Heterobifunctional compounds and methods of treating disease

Abstract

The invention provides heterobifunctional compounds, pharmaceutical compositions, and their use in treating disease, such as cancer.

Description

HETEROBIFUNCTIONAL COMPOUNDS AND METHