 and X 16 is N. In an alternative embodiment, a and b are both 1 and X 16 For CH.

[0569] In one embodiment of the compound of formula (VII), a tautomer or salt thereof, a is 0, b is 1, and X 16 is N.

[0570] In one embodiment of the compound of formula (VII), a tautomer or salt thereof, a and b are both 0 and X 16 For CH.

[0571] In one embodiment of the compound of formula (VII), a tautomer or a salt thereof, R 34 In a more specific embodiment, R 34 For hydrogen.

[0572] In one embodiment of the compound of formula (VII), a tautomer or a salt thereof:

[0573] c and d are each 0; or

[0574] c is 1 and d is 0; or

[0575] c and d are each 1.

[0576] In one embodiment of the compound of formula (VII), a tautomer or a salt thereof, R 37 is H. In an alternative embodiment, R 37 It is a methyl group.

[0577] In one embodiment of the compound of formula (VII), a tautomer or a salt thereof, R 42 is hydrogen, methyl, fluorine or CN. In a more specific embodiment, R 42 For hydrogen.

[0578] In one embodiment of the compound of formula (VII), a tautomer or a salt thereof, R 38 、R 39 、R 40 and R 41 In a more specific embodiment, R 38 、R 39 、R 40 and R 41 In a more specific embodiment, R 38 、R 39 、R 40 and R 41 Each is H.

[0579] In a specific embodiment of the compound of formula (VII), a tautomer or a salt thereof:

[0580] X 10 N and X 11 CR 34 ;

[0581] s is 0;

[0582] u is 0 or 1;

[0583] v is 0, 1, or 2; and

[0584] R 34 is hydrogen or halogen.

[0585] In the compound of formula (VII), its tautomer or salt (wherein X 10 is N and X 11 CR 34 ), s is 0, u is 1, v is 0 and R 34 is hydrogen or halogen. In a specific embodiment, R 34 For H.

[0586] In the compound of formula (VII), its tautomer or salt (wherein X 10 is N and X 11 CR 34 ), s is 0, u is 0, v is an integer between 0 and 2, and R 34 is hydrogen or halogen. In one embodiment, v is 0. In another embodiment, v is 1. In a further embodiment, v is 2. In a specific embodiment, R 34 For H.

[0587] In various embodiments of the compound of formula (VII), its tautomers or salts:

[0588] X 10 is CH and X 11 is CH or N;

[0589] s is 0 or 1;

[0590] u is 0 or 1; and

[0591] v is 0 or 1.

[0592] In a more specific embodiment:

[0593] X 10 is CH and X 11 It is N;

[0594] s is 0 or 1; and

[0595] u and v are both 1.

[0596] In alternative embodiments of the compound of formula (VII), a tautomer or a salt thereof, X 10 and X 11 Each is CH, and s, u and v are each 0.

[0597] In a specific embodiment of the compound of formula (VII), a tautomer or a salt thereof, R 16 It is chlorine or CF3.

[0598] In a specific embodiment of the compound of formula (VII), a tautomer or a salt thereof, R 17、R 18 、R 19 and R 20 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 Each is H.

[0599] In a specific embodiment of the compound of formula (VII), a tautomer or a salt thereof,

[0600] X7 and X8 are N and X9 is CH; or

[0601] X8 and X9 are N and X7 is CH; or

[0602] X7 and X9 are N and X8 is CH; or

[0603] X7 is N and X8 and X9 are CH; or

[0604] X8 is N and X7 and X9 are CH; or

[0605] X7 is CF and X8 and X9 are CH; or

[0606] X7, X8 and X9 are each CH.

[0607] In more specific embodiments of the compound of formula (VII), its tautomers or salts, X7 and X8 are N, and X9 is CH. In specific embodiments wherein X7 and X8 are N, and X9 is CH, R 17 、R 18 、R 19 and R 20 Each is H.

[0608] In more specific embodiments of the compound of formula (VII), its tautomers or salts, X7 and X9 are N and X8 is CH. In specific embodiments wherein X7 and X9 are N and X8 is CH, R 17 、R 18 、R 19 and R 20 Each is H.

[0609] In a specific embodiment, the present invention provides a compound of formula (XXXXV), a tautomer of a compound of formula (XXXXV), or a salt thereof:

[0610]

[0611] in:

[0612] X1 is N or CR 2 , where R 2 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and -CONR 5 R 6 ;

[0613] X4 for CR 7 or N, where R 7 Selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 alkoxy;

[0614] X2 and X3 are independently selected from N or CH;

[0615] X 15 and X 22 are independently selected from N or C, wherein when X 15 When N, X 22 is C;

[0616] r is 0, 1, or 2;

[0617] a is 0, 1 or 2, and b and j are independently 0 or 1, provided that b and j cannot both be 0;

[0618] X 16 N or CH;

[0619] X 18 CR 35 , where R 35 is hydrogen or halogen;

[0620] X 25 CR 12 R 13 or O;

[0621] R 5 and R 6 are independently selected from hydrogen or C 1-4 alkyl;

[0622] R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 and R 15 independently selected from hydrogen or halogen;

[0623] R 36 and R37 are independently hydrogen or methyl;

[0624] v is 0, 1, or 2;

[0625] X7, X8 and X9 are independently CH, CF or N;

[0626] X 24 is CH or N;

[0627] R 16 is halogen or CF3; and

[0628] R 21 、R 22 、R 23 and R 24 are independently H or C 1-4 alkyl.

[0629] The compound of formula (XXXXV), its tautomer or salt comprises an androgen receptor binding portion of formula (IIIb). The androgen receptor binding portion of formula (IIIb) can bind to certain mutant versions of the androgen receptor, including double mutant (T878A / L702H) androgen receptor. It is expected that the compound of formula (XXXXV), its tautomer or salt can be used to treat castration-resistant prostate cancer.

[0630] In one embodiment of the compound of formula (XXXXV), a tautomer or a salt thereof, X 22 is N. In which X 22 In certain embodiments where X1, X2, X3, or X4 is N, one or more of X1, X2, X3, or X4 is additionally N.

[0631] In one embodiment of the compound of formula (XXXXV), a tautomer or a salt thereof, X 15 For C.

[0632] In one embodiment of the compound of formula (XXXXV), a tautomer or a salt thereof, X1 is N or CH.

[0633] In another embodiment of Formula (XXXXV), a tautomer or a salt thereof, X1 is CR 2 , where R 2 is selected from CF3, F or Cl. In a more specific embodiment, X1 is CR 2 , where R 2 Selected from F or Cl.

[0634] In one embodiment of the compound of formula (XXXXV), its tautomer or salt, X4 is CR 7 In a more specific embodiment, X4 is CR 7 , where R7 In one embodiment, X4 is CR 7 , where R 7 In another embodiment, X4 is CH. In an alternative embodiment, X4 is N.

[0635] In one embodiment of the compound of formula (XXXXV), a tautomer or a salt thereof,

[0636] X 22 and X2 is N, and X1, X3 and X4 are CH, and X 15 C; or

[0637] X 22 and X3 is N, and X1, X2 and X4 are CH, and X 15 C; or

[0638] X 22 and X4 is N, and X1, X2 and X3 are CH, and X 15 C; or

[0639] X 22 , X2 and X3 are N, and X and X4 are CH, and X 15 C; or

[0640] X 22 , X3 and X4 are N, and X1 and X2 are CH, and X 15 C; or

[0641] X 22 , X2 and X4 are N, and X1 and X3 are CH, and X 15 For C.

[0642] In one embodiment of the compound of formula (XXXXV), a tautomer or a salt thereof, X 18 For CH.

[0643] In one embodiment of the compound of formula (XXXXV), a tautomer or a salt thereof, r is 0 or 1. In one embodiment of the compound of formula (XXXXV), a tautomer or a salt thereof, r is 0. In an alternative embodiment, r is 1 and R 36 is H. In an alternative embodiment, r is 1 and R 36 It is a methyl group.

[0644] In an alternative embodiment of the compound of formula (XXXXV), a tautomer or a salt thereof, r is 2 and each R 36 For H.

[0645] In one embodiment of the compound of formula (XXXXV), a tautomer or a salt thereof, R 35For H.

[0646] In one embodiment of the compound of formula (XXXXV), a tautomer or a salt thereof, X 16 is N.

[0647] In one embodiment of the compound of formula (XXXXV), a tautomer or salt thereof, a tautomer or salt thereof, X 25 CR 12 R 13 .

[0648] In one embodiment of the compound of formula (XXXXV), a tautomer or salt thereof, j is 1 and a and b are independently 0 or 1. In a more specific embodiment, X 16 N, X 25 CR 12 R 13 , j is 1 and a and b are independently 0 or 1. In a more specific embodiment, X 16 N, X 25 CR 12 R 13 , and a, b and j are each 1.

[0649] In one embodiment of the compound of formula (XXXXV), a tautomer or salt thereof, a is 0 and b and j are each 1, X 16 N and X 25 CR 12 R 13 .

[0650] In one embodiment of the compound of formula (XXXXV), a tautomer or a salt thereof, R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 and R 15 In another embodiment, R 8 and R 9 are independently selected from H or halogen, and R 10 、R 11 、R 12 、R 13 、R 14 and R 15 Each is H. In a more specific embodiment, R 8 and R 9 are independently selected from H or fluorine, and R 10 、R 11 、R 12 、R 13 、R14 and R 15 Each is H. In another embodiment, R 12 and R 13 are independently selected from H or halogen, and R 8 、R 9 、R 10 、R 11 、R 14 and R 15 Each is H. In a more specific embodiment, R 12 and R 13 are independently selected from H or fluorine, and R 8 、R 9 、R 10 、R 11 、R 14 and R 15 Each is H. In a more specific embodiment, R 8 、R 9 R 10 、R 11 、R 12 、R 13 、R 14 and R 15 Each is H.

[0651] In a specific embodiment of the compound of formula (XXXXV), a tautomer or a salt thereof, v is 1.

[0652] In a specific embodiment of the compound of formula (XXXXV), a tautomer or a salt thereof, R 37 It's hydrogen.

[0653] In a specific embodiment of the compound of formula (XXXXV), a tautomer or a salt thereof, R 16 is chlorine or CF3. In a specific embodiment of the compound of formula (XXXXV), its tautomer or salt, R 16 For chlorine.

[0654] In a specific embodiment of the compound of formula (XXXXV), a tautomer or a salt thereof, R 21 、R 22 、R 23 and R 24 Each is a methyl group.

[0655] In a more specific embodiment of the compound of formula (XXXXV), a tautomer or a salt thereof,

[0656] X7 and X8 are N, and X9 and X 24 is CH; or

[0657] X8 and X9 are N, and X7 and X 24is CH; or

[0658] X7 is N, and X8, X9 and X 24 is CH; or

[0659] X7 and X 24 is N, and X8 and X9 are CH.

[0660] In a specific embodiment, the present invention provides a compound of formula (XXXXVI), a tautomer of a compound of formula (XXXXVI), or a salt thereof:

[0661]

[0662] in:

[0663] X1 is N or CR 2 , where R 2 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and -CONR 5 R 6 ;

[0664] X4 for CR 7 or N, where R 7 Selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 alkoxy;

[0665] X2 and X3 are independently selected from N or CH;

[0666] X 15 and X 22 are independently selected from N or C, wherein when X 15 When N, X 22 is C;

[0667] r is 0, 1, or 2;

[0668] a is 0, 1 or 2, and b and j are independently 0 or 1, provided that b and j cannot both be 0;

[0669] X 16 N or CH;

[0670] X 18 CR 35 , where R 35 is hydrogen or halogen;

[0671] X 25 CR 12 R 13 or O;

[0672] R 5 and R 6 are independently selected from hydrogen or C 1-4 alkyl;

[0673] R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 and R 15 independently selected from hydrogen or halogen;

[0674] R 36 and R 37 are independently hydrogen or methyl;

[0675] v is 0, 1, or 2;

[0676] X7, X8 and X9 are independently CH, CF or N;

[0677] R 21 、R 22 、R 23 and R 24 are independently H or C 1-4 alkyl.

[0678] In one embodiment of the compound of formula (XXXXVI), a tautomer or a salt thereof, X 22 is N. In which X 22 In certain embodiments where X1, X2, X3, or X4 is N, one or more of X1, X2, X3, or X4 is additionally N.

[0679] In one embodiment of the compound of formula (XXXXVI), a tautomer or a salt thereof, X 15 For C.

[0680] In one embodiment of the compound of formula (XXXXVI), a tautomer or a salt thereof, X1 is N or CH.

[0681] In another embodiment of Formula (XXXXVI), a tautomer or a salt thereof, X1 is CR 2 , where R 2 is selected from CF3, F or Cl. In a more specific embodiment, X1 is CR 2 , where R 2 Selected from F or Cl.

[0682] In one embodiment of the compound of formula (XXXXVI), its tautomer or salt, X4 is CR 7 In a more specific embodiment, X4 is CR 7, where R 7 In one embodiment, X4 is CR 7 , where R 7 In another embodiment, X4 is CH. In an alternative embodiment, X4 is N.

[0683] In one embodiment of the compound of formula (XXXXVI), a tautomer or a salt thereof,

[0684] X 22 and X2 is N, and X1, X3 and X4 are CH, and X 15 C; or

[0685] X 22 and X3 is N, and X1, X2 and X4 are CH, and X 15 C; or

[0686] X 22 and X4 is N, and X1, X2 and X3 are CH, and X 15 C; or

[0687] X 22 , X2 and X3 are N, and X and X4 are CH, and X 15 C; or

[0688] X 22 , X3 and X4 are N, and X1 and X2 are CH, and X 15 C; or

[0689] X 22 , X2 and X4 are N, and X1 and X3 are CH, and X 15 For C.

[0690] In one embodiment of the compound of formula (XXXXVI), a tautomer or a salt thereof, X 18 For CH.

[0691] In one embodiment of the compound of formula (XXXXVI), a tautomer or a salt thereof, r is 0 or 1. In one embodiment of the compound of formula (XXXXVI), a tautomer or a salt thereof, r is 0. In an alternative embodiment, r is 1 and R 36 is H. In an alternative embodiment, r is 1 and R 36 It is a methyl group.

[0692] In an alternative embodiment of the compound of formula (XXXXVI), a tautomer or a salt thereof, r is 2 and each R 36 For H.

[0693] In one embodiment of the compound of formula (XXXXVI), a tautomer or a salt thereof, X16 is N.

[0694] In one embodiment of the compound of formula (XXXXV), a tautomer or salt thereof, a tautomer or salt thereof, X 25 CR 12 R 13 .

[0695] In one embodiment of the compound of formula (XXXXVI), a tautomer or salt thereof, j is 1 and a and b are independently 0 or 1. In a more specific embodiment, X 16 N, X 25 CR 12 R 13 , j is 1 and a and b are independently 0 or 1. In a more specific embodiment, X 16 N, X 25 CR 12 R 13 And a, b and j are each 1.

[0696] In one embodiment of the compound of formula (XXXXVI), a tautomer or salt thereof, a is 0 and b and j are each 1, X 16 is N and X 25 CR 12 R 13 .

[0697] In one embodiment of the compound of formula (XXXXVI), a tautomer or a salt thereof, R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 and R 15 In another embodiment, R 8 and R 9 are independently selected from H or halogen, and R 10 、R 11 、R 12 、R 13 、R 14 and R 15 Each is H. In a more specific embodiment, R 8 and R 9 are independently selected from H or fluorine, and R 10 、R 11 、R 12 、R 13 、R 14 and R 15 Each is H. In another embodiment, R 12 and R13 are independently selected from H or halogen, and R 8 、R 9 、R 10 、R 11 、R 14 and R 15 Each is H. In a more specific embodiment, R 12 and R 13 are independently selected from H or fluorine, and R 8 、R 9 、R 10 、R 11 、R 14 and R 15 Each is H. In a more specific embodiment, R 8 、R 9 R 10 、R 11 、R 12 、R 13 、R 14 and R 15 Each is H.

[0698] In a specific embodiment of the compound of formula (XXXXVI), a tautomer or a salt thereof, v is 1.

[0699] In a specific embodiment of the compound of formula (XXXXVI), a tautomer or a salt thereof, R 37 It's hydrogen.

[0700] In a specific embodiment of the compound of formula (XXXXVI), a tautomer or a salt thereof, R 21 、R 22 、R 23 and R 24 Each is a methyl group.

[0701] In a specific embodiment of the compound of formula (XXXXVI), a tautomer or a salt thereof,

[0702] X7 and X8 are N and X9 is CH; or

[0703] X8 and X9 are N and X7 is CH; or

[0704] X7 and X9 are N and X8 is CH; or

[0705] X7 is N and X8 and X9 are CH; or

[0706] X8 is N and X7 and X9 are CH; or

[0707] X7 is CF and X8 and X9 are CH; or

[0708] X7, X8 and X9 are each CH.

[0709] In a more specific embodiment of the compound of formula (XXXXVI), a tautomer or a salt thereof,

[0710] X7 and X8 are N and X9 is CH; or

[0711] X7 is N and X8 and X9 are CH; or

[0712] X8 is N and X7 and X9 are CH.

[0713] 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 (shown in the structures). It will be understood that any reference to a named compound or a structurally described compound is intended to encompass all tautomers of such compounds.

[0714] In one embodiment, the present invention provides a compound of formula (I), a tautomer or a pharmaceutically acceptable salt thereof, which is selected from ECB1-53, a tautomer or a pharmaceutically acceptable salt thereof.

[0715] In one embodiment, the present invention provides a compound of formula (I), a tautomer or a pharmaceutically acceptable salt thereof, which is selected from EAR1-273, a tautomer or a pharmaceutically acceptable salt thereof.

[0716] 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, a tautomer or a pharmaceutically acceptable salt thereof. 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 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.

[0717] 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, a tautomer or a pharmaceutically acceptable salt thereof.

[0718] 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, a tautomer or a pharmaceutically acceptable salt thereof.

[0719] 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, a tautomer or a pharmaceutically acceptable salt thereof.

[0720] 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, a tautomer or a pharmaceutically acceptable salt thereof.

[0721] 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, a tautomer or a pharmaceutically acceptable salt thereof.

[0722] 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, a tautomer or a pharmaceutically acceptable salt thereof.

[0723] 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, a tautomer or a pharmaceutically acceptable salt thereof.

[0724] 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, a tautomer or a pharmaceutically acceptable salt thereof.

[0725] 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, a tautomer or a pharmaceutically acceptable salt thereof.

[0726] 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, a tautomer or a pharmaceutically acceptable salt thereof.

[0727] 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, a tautomer or a pharmaceutically acceptable salt thereof.

[0728] 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, a tautomer or a pharmaceutically acceptable salt thereof.

[0729] 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, a tautomer or a pharmaceutically acceptable salt thereof.

[0730] 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, a tautomer or a pharmaceutically acceptable salt thereof.

[0731] 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, a tautomer or a pharmaceutically acceptable salt thereof.

[0732] 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, a tautomer or a pharmaceutically acceptable salt thereof.

[0733] 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, a tautomer or a pharmaceutically acceptable salt thereof.

[0734] 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, a tautomer or a pharmaceutically acceptable salt thereof.

[0735] 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, a tautomer or a pharmaceutically acceptable salt thereof.

[0736] 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, a tautomer or a pharmaceutically acceptable salt thereof.

[0737] 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, a tautomer or a pharmaceutically acceptable salt thereof.

[0738] 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, a tautomer or a pharmaceutically acceptable salt thereof.

[0739] 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, a tautomer or a pharmaceutically acceptable salt thereof.

[0740] 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, a tautomer or a pharmaceutically acceptable salt thereof.

[0741] 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, a tautomer or a pharmaceutically acceptable salt thereof.

[0742] 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, a tautomer or a pharmaceutically acceptable salt thereof.

[0743] 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, a tautomer or a pharmaceutically acceptable salt thereof.

[0744] In one embodiment, the present invention provides a tautomer or a pharmaceutically acceptable salt thereof.

[0745] Due to their use in medicine, salts of PROTACs including PROTACs of formula (VII), (XXXXV) and (XXXXVI) are preferably pharmaceutically acceptable.

[0746] Pharmaceutically acceptable salts include, inter alia, those described in Berge, J. Pharm. Sci., 1977, 66, 1-19 or those listed in PH Stahl and CG Wermuth, editors, Handbook of Pharmaceutical Salts; Properties, Selection and Use, Second Edition Stahl / Wermuth: Wiley-VCH / VHCA, 2011 (see http: / / www.wiley.com / WileyCDA / WileyTitle / productCd-3906390519.html).

[0747] Suitable pharmaceutically acceptable salts include acid addition salts. Such acid addition salts can be formed by reacting a compound of Formula (I), (Ia), (Ib), (Ic), (VII), (XXXXV), or (XXXXVI) (e.g., which contains a basic amine or other basic functional group) with an appropriate acid, optionally in a suitable solvent (e.g., an organic solvent), to provide a salt that can be isolated by various methods, including crystallization and filtration.

[0748] 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). If 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, including treating the salt with an inorganic or organic base. Similarly, if 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, including treating the salt with an inorganic or organic acid.

[0749] 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), and benzoate. ate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate, succinate, dodecyl sulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane-1,2-disulfonate (edisylate), ethanesulfonate (esylate), formate, fumarate, galactarate (mucate), gentisate (2,5- dihydroxybenzoate), gluconate (glucoheptonate), gluconate, glucuronate, glutamate, glutarate, glycerophosphate, 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 (naphthalenedisulfonate), naphthalene-2-sulfonate (naphthalenesulfonate), nicotinate, nitric acid

[0014] The present invention also includes salts of formula (I), (Ia), (Ib), (Ic), (VII), (XXXXV), or (XXXXVI) and salts thereof. ...Such salts will contain one, two or more acid counterions, for example dihydrochloride.

[0750] 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 substoichiometric salts, e.g., wherein the counterion contains more than one acidic proton.

[0751] Methods for preparing compounds

[0752] The method used to prepare the compounds described herein depends on the desired compound. Factors such as the choice of a particular substituent and the various possible positions of a particular substituent play a role in the path to be followed to prepare a particular compound of the present invention. Those skilled in the art will readily recognize these factors.

[0753] In general, the compounds of the present invention can be prepared by standard techniques known in the art and known methods similar thereto. The general method for preparing compounds of formula (Iaa), (Ibb), (III), (IV) and (V) is as follows. All starting materials and reagents described in the following general experimental scheme are commercially available, or can be prepared by methods known to those skilled in the art. For the sake of completeness, it should be noted that group L is not usually synthesized as a separate intermediate. On the contrary, L can be connected to a compound of formula (Iaa) or (Ibb) or a target binding moiety by the standard techniques of this area, or a portion of L can be connected to a compound of formula (Iaa) or (Ibb) for synthesis, and another portion of L is connected to a target binding moiety for synthesis.

[0754] Those skilled in the art will appreciate that if a substituent described herein is incompatible 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 may be removed at a suitable point in the reaction sequence to provide the desired intermediate or target compound. Suitable protecting groups and methods for protecting and deprotecting various substituents using such suitable protecting groups are well known to those skilled in the art; examples of which can be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999). In some cases, a substituent may be specifically selected to be reactive under the reaction conditions employed. In these cases, the reaction conditions convert the selected substituent into another substituent that can be used as an intermediate compound or as a desired substituent in the target compound.

[0755] General Scheme 1 provides the preparation of compounds of formula (Iaa) (wherein X 16In general scheme 1, X1, X2, X3, X4, X 15 、X 18 、X 22 、X 25 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 36 , a, b and r are as defined in formula (Iaa), PG1 and PG2 are suitable protecting groups, L is a suitable leaving group, and Hal is Br or I. The compound of formula (XXXXI) can be prepared by the method described in Chemistry-A European Journal (2011), 17 (49), 13698-13705. It is worth noting that when the amine version of compound (XVIII) is not readily available, it can be prepared by reducing the nitro version of compound (XIX) with iron in the presence of ammonium chloride. Those skilled in the art will also recognize that the compound of formula (Iaa) (wherein X 16 Compounds of formula (Icc) can be prepared in an analogous manner without the need to protect the nitrogen.

[0756] General plan 1

[0757]

[0758]

[0759] When L is bromo or methylsulfonyloxy, steps (i) and (vii) may comprise treatment with sodium hydride followed by reaction with 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 (e.g., cesium carbonate).

[0760] Step (ii) is a reductive amination reaction using a suitable reducing agent (such as sodium triacetoxyborohydride or sodium cyanoborohydride) with acetic acid. The reaction occurs at a suitable temperature (such as 0°C to room temperature).

[0761] Step (iii) is a dehydrogenation reaction with a suitable oxidant such as DDQ. Step (ii) occurs in the presence of a suitable solvent such as THF at a suitable temperature (eg, between 0°C and room temperature).

[0762] Steps (iv) and (xiii) are amination reactions. This reaction can be catalyzed by a palladium catalyst / ligand system (e.g., BrettPhos Pd G3 precatalyst and BrettPhos ligand) in the presence of a suitable base (e.g., tripotassium phosphate). Alternatively, it can be catalyzed by copper (I) iodide in the presence of trans-N,N'-dimethylcyclohexane-1,2-diamine and a suitable base (e.g., potassium carbonate).

[0763] Steps (v) and (x) are deprotection reactions. When PG2 is a trimethylsilylethoxymethyl group, deprotection can be achieved by treatment with trifluoroacetic acid.

[0764] Steps (vi) and (ix) are also deprotection reactions. When PG1 is a benzyl carboxylate, deprotection can be achieved by treating with Pd-C 10% on carbon. When PG1 is a tert-butyloxycarbonyl group, deprotection can be achieved by treating with trifluoroacetic acid.

[0765] Step (viii) comprises treating the compound of formula (IX) with acrylic acid followed by urea.

[0766] Step (xi) is to react with an amine in the presence of HATU and a suitable base (eg, DIPEA or triethylamine) to form an amide.

[0767] Step (xii) is a two-part reaction wherein a compound of formula (XXXIII) is treated with phosphorus oxychloride followed by treatment with di-tert-butyl dicarbonate in the presence of a suitable base such as triethylamine.

[0768] General Scheme 2 provides the preparation of compounds of formula (Ibbb) (wherein X 15 is C and X 22 In general scheme 2, X2, X3, X4, R 3 and R 4 As defined in formula (Ibbb), and PG3 is a suitable protecting group. 15 is N and X 22 Compounds of formula C) and (Ibb) can be prepared according to methods known to those skilled in the art.

[0769] General Scheme 2

[0770]

[0771] Step (i) involves reaction with 2-iodopropane in the presence of a suitable base such as cesium carbonate.

[0772] Step (ii) involves reaction with benzophenone imine in the presence of BINAP, Pd2(dba)3 and a suitable base (eg cesium carbonate).

[0773] Step (iii) is a deprotection reaction where PG3 is a methyl group, which may involve treatment with sodium hydroxide.

[0774] Step (iv) comprises treating the compound of formula (XXIII) with acrylic acid followed by urea.

[0775] Step (v) is an amide formation step by reaction with an amine in the presence of HATU and a suitable base (such as triethylamine or DIPEA).

[0776] General Scheme 3 provides an exemplary synthetic method for preparing compounds of formula (III). In General Scheme 3, A, B, X 23 and R 16 As defined in formula (III), PG4 and PG5 are suitable protecting groups.

[0777] General Scheme 3

[0778]

[0779] Step (i) is treated with sodium hydride and then reacted with a compound of formula (XXVI).

[0780] Step (ii) is a deprotection reaction. When PG4 is tert-butyloxycarbonyl, deprotection can be achieved by treating with an acid such as HCl or TFA.

[0781] Step (iii) is also a deprotection reaction. When PG5 is a methyl group or an ethyl group, deprotection can be achieved by treating with a base such as sodium hydroxide.

[0782] Step (iv) is to form an amide by reaction with an amine in the presence of HATU and a suitable base such as DIPEA or triethylamine. Alternatively, PyBOP can be used as a reagent in the presence of ethyl (E)-2-cyano-2-(hydroxyimino)acetate and N-methylmorpholine or OxymaPure and DIPEA.

[0783] General Scheme 4 provides an exemplary synthetic method for preparing compounds of formula (IV). In General Scheme 4, R 25 、R 26 and R 27 As defined in formula (IV).

[0784] General Scheme 4

[0785]

[0786] Step (i) is a hydrogenation reaction. Palladium on carbon (10 wt%) can be used as a catalyst, wherein the reaction is carried out under a hydrogen atmosphere. Alternatively, the reaction can include reaction with ammonium chloride and iron.

[0787] Step (ii) is an alkylation reaction. 26 and R 27 In the case of methyl, the reaction involves reaction with methyl 2-bromo-2-methylpropanoate in the presence of a suitable base such as DIPEA.

[0788] Step (iii) is a cyclization reaction which comprises reacting with a compound of formula (XXXIV) in the presence of a suitable solvent (eg, a mixture of isopropyl acetate and DMSO).

[0789] General Scheme 5 provides an exemplary synthetic method for preparing compounds of Formula (V). In General Scheme 5, R 29 、R 30 、R 31 、R 32 and R 33 As defined in formula (V).

[0790] General Scheme 5

[0791]

[0792] Step (i) typically takes place in the presence of a suitable base, such as potassium carbonate.

[0793] Step (ii) is a deprotection reaction. When PG7 is tert-butyl carboxylate, deprotection can be achieved by treating with an acid (eg, hydrochloric acid).

[0794] Step (iii) involves reaction with phenyl chloroformate in the presence of a suitable base such as DIPEA.

[0795] Step (iv) takes place in a suitable solvent such as MeCN.

[0796] Pharmaceutical composition

[0797] The PROTACs of the present invention, or pharmaceutically acceptable salts thereof, may be administered by any convenient route. In specific embodiments, the PROTACs or pharmaceutically acceptable salts thereof may be administered orally, parenterally, intranasally, or by inhalation. In one embodiment, the PROTACs or pharmaceutically acceptable salts thereof are administered as a pharmaceutical composition. In one embodiment, the PROTACs or pharmaceutically acceptable salts thereof are formulated in a pharmaceutical composition suitable for oral or parenteral administration or suitable for intranasal or inhalation administration. Appropriate dosages will be readily apparent to those skilled in the art.

[0798] According to one aspect, the present invention provides a pharmaceutical composition comprising a PROTAC or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. According to another aspect, the present invention provides a method for preparing a pharmaceutical composition comprising mixing a PROTAC or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable excipient.

[0799] Pharmaceutical formulations suitable 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 liquid emulsions or water-in-oil liquid emulsions.

[0800] Pharmaceutical formulations suitable for nasal administration may include coarse powders having a particle size, for example, in the range of 20 to 500 microns, which are administered in the manner of snuff, i.e., by rapid inhalation through the nasal cavity from a powder container held close to the nose. Suitable formulations in which the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oily solutions of the PROTAC or a pharmaceutically acceptable salt thereof.

[0801] Pharmaceutical formulations suitable for administration by inhalation include fine particle dusts or mists which can be generated by means of various types of metered, dosed pressurized aerosols, nebulizers or insufflators.

[0802] Pharmaceutical preparations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that make the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The preparations may be present in unit dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in freeze-dried (lyophilized) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets.

[0803] It should be understood that in addition to the ingredients particularly mentioned above, the formulations described herein may include 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.

[0804] The present invention also provides single pharmaceutical compositions in which a PROTAC or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents can be administered together. When a PROTAC or a pharmaceutically acceptable salt thereof is used in combination with a second therapeutic agent, the dosage of each therapeutic agent may differ from the dosage when the therapeutic agent is used alone.

[0805] Medical uses

[0806] The compounds of Formula (I), (Ia), (Ib), (Ic), or their tautomers or pharmaceutically acceptable salts (where q is 1) can degrade proteins targeted by TBM. When the protein is a potential therapeutic target, the compounds of Formula (I), (Ia), (Ib), (Ic), or their tautomers or pharmaceutically acceptable salts (where q is 1) can be used in medicine.

[0807] Thus, in one aspect, the present invention provides a compound of formula (I), (Ia), (Ib), (Ic), or a tautomer or pharmaceutically acceptable salt thereof, wherein q is 1, for use in therapy.

[0808] When TBM is the androgen receptor binding moiety described herein, the compound of Formula (I), (Ia), (Ib) or (Ic), a tautomer or a pharmaceutically acceptable salt thereof (wherein q is 1) can be used to treat cancer, benign prostatic hyperplasia, ovarian cysts, polycystic ovary syndrome or Kennedy's disease.

[0809] Thus, in one aspect, the present invention provides a compound of formula (I), (Ia), (Ib), (Ic), a tautomer or a pharmaceutically acceptable salt thereof, wherein q is 1 and TBM is an androgen receptor binding moiety, for use in treating cancer, benign prostatic hyperplasia, ovarian cysts, polycystic ovary syndrome or Kennedy's disease.

[0810] In another embodiment, the present invention provides the use of a compound of formula (I), (Ia), (Ib) or (Ic), a tautomer or a pharmaceutically acceptable salt thereof, wherein q is 1 and TBM is an androgen receptor binding moiety, in the preparation of a medicament for the treatment of cancer, benign prostatic hyperplasia, ovarian cysts, polycystic ovary syndrome or Kennedy's disease.

[0811] In another embodiment, the present invention provides a method of treating cancer, benign prostatic hyperplasia, ovarian cysts, polycystic ovary syndrome, or Kennedy's disease, comprising administering to the subject a compound of Formula (I), (Ia), (Ib), or (Ic), a tautomer, or a pharmaceutically acceptable salt thereof (wherein q is 1 and TBM is an androgen receptor binding moiety).

[0812] Suitably, the subject is a mammal. In particular embodiments, the subject is a human.

[0813] 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 specific embodiment, the cancer is selected from prostate cancer or breast cancer.

[0814] In one embodiment, the prostate cancer is androgen-dependent prostate cancer. In another embodiment, treatment is secondary to androgen ablation therapy. In one embodiment, treatment is secondary to treatment with abiraterone acetate or hydroxyflutamide.

[0815] In a more specific embodiment, the prostate cancer is castration-resistant prostate cancer. In one embodiment, the prostate cancer is metastatic castration-resistant prostate cancer. In another embodiment, the prostate cancer is non-metastatic castration-resistant prostate cancer. In one embodiment, the prostate cancer is locally advanced prostate cancer.

[0816] In one embodiment, the breast cancer is triple-negative breast cancer.

[0817] In one embodiment, the disorder treated is Kennedy's disease.

[0818] When a compound of Formula (I), (Ia), (Ib) or (Ic), a tautomer 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 may be used in combination with one or more additional anticancer agents, such as PARP inhibitors. Thus, in one embodiment, the present invention provides a combination of a compound of Formula (I), (Ia), (Ib) or (Ic), a tautomer 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 anticancer agent, such as a PARP inhibitor.

[0819] Numbered implementation plans: Group 1

[0820] Embodiment 1. Compound of formula (I), tautomer of compound of formula (I), or salt thereof

[0821]

[0822] in:

[0823] X1 is N or CR 2 , where R 2 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, -CONR 5 R 6 and-CONR 3 R 4 (L)p(TBM)q;

[0824] X4 for CR 7 or N, where R 7 Selected from hydrogen, halogen, C 1-3 Alkyl, C1-3 Haloalkyl and C 1-3 alkoxy;

[0825] X2 and X3 are independently selected from N or CH;

[0826] X 15 and X 22 independently selected from N or C;

[0827] or R 3 and R 4 Together with the nitrogen atom to which they are attached, they are linked together to form a monocyclic or spirocyclic nitrogen-containing heterocycle, or R 3 H or C 1-4 Alkyl and R 4 -(CH2) n R 28 , where R 28 It is a monocyclic or spirocyclic nitrogen-containing heterocycle;

[0828] n is 0 or 1;

[0829] R 5 and R 6 Independently selected from H or C 1-4 alkyl;

[0830] R 1 C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or a group of formula (II), wherein * represents the position of attachment to the compound of formula (I):

[0831]

[0832]

[0833] a and b are independently 0 or 1;

[0834] X 16 N or CH;

[0835] X 17 CR 34 R 35 , where R 34 and R 35 together with the carbon atoms to which they are attached to form a cyclobutyl ring, or wherein R 34 -(CHR 36 )- or a bond to a compound of formula (I), and R 35 is H or halogen;

[0836] R 36 is hydrogen or methyl;

[0837] R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 and R 15 independently selected from H or halogen;

[0838] L is a chemical linker;

[0839] TBM is the target binding moiety;

[0840] p and q are independently 0 and 1;

[0841] When X 15 When N, X 22 is CH; and

[0842] When X1 is -CONR 3 R 4 (L)p(TBM)q, then R 1 C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 Alkoxy.

[0843] Embodiment 2. A compound of formula (I), a tautomer or a salt thereof according to embodiment 1, which has formula (Ia):

[0844]

[0845] in:

[0846] X1 is N or CR 2 , where R 2 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and -CONR 5 R 6 ;

[0847] X4 for CR 7 or N, where R 7 Selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 alkoxy;

[0848] X2 and X3 are independently selected from N or CH;

[0849] X 15 and X 22 independently selected from N or C;

[0850] X 16 N or CH;

[0851] X 18 CR 35 , where R 35 is H or halogen;

[0852] r is 0 or 1;

[0853] R 5 and R 6 Independently selected from H or C 1-4 alkyl;

[0854] R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 and R 35 are independently selected from H or halogen; and

[0855] R 36 is hydrogen or methyl.

[0856] L is a chemical linker;

[0857] TBM is the target binding moiety;

[0858] p and q are independently 0 and 1; and

[0859] When X 15 When N, X 22 For CH.

[0860] Embodiment 3. A compound of formula (Ia), a tautomer or a salt thereof according to Embodiment 2, wherein X1 is N or CH.

[0861] Embodiment 4. A compound of formula (Ia), a tautomer or a salt thereof according to Embodiment 2 or Embodiment 3, wherein X4 is CR 7 .

[0862] Embodiment 5. A compound of formula (Ia), a tautomer or a salt thereof according to Embodiment 2 or Embodiment 3, wherein X4 is N.

[0863] Embodiment 6. A compound of formula (Ia), a tautomer or a salt thereof according to any one of claims 2 to 5, wherein X2 is CH.

[0864] Embodiment 7. A compound of formula (Ia), a tautomer or a salt thereof according to any one of Embodiments 2 to 6, wherein X3 is CH.

[0865] Embodiment 8. A compound of formula (Ia), a tautomer or a salt thereof according to any one of Embodiments 2 to 7, wherein X 15 For C.

[0866] Embodiment 9. A compound of formula (Ia), a tautomer or a salt thereof according to any one of Embodiments 2 to 8, wherein X 22 is N.

[0867] Embodiment 10. A compound of formula (Ia), a tautomer or a salt thereof according to any one of Embodiments 2 to 9, wherein a and b are both 1 and X 16 is N.

[0868] Embodiment 11. A compound of formula (Ia), a tautomer or a salt thereof according to any one of Embodiments 2 to 10, wherein r is 0.

[0869] Embodiment 12. A compound of formula (Ia), a tautomer or a salt thereof according to any one of Embodiments 2 to 11, wherein:

[0870] R 8 、R 9 and R 35 are independently selected from H or halogen; and

[0871] R 10 、R 11 、R 12 、R 13 、R 14 and R 15 Each is H.

[0872] Embodiment 13. The compound of formula (I), its tautomer or salt according to embodiment 1, which has formula (Ib)

[0873]

[0874] in:

[0875] R 1 C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 alkoxy;

[0876] X2 and X3 are independently selected from N or CH;

[0877] X 15 and X 22 independently selected from N or C;

[0878] X4 for CR 7 or N, where R 7 Selected from hydrogen, halogen, C1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 alkoxy;

[0879] or R 3 and R 4 Together with the nitrogen atom to which they are attached, they are linked together to form a monocyclic or spirocyclic nitrogen-containing heterocycle, or R 3 H or C 1-4 Alkyl and R 4 -(CH2) n R 28 , where R 28 It is a monocyclic or spirocyclic nitrogen-containing heterocycle;

[0880] n is 0 or 1;

[0881] L is a chemical linker;

[0882] TBM is a target binding moiety; and

[0883] p and q are independently 0 and 1; and

[0884] When X 15 When N, X 22 For CH.

[0885] Embodiment 14. A compound of formula (Ib), a tautomer or a salt thereof according to embodiment 13, wherein X4 is N or CH.

[0886] Embodiment 15. A compound of formula (Ib), a tautomer or a salt thereof according to embodiment 14, wherein X4 is CH.

[0887] Embodiment 16. A compound of formula (Ib), a tautomer or a salt thereof according to any one of Embodiments 13 to 15, wherein X2 is CH.

[0888] Embodiment 17. A compound of formula (Ib), a tautomer or a salt thereof according to any one of Embodiments 13 to 16, wherein X3 is CH.

[0889] Embodiment 18. A compound of formula (Ib), a tautomer or a salt thereof according to any one of Embodiments 13 to 16, wherein X 15 For C.

[0890] Embodiment 19. A compound of formula (Ib), a tautomer or a salt thereof according to any one of Embodiments 13 to 18, wherein X 22 is N.

[0891] Embodiment 20. A compound of formula (Ib), a tautomer or a salt thereof according to any one of Embodiments 13 to 19, wherein R 3H or C 1-4 Alkyl and R 4 -(CH2) n R 28 , where R 28 It is a monocyclic nitrogen-containing heterocycle.

[0892] Embodiment 21. A compound of formula (Ib), a tautomer or a salt thereof according to any one of embodiments 13 to 19, wherein the group NR 3 R 4 Having a structure selected from the following:

[0893]

[0894] Where the asterisk represents the position of attachment to the carbonyl group, and # represents the point of attachment to L.

[0895] Embodiment 22. A compound of formula (Ib), a tautomer or a salt thereof according to any one of Embodiments 13 to 21, wherein R 1 C 1-4 alkyl.

[0896] Embodiment 23. A compound of formula (Ib), a tautomer or a salt thereof according to embodiment 22, wherein R 1 It is isopropyl.

[0897] Embodiment 24. A compound of formula (I), (Ia), (Ib), a tautomer or a salt thereof according to any preceding embodiment, wherein q is 1 and TBM is an androgen receptor binding moiety.

[0898] Embodiment 25. The compound of formula (I), (Ia), (Ib), a tautomer or a salt thereof according to embodiment 24, wherein the androgen receptor binding portion has the structure of formula (III)

[0899]

[0900] The connection position with L is indicated by an asterisk;

[0901] A is selected from: cyclohexyl, cyclobutyl or 6-membered nitrogen-containing heterocyclic ring, wherein the cyclohexyl, cyclobutyl or 6-membered nitrogen-containing heterocyclic ring may be optionally replaced by up to 4 C 1-4 Alkyl group substitution;

[0902] B is selected from phenyl, a 6-membered nitrogen-containing heteroaryl group or a fused bicyclic nitrogen-containing heterocycle, wherein B is optionally substituted with one or more halogen groups; and

[0903] R 16 Selected from halogen or CF3.

[0904] Embodiment 26. The compound of formula (I), (Ia), (Ib), a tautomer or a salt thereof according to embodiment 25, wherein the androgen receptor binding portion has the structure of formula (IIIa)

[0905]

[0906] The connection position with L is indicated by an asterisk;

[0907] X7, X8 and X9 are independently CH, CF or N;

[0908] R 16 Selected from halogen or CF3;

[0909] R 17 、R 18 、R 19 and R 20 are independently H or C 1-4 alkyl.

[0910] Embodiment 27. A compound of formula (I), (Ia), (Ib), a tautomer or a salt thereof according to Embodiment 26, wherein X7 and X8 are N and X9 is CH.

[0911] Embodiment 28. A compound of formula (I), (Ia), (Ib), a tautomer or a salt thereof according to Embodiment 26 or Embodiment 27, wherein R 17 、R 18 、R 19 and R 20 Each is H.

[0912] Embodiment 29. The compound of formula (I), (Ia), (Ib), a tautomer or a salt thereof according to embodiment 25, wherein the androgen receptor binding portion has the structure of formula (IIIb):

[0913]

[0914] The connection position with L is indicated by an asterisk;

[0915] X7, X8 and X9 are independently CH or N;

[0916] R 16 is selected from halogen or CF3; and

[0917] R 21 、R 22 、R 23 and R 24 are independently H or C 1-4 alkyl.

[0918] Embodiment 30. The compound of formula (I), (Ia), (Ib), a tautomer or a salt thereof according to embodiment 29, wherein R 21 、R 22 、R 23 and R 24 Each is a methyl group.

[0919] Embodiment 31. A compound of formula (I), (Ia), (Ib), a tautomer or a salt thereof according to embodiment 24, wherein the androgen receptor binding portion has the structure of formula (IV):

[0920]

[0921] The connection position with L is indicated by an asterisk;

[0922] R 25 is selected from halogen or CF3; and

[0923] R 26 and R 27 are independently H or C 1-4 alkyl.

[0924] Embodiment 32. The compound of formula (I), (Ia), (Ib), a tautomer or a salt thereof according to embodiment 31, wherein R 26 and R 27 Each is a methyl group.

[0925] Embodiment 33. A compound of formula (I), (Ia), (Ib), a tautomer or a salt thereof according to any one of Embodiments 24 to 32, wherein p is 1 and L is a group of formula (VI):

[0926]

[0927] wherein * represents a connection to the androgen receptor binding moiety, and # represents a connection to the compound of formula (I);

[0928] D is a nitrogen-containing heterocycle, which is optionally substituted with one or more substituents selected from methyl, halogen, CF3 and CN;

[0929] R 37 is methyl or hydrogen;

[0930] s is 0 or 1;

[0931] t is 0 or 1;

[0932] u is 0 or 1;

[0933] v is 0, 1, or 2;

[0934] w is 0 or 1;

[0935] x is 0, 1, 2, 3, or 4

[0936] When v is 0, u and w are not both 1;

[0937] When t is 0, s and u are not both 1.

[0938] Embodiment 34. A compound of formula (I), (Ia), (Ib), a tautomer or a salt thereof according to embodiment 33, wherein L is a group of formula (VIa):

[0939]

[0940] wherein * represents a connection to the androgen receptor binding moiety, and # represents a connection to the compound of formula (I);

[0941] X 10 is CH or N;

[0942] X 11 CR 42 or N;

[0943] c is 0 or 1;

[0944] d is 0 or 1;

[0945] s is 0 or 1;

[0946] u is 0 or 1;

[0947] v is 0, 1, or 2;

[0948] w is 0 or 1;

[0949] x is 0, 1, or 2;

[0950] R 37 is H or methyl; and

[0951] R 38 、R 39 、R 40 、R 41 and R 42 Independently selected from H, halogen, methyl, CF3 and CN.

[0952] Embodiment 35. A compound of formula (I), (Ia), (Ib), a tautomer or a salt thereof according to embodiment 34, wherein:

[0953] X 10 is N and X 11 CR 42 or N;

[0954] c is 0 or 1;

[0955] d is 0 or 1;

[0956] s is 0;

[0957] u is 0 or 1; and

[0958] v is 0, 1, or 2;

[0959] w is 0 or 1;

[0960] x is 0, 1, or 2; and

[0961] R 37 、R 38 、R 39 、R 40 、R 41 and R 42 Independently selected from H or methyl.

[0962] Embodiment 36. A pharmaceutical composition comprising a compound according to any one of embodiments 24-35, a tautomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0963] Embodiment 37. A compound of formula (I), (Ia), (Ib), a tautomer or a pharmaceutically acceptable salt thereof according to 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.

[0964] Embodiment 38. Use of a compound as defined in any one of Embodiments 24-35, a tautomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer, benign prostatic hyperplasia, ovarian cysts, polycystic ovary syndrome or Kennedy's disease.

[0965] Embodiment 39. A method of treating a disorder selected from cancer, benign prostatic hyperplasia, ovarian cysts, polycystic ovary syndrome or Kennedy's disease, comprising administering to a human in need thereof a therapeutically effective amount of a compound as defined in any one of Embodiments 24-35, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 36.

[0966] Embodiment 40. A compound of formula (I), (Ia), (Ib), a tautomer 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.

[0967] Embodiment 41. A compound of formula (Ia), a tautomer or a salt thereof according to Embodiment 9, which is not 1-(1-(piperidin-4-yl)-1H-indol-4-yl)dihydropyrimidine-2,4-(1H,3H)-dione.

[0968] Numbered implementation: Group 2

[0969] Embodiment 1. Compound of formula (I), tautomer of compound of formula (I), or salt thereof:

[0970]

[0971] in:

[0972] X1 is N or CR 2 , where R 2 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, -CONR 5 R 6 and-(CONR 3 R 4 )m(L)p(TBM)q;

[0973] X4 for CR 7 or N, where R 7 Selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 alkoxy;

[0974] X2 and X3 are independently selected from N or CH;

[0975] X 15 and X 22 independently selected from N or C;

[0976] or R 3 and R 4 Together with the nitrogen atom to which they are attached, they are linked together to form a monocyclic or spirocyclic nitrogen-containing heterocycle, or R 3 H or C 1-4 Alkyl and R 4 -(CH2) n R 28 , where R 28 It is a monocyclic or spirocyclic nitrogen-containing heterocycle;

[0977] n is 0 or 1;

[0978] R 5 and R 6 Independently selected from H or C 1-4 alkyl;

[0979] R 1 C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or a group of formula (II), wherein * represents the position of attachment to the compound of formula (I):

[0980]

[0981] a and b are independently 0 or 1;

[0982] X 16 N or CH;

[0983] X 17 CR 34 R 35 , where R 34 and R 35 together with the carbon atoms to which they are attached to form a cyclobutyl ring, or wherein R 34 -(CHR 36 )r- or a bond to the compound of formula (I), and R 35 is H or halogen;

[0984] r is 0, 1, or 2;

[0985] a is 0, 1 or 2, and b and j are independently 0 or 1, provided that b and j cannot both be 0;

[0986] R 36 is hydrogen or methyl;

[0987] R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 and R 15 independently selected from H or halogen;

[0988] L is a chemical linker;

[0989] TBM is the target binding moiety;

[0990] m, p, and q are independently 0 and 1;

[0991] When X 15 When N, X 22 is C; and

[0992] When X1 is -(CONR 3 R 4 )m(L)p(TBM)q, then R 1 C1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 Alkoxy.

[0993] Embodiment 2. A compound of formula (I), a tautomer or a salt thereof according to embodiment 1, which has formula (Ia):

[0994]

[0995] in:

[0996] X1 is N or CR 2 , where R 2 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and -CONR 5 R 6 ;

[0997] X4 for CR 7 or N, where R 7 Selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 alkoxy;

[0998] X2 and X3 are independently selected from N or CH;

[0999] X 15 and X 22 independently selected from N or C;

[1000] r is 0, 1, or 2;

[1001] a is 0, 1 or 2, and b and j are independently 0 or 1, provided that b and j cannot both be 0;

[1002] X 16 N or CH;

[1003] X 18 CR 35 , where R 35 is H or halogen;

[1004] R 5 and R 6 Independently selected from H or C 1-4 alkyl;

[1005] R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R15 and R 35 independently selected from H or halogen;

[1006] R 36 is hydrogen or methyl;

[1007] L is a chemical linker;

[1008] TBM is the target binding moiety;

[1009] p and q are independently 0 and 1; and

[1010] When X 15 When N, X 22 For CH.

[1011] Embodiment 3. A compound of formula (Ia), a tautomer or a salt thereof according to Embodiment 2, wherein X1 is N or CH.

[1012] Embodiment 4. A compound of formula (Ia), a tautomer or a salt thereof according to Embodiment 2 or Embodiment 3, wherein X4 is CR 7 .

[1013] Embodiment 5. A compound of formula (Ia), a tautomer or a salt thereof according to Embodiment 2 or Embodiment 3, wherein X4 is N.

[1014] Embodiment 6. A compound of formula (Ia), a tautomer or a salt thereof according to any one of claims 2 to 5, wherein X2 is CH.

[1015] Embodiment 7. A compound of formula (Ia), a tautomer or a salt thereof according to any one of Embodiments 2 to 6, wherein X3 is CH.

[1016] Embodiment 8. A compound of formula (Ia), a tautomer or a salt thereof according to any one of Embodiments 2 to 7, wherein X 15 For C.

[1017] Embodiment 9. A compound of formula (Ia), a tautomer or a salt thereof according to any one of Embodiments 2 to 8, wherein X 22 is N.

[1018] Embodiment 10. A compound of formula (Ia), a tautomer or a salt thereof according to any one of Embodiments 2 to 9, wherein X 16 is N, j is 1, and a and b are independently 0 or 1.

[1019] Embodiment 11. A compound of formula (Ia), a tautomer or a salt thereof according to any one of Embodiments 2 to 10, wherein r is 0.

[1020] Embodiment 12. A compound of formula (Ia), a tautomer or a salt thereof according to any one of Embodiments 2 to 11, wherein:

[1021] R 8 、R 9 and R 35 are independently selected from H or halogen; and

[1022] R 10 、R 11 、R 12 、R 13 、R 14 and R 15 Each is H.

[1023] Embodiment 13. A compound of formula (Ia), a tautomer or a salt thereof according to any one of Embodiments 2 to 12, which has formula (Iaaaa):

[1024]

[1025] Embodiment 14. The compound of formula (I), its tautomer or salt according to embodiment 1, which has formula (Ib)

[1026]

[1027] in:

[1028] R 1 C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 Alkoxy, wherein the C 1-4 The alkyl group is optionally replaced by a C 1-4 Alkoxy group substitution;

[1029] X2 and X3 are independently selected from N or CH;

[1030] X 15 and X 22 independently selected from N or C;

[1031] X4 for CR 7 or N, where R 7 Selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 alkoxy;

[1032] or R 3 and R 4 Together with the nitrogen atom to which they are attached, they are linked together to form a monocyclic or spirocyclic nitrogen-containing heterocycle, or R 3 H or C 1-4 Alkyl and R4 -(CH2) n R 28 , where R 28 It is a monocyclic or spirocyclic nitrogen-containing heterocycle;

[1033] m is 1 or 1;

[1034] n is 0 or 1;

[1035] L is a chemical linker;

[1036] TBM is a target binding moiety; and

[1037] p and q are independently 0 and 1; and

[1038] When X 15 When N, X 22 For CH.

[1039] Embodiment 15. A compound of formula (Ib), a tautomer or a salt thereof according to embodiment 14, wherein X4 is N or CH.

[1040] Embodiment 16. A compound of formula (Ib), a tautomer or a salt thereof according to embodiment 15, wherein X4 is CH.

[1041] Embodiment 17. A compound of formula (Ib), a tautomer or a salt thereof according to any one of Embodiments 14 to 16, wherein X2 is CH.

[1042] Embodiment 18. A compound of formula (Ib), a tautomer or a salt thereof according to any one of Embodiments 14 to 17, wherein X3 is CH.

[1043] Embodiment 19. A compound of formula (Ib), a tautomer or a salt thereof according to any one of Embodiments 14 to 18, wherein X 15 For C.

[1044] Embodiment 20. A compound of formula (Ib), a tautomer or a salt thereof according to any one of Embodiments 14 to 19, wherein X 22 is N.

[1045] Embodiment 21. A compound of formula (Ib), a tautomer or a salt thereof according to any one of Embodiments 14 to 20, wherein m is 1.

[1046] Embodiment 22. A compound of formula (Ib), a tautomer or a salt thereof according to any one of Embodiments 14 to 21, wherein R 3 H or C 1-4 Alkyl and R 4 -(CH2) n R 28, where R 28 It is a monocyclic nitrogen-containing heterocycle.

[1047] Embodiment 23. A compound of formula (Ib), a tautomer or a salt thereof according to any one of embodiments 14 to 21, wherein the group NR 3 R 4 Having a structure selected from the following:

[1048]

[1049] Where the asterisk represents the position of attachment to the carbonyl group, and # represents the point of attachment to L.

[1050] Embodiment 24. A compound of formula (Ib), a tautomer or a salt thereof according to any one of Embodiments 14 to 23, wherein R 1 C 1-4 alkyl.

[1051] Embodiment 25. A compound of formula (Ib), a tautomer or a salt thereof according to embodiment 24, wherein R 1 It is isopropyl.

[1052] Embodiment 26. A compound of formula (Ib), a tautomer or a salt thereof according to any one of Embodiments 2 to 12, having formula (Ibbbb):

[1053]

[1054] Embodiment 27. A compound of formula (I), (Ia), (Iaaaa), (Ib), (Ibbbb), a tautomer or a salt thereof according to any preceding embodiment, wherein q is 1 and TBM is an androgen receptor binding moiety.

[1055] Embodiment 28. A compound of formula (I), (Ia), (Iaaaa), (Ib), (Ibbbb), a tautomer or a salt thereof according to embodiment 27, wherein the androgen receptor binding portion has the structure of formula (III)

[1056]

[1057] The connection position with L is indicated by an asterisk;

[1058] A is selected from: cyclohexyl, cyclobutyl or 6-membered nitrogen-containing heterocyclic ring, wherein the cyclohexyl, cyclobutyl or 6-membered nitrogen-containing heterocyclic ring may be optionally replaced by up to 4 C 1-4 Alkyl group substitution;

[1059] B is selected from phenyl, a 6-membered nitrogen-containing heteroaryl group or a fused bicyclic nitrogen-containing heterocycle, wherein B is optionally substituted with one or more halogen groups; and

[1060] R 16 Selected from halogen or CF3.

[1061] Embodiment 29. A compound of formula (I), (Ia), (Iaaaa), (Ib), (Ibbbb), a tautomer or a salt thereof according to embodiment 28, wherein the androgen receptor binding portion has the structure of formula (IIIa)

[1062]

[1063] The connection position with L is indicated by an asterisk;

[1064] X7, X8 and X9 are independently CH, CF or N;

[1065] R 16 Selected from halogen or CF3;

[1066] R 17 、R 18 、R 19 and R 20 are independently H or C 1-4 alkyl.

[1067] Embodiment 30. A compound of formula (I), (Ia), (Iaaaa), (Ib), (Ibbbb), a tautomer or a salt thereof according to Embodiment 29, wherein X7 and X8 are N and X9 is CH.

[1068] Embodiment 31. A compound of formula (I), (Ia), (Iaaaa), (Ib), (Ibbbb), a tautomer or a salt thereof according to Embodiment 29 or Embodiment 30, wherein R 17 、R 18 、R 19 and R 20 Each is H.

[1069] Embodiment 32. A compound of formula (I), (Ia), (Iaaaa), (Ib), (Ibbbb), a tautomer or a salt thereof according to Embodiment 28, wherein the androgen receptor binding portion has the structure of formula (IIIb):

[1070]

[1071] The connection position with L is indicated by an asterisk;

[1072] X7, X8 and X9 are independently CH or N;

[1073] R 16 is selected from halogen or CF3; and

[1074] R21 、R 22 、R 23 and R 24 are independently H or C 1-4 alkyl.

[1075] Embodiment 33. A compound of formula (I), (Ia), (Iaaaa), (Ib), (Ibbbb), a tautomer or a salt thereof according to embodiment 32, wherein R 21 、R 22 、R 23 and R 24 Each is a methyl group.

[1076] Embodiment 34. A compound of formula (I), (Ia), (Iaaaa), (Ib), (Ibbbb), a tautomer or a salt thereof according to embodiment 27, wherein the androgen receptor binding portion has the structure of formula (IV):

[1077]

[1078] The connection position with L is indicated by an asterisk;

[1079] R 25 is selected from halogen or CF3; and

[1080] R 26 and R 27 are independently H or C 1-4 alkyl.

[1081] Embodiment 35. A compound of formula (I), (Ia), (Iaaaa), (Ib), (Ibbbb), a tautomer or a salt thereof according to embodiment 34, wherein R 26 and R 27 Each is a methyl group.

[1082] Embodiment 36. A compound of formula (I), (Ia), (Iaaaa), (Ib), (Ibbbb), a tautomer or a salt thereof according to any one of Embodiments 27 to 35, wherein p is 1 and L is a group of formula (VI):

[1083]

[1084] wherein * represents a connection to the androgen receptor binding moiety, and # represents a connection to the compound of formula (I);

[1085] D is a nitrogen-containing heterocycle, which is optionally substituted with one or more substituents selected from methyl, halogen, CF3 and CN;

[1086] R 37 is methyl or hydrogen;

[1087] s is 0 or 1;

[1088] t is 0 or 1;

[1089] u is 0 or 1;

[1090] v is 0, 1, or 2;

[1091] w is 0 or 1;

[1092] x is 0, 1, 2, 3, or 4

[1093] When v is 0, u and w are not both 1;

[1094] When t is 0, s and u are not both 1.

[1095] Embodiment 37. A compound of formula (I), (Ia), (Ib), a tautomer or a salt thereof according to embodiment 36, wherein L is a group of formula (VIa):

[1096]

[1097] wherein * represents a connection to the androgen receptor binding moiety, and # represents a connection to the compound of formula (I);

[1098] X 10 is CH or N;

[1099] X 11 CR 42 or N;

[1100] c is 0 or 1;

[1101] d is 0 or 1;

[1102] s is 0 or 1;

[1103] u is 0 or 1;

[1104] v is 0, 1, or 2;

[1105] w is 0 or 1;

[1106] x is 0, 1, or 2;

[1107] R 37 is H or methyl; and

[1108] R 38 、R 39 、R 40 、R 41 and R 42 Independently selected from H, halogen, methyl, CF3 and CN.

[1109] Embodiment 38. The compound of formula (I), (Ia), (Ib), a tautomer or a salt thereof according to Embodiment 37, wherein:

[1110] X 10 N and X 11 CR 42 or N;

[1111] c is 0 or 1;

[1112] d is 0 or 1;

[1113] s is 0;

[1114] u is 0 or 1; and

[1115] v is 0, 1, or 2;

[1116] w is 0 or 1;

[1117] x is 0, 1, or 2; and

[1118] R 37 、R 38 、R 39 、R 40 、R 41 and R 42 Independently selected from H or methyl.

[1119] 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, a tautomer or a salt thereof.

[1120] Embodiment 40. A pharmaceutical composition comprising a compound according to any one of embodiments 27-39, a tautomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[1121] Embodiment 41. A compound of formula (I), (Ia), (Ib), a tautomer or a pharmaceutically acceptable salt thereof according to 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.

[1122] Embodiment 42. Use of a compound as defined in any one of Embodiments 27-39, a tautomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer, benign prostatic hyperplasia, ovarian cysts, polycystic ovary syndrome or Kennedy's disease.

[1123] Embodiment 43. A method of treating a disorder selected from cancer, benign prostatic hyperplasia, ovarian cysts, polycystic ovary syndrome or Kennedy's disease, comprising administering to a human in need thereof a therapeutically effective amount of a compound as defined in any one of Embodiments 27-39, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 40. Example

[1124] abbreviation

[1125] aq aqueous solution

[1126] BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

[1127] Boc tert-butyloxycarbonyl

[1128] BrettPhos 2-Dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl

[1129] DavePhos 2-Dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl

[1130] DCE 1,2-dichloroethane

[1131] DCM dichloromethane

[1132] DIAD Diisopropyl azodicarboxylate

[1133] DIBAL-H Diisobutylaluminum hydride

[1134] DIPEA N,N-Diisopropylethylamine

[1135] DDQ 2,3-Dichloro-5,6-dicyano-p-benzoquinone

[1136] DMA N,N-dimethylacetamide

[1137] DMP Dess-Martin Periodinane

[1138] DMAP 4-(dimethylamino)pyridine

[1139] DMF N,N-dimethylformamide

[1140] DMSO dimethyl sulfoxide

[1141] EtOAc

[1142] EtOH

[1143] FHT Fixed Hold Time

[1144] GCMS gas chromatography mass spectrometry

[1145] h hour

[1146] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate

[1147] LCMS liquid chromatography mass spectrometry

[1148] MDAP Mass Spectrometry-Directed Automated Preparative HPLC

[1149] MeCN Acetonitrile

[1150] MeOH methanol

[1151] min

[1152] MsCl methanesulfonyl chloride

[1153] MTBE tert-butyl methyl ether

[1154] NMP N-Methyl-2-pyrrolidone

[1155] NMR Nuclear Magnetic Resonance

[1156] OxymaPure ethyl 2-cyano-2-(hydroxyimino)acetate

[1157] PCC Pyridinium Chlorochromate

[1158] Pd2(dba)3 tris(dibenzylideneacetone)dipalladium

[1159] PPh3 triphenylphosphine

[1160] PyBOP (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate

[1161] Pd-PEPPSI-IPent Dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)

[1162] Rt retention time

[1163] RT Room temperature

[1164] TBDMS tert-butyldimethylsilyl

[1165] TBME tert-butyl methyl ether

[1166] TEA trimethylamine

[1167] TFA trifluoroacetic acid

[1168] THF Tetrahydrofuran

[1169] TMU Tetramethylurea

[1170] Tosyl-Cl 4-Toluenesulfonyl chloride

[1171] XantPhos Bis(diphenylphosphine)-9,9-dimethylxanthene

[1172] Purification method

[1173] GCMS was performed using a 30 mm × 0.32 mm, 0.25 μm HP5 column and an Agilent 5977B MS detector.

[1174] LCMS was performed using one of the following methods:

[1175] Formic A Method ("Formic A")

[1176] LC conditions

[1177] Column: 30mm×2.1mm×1.7μm, or 50mm×2.1mm, 1.7μm CSH C18

[1178] Temperature: 40℃

[1179] Injection volume: 0.2 or 0.3 μL

[1180] Mobile phase: A = 0.1% v / v formic acid in water, and B = 0.1% v / v formic acid in acetonitrile

[1181] Flow rate = 1 mL / min

[1182] gradient:

[1183] Time (min) ％A ％B 0 97 3 1.5 3 97 1.9 3 97 2.0 98 2

[1184] UV detection is the total signal from 210 nm to 350 nm.

[1185] MS conditions

[1186] MS: Waters QDA

[1187] Ionization mode: alternating scanning positive and negative electrospray

[1188] Scan range: 100 to 1000 AMU

[1189] Scanning frequency: 5 Hz

[1190] Formic Acid Method B ("Formic Acid B")

[1191] LC conditions

[1192] Column: 30 mm × 2.1 mm × 3.5 μm Sunfire C18

[1193] Injection volume: 0.4 μL

[1194] Mobile phase: A = 0.1% formic acid in water and B = 0.1% formic acid in MeCN

[1195] gradient:

[1196]

[1197] High pH Method A ("High pH A")

[1198] LC conditions

[1199] Column: 30mm×2.1mm×1.7μm, or 50mm×2.1mm, 1.7μm CSH C18

[1200] Temperature: 40℃

[1201] Injection volume: 0.3 μL

[1202] Mobile phase: A = 10 mM ammonium bicarbonate in water (adjusted to pH 10 with aqueous ammonia) and B = MeCN

[1203] Flow rate = 1 mL / min

[1204] gradient:

[1205] Time (min) ％A ％B 0 100 0 0.05 100 0 1.5 3 97 1.9 3 97 2 100 0

[1206] UV detection is the total signal from 210 nm to 350 nm.

[1207] MS conditions

[1208] MS: Waters QDA

[1209] Ionization mode: alternating scanning positive and negative electrospray

[1210] Scan range: 100 to 1000 AMU

[1211] Scanning frequency: 5 Hz

[1212] High pH Method B ("High pH B")

[1213] LC conditions

[1214] Column: 50mm×4.6mm×3.5μm Xbridge C8

[1215] Injection volume: 0.2 μL

[1216] Mobile phase: A = 10 mM ammonium bicarbonate in water, and B = MeCN

[1217] Flow rate = 1.2 mL / min

[1218] gradient:

[1219]

[1220]

[1221] TFA Method A ("TFA A")

[1222] Column: 30 mm × 2.1 mm, 1.7 μm CSH C18

[1223] Temperature: 45°C

[1224] Injection volume: 0.5 μL

[1225] Mobile phase: A = 0.1% v / v TFA in water, B = 0.1% v / v TFA in MeCN

[1226] Flow rate = 1.3 mL / min

[1227] gradient:

[1228] Time (min) ％A ％B 0 99 1 1.85 0 100 1.9 0 100 2.0 99 1

[1229] UV detection is the average signal from wavelengths 210 nm to 350 nm.

[1230] MS conditions (Waters SQD or QDa)

[1231] QDa Settings:

[1232] MS: Waters Acquity QDa mass spectrometer

[1233] Ionization mode: alternating scanning positive and negative electrospray

[1234] Scan range: 100 to 1000 AMU

[1235] Target sampling frequency: 8Hz

[1236] SQD settings:

[1237] MS:Waters Acquity SQD

[1238] Ionization mode: alternating scanning positive and negative electrospray

[1239] Scan range: 100 to 1000 AMU

[1240] Scan time: 0.1 seconds

[1241] TFA method B ("TFA B")

[1242] Column: 50 mm × 4.6 mm, 5.0 μm Atlantis C18

[1243] Injection volume: 2.0 μL

[1244] Mobile phase: A = 0.1% v / v TFA in water, B = MeOH

[1245] Flow rate = 1.0 mL / min

[1246] gradient:

[1247] Time (min) ％B 0 5 5 95 6.5 95 6.8 5 8.0 5

[1248] Mass directed automated purification (MDAP) was performed using any of these methods:

[1249] MDAP formate

[1250] Column: 150mm×30mm, 5μm or 75mm×30mm, 5μm Xselect CSH C18

[1251] Mobile phase A: 0.1% v / v formic acid in water

[1252] Mobile phase B: 0.1% v / v formic acid in MeCN.

[1253] Total flow rate: 40 mL / min

[1254] Temperature: Ambient temperature

[1255] Injection volume: Varies

[1256] Instrument name: Waters MDAP

[1257] UV detection parameters: 210-350nm

[1258] gradient:

[1259] The gradient ranged from 100% A and 0% B to 0% A and 100% B over various time lengths, up to 32 min.

[1260] MDAP High pH

[1261] Column: 150mm×30mm, 5μm or 100mm×19mm, 5μm or 75mm×30mm, 5μm Xselect CSH C18

[1262] Mobile phase A: 10 mM ammonium bicarbonate in water, pH adjusted to 10 with ammonia

[1263] Mobile phase B: MeCN

[1264] Total flow rate: 40 mL / min

[1265] Temperature: Ambient temperature

[1266] Injection volume: Varies

[1267] Instrument name: Waters MDAP

[1268] UV detection parameters: 210-350nm (1.2nm resolution; 1Hz)

[1269] gradient:

[1270] The gradient ranged from 100% A and 0% B to 0% A and 100% B over various time lengths, up to 32 min.

[1271] MDAP TFA

[1272] Column: 150 mm × 30 mm, 5 μm Sunfire C18

[1273] Mobile phase A: 0.1% TFA in water

[1274] Mobile phase B: MeOH

[1275] Total flow rate: 40 mL / min

[1276] Temperature: Ambient temperature

[1277] Injection volume: Variable, typically 300-350 μL

[1278] Instrument name: Waters MDAP

[1279] UV detection parameters: 210-350nm (1.2nm resolution; 1Hz)

[1280] MS detection parameters: Waters QDa; ESI + / -; 100-1000 AMU; 0.3 s / scan; 0.1 s interscan delay

[1281] Collection mode: Fractionated by UV (DAD) and MS (+ / -)

[1282] The gradient was delivered by two pumps so that on-column dilution was used when injecting the sample. The gradient program used for the purification is summarized below:

[1283]

[1284] SFC1

[1285] Column: 150 mm × 30 mm, 5 μm, Reprospher PEI

[1286] Mobile phase A: CO2

[1287] Mobile phase B: 0.5% v / v isopropylamine in methanol

[1288] Total flow rate: 120 mL / min

[1289] Temperature: 55°C

[1290] Injection volume: 2000 μL every 6.5 min

[1291] Instrument: PIC Solutions 'Sapphire (PIC-1)' preparative SFC

[1292] Outlet pressure: 130 bar

[1293] UV detection parameters: 220nm

[1294] MS detection parameters: None

[1295] Collection mode: Grading by time and UV (DAD)

[1296] Time (min) ％B 0 35 0.25 35 3.75 50 4.1 35 4.5 35 5.5 35

[1297] SFC2

[1298] Column: 150 mm × 30 mm, 5 μm, Reprospher PEI

[1299] Mobile phase A: CO2

[1300] Mobile phase B: 0.5% v / v isopropylamine in MeOH

[1301] Total flow rate: 120 mL / min

[1302] Temperature: 55°C

[1303] Injection volume: 400 μL every 6.5 min

[1304] Instrument: PIC Solutions 'Sapphire (PIC-1)' preparative SFC

[1305] Outlet pressure: 130 bar

[1306] UV detection parameters: 220nm

[1307] MS detection parameters: None

[1308] Collection mode: Grading by time and UV (DAD)

[1309] Time (min) ％B 0 35 0.25 35 3.75 50 4.1 55 5.49 55 5.5 35 5.9 35

[1310] The appropriate fractions were combined and then evaporated to dryness using a rotary evaporator. The dried sample was then transferred to a small amount of MeOH and placed in a final vial. The sample was then blown dry at 25°C under a stream of nitrogen to give the title compound.

[1311] intermediates

[1312] Description 1

[1313] 3-((2-(Trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (D1)

[1314] Dihydropyrimidine-2,4(1H,3H)-dione (50g x 2, 438mmol) was suspended in DMF (500mL) and heated to 140°C until the solution became clear. The reaction mixture was cooled to room temperature and CsCO (214g, 657mmol) was added portionwise over a period of 30min. The reaction mixture was further cooled to 10°C and (2-(chloromethoxy)ethyl)trimethylsilane (29.2g, 175mmol) was added dropwise, and the reaction was then stirred at room temperature for 48h. The reaction mixture was filtered under vacuum. The filtrate was diluted with water (2L) and extracted with EtOAc (2x1L). The combined organic layers were evaporated under reduced pressure to obtain the crude compound. The crude product was purified in batches, dissolved in DCM (200 mL), and purified using a 330 g silica column eluted with 50-100% EtOAc: petroleum ether. The desired fractions were combined and concentrated in vacuo to afford the title compound as a colorless sticky solid (47 g, 187 mmol, 21% yield). GCMS: Rt = 4.94 min, MH - =243.1

[1315] Description 2

[1316] Benzyl 4-(4-bromoindolin-1-yl)piperidine-1-carboxylate (D2)

[1317] 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) and stirred for 1 h, then cooled in an ice bath and sodium triacetoxyborohydride (12.84 g, 60.6 mmol) was added. The mixture was stirred for 18 h, then evaporated to about half of its original volume, diluted with water (200 mL) and extracted with EtOAc (2 x 200 mL). The combined organics were washed with water and sodium bicarbonate solution (200 mL each), then dried and evaporated in vacuo to give the title compound as a light 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

[1318] Description 3

[1319] Benzyl 4-(4-bromo-1H-indol-1-yl)piperidine-1-carboxylate (D3)

[1320] Benzyl 4-(4-bromoindolin-1-yl)piperidine-1-carboxylate (prepared as described in Description 2; 20 g, 38.5 mmol) (crude, assumed to be approximately 80% pure) was dissolved in THF (60 mL) and cooled in an ice bath, followed by the addition of DDQ (8.74 g, 38.5 mmol) and the mixture stirred for 10 min before warming 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), and the organic layer was dried and evaporated in vacuo to afford a dark brown gum. The crude product was dissolved in DCM and loaded onto a 330 g silica column, which was then eluted with 0-50% MTBE / cyclohexane, and the fractions containing the product were evaporated in vacuo to afford the title compound (15.7 g, 38.0 mmol, 99% yield) as a light yellow gum. LCMS (high pH A): Rt=1.52min, MH + =413.1,415.1.

[1321] Description 4

[1322] Benzyl 4-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)-1H-indol-1-yl)piperidine-1-carboxylate (D4)

[1323] 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 tripotassium phosphate (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 x 3) and then heated to 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 column. A gradient of 0-60% EtOAc in cyclohexane was used for 30 min. The desired 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

[1324] Description 5

[1325] Benzyl 4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-indol-1-yl)piperidine-1-carboxylate (D5)

[1326] Benzyl 4-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)-1H-indol-1-yl)piperidine-1-carboxylate (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 before evaporation in vacuo to afford a brown oil. This was suspended in MeOH (30 mL) and treated with SG0.88 ammonium hydroxide (20 mL) and stirred for 10 min before being diluted with DCM (100 mL) and washed with saturated sodium bicarbonate solution. The organic layer was dried and evaporated in vacuo to afford a beige solid. The crude product was dissolved in DCM and loaded onto a 120 g silica column, then eluted with 0-100% EtOAc / cyclohexane, and the fractions containing the product 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.

[1327] Description 6

[1328] tert-Butyl 4-((4-bromo-1H-indol-1-yl)methyl)piperidine-1-carboxylate (D6)

[1329] To a stirred solution of 4-bromo-1H-indole (0.3 mL, 2.392 mmol) in DMF (13 mL) was added 60% sodium hydride (0.124 g, 3.11 mmol) in portions under nitrogen. The reaction mixture was stirred at 0°C for 5 min. 4-(bromomethyl)piperidine-1-carboxylic acid tert-butyl ester (0.8 g, 2.88 mmol) and potassium iodide (0.476 g, 2.87 mmol) were added to the reaction mixture. The reaction mixture was stirred at 60°C for 1.5 h and then cooled to room temperature. The reaction was quenched by adding saturated aqueous ammonium chloride (50 mL) and the mixture was extracted with EtOAc (3 x 50 mL). The organics were combined, washed with 5% aq. LiCl (4 x 25 mL), brine (40 mL), dried by passing through a hydrophobic frit, and the solvent 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 silica was eluted with 100% EtOAc (user error) by Combiflash. The fractions containing the crude product were collected and the solvent was removed in vacuo. The obtained crude jelly was dissolved in DCM (1 mL) and loaded onto 80 g Redisep silica columns pretreated with cyclohexane. The crude material on silica was purified by Combiflash using a gradient of 0-20% TBME / cyclohexane over 12 column volumes and then a gradient of 20-30% TBME / cyclohexane over 3 column volumes. The fractions containing the desired product were collected and the solvent was removed in vacuo to give a light yellow jelly (measured by NMR, containing 5% cyclohexane and 8% TBME). The sample was further dried in a vacuum oven to give the title compound as a light yellow solid (560 mg, 1.424 mmol, 60% yield). LCMS (high pH A):Rt=1.52 min, MH + =337,339.

[1330] Description 7:

[1331] 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)

[1332] 3-((2-(Trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (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 (prepared as described in Description 6; 560 mg, 1.424 mmol) were combined in anhydrous 1,4-dioxane (16.4 mL) 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). To 4-[4-(4-oxo-1-yl)-1-oxo-2-oxo-4-oxo-5-nitropropene]-2-oxo-2-oxo-2-nitropropene]-2-oxo-2-oxo-4 ... + =574.

[1333] Description 8

[1334] tert-Butyl 4-(4-bromo-1H-indol-1-yl)-3,3-difluoropiperidine-1-carboxylate (D8)

[1335] 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 min 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 h and then overnight. The reaction was diluted with ether and 1M NaOH solution. The organic phase was washed with brine (twice), dried (MgSO4), filtered and evaporated in vacuo. The residue was dissolved in THF (10.00 mL), cooled to 0 ° C, treated with DDQ (1.719 g, 7.57 mmol) and warmed to room temperature. After 1 h, the reaction mixture was diluted with EtOAc and washed with NaOH solution, sodium bicarbonate solution and brine, dried (MgSO4), filtered and evaporated in vacuo to give a brown oil. The material was purified by flash chromatography (silica, 120 g, 0-30% EtOAc / cyclohexane) to give the title compound as a pale yellow collapsed foam (1.35 g, 3.09 mmol, 61% yield). LCMS (high pH A): Rt = 1.41 min, MH + =415,417.

[1336] Description 9

[1337] Benzyl 4-(4-bromo-6-fluoro-1H-indol-1-yl)piperidine-1-carboxylate (D9)

[1338] A mixture of 4-bromo-6-fluoro-1H-indole (917 mg, 4.28 mmol), 4-((methylsulfonyl)oxy)piperidine-1-formic acid benzyl ester (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 cooled to room temperature and diluted with EtOAc (50 mL). The solution was washed with water (50 mL), 5% LiCl (aq) (50 mL) and brine (50 mL) in sequence. The organic layer was passed through a hydrophobic glass frit, and the filtrate was evaporated in vacuo. The oil (about 1.8 g) was purified by reverse phase flash chromatography on a 100 g C18 column, eluted with a flow rate of 60 mL / min for 22 min using a 30-95% gradient of MeCN and 10 mM ammonium carbonate in water (adjusted to pH 10 with aqueous ammonia). 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.

[1339] Description 10

[1340] 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)

[1341] 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, the vessel sealed, evacuated, and purged with nitrogen (x3). The mixture was stirred at 140°C for 4 h. The reaction was cooled to room temperature, the lid was removed, and copper (I) iodide (24 mg) and trans-N, N'-dimethylcyclohexane-1,2-diamine (0.019 mL, 0.123 mmol) were further added. The vial was sealed, vacuumed and purged with nitrogen (x3). The mixture was stirred at 140 ° C for 16 h. The reaction was cooled to room temperature, the suspension was diluted with DCM (5 mL), and passed through a hydrophobic glass frit. The filtrate was evaporated in vacuo, and the residue was loaded into DCM (3 mL) and purified on a 24 g silica column using a gradient of 0-75% EtOAc in cyclohexane solution over 14 column volumes. Appropriate fractions were combined and the solvent was evaporated in vacuo to give the title compound as a light brown jelly (270 mg, 0.454 mmol, 74% yield). LCMS (high pH A): Rt=1.42 min, M-C2H6 + 567.

[1342] Description 11

[1343] 1-(6-Fluoro-1-(piperidin-4-yl)-1H-indol-4-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (D11)

[1344] A flask containing 10 wt.% palladium on carbon (22 mg, 0.021 mmol) was evacuated and purged with nitrogen (x3), 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 (which can be prepared as described in Description 10; 235 mg, 0.395 mmol) in ethanol (20 mL) was added. The mixture was evacuated and purged with nitrogen (x3) and stirred at room temperature under atmospheric pressure of hydrogen for 16 h. The mixture was evacuated and purged with nitrogen (x3) and then 10 wt.% palladium on carbon (22 mg, 0.021 mmol) was added. The mixture was evacuated and purged with nitrogen (x3) and stirred at room temperature under atmospheric pressure of hydrogen for 24 h. 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 light green gum (155 mg, 0.336 mmol). LCMS (high pH A): Rt = 1.22 min, MH + =461.

[1345] Description 12

[1346] tert-Butyl 4-(4-bromo-1H-indazol-1-yl)piperidine-1-carboxylate (D12)

[1347] 4-Bromo-1H-indazole (38 g, 193 mmol) was dissolved in DMF (400 mL). Cs2CO3 (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 adding water (500 mL) and extracted with EtOAc (2×500 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 column using a hexane solution of EtOAc as an eluent to give the title compound as an orange sticky solid (29 g, 76 mmol, 40% yield). LCMS (formic acid A): Rt=1.33 min, M- t Bu + =324.

[1348] Description 13:

[1349] tert-Butyl 4-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)-1H-indazol-1-yl)piperidine-1-carboxylate (D13)

[1350] To 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)-N1,N2-dimethylcyclohexane-1,2-diamine (0.224 g, 1.578 mmol), and K2CO3 (0.909 g, 6.57 mmol) in 1,4-dioxane (20 mL) was purged with nitrogen for 5 min. Copper(I) iodide (0.100 g, 0.526 mmol) was added, and the mixture was purged with nitrogen for 5 min. The reaction was stirred in a microwave oven at 120°C for 3 h. This reaction procedure was repeated for an additional 5× batches. 6 × reaction mixtures were filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The substance was washed with water (100 mL) and dried under vacuum. The substance was dissolved in DCM (20 mL) and loaded onto a 120 g silica column and purified using a 40% EtOAc hexane solution to obtain the title compound as an orange viscous liquid (4.7 g, 8.46 mmol, 54% yield). LCMS (formic acid A): Rt=1.31 min, M-C6H 11 + =460.

[1351] Description 14

[1352] tert-Butyl 4-(6-chloro-4-iodo-1H-indazol-1-yl)piperidine-1-carboxylate (D14)

[1353] A mixture of 6-chloro-4-iodo-1H-indazole (216 mg, 0.776 mmol), tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-formate (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 h. 4-((methylsulfonyl)oxy)piperidine-1-formate tert-butyl ester (390 mg) was further added and the mixture was stirred at 60 ° C for 18 h. The reaction mixture was cooled to room temperature and diluted with EtOAc (20 mL). The solution was washed with water (20 mL), 5% LiCl (aq) (20 mL) and brine (20 mL) in sequence. The organic layer was passed through a hydrophobic glass frit, and the filtrate was evaporated in vacuo. The resulting oil was taken up in DCM (3 mL) and purified on a 24 g silica column using a gradient of 0-40% EtOAc in cyclohexane over 12 column volumes. The 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.

[1354] Description 15

[1355] 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)

[1356] 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 (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 (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, the vessel was sealed, evacuated, and purged with nitrogen (x3). The mixture was stirred in a sealed vessel at 120°C for 16 h. The reaction was cooled to room temperature, the suspension was filtered through celite, and the celite was washed with EtOAc (10 mL). The filtrate was evaporated in vacuo, and the residue was charged into DCM (3 mL) and purified over 12 column volumes using a gradient of 0-80% EtOAc in cyclohexane on a 24 g silica column. The appropriate fractions were combined and the solvent was evaporated in vacuo to give the title compound as a white solid (136 mg, 0.235 mmol, 68% yield). LCMS (high pHA): Rt=1.47 min, MH - =576,578.

[1357] Description 16

[1358] 4-Bromo-N,N-dimethyl-1H-indole-6-carboxamide (D16)

[1359] 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), and the solution was placed in a stoppered container and allowed to stand at room temperature for 20 min. It was then treated with a 2M dimethylamine solution in THF (12 mL, 24.00 mmol) and allowed to stand for 16 h. The reaction mixture was evaporated under vacuum (do not evaporate to dryness), and the remaining solution was diluted with EtOAc (30 mL). The solution was washed sequentially with water (30 mL), 1M HCl (aq) (30 mL), saturated NaHCO (aq) (30 mL), and brine (30 mL), and passed through a hydrophobic glass frit. The solid was collected on the glass frit, suspended in water (10 mL), filtered, and washed with water (30 mL). The solid was added to the EtOAc filtrate from the hydrophobic glass frit and evaporated in vacuo. The solid was dissolved in MeOH (30 mL) and pre-adsorbed onto Florisil. The material was purified over 14 column volumes using a gradient of 0-90% EtOAc: ethanol (3: 1) in TBME on a 40 g silica column. 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 an off-white solid (586 mg, 2.194 mmol, 59% yield). LCMS (high pH A): Rt = 0.90 min, MH + =267,269.

[1360] Description 17

[1361] Benzyl 4-(4-bromo-6-(dimethylcarbamoyl)-1H-indol-1-yl)piperidine-1-carboxylate (D17)

[1362] By 4- bromo-N, N- dimethyl -1H- indole -6- formamide (can be prepared as described in Description 16; 584mg, 2.186mmol), 4- ((methylsulfonyl) oxy) piperidine -1- benzyl formate (1400mg, 4.47mmol) and cesium carbonate (1400mg, 4.30mmol) in anhydrous DMF (12mL) evacuate and purge with nitrogen (x3). The reaction is stirred at 100 DEG C under nitrogen for 74h. The reaction mixture is cooled to room temperature and diluted with EtOAc (25mL). The organic solution is washed successively with water (30mL), 5% LiCl (aq) (30mL) and brine (30mL), and passed through a hydrophobic glass frit. The filtrate is evaporated in vacuo. The residue is loaded into DCM (10mL) and purified on an 80g silica column 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.

[1363] Description 18

[1364] 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)

[1365] 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-(dimethylcarbamoyl)-1H-indol-1-yl)piperidine-1-carboxylate (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, the vessel sealed, evacuated, and purged with nitrogen (x3). The mixture was stirred at 140°C for 21 h and then cooled to room temperature. Remove the lid and add copper (I) iodide (12 mg, 0.063 mmol) and trans-N, N'-dimethylcyclohexane-1,2-diamine (0.019 mL, 0.123 mmol). Seal the container, evacuate and purge with nitrogen (x3). The mixture is stirred at 140 ° C for 16 h. The reaction is cooled to room temperature, the suspension is filtered through celite, and the celite is washed with 1: 1 MeOH: MeCN (10 mL). The filtrate is evaporated in vacuo, the residue is loaded into DCM (3 mL) and purified over 14 column volumes using a gradient of 0-5% MeOH in DCM on a 40 g silica column. The appropriate fractions are combined and the solvent is 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.

[1366] Description 19

[1367] 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)

[1368] A flask containing 10 wt.% palladium on carbon (20 mg, 0.019 mmol) was evacuated and purged with nitrogen (x3), 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 (which can be prepared as described in Description 18; 148 mg, 0.228 mmol) in ethanol (12 mL) was added. The mixture was evacuated and purged with nitrogen (x3) and stirred at room temperature under atmospheric pressure of hydrogen 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 10% Pd / C CatCart30 as a 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.

[1369] Description 20

[1370] tert-Butyl 4-(4-bromo-1H-pyrrolo[2,3-c]pyridin-1-yl)piperidine-1-carboxylate (D20)

[1371] 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 h and then allowed to stand at room temperature for 2 days. The mixture 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 h. The reaction mixture was evaporated in vacuo, then partitioned between water and EtOAc, washed with water and brine, dried (MgSO4), filtered, and evaporated to give a brown oil. Flash chromatography on 330 g of silica eluting with 50-100% EtOAc in cyclohexane afforded, after evaporation of fractions, the title compound as a colorless oil which solidified to a hard white solid upon standing (15 g, 35.5 mmol, 70% yield). LCMS (high pH A): Rt = 1.24 min, MH + =380,382.

[1372] Description 21

[1373] 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)

[1374] 4-Bromo-1H-pyrazolo[4,3-c]pyridine (2.16 g, 10.91 mmol) and DMF (30 mL) were combined and stirred at room temperature and treated with 60% NaH (0.873 g, 21.82 mmol). The mixture was stirred for 15 min, treated with benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (3.14 g, 10.9 mmol), and heated to 80°C. After approximately 1 h, benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (3.14 g, 10.9 mmol) was added. After an additional 1 h, 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 h. The reaction mixture was diluted with EtOAc and NHCl, washed twice with brine, dried (MgSO), filtered, and evaporated in vacuo. Purification by flash column chromatography (120 g, silica, 0-70% EtOAc / cyclohexane) afforded, after evaporation of the fractions, a mixture of the 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 twice with brine, dried (MgSO ), filtered and evaporated in vacuo to give a brown oil. Purified 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 NH 4 CO 2 H / water-MeCN)) to give 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.

[1375] Description 22

[1376] tert-Butyl 4-(4-bromo-1H-pyrazolo[3,4-c]pyridin-1-yl)piperidine-1-carboxylate (D22)

[1377] 4-Bromo-1H-pyrazolo[3,4-c]pyridine (7.17 g, 36.2 mmol) was mixed with DMF (100 mL) and stirred at room temperature, treated with 60% NaH (2.90 g, 72.4 mmol), stirred for 15 min, 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 2 / 3 was added at intervals of about 1 h. After 1 h, 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 eluted with 0-100% EtOAc: cyclohexane. The fractions containing the product 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 portion was further purified using a 150 g C18 column, eluted with 30-85% MeCN: 10 mM aqueous ammonium bicarbonate solution, and 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.

[1378] Description 23

[1379] 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)

[1380] 3-((2-(Trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (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 (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 combined, degassed with N2 for 10 min, and then heated at 120°C (block temperature) for 36 h. The resulting mixture was filtered through celite, evaporated in vacuo, dissolved in EtOAc, washed with water and brine, dried (MgSO ), filtered and evaporated in vacuo to give a green oil. An 80 g silica column was used with 0-8% 4M NH 3 -MeOH): DCM to elute the purified crude product, the desired fractions were combined and concentrated in vacuo to give the title compound as a light yellow viscous jelly (4.5 g, 7.43 mmol, 47% yield). LCMS (high pH A): Rt=1.27 min, MH + =545.

[1381] Description 24

[1382] Benzyl 4-(6-chloro-4-nitro-1H-indol-1-yl)piperidine-1-carboxylate (D24)

[1383] A mixture of 6-chloro-4-nitro-1H-indole (900mg, 4.58mmol), 4-((methylsulfonyl)oxy)piperidine-1-formic acid benzyl ester (2.15g, 6.86mmol) and cesium carbonate (2.25g, 6.91mmol) in anhydrous DMF (10mL) was evacuated and purged with nitrogen (x3). The reaction was stirred at 85°C under nitrogen for 40h. 4-((methylsulfonyl)oxy)piperidine-1-formic acid benzyl ester (2.15g, 6.86mmol) and cesium carbonate (2.25g, 6.91mmol) were further added and the reaction was stirred at 100°C under nitrogen for 3 days. The reaction mixture was diluted with EtOAc (50mL) and washed with water (50mL) and brine (25mL) in sequence. The organic phase was dried (MgSO4), filtered and evaporated to dryness. The resulting residue was dissolved in DCM and purified by flash column chromatography (silica, 80 g, eluted with a gradient of 0-80% cyclohexane / EtOAc over 14 column volumes). The 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 crude in the next step. LCMS (high pHA): Rt = 1.44 min, MH + =414.

[1384] Description 25

[1385] Benzyl 4-(4-amino-6-chloro-1H-indol-1-yl)piperidine-1-carboxylate (D25)

[1386] A solution of benzyl 4-(6-chloro-4-nitro-1H-indol-1-yl)piperidine-1-carboxylate (which 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 cooled to room temperature and filtered through a 10 g celite column and washed with ethanol. The filtrate was evaporated, diluted with EtOAc (100 mL) and washed successively with water (100 mL) and brine (100 mL). The organic layer was then evaporated to dryness to give the title compound as a dark brown gum (268 mg, 0.698 mmol), which was used crude in the next step. LCMS (high pH A): Rt=1.26 min, MH + =384.

[1387] Description 26

[1388] Benzyl 4-(6-chloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-indol-1-yl)piperidine-1-carboxylate (D26)

[1389] 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 h, then at 70°C for 4 h, and then at 40°C for 24 h. More acrylic acid (0.048 mL) was added, and the mixture was stirred at 70°C for 5 h. The reaction mixture was evaporated, dissolved in acetic acid (2.5 mL), treated with urea (189 mg, 3.14 mmol), and heated at 140°C for 24 h. The reaction mixture was evaporated in vacuo and partitioned between saturated sodium bicarbonate (10 mL) and EtOAc (50 mL). The organic phase was washed sequentially 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, eluted with a gradient of 0-80% 3:1 EtOAc:ethanol in TBME over 14 column volumes. The appropriate fractions were combined and evaporated to dryness to afford the title compound as an orange solid (98 mg, 0.137 mmol, 20% yield). LCMS (high pH A): Rt = 1.14 min, MH + =481.

[1390] Description 27

[1391] Benzyl 4-(4-amino-6-fluoro-1H-indazol-1-yl)piperidine-1-carboxylate (D27)

[1392] 6-Fluoro-1H-indazol-4-amine (3 g, 19.85 mmol) and DMF (30 mL) were mixed and stirred at room temperature, treated with NaH (1.588 g, 39.7 mmol), stirred for 15 min, then benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (6.22 g, 19.8 mmol) was added and heated to 80°C. After approximately 1 h, benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (6.22 g, 19.8 mmol) was added. After another 1 h, 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 h. The reaction mixture was diluted with EtOAc and NH4Cl, washed with brine (twice), dried (MgSO4), filtered, evaporated in vacuo and purified by flash column chromatography (120 g, silica, 0-70% EtOAc / cyclohexane) to afford the title compound after evaporation of the fractions as a colorless gum (2.1 g, 5.70 mmol, 29% yield). LCMS (high pH A): Rt = 1.11 min, MH+ =369.2.

[1393] Description 28

[1394] tert-Butyl 4-fluoro-4-formylpiperidine-1-carboxylate (D28)

[1395] Dess-Martin periodinane (635 mg, 1.498 mmol) was added in portions 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). 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 (2x5 mL). The combined organics were dried and evaporated to give the title compound as a colorless solid (231 mg, 0.999 mmol, 100% yield).

[1396] Description 29

[1397] 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)

[1398] A mixture of 1-(1-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione (can be prepared as described in Example CB6; 100 mg, 0.319 mmol) and tert-butyl 4-fluoro-4-formylpiperidine-1-carboxylate (can be prepared as described in Description 28; 148 mg, 0.638 mmol) in DCM (5 mL) was stirred at room temperature for 1 h. 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 h and then allowed to stand for 16 h. Saturated sodium bicarbonate solution (10 mL) was added. The mixture was stirred for 10 min. The organic phase was separated. The aqueous phase was extracted with DCM (5 mL). The combined organics were dried and evaporated. The residue was chromatographed [0-20% ethanol / EtOAc] to afford the title compound as a colorless solid (90 mg, 0.170 mmol, 53% yield). LCMS (high pH A): Rt = 1.04 min, MH + =529

[1399] Description 30

[1400] tert-Butyl 2-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-indol-1-yl)piperidin-1-yl)acetate (D30)

[1401] 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, evacuated and purged with nitrogen (x3), and then stirred at room temperature for 4 h. The mixture was diluted with EtOAc (30 mL) and washed with brine (2x20 mL). A solid formed between partitions, separated 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

[1402] Description 31

[1403] tert-Butyl 4-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-indol-1-yl)piperidin-1-yl)benzoate (D31)

[1404] 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) in a 2.0-5.0 mL vial was treated with DIPEA (210 μL, 1.200 mmol). The vial was sealed, stirred, and heated conventionally at 140°C for 88 h. The reaction mixture was then diluted in water (10 mL), 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 a rotary evaporator. The resulting sample was taken up in DCM (5 mL) and purified on a 40 g silica column using a gradient of 0-100% EtOAc in cyclohexane over 14 column volumes. The appropriate fractions were combined and the solvent removed by rotary evaporation to afford 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

[1405] Description 32

[1406] 4-Bromo-1-isopropyl-1H-indole-6-carboxylic acid methyl ester (D32)

[1407] 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 distributed between saturated NaHCO3 (aq) and EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated to a brown residue. It was purified on a 300 g silica column using a gradient elution of 5-50% EtOAc in hexane to give the title compound as a yellow solid (29.22 g, 99 mmol, 84% yield). LCMS (TFAA): Rt = 1.27 min, MH + =296,298

[1408] Description 33

[1409] 4-Amino-1-isopropyl-1H-indole-6-carboxylic acid methyl ester (D33)

[1410] 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 a brown residue. The residue was dissolved in THF (300 mL), and 3N HCl(aq) (34.4 mL, 103 mmol) was added. The mixture was stirred at room temperature for 2 h. Na2CO3 was added to the mixture in portions until pH ~ 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 a brown residue. The residue was purified on a 330g silica column using a gradient of 5-50% 3:1 EtOAc: ethanol in hexane to give the title compound as a yellow oil which solidified under high vacuum to a yellow foam (7.48g, 32.2mmol, 62% yield). LCMS (formic acid A): Rt = 0.68min, MH + =233

[1411] Description 34

[1412] 4-Amino-1-isopropyl-1H-indole-6-carboxylic acid (D34)

[1413] 4-Amino-1-isopropyl-1H-indole-6-carboxylic acid methyl ester (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 water) (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 contained impurities and was therefore discarded. Concentrated HCl (aq) (40 mL) was added dropwise to the aqueous layer to pH ~ 5. The resulting black oil was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, 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

[1414] Description 35

[1415] 4-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)-1-isopropyl-1H-indole-6-carboxylic acid (D35)

[1416] 4-Amino-1-isopropyl-1H-indole-6-carboxylic acid (prepared as described in Description 34; 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 h. Further acrylic acid (6.82 mL, 99 mmol) was added and heated at 60°C for 48 h. 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)dipropanoic acid (9.62 g) as a black oil. The mixture was dissolved in acetic acid (50 mL), and urea (9.95 g, 166 mmol) was added and heated at 130°C for 16 h. 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 afford 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

[1417] Description 36

[1418] tert-Butyl 4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-isopropyl-1H-indole-6-carbonyl)piperazine-1-carboxylate (D36)

[1419] 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 x 50 mL), dried (MgSO₄), filtered, and evaporated to dryness. The product was purified by silica chromatography using a gradient elution from 0% to 10% MeOH in DCM to afford the title compound (4.3 g, 8.89 mmol, 80% yield). LCMS (formic acid A): Rt = 0.96 min, M- t Bu + =428

[1420] Description 37

[1421] tert-Butyl 4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-isopropyl-N-methyl-1H-indole-6-carboxamido)piperidine-1-carboxylate (D37)

[1422] A mixture of 4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-isopropyl-1H-indole-6-carboxylic acid (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) 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 x 50 mL), dried, filtered and evaporated to dryness. The product was purified by C18 silica chromatography using a gradient elution of 30% to 70% MeCN in 10 mM aqueous ammonium bicarbonate (pH 10) to afford the title compound (2.6 g, 5.08 mmol, 80% yield). LCMS (high pH A): Rt = 0.98 min, M + Na + =534M-Boc+H + =412.

[1423] Description 38

[1424] tert-Butyl 4-((4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-isopropyl-N-methyl-1H-indole-6-carboxamido)methyl)piperidine-1-carboxylate (D38)

[1425] A mixture of 4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-isopropyl-1H-indole-6-carboxylic acid (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 x 50 mL), dried, filtered, and evaporated to dryness. The product was purified by silica chromatography using a gradient elution from 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.

[1426] Description 39

[1427] 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)

[1428] HATU (149 mg, 0.392 mmol) is carefully added to a mixture of DIPEA (0.170 mL, 0.980 mmol), 4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1-isopropyl-1H-indole-6-carboxylic acid (which can be 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). The reaction mixture is stirred at room temperature for 2 h. The reaction mixture is diluted in EtOAc (20 mL) and quenched with sodium bicarbonate solution (15 mL). The organic layer is separated and washed with 1 M hydrochloric acid (15 mL) and then with brine (15 mL). The organic layer is 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

[1429] Description 40

[1430] tert-Butyl 9-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-isopropyl-1H-indole-6-carbonyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate hydrochloride (D40)

[1431] HATU (145 mg, 0.381 mmol) is carefully added to a mixture of DIPEA (0.165 mL, 0.951 mmol), 4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1-isopropyl-1H-indole-6-carboxylic acid (which can be 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). The reaction mixture is stirred at room temperature for 90 min. The reaction mixture is diluted in EtOAc (20 mL) and quenched with sodium bicarbonate solution (15 mL). The organic layer is separated and washed with 1 M hydrochloric acid (15 mL) and then with brine (15 mL). The organic layer is dried and evaporated to give the title compound as a brown gum (191 mg, 0.346 mmol). LCMS (high pH A): Rt=0.68min, MH + =452

[1432] Description 41

[1433] 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)

[1434] HATU (145 mg, 0.381 mmol) was carefully added 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 (which can be 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). The reaction mixture was stirred at RT for 90 min. 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 with brine (15 mL). The organic layer was dried and evaporated. The residue was chromatographed [0-100% EtOAc / cyclohexane, 0-10% ethanol / EtOAc] to afford 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

[1435] Description 42

[1436] Tert-Butyl ((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamate (D42)

[1437] 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), and the reaction mixture was stirred for 20 min, then 2-chloro-4-fluorobenzonitrile (12.16 g, 78 mmol) was added in small portions (bubbling), 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 light yellow solid. The crude product was dissolved in DCM (100 mL) and washed with water (100 mL), then the organics were dried and evaporated in vacuo to give the title compound as a colorless solid (28.6 g, 82 mmol). The material was used in the next step without purification. LCMS (formic acid A): Rt=1.33 min, M- t Bu + =295,297.

[1438] Description 43

[1439] Tert-Butyl ((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)carbamate (D43)

[1440] In an ice bath, 60% NaH in mineral oil (1.393g, 34.8mmol) was added to a stirred solution of 4-fluoro-2-(trifluoromethyl)benzonitrile (5.27g, 27.9mmol) and ((1r, 4r)-4-hydroxycyclohexyl) tert-butyl carbamate (5g, 34.8mmol) in DMF (100mL), and the reaction mixture was stirred for 3h under a nitrogen atmosphere. The reaction mixture was diluted with water (100mL) and extracted with EtOAc (3x200mL). The organic layers were combined, passed through a hydrophobic glass frit, and the solvent was removed in vacuo. The residue was divided into two batches, both purified by normal phase column chromatography (0-30%, EtOAc in cyclohexane, 330g silica, 10 column volumes), and then combined to give the title compound as a white solid (7.32g, 19.04mmol, 82% yield). LCMS (high pHA): Rt=1.34 min, M-Boc+285.

[1441] Description 44

[1442] Tert-Butyl ((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamate (D44)

[1443] 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) and the reaction mixture was stirred for 20 min. 2-Chloro-4-fluorobenzonitrile (0.703 g, 4.52 mmol) was then added in small portions (bubbling) and the mixture was stirred for 2 h, allowed to warm to room temperature. The mixture was quenched with water (100 mL) and the resulting suspension was stirred for 30 min. The product was then collected by filtration and washed with water to give a pale yellow solid. The crude product was dissolved in DCM and loaded onto a 40 g silica column, then eluted with 0-50% EtOAc / cyclohexane and the product-containing fractions were evaporated in vacuo to afford 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.

[1444] Description 45

[1445] 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile hydrochloride (D45)

[1446] To tert-butyl ((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamate (prepared as described in Description 42; 7.1204 g, 20.30 mmol) was added 4M 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 afford 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.

[1447] Description 46

[1448] 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile (D46)

[1449] 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) and 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 basified with potassium carbonate and extracted with DCM (2×200 mL), the organics were 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

[1450] Description 47

[1451] 4-(((1r,4r)-4-Aminocyclohexyl)oxy)-2-chlorobenzonitrile 2,2,2-trifluoroacetate (D47)

[1452] A solution of tert-butyl ((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamate (which 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 slowly added. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 18 h. TFA (20 mL) was slowly added and the reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with diethyl ether (200 mL) and stirred for 30 min. The precipitate was filtered off, 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.

[1453] Description 48

[1454] 4-(((1r,4r)-4-Aminocyclohexyl)oxy)-2-(trifluoromethyl)benzonitrile hydrochloride (D48)

[1455] To tert-butyl ((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)carbamate (prepared as described in Description 43; 7.32 g, 19.04 mmol) was added 4M 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 afford the title compound (6.67 g, 19.34 mmol, 102% yield) as a white solid. The product was carried on to the next step without purification. LCMS (high pH A): Rt = 0.99 min, MH + =285.

[1456] Description 49

[1457] 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutyloxy)-2-chlorobenzonitrile (D49)

[1458] TFA (3 mL, 38.9 mmol) was added 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) and the mixture was stirred at room temperature for 2 h and then evaporated in vacuo. The viscous residue was stirred in water and 1M HCl (20 mL each) to give a thick suspension. The mixture was basified with solid potassium carbonate and extracted with DCM (3x20 mL), the organics were dried and evaporated in vacuo to give the title compound as a colorless solid (1.05 g, 3.77 mmol, 90% yield). The next step was carried out without purification. LCMS (formic acid A): Rt=0.64 min, MH + =279,281.

[1459] Description 50

[1460] 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutyloxy)-2-(trifluoromethyl)benzonitrile hydrochloride (D50)

[1461] A solution of tert-butyl ((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamate (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 h. The mixture was dried with a stream of nitrogen to provide the title compound. LCMS (formic acid A): Rt = 0.69 min, MH + =313.

[1462] Description 51

[1463] Methyl 5-(4-(hydroxymethyl)piperidin-1-yl)pyrazine-2-carboxylate (D51)

[1464] A solution of methyl 5-chloropyrazine-2-carboxylate (5 g, 29.0 mmol) and piperidin-4-ylmethanol (4.00 g, 34.8 mmol) in DCM (40 mL) 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 afford the title compound (6.6 g, 26.3 mmol, 91% yield). LCMS (formic acid A): Rt = 0.62 min, MH + =252

[1465] Description 52

[1466] Methyl 6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxylate (D52)

[1467] 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 h. 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 gray solid (5.4 g, 21.49 mmol, 62% yield). LCMS (formic acid A): Rt = 0.50 min, MH + =252.

[1468] Description 53

[1469] Ethyl 2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidine-5-carboxylate (D53)

[1470] 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.

[1471] Description 54

[1472] Methyl 6-(4-(Hydroxymethyl)piperidin-1-yl)nicotinate (D54)

[1473] 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 distributed between DCM (50 mL) and water (20 mL), and the organic phase was evaporated to dryness to give a light yellow solid. The crude product was dissolved in DCM and loaded onto a 120 g silica column, then eluted with 0-100% EtOAc / cyclohexane, and the fraction containing the product was 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.

[1474] Description 55

[1475] Methyl 6-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)pyridazine-3-carboxylate (D55)

[1476] 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 container and heated at 90 ° C for 45 min using a high absorption setting in a Biotage Initiator microwave oven. The reaction mixture was allowed to cool to room temperature, then 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 glass 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.

[1477] Description 56

[1478] Methyl 6-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-1-yl)pyridazine-3-carboxylate (D56)

[1479] DIPEA (3.34 mL, 19.12 mmol) was added 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). The mixture was stirred at 90 ° C for 45 min in a Biotage microwave oven (cooling - 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.

[1480] Description 57

[1481] Methyl 4-(3-hydroxypropyl)benzoate (D57)

[1482] Under nitrogen, palladium (II) acetate (112 mg, 5 mol%) was added 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 anhydrous MeCN (40 mL). The reaction mixture was stirred at 40 ° C for 18 h. The reaction mixture was cooled to 0 ° C. Sodium borohydride (1.135 g, 30 mmol) was added in portions over 10 min. After the addition was complete, the reaction mixture was stirred at room temperature for 2 h. Saturated ammonium chloride solution (50 mL) was slowly added. The mixture was stirred at room temperature for 10 min. The mixture was extracted with EtOAc (3x25 mL). The combined extracts were washed with brine (30 mL), dried and evaporated. The residue was chromatographed [0-60% EtOAc / cyclohexane] to afford 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.

[1483] Description 58

[1484] Methyl 4-(5-hydroxypentyl)benzoate (D58)

[1485] Under nitrogen, palladium (II) acetate (112 mg, 5 mol%) was added 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 anhydrous MeCN (40 mL). The reaction mixture was stirred at 40 ° C for 18 h. The reaction mixture was cooled to 0 ° C. Sodium borohydride (1.135 g, 30 mmol) was added in portions over 10 min. After the addition was complete, the reaction mixture was stirred at room temperature for 2 h. Saturated ammonium chloride solution (50 mL) was slowly added. The mixture was stirred at room temperature for 10 min. The mixture was extracted with EtOAc (3x25 mL). The combined extracts were washed with brine (30 mL), dried and evaporated. The residue was chromatographed [0-60% EtOAc / cyclohexane] to afford the title compound as a colorless oil (1.69 g, 7.60 mmol, 76% yield).LCMS (high pH A): Rt = 1.01 min, poor ionization.

[1486] Description 59

[1487] Methyl 4-(6-hydroxyhex-1-yn-1-yl)benzoate (D59)

[1488] A mixture 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 (repeated 4 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). The mixture was then stirred at ambient temperature for an additional 2 h. The mixture was treated with aqueous ammonium chloride (10%, 50 mL) and extracted with methyl tert-butyl ether (3 x 40 mL). The combined organics were washed with brine (40 mL), then dried (MgSO4), filtered and evaporated to dryness. The product was purified by silica chromatography using a gradient of 0% to 50% EtOAc in DCM to afford the title compound (2.43 g, 10.46 mmol, 91% yield). LCMS (formic acid A): Rt = 0.99 min, MH + =233.

[1489] Description 60

[1490] Methyl 4-(6-hydroxyhexyl)benzoate (D60)

[1491] A solution of methyl 4-(6-hydroxyhex-1-yn-1-yl)benzoate (prepared as described in Description 59; 2.5 g, 10.76 mmol) in MeOH (20 mL) was added to palladium / carbon (10% Degussa type) (100 mg, 0.940 mmol) under nitrogen and stirred under hydrogen for 6 h. The mixture was filtered through a bed of magnesium silicate 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.

[1492] Description 61

[1493] 6-(4-(Hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxylic acid (D61)

[1494] A solution of methyl 6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxylate (which can be prepared as described in Description 52; 17 g, 67.7 mmol) in MeOH (50 mL) was treated with 2M aqueous sodium hydroxide solution (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 allowed to stand at room temperature over the weekend to give a thick suspension. The solid was collected by filtration and washed with water, 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.

[1495] Description 62

[1496] 5-(4-(Hydroxymethyl)piperidin-1-yl)pyrazine-2-carboxylic acid (D62)

[1497] A solution of methyl 5-(4-(hydroxymethyl)piperidin-1-yl)pyrazine-2-carboxylate (prepared as described in Description 51; 7.2 g, 28.7 mmol) in MeOH (50 mL) was treated with 2 M aqueous sodium hydroxide solution (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 addition of 6 M aqueous HCl and then cooled in an ice-water bath, and the precipitated product was filtered off, washed with minimal ice / water, then with minimal 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.

[1498] Description 63

[1499] 2-(4-(Hydroxymethyl)piperidin-1-yl)pyrimidine-5-carboxylic acid (D63)

[1500] A solution of ethyl 2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidine-5-carboxylate (prepared as described in Description 53; 7.1 g, 26.8 mmol) in MeOH (50 mL) was treated with 2 M aqueous sodium hydroxide solution (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 addition of 6 M aqueous HCl, then cooled in an ice-water bath, and the precipitated product was filtered off, washed with minimal ice / water, then with minimal 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.

[1501] Description 64

[1502] 6-(4-(Hydroxymethyl)piperidin-1-yl)nicotinic acid (D64)

[1503] A solution of methyl 6-(4-(hydroxymethyl)piperidin-1-yl)nicotinate (prepared as described in Description 54; 5.2 g, 20.78 mmol) in MeOH (50 mL) was treated with 2 M aqueous sodium hydroxide solution (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 the addition of 6 M aqueous HCl, then cooled in an ice-water bath, and the precipitated product was filtered off, washed with minimal ice / water, then with minimal 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

[1504] Description 65

[1505] 6-(4-(2-((tert-Butyldimethylsilyl)oxy)ethyl)piperidin-1-yl)pyridazine-3-carboxylic acid (D65)

[1506] 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 2M aqueous sodium hydroxide solution (4.84 mL, 9.68 mmol) and stirred at room temperature in a stoppered vessel for 22 h. The reaction mixture was evaporated in vacuo and water (5 mL) was added. The mixture was carefully acidified to pH ˜6-7 with 2M HCl(aq). The aqueous phase was extracted with EtOAc (2×25 mL), and the extracts were 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.

[1507] Description 66

[1508] Sodium 6-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)pyridazine-3-carboxylate (D66)

[1509] A mixture of methyl 6-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)pyridazine-3-carboxylate (prepared as described in Description 55; 2.2 g, 7.88 mmol) and 2M aqueous sodium hydroxide solution (11.82 mL, 23.63 mmol) was diluted in MeOH (15 mL) and THF (15 mL) and stirred at 45°C in a stoppered container for 2 h. The reaction mixture was then evaporated using a rotary evaporator, and the resulting gum was acidified to pH 5 with 2M aqueous HCl. The solution was then extracted with DCM (150 mL), and the organic layer was 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]dec-8-yl)pyridazine-3-carboxylic acid as a light 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.

[1510] Description 67

[1511] 4-(3-Hydroxypropyl)benzoic acid (D67)

[1512] 2M sodium hydroxide (5mL, 10mmol) was added to a stirred solution of methyl 4-(3-hydroxypropyl)benzoate (which can be prepared as described in Description 57; 1.36g, 7.00mmol) in ethanol (5mL). The reaction mixture was stirred at room temperature for 18h. The ethanol was evaporated. The residue was diluted with water (20mL). The mixture was acidified by dropwise addition of 5M hydrochloric acid. The mixture was extracted with EtOAc (3x25mL). The combined extracts were dried and evaporated to give the title compound as a yellow solid (1.20g, 6.66mmol, 95% yield). LCMS (formic acid A): Rt = 0.60min, weak ionization.

[1513] Description 68

[1514] 4-(5-Hydroxypentyl)benzoic acid (D68)

[1515] 2M sodium hydroxide (10mL, 20mmol) was added to a stirred solution of methyl 4-(5-hydroxypentyl)benzoate (which can be prepared as described in Description 58; 1.60g, 7.20mmol) in ethanol (10mL). The reaction mixture was stirred at room temperature for 2h and then allowed to stand for 18h. The ethanol was evaporated. The residue was diluted with water (15mL). The mixture was acidified by dropwise addition of 5M hydrochloric acid. The mixture was extracted with EtOAc (3x10mL). The combined extracts were dried and evaporated to give the title compound as a colorless solid (1.31g, 6.29mmol, 87% yield). LCMS (formic acid A): Rt=0.78min, MH + =209.

[1516] Description 69

[1517] 4-(6-Hydroxyhexyl)benzoic acid (D69)

[1518] A solution of methyl 4-(6-hydroxyhexyl)benzoate (which can be prepared as described in Description 60; 2 g, 8.46 mmol) in ethanol (10 mL) was treated with aqueous sodium hydroxide solution (2 M) (6.35 mL, 12.70 mmol), and the mixture was stirred at 50 ° C for 2 h. The volume of the mixture was reduced by half and then treated with water (10 mL). The solution was treated dropwise with aqueous hydrochloric acid solution (2 M) until the pH reached 4 and a white suspension was produced. 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, poor ionization.

[1519] Description 70

[1520] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxamide (D70)

[1521] 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 h, 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 product 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 fractions containing the product were 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

[1522] Description 71

[1523] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-1-yl)nicotinamide (D71)

[1524] 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 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 light yellow gum (3.4 g) containing residual DCM and TMU. It was used in the next step without purification. LCMS (high pH A): Rt = 1.07 min, MH + =469,471.

[1525] Description 72

[1526] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxamide (D72)

[1527] 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 h, 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 product 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 fractions containing the product were 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.

[1528] Description 73

[1529] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-(hydroxymethyl)piperidin-1-yl)pyrazine-2-carboxamide (D73)

[1530] 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 h, then the mixture was washed with water (40 mL), the organic layer was dried and evaporated in vacuo to give the title compound as a brown gum. The compound was carried on to the next step without purification. LCMS (high pH A): Rt = 1.29 min, MH + =496,498.

[1531] Description 74

[1532] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidine-5-carboxamide (D74)

[1533] 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 at room temperature in a stoppered vessel for 20 min (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 at room temperature in a stoppered vessel for 1 h (a suspension formed during this time). The reaction mixture was diluted with water (25 mL) and filtered. The solid was washed 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). The compound was carried on to the next step without purification. LCMS (high pH A): Rt = 1.24 min, MH + =498,500.

[1534] Description 75

[1535] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(hydroxymethyl)piperidin-1-yl)nicotinamide (D75)

[1536] 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile (can be prepared as described in 49; 0.5 g, 1.794 mmol), 6-(4-(hydroxymethyl)piperidin-1-yl)nicotinic acid (can be prepared as described in 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 h 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). The compound was carried on to the next step without purification. LCMS (formic acid A): Rt = 1.02 min, MH + =497,499.

[1537] Description 76

[1538] N-((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxamide (D76)

[1539] To a suspension of 6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxylic acid (prepared as described in Description 61; 0.814 g, 3.43 mmol), 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-(trifluoromethyl)benzonitrile hydrochloride (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 with water (70 mL), 5% LiCl (aq) (70 mL) and brine (70 mL) in sequence. The aqueous layer was further extracted with EtOAc (3x80 mL). The organic layers were combined and washed with brine (100 mL), and the organic layer was then passed through a hydrophobic glass frit and the solvent was 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). LCMS (formic acid A): Rt=1.06 min, MH + =504.

[1540] Description 77

[1541] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-(hydroxymethyl)piperidin-1-yl)pyrazine-2-carboxamide (D77)

[1542] 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 containing approximately 1 equivalent of tetramethylurea. It was used in the next step without purification. LCMS (high pHA): Rt = 1.12 min, MH + =470,472.

[1543] Description 78

[1544] N-((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)-2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidine-5-carboxamide (D78)

[1545] 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 afford the title compound as a light brown solid (922 mg, 1.831 mmol). LCMS (high pH A): Rt = 1.12 min, MH + =504.

[1546] Description 79

[1547] N-((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)-5-(4-(hydroxymethyl)piperidin-1-yl)pyrazine-2-carboxamide (D79)

[1548] 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 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. The next step was carried on without further purification. LCMS (high pHA): Rt = 1.15 min, MH + =504.

[1549] Description 80

[1550] N-((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-1-yl)nicotinamide (D80)

[1551] 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 h, 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 product was dissolved in DCM and loaded onto a 40 g silica column, then eluted with 0-100% EtOAc / cyclohexane and the fractions containing the product 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.

[1552] Description 81

[1553] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidine-5-carboxamide (D81)

[1554] 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 min (a solution formed during this time). 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile (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 afford the title compound as a light brown solid (879 mg, 1.870 mmol). LCMS (high pH A): Rt = 1.08 min, MH + =470,472

[1555] Description 82

[1556] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(hydroxymethyl)benzamide (D82)

[1557] 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 product was dissolved in EtOAc (50 mL, reflux), then cooled 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.

[1558] Description 83

[1559] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(3-hydroxypropyl)benzamide (D83)

[1560] 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 2M 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 afford 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.

[1561] Description 84

[1562] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(5-hydroxypentyl)benzamide (D84)

[1563] 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 2M 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 afford 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.

[1564] Description 85

[1565] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(6-hydroxyhexyl)benzamide (D85)

[1566] A mixture of 4-(6-hydroxyhexyl)benzoic acid (500 mg, 2.249 mmol), 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile hydrochloride (can be 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 2M 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 afford the title compound as a white solid (863 mg, 1.897 mmol, 84% yield). LCMS (formic acid A): Rt = 1.22 min, MH + =455.

[1567] Description 86

[1568] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(2-hydroxyethyl)piperidin-1-yl)pyridazine-3-carboxamide (D86)

[1569] A suspension of 6-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-1-yl)pyridazine-3-carboxylic acid (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 (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 in a stoppered vessel at room temperature 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 glass frit, and the filtrate was evaporated in vacuo. The resulting jelly was dissolved in MeOH (15 mL) and treated with 2M HCl (aq) (5.0 mL, 10.00 mmol). The solution was placed in a stoppered container and allowed to stand for 2 h at room temperature. The mixture was alkalized to about pH = 10 with 2M NaOH (aq) and partially evaporated in vacuo. The remaining aqueous solution was extracted with EtOAc (25 mL), and the organic layer was washed with saturated NaHCO (aq) (25 mL) and brine (25 mL) in sequence. The organic layer was passed through a hydrophobic glass frit, and the filtrate was evaporated in vacuo. The residue was loaded into DCM (5 mL) and purified over 12 column volumes using a gradient of 0-75% EtOAc: ethanol (3: 1) TBME solution on an 80 g silica column. 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 an off-white solid (835 mg, 1.725 mmol). LCMS (formic acid A): Rt = 1.03 min, MH + =484,486.

[1570] Description 87

[1571] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(3-hydroxypiperidin-1-yl)benzamide (D87)

[1572] A mixture of 4-(3-hydroxypiperidin-1-yl)benzoic acid (100 mg, 0.452 mmol), 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile trifluoroacetate (can be 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 pHA): Rt = 1.10 min, MH + =454,456.

[1573] Description 88

[1574] N-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(6-hydroxyhexyl)benzamide (D88)

[1575] A mixture of 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-(trifluoromethyl)benzonitrile hydrochloride (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 organics were evaporated to dryness. The product was purified by silica chromatography using a gradient elution from 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.

[1576] Description 89

[1577] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)pyridazine-3-carboxamide (D89)

[1578] A mixture of sodium 6-(1,4-dioxa-8-azaspiro[4.5]dec-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. 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile (prepared as described in Description 46; 1.75 g, 6.09 mmol) was then added to the mixture, which was then stirred at room temperature for 16 h. The mixture was diluted with water (30 mL), extracted with EtOAc (100 mL), and washed with 5% aq LiCl solution (20 mL). The organic layer was then passed through a hydrophobic glass frit, and the filtrate was evaporated to dryness. The resulting residue was then loaded into DCM (10 mL) and purified on a 40 g silica column using a gradient of 0-60% EtOAc: ethanol (3: 1) in TBME over 14 column volumes. Appropriate fractions were combined and the solvent was 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.

[1579] Description90

[1580] 6-Chloro-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide (D90)

[1581] A mixture of 6-chloropyridazine-3-carboxylic acid (0.5 g, 3.15 mmol), 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile trifluoroacetate (can be 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 afford 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.

[1582] Description 91

[1583] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(3-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxamide (D91)

[1584] 6-Chloro-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide (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 added to a microwave vial, DMSO (1 mL) was added and the mixture was heated at 70° C. for 2 h, then diluted with water and extracted with EtOAc. The organics were washed with water, dried and evaporated in vacuo to give a light yellow gum. This was dissolved in DCM and loaded onto a 24 g silica column, then eluted with 0-100% (25% ethanol / EtOAc 1% NH4OH) / cyclohexane, and the fractions containing the product were evaporated in vacuo to give the title compound (232 mg, 0.494 mmol, 97% yield) as a light yellow gum. LCMS (high pH A): Rt = 1.10 min, MH + =470,472.

[1585] Description 92

[1586] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-formylpiperidin-1-yl)pyrazine-2-carboxamide (D92)

[1587] 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) and cooled in an ice bath, and 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 product 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 fractions containing the product were evaporated in vacuo to give the title compound as a light yellow solid (0.76 g, 1.532 mmol, 72% yield). LCMS (formic acid A): Rt=1.35 min, M+MeOH+528,530

[1588] Description 93

[1589] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-formylpiperidin-1-yl)pyrimidine-5-carboxamide (D93)

[1590] 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, then the mixture was 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 column using a gradient of 0-100% EtOAc in cyclohexane over 12 column volumes. The appropriate fractions were combined and the solvent 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.

[1591] Description 94

[1592] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-formylpiperidin-1-yl)nicotinamide (D94)

[1593] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-1-yl)nicotinamide (prepared as described in Description 71; 3.4 g, 4.35 mmol) was dissolved in DCM (20 mL) and cooled in an ice bath, and Des-Martin iodinane (2.398 g, 5.65 mmol) was added. The mixture was then stirred at room temperature for 2 h and then evaporated in vacuo to give a colorless gum / solid. The crude product was suspended in DCM, filtered, and the filtrate was purified by chromatography on a 40 g silica column eluting with 0-100% EtOAc / cyclohexane. Fractions containing product were evaporated in vacuo to give the title compound (1.72 g, 3.68 mmol, 85% yield) containing ~0.5 eq of TMU from the earlier HATU step. LCMS (high pH A): Rt=1.11min, MH + =467,469.

[1594] Description 95

[1595] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-formylpiperidin-1-yl)pyridazine-3-carboxamide (D95)

[1596] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxamide (prepared as described in Description 70; 3.8 g, 8.09 mmol) was dissolved in DCM (20 mL) and cooled in an ice bath, and Dess-Martin periodinane (5.14 g, 12.13 mmol) was added, and the mixture was stirred at room temperature for 2 h before being evaporated in vacuo to give a sticky solid. The crude product was suspended in DCM and loaded onto a 24 g silica column, which was then eluted with 0-100% EtOAc / cyclohexane, and the fractions containing the product 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.

[1597] Description 96

[1598] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-formylpiperidin-1-yl)nicotinamide (D96)

[1599] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(hydroxymethyl)piperidin-1-yl)nicotinamide (prepared as described in Description 75; 720 mg, 1.449 mmol) was dissolved in DCM (20 mL) and cooled in an ice bath, and Dess-Martin periodinane (799 mg, 1.883 mmol) was added. The mixture was then stirred at room temperature for 2 h and then evaporated in vacuo to give a colorless gum / solid. The crude product was suspended in DCM, filtered, and the filtrate was purified by chromatography on a 12 g silica column eluting with 0-100% EtOAc / cyclohexane. Fractions containing product 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=1.35min, MH + =495,497.

[1600] Description 97

[1601] N-((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)-6-(4-formylpiperidin-1-yl)pyridazine-3-carboxamide (D97)

[1602] 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 pretreated with cyclohexane and purified by Combiflash using a gradient of 0-100% EtOAc in cyclohexane over 15 column volumes. The fractions containing the desired product were collected and the solvent was removed in vacuo to give the title compound as a yellow gum (495 mg, 0.592 mmol, 53% yield). LCMS (high pHA): Rt = 1.20 min, MH + =502

[1603] Description 98

[1604] N-((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)-5-(4-formylpiperidin-1-yl)pyrazine-2-carboxamide (D98)

[1605] 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) and cooled in an ice bath, b2 Dess-Martin periodinane (1.2 g, 2.83 mmol) was added, and the mixture was stirred at room temperature for 2 h before being evaporated in vacuo to give a yellow gum. The crude product 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 fractions containing the product were evaporated in vacuo to give the title compound as a light yellow gum (0.68 g, 1.356 mmol, 72% yield). LCMS (high pH A): Rt = 1.20 min, MH + =502.

[1606] Description99

[1607] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-formylpiperidin-1-yl)pyrazine-2-carboxamide (D99)

[1608] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-(hydroxymethyl)piperidin-1-yl)pyrazine-2-carboxamide (prepared as described in Description 77; 1.3 g, 1.936 mmol) was dissolved in DCM (20 mL) and cooled in an ice bath, and Dess-Martin periodinane (1.2 g, 2.83 mmol) was added, and the mixture was stirred at room temperature for 2 h before being evaporated in vacuo to give a colorless gum / solid. The crude product was suspended in DCM, filtered, and the filtrate was purified by chromatography on a 12 g silica column eluting with 0-100% EtOAc / cyclohexane. Fractions containing product 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.

[1609] Description 100

[1610] N-((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)-2-(4-formylpiperidin-1-yl)pyrimidine-5-carboxamide (D100)

[1611] 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) and Dess-Martin periodinane (1100 mg, 2.59 mmol) was added, and the mixture was stirred at room temperature for 4 h before being evaporated in vacuo. The crude product 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 fractions containing the product were 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 vacuo to give the title compound (142 mg, 0.283 mmol). LCMS (formic acid A): Rt = 1.19 min, MH + =502.

[1612] Description 101

[1613] N-((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)-6-(4-formylpiperidin-1-yl)nicotinamide (D101)

[1614] 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) and cooled in an ice bath, and Dess-Martin periodinane (760 mg, 1.791 mmol) was added, and the mixture was stirred at room temperature for 2 h before being evaporated in vacuo to give a colorless gum / solid. The crude product was suspended in DCM, filtered, and the filtrate was purified by chromatography on a 24 g silica column eluting with 0-100% EtOAc / cyclohexane. The fractions containing the product 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.

[1615] Description 102

[1616] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(3-formylpiperidin-1-yl)pyridazine-3-carboxamide (D102)

[1617] Dess-Martin periodinane (180 mg, 0.426 mmol) was added to a solution of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(3-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxamide (prepared as described in Description 91; 200 mg, 0.426 mmol) in DCM (20 mL) at room temperature and the mixture was stirred for 2 h, then quenched with saturated sodium bicarbonate solution, and the organic layer was separated, dried and evaporated in vacuo to give a white sticky solid. This was triturated with DCM (10 mL) and filtered; the filtrate was evaporated in vacuo to give the title compound as a light yellow gum (183 mg, 0.391 mmol, 92% yield). LCMS (high pH A): Rt = 1.18 min, MH + =468,470.

[1618] Description 103

[1619] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-2-(4-formylpiperidin-1-yl)pyrimidine-5-carboxamide (D103)

[1620] 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) and Dess-Martin periodinane (1100 mg, 2.59 mmol) was added, and the mixture was stirred at room temperature for 4 h before being evaporated in vacuo. The crude product 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 fractions containing the product were 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 (80 mg, 1.16 mmol, 9% yield). LCMS (formic acid A): Rt = 1.09 min, MH + =468,470.

[1621] Description 104

[1622] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-formylpiperidin-1-yl)pyridazine-3-carboxamide (D104)

[1623] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxamide (prepared as described in Description 72; 90 mg, 0.181 mmol) was dissolved in DCM (20 mL) and cooled in an ice bath, and Dess-Martin periodinane (115 mg, 0.271 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 product 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 fractions containing the product 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.

[1624] Description 105

[1625] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-formylbenzamide (D105)

[1626] Dess-Martin periodinane (2.64 g, 6.24 mmol) was added to N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(hydroxymethyl)benzamide (prepared as described in Description 82; 2.0 g, 5.20 mmol) in DCM (40 mL) and stirred at room temperature for 2 h. The mixture was quenched with aq sodium thiosulfate solution (5% aq, 40 mL) and 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.

[1627] Description 106

[1628] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(3-oxopropyl)benzamide (D106)

[1629] Dess-Martin periodinane (61.6 mg, 0.145 mmol) was added to N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(3-hydroxypropyl)benzamide (prepared as described in Description 83; 50 mg, 0.121 mmol) in DCM (2 mL) and stirred at room temperature for 2 h. Another portion of Dess-Martin periodinane (61.6 mg, 0.145 mmol) was added and stirring was continued at RT for another 3 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (10 mL). The organic layer was separated and the aqueous layer was extracted with DCM (3 x 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 pHA): Rt = 1.16 min, MH + =411,413.

[1630] Description 107

[1631] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(5-oxopentyl)benzamide (D107)

[1632] Dess-Martin periodinane (57.7 mg, 0.136 mmol) was added to N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(5-hydroxypentyl)benzamide (which can be prepared as described in Description 84; 50 mg, 0.113 mmol) in DCM (2 mL) 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 (3x10 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.

[1633] Description 108

[1634] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(6-oxohexyl)benzamide (D108)

[1635] Dess-Martin periodinane (134 mg, 0.316 mmol) was added to N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(6-hydroxyhexyl)benzamide (which can be prepared as described in Description 85; 120 mg, 0.264 mmol) in DCM (4 mL) and stirred at room temperature for 2 h. Another portion of Dess-Martin periodinane (134 mg, 0.316 mmol) was added and stirring was continued for 30 min. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (10 mL). The organic layer was separated and the aqueous layer was extracted with DCM (3x10 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 for further experiments without purification. LCMS (high pH A): Rt=1.28 min, MH + =452.

[1636] Description 109

[1637] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-oxopiperidin-1-yl)pyridazine-3-carboxamide (D109)

[1638] A mixture of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)pyridazine-3-carboxamide (can be prepared as described in Description 89; 700 mg, 1.406 mmol) and aq 2M HCl (10 mL, 20.00 mmol) was stirred at 60 °C in a stoppered vessel for 3 h. The mixture was then cooled to room temperature and then neutralized with 2M aq NaOH solution. The mixture was then extracted with EtOAc (75 mL) and the organic layer was passed through a hydrophobic glass 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.

[1639] Description 110

[1640] (1-(6-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)pyridazin-3-yl)piperidin-4-yl)methyl methanesulfonate (D110)

[1641] Ms-Cl (0.052 mL, 0.663 mmol) was added 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 (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, and the mixture was stirred for 2 h, allowed to warm to room temperature, then washed with water (20 mL), and 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, and the fractions containing the product 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.

[1642] Description 111

[1643] 6-(4-(((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)hexyl 4-methylbenzenesulfonate (D111)

[1644] A mixture of N-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(6-hydroxyhexyl)benzamide (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 organics were evaporated to dryness. The product was purified by silica chromatography using a gradient elution from 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.

[1645] Description 112

[1646] 6-(4-(2-Bromoethyl)piperidin-1-yl)-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide (D112)

[1647] A solution of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(2-hydroxyethyl)piperidin-1-yl)pyridazine-3-carboxamide (can be 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 in a stoppered vessel at room temperature for 2 h. The solution was purified on a 12 g silica column using a gradient of 0-100% EtOAc:ethanol (3:1) in TBME over 18 column volumes. The appropriate fractions were combined and the solvent 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, MH + =546,548,550.

[1648] Description 113

[1649] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-hydroxypicolinamide (D113)

[1650] A mixture of 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile (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 x 50 mL), dried (MgSO₄), filtered and evaporated to dryness. The product was purified by chromatography on C18 silica using a gradient elution from 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.

[1651] Description 114

[1652] 5-(3-Bromopropoxy)-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)picolinamide (D114)

[1653] A mixture of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-hydroxypicolinamide (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 purified 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.

[1654] Description 115

[1655] 5-(4-Bromobutoxy)-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)picolinamide (D115)

[1656] A mixture of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-hydroxypicolinamide (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 was 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.

[1657] Description 116

[1658] 1-(4-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)phenyl)piperidin-3-yl 4-methylbenzenesulfonate (D116)

[1659] A mixture of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(3-hydroxypiperidin-1-yl)benzamide (prepared as described in Description 87; 73.1 mg, 0.161 mmol) and sodium hydride (60% by weight) (26 mg, 0.650 mmol) in THF (5 mL) was stirred at 60° C. for 15 min. 4-Methylbenzenesulfonyl chloride (125 mg, 0.656 mmol) was then added, and the mixture was stirred at 60° C. for 4 h. Sodium hydride (60% by weight) (37.1 mg, 0.928 mmol) was further added, and the reaction mixture was stirred at 60° C. for 5 min. 4-Methylbenzenesulfonyl chloride (168 mg, 0.881 mmol) was then added, and the mixture was stirred at 60° C. for 1 h. Sodium hydride (60% by weight) (37.1 mg, 0.928 mmol) was added again, and the reaction mixture was stirred at 60 ° C for 5 min. 4-Methylbenzenesulfonyl chloride (165 mg, 0.866 mmol) was then added, and the mixture was stirred at 60 ° C for 1.5 h. The reaction mixture was cooled for 16 h. The reaction mixture was distributed 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 transparent colloid (22 mg, 0.036 mmol, 22% yield). LCMS (formic acid A): Rt=1.38 min, MH + =608,610.

[1660] Description 117

[1661] 1-(5-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyrimidin-2-yl)piperidine-4-carboxylic acid (D117)

[1662] 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) and Dess-Martin periodinane (1100 mg, 2.59 mmol) was added and the mixture was stirred at room temperature for 4 h before being evaporated in vacuo. The crude product 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 appropriate fractions were combined and the solvent 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 alkaline washings were acidified to pH = 2 with 2M HCl (aq) and extracted with DCM (2 x 10 mL). The organic extracts were combined and passed through a hydrophobic frit to afford 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.

[1663] Description 118

[1664] 1-(5-(((1r,4r)-4-(4-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl)carbamoyl)pyrimidin-2-yl)piperidine-4-carboxylic acid (D118)

[1665] 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) and Dess-Martin periodinane (1100 mg, 2.59 mmol) was added and the mixture was stirred at room temperature for 4 h before being evaporated in vacuo. The crude product 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 x 10 mL) (4 mL of brine was added to aid separation). The alkaline washings were acidified to pH = 2 with 2M HCl (aq) and extracted with DCM (2 x 10 mL). The organic extracts were combined and passed through a hydrophobic frit to afford 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.

[1666] Description 119

[1667] 1-(5-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)pyrimidin-2-yl)piperidine-4-carboxylic acid (D119)

[1668] 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, then the mixture was 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 column using a gradient of 0-100% EtOAc in cyclohexane over 12 column volumes. The appropriate fractions were combined and the solvent 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 alkaline washings were acidified to pH = 2 with 2M HCl (aq) and extracted with DCM (2 x 10 mL). The organic extracts were combined and passed through a hydrophobic frit to afford 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.

[1669] Description 120

[1670] tert-Butyl 4-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperazine-1-carboxylate (D120)

[1671] 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 h. The reaction mixture was left at room temperature overnight. The reaction mixture was diluted with water (25 mL) and stirred for 30 min. The precipitate was filtered off, washed with water and dried. The solid was suspended in diethyl ether (25 mL). The suspension was stirred for 10 min. The solid was filtered off 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.

[1672] Description 121

[1673] N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(piperazin-1-yl)pyridazine-3-carboxamide 2,2,2-trifluoroacetate (D121)

[1674] TFA (1 mL) was added 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). 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 was decanted. 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.

[1675] Description 122

[1676] 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)

[1677] A mixture of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(piperazin-1-yl)pyridazine-3-carboxamide trifluoroacetate (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 purified directly 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.

[1678] Description 123

[1679] 6-(4-(2-(2-aminoethoxy)ethyl)piperazin-1-yl)-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide 2,2,2-trifluoroacetate (D123)

[1680] 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 pHA): Rt = 1.02 min, MH + =528,530.

[1681] Description 124

[1682] 1-(4-Nitrophenyl)piperidin-4-ol (D124)

[1683] 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 piperidine-4-ol (1.004 g, 9.92 mmol) in DMSO (20 mL) was heated to 80 ° C for 3 h and 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 glass 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.

[1684] Description 125

[1685] (1-(4-Nitrophenyl)piperidin-4-yl)methanol (D125)

[1686] 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 and then cooled to room temperature. The yellow solution was poured into 200 mL of water, at which time a precipitate was formed. The mixture was filtered, washed with water (30 mL), and the solid (washed into a new flask using MeOH) was concentrated in vacuo to give the title compound as a bright yellow solid (2.14 g, 9.06 mmol, 91% yield). LCMS (high pH A): Rt = 0.90 min, MH + =237.

[1687] Description 126

[1688] 2-(1-(4-Nitrophenyl)piperidin-4-yl)ethan-1-ol (D126)

[1689] 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 RT 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 glass 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.

[1690] Description 127

[1691] 1-(4-Aminophenyl)piperidin-4-ol (D127)

[1692] A solution of 1-(4-nitrophenyl)piperidin-4-ol (prepared as described in Description 124; 2.08 g, 9.36 mmol) in ethanol (100 mL) was added to a flask containing palladium on carbon (10 wt %) (0.996 g, 0.936 mmol) under nitrogen, and the flask was filled with hydrogen and stirred under hydrogen for 22 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 very light pink solid (1.73 g, 9.00 mmol, 96% yield). LCMS (high pH A): Rt = 0.48 min, MH + =193.

[1693] Description 128

[1694] (1-(4-Aminophenyl)piperidin-4-yl)methanol (D128)

[1695] 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 at reflux for 24 h. The mixture was filtered through celite and washed with ethanol (100 mL). The ethanol was removed in vacuo, and 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 aq. sodium bicarbonate (100 mL) and then extracted with EtOAc (2 x 200 mL) and then with DCM (2 x 200 mL). The combined organic fractions were dried, filtered and concentrated in vacuo to afford the title compound as a black solid (981 mg, 4.76 mmol, 53% yield). LCMS (high pH A): Rt = 0.56 min, MH + =207.

[1696] Description 129

[1697] 2-(1-(4-Aminophenyl)piperidin-4-yl)ethan-1-ol (D129)

[1698] A solution of 2-(1-(4-nitrophenyl)piperidin-4-yl)ethan-1-ol (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 wt %) (1.105 g, 1.039 mmol) under nitrogen, and the flask was filled with hydrogen 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 light pink solid (2.01 g, 9.12 mmol, 88% yield). LCMS (high pH A): Rt = 0.62 min, MH + =221.

[1699] Description 130

[1700] Methyl 2-((4-(4-hydroxypiperidin-1-yl)phenyl)amino)-2-methylpropanoate (D130)

[1701] To 1-(4-aminophenyl)piperidin-4-ol (which can be 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 and then 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 glass frit, and concentrated in vacuo. The residue was purified using an 80 g silica column eluted 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=0.77min, MH + =293.

[1702] Description 131

[1703] Methyl 2-((4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)amino)-2-methylpropanoate. (D131)

[1704] 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 and then 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, and the desired fractions were combined and concentrated in vacuo to afford the title compound as a brown oil (683 mg, 2.229 mmol, 62% yield). LCMS (high pH A): Rt = 0.82 min, MH + =307.

[1705] Description 132

[1706] Methyl 2-((4-(4-(2-hydroxyethyl)piperidin-1-yl)phenyl)amino)-2-methylpropanoate (D132)

[1707] To 2-(1-(4-aminophenyl)piperidin-4-yl)ethan-1-ol (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 and then 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 eluted 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.

[1708] Description 133

[1709] 4-(3-(4-(4-hydroxypiperidin-1-yl)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (D133)

[1710] 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 and 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, and 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=1.15min, MH + =489.

[1711] Description 134

[1712] 4-(3-(4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (D134)

[1713] 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, and 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=1.20min, MH + =503.

[1714] Description 135

[1715] 4-(3-(4-(4-(2-hydroxyethyl)piperidin-1-yl)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (D135)

[1716] 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 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 eluted with 0-100% EtOAc:cyclohexane, and 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=1.26min, MH + =517.

[1717] Description 136

[1718] 1-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenyl)piperidin-4-yl 4-methylbenzenesulfonate (D136)

[1719] 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 eluted 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 upon standing (750 mg, 1.167 mmol, 43% yield). LCMS (high pHA): Rt = 1.43 min, MH + =643.

[1720] Description 137

[1721] 1-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenyl)piperidin-4-yl)methyl 4-methylbenzenesulfonate (D137)

[1722] 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 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 eluted 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.

[1723] Description 138

[1724] 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)

[1725] 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 eluted 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.

[1726] Description 139

[1727] 4-(3-(4-(3-hydroxypropyloxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (D139)

[1728] To a stirred suspension of 4-(3-(4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (commercially available from, for example, 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 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 afford the title compound as a colorless oil (262 mg, 0.565 mmol, 115% yield). LCMS (high pH A): Rt = 1.16 min, MH + =464.

[1729] Description 140

[1730] 4-(3-(4-(4-hydroxybutoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (D140)

[1731] To a stirred suspension of 4-(3-(4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (commercially available from, for example, 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), followed by stirring for 64 h. Another portion of 4-bromobutan-1-ol (0.104 mL, 0.987 mmol) was added, followed by another portion of potassium carbonate (170 mg, 1.233 mmol) and stirred for 24 h. The pale yellow mixture was heated to 60 ° C for 5 h, then cooled to room temperature. The last portion of potassium carbonate (170mg, 1.233mmol) and 4-bromobutan-1-ol (0.104mL, 0.987mmol) was added and stirred for 16h. The pale yellow solution was diluted with EtOAc (20mL) and water (20mL). The layers were separated and the aqueous layer was extracted with EtOAc (20mL). The combined organic layers were filtered through a hydrophobic glass frit and concentrated in vacuo. The crude product was loaded onto a 24g silica column using 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 (151mg, 0.316mmol, 64% yield). LCMS (high pH A): Rt=1.20min, MH + =478.

[1732] Description 141

[1733] 3-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenoxy)propyl 4-methylbenzenesulfonate (D141)

[1734] 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) and then stirred 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 eluted 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.

[1735] Description 142

[1736] 4-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenoxy)butyl 4-methylbenzenesulfonate (D142)

[1737] 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) and then stirred 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 eluted 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.

[1738] Description 143

[1739] Tert-Butyl (2R,5S)-4-(3-chloro-4-cyanophenyl)-2,5-dimethylpiperazine-1-carboxylate (D143)

[1740] A mixture of 2-chloro-4-fluorobenzonitrile (5g, 32.1mmol), potassium carbonate (8.88g, 64.3mmol) and (2R, 5S)-2,5-dimethylpiperazine-1-tert-butyl formate (6g, 28.0mmol) in DMSO (40mL) and water (4mL) was stirred at 60°C for 46h. The mixture was allowed to cool to room temperature, diluted with water (40mL), and then extracted with EtOAc (2x40mL). The organic extracts were combined, washed with brine (50mL), and passed through a hydrophobic glass frit. The filtrate was concentrated under vacuum, and the colloid was loaded into CHCl3 (10mL) and purified on a 120g silica column using a gradient of 0-50% EtOAc in cyclohexane over 10 column volumes. Appropriate fractions were combined and the solvent was evaporated in vacuo to obtain the title compound as a light yellow solid (7.2g, 20.58mmol, 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.

[1741] Description 142

[1742] 2-Chloro-4-((2S,5R)-2,5-dimethylpiperazin-1-yl)benzonitrile (D142)

[1743] 4M HCl in dioxane (20 mL, 80 mmol) was added to a solution of tert-butyl (2R,5S)-4-(3-chloro-4-cyanophenyl)-2,5-dimethylpiperazine-1-carboxylate (prepared as described in Description 143; 7.2 g, 20.58 mmol) in DCM (40 mL) and the mixture was stirred at room temperature overnight. The resulting suspension was diluted with MTBE (50 mL) and filtered to give a hygroscopic solid. The solid was dissolved in water (50 mL), basified with solid potassium carbonate (10 g), then extracted with EtOAc (2 x 50 mL), and the organics were dried and evaporated in vacuo to give the title compound as a light yellow gum (4.7 g, 18.82 mmol, 91% yield). LCMS (high pH A): Rt = 0.95 min, MH + =250,252.

[1744] Description 143 ...

Claims

1. A compound of formula (I), a tautomer of a compound of formula (I), or a salt thereof: in: X1 is N or CR 2 , where R 2 Selected from 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 for CR 7 or N, where R 7 Selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 Alkoxy; X2 and X3 are independently selected from N or CH; X 15 and X 22 independently selected from N or C; or R 3 and R 4 Together with the nitrogen atom to which they are attached, they are linked together to form a monocyclic or spirocyclic nitrogen-containing heterocyclic ring, or R 3 H or C 1-4 Alkyl and R 4 -(CH2) n R 28 , where R 28 It is a monocyclic or spirocyclic nitrogen-containing heterocyclic ring; n is 0 or 1; R 5 and R 6 are independently selected from hydrogen or C 1-4 alkyl; R 1 C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or a group of formula (II), wherein * represents the position of attachment to the compound of formula (I): a and b are independently 0 or 1; X 16 N or CH; X 17 CR 34 R 35 , where R 34 and R 35 together with the carbon atoms to which they are attached to form a cyclobutyl ring, or wherein R 34 =CHR 36 )r- or a bond to the compound of formula (I), and R 35 is hydrogen or 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 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; When X 15 When N is X 22 is C; and When X1 is -(CONR 3 R 4 )m(L)p(TBM)q, then R 1 C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 Alkoxy.

2. A compound of formula (I) according to claim 1, a tautomer or a salt thereof, which has formula (Ia): in: X1 is N or CR 2 , where R 2 Selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and -CONR 5 R 6 ; X4 for CR 7 or N, where R 7 Selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 Alkoxy; X2 and X3 are independently selected from N or CH; X 15 and X 22 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 N or CH; X 18 CR 35 , where R 35 is hydrogen or halogen; X 25 CR 12 R 13 or O; R 5 and R 6 are independently selected from 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; L is a chemical linker; TBM is the target binding moiety; p and q are independently 0 and 1; and When X 15 When N is X 22 For CH.

3. A compound of formula (Ia) according to claim 2, a tautomer or a salt thereof, wherein X1 is N or CH.

4. A compound of formula (Ia) according to claim 2 or claim 3, a tautomer or a salt thereof, wherein X4 is CR 7 .

5. A compound of formula (Ia) according to claim 2 or claim 3, a tautomer or a salt thereof, wherein X4 is N.

6. A compound of formula (Ia), a tautomer or a salt thereof according to any one of claims 2 to 5, wherein X2 is CH.

7. A compound of formula (Ia), a tautomer or a salt thereof according to any one of claims 2 to 6, wherein X3 is CH.

8. A compound of formula (Ia), a tautomer or a salt thereof according to any one of claims 2 to 7, wherein X 15 For C.

9. A compound of formula (Ia), a tautomer or a salt thereof according to any one of claims 2 to 8, wherein X 22 is N.

10. A compound of formula (Ia), a tautomer or a salt thereof according to any one of claims 2 to 9, wherein X 16 N, X 25 CR 12 R 13 , j is 1 and a and b are independently 0 or 1.

11. A compound of formula (Ia), a tautomer or a salt thereof according to any one of claims 2 to 10, wherein r is 0.

12. A compound of formula (Ia), a tautomer or a salt thereof according to any one of claims 2 to 11, wherein: R 8 , R 9 and R 35 are independently selected from hydrogen or halogen; and R 10 , R 11 , R 12 , R 13 , R 14 and R 15 Each is hydrogen.

13. A compound of formula (Ia), a tautomer or a salt thereof according to any one of claims 2 to 12, having formula (Iaaaa):

14. A compound of formula (I), a tautomer or a salt thereof according to claim 1, which has the formula (Ib) in: R 1 C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 Alkoxy, wherein the C 1-4 The alkyl group is optionally replaced by a C 1-4 Alkoxy group substitution; X2 and X3 are independently selected from N or CH; X 15 and X 22 independently selected from N or C; X4 for CR 7 or N, where R 7 Selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 Alkoxy; or R 3 and R 4 Together with the nitrogen atom to which they are attached, they are linked together to form a monocyclic or spirocyclic nitrogen-containing heterocyclic ring, or R 3 H or C 1-4 Alkyl and R 4 -(CH2) n R 28 , where R 28 It is a monocyclic or spirocyclic nitrogen-containing heterocyclic ring; m is 0 or 1; n is 0 or 1; L is a chemical linker; TBM is a target binding moiety; and p and q are independently 0 and 1; and When X 15 When N is X 22 For CH.

15. A compound of formula (Ib), a tautomer or a salt thereof according to claim 14, wherein X4 is N or CH.

16. A compound of formula (Ib), a tautomer or a salt thereof according to claim 15, wherein X4 is CH.

17. A compound of formula (Ib), a tautomer or a salt thereof according to any one of claims 14 to 16, wherein X2 is CH.

18. A compound of formula (Ib), a tautomer or a salt thereof according to any one of claims 14 to 17, wherein X3 is CH.

19. A compound of formula (Ib), a tautomer or a salt thereof according to any one of claims 14 to 18, wherein X 15 For C.

20. A compound of formula (Ib), a tautomer or a salt thereof according to any one of claims 14 to 19, wherein X 22 is N.

21. A compound of formula (Ib), a tautomer or a salt thereof according to any one of claims 14 to 20, wherein m is 1.

22. A compound of formula (Ib), a tautomer or a salt thereof according to any one of claims 14 to 21, wherein R 3 H or C 1-4 Alkyl and R 4 -(CH2) n R 28 , where R 28 It is a monocyclic nitrogen-containing heterocycle.

23. A compound of formula (Ib), a tautomer or a salt thereof according to any one of claims 14 to 21, wherein the group NR 3 R 4 Having a structure selected from the following: Where the asterisk represents the position of attachment to the carbonyl group and the # represents the point of attachment to L.

24. A compound of formula (Ib), a tautomer or a salt thereof according to any one of claims 14 to 23, wherein R 1 C 1-4 alkyl.

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

26. A compound of formula (Ib), a tautomer or a salt thereof according to any one of claims 2 to 12, having formula (Ibbbb):

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

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

29. The compound of formula (Iaaaa), its tautomer or salt according to claim 13, which is a compound of formula (XXXXV), a tautomer of a compound of formula (XXXXV) or a salt thereof: in: X7, X8 and X9 are independently CH, CF or N; X 24 is CH or N; R 16 is halogen or CF3; and R 21 , R 22 , R 23 and R 24 are independently hydrogen or C 1-4 alkyl.

30. A compound of formula (XXXXV) according to claim 29, a tautomer or a salt thereof, wherein R 16 It is chlorine or CF3.

31. A compound of formula (XXXXV), a tautomer or a salt thereof according to claim 29 or claim 30, wherein: 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.

32. The compound of formula (Iaaaa), its tautomer or salt according to claim 13, which is a compound of formula (XXXXVI), a tautomer of a compound of formula (XXXXVI) or a salt thereof: in: X7, X8 and X9 are independently CH, CF or N; and R 21 , R 22 , R 23 and R 24 are independently hydrogen or C 1-4 alkyl.

33. A compound of formula (XXXXV) or (XXXXVI), a tautomer or a salt thereof according to any one of claims 29 to 32, wherein: X 22 and X2 is N, and X1, X3 and X4 are CH, and X 15 is C; or X 22 and X3 is N, and X1, X2 and X4 are CH, and X 15 is C; or X 22 and X4 is N, and X1, X2 and X3 are CH, and X 15 is C; or X 22 , X2 and X3 are N, and X and X4 are CH, and X 15 is C; or X 22 , X3 and X4 are N, and X1 and X2 are CH, and X 15 is C; or X 22 , X2 and X4 are N, and X1 and X3 are CH, and X 15 For C.

34. A compound of formula (XXXXV) or (XXXXVI), a tautomer or a salt thereof according to any one of claims 29 to 33, wherein X 18 It is CH.

35. A compound of formula (XXXXV) or (XXXXVI), a tautomer or a salt thereof according to any one of claims 29 to 34, wherein r is 0.

36. A compound of formula (XXXXV) or (XXXXVI), a tautomer or a salt thereof according to any one of claims 29 to 35, wherein X 16 It is N.

37. A compound of formula (XXXXV) or (XXXXVI), a tautomer or a salt thereof according to any one of claims 29 to 36, wherein a, b and j are each 1 and X 25 CR 12 R 13 .

38. A compound of formula (XXXXV) or (XXXXVI), a tautomer or a salt thereof according to any one of claims 29 to 37, wherein R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 Each is hydrogen.

39. A compound of formula (XXXXV) or (XXXXVI), a tautomer or a salt thereof according to any one of claims 29 to 38, wherein v is 1.

40. A compound of formula (XXXXV) or (XXXXVI), a tautomer or a salt thereof according to any one of claims 29 to 39, wherein R 37 It's hydrogen.

41. A compound of formula (XXXXV) or (XXXXVI), a tautomer or a salt thereof according to any one of claims 29 to 40, wherein R 21 , R 22 , R 23 and R 24 Each is a methyl group.

42. A compound of formula (XXXXVI), a tautomer or a salt thereof according to any one of claims 32 to 41, wherein: 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.

43. A pharmaceutical composition comprising a compound according to any one of claims 28 to 42, a tautomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

44. A compound of formula (I), (Ia), (Ib), a tautomer or a pharmaceutically acceptable salt thereof according to any one of claims 28 to 42 for use in the treatment of cancer, benign prostatic hyperplasia, ovarian cysts, polycystic ovary syndrome or Kennedy's disease.

45. Use of a compound as defined in any one of claims 28 to 42, a tautomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer, benign prostatic hyperplasia, ovarian cysts, polycystic ovary syndrome or Kennedy's disease.

46. ​​A method for treating a disease selected from cancer, benign prostatic hyperplasia, ovarian cysts, polycystic ovary syndrome and Kennedy's disease, comprising administering to a human in need thereof a therapeutically effective amount of a compound as defined in any one of claims 28 to 42, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 43.

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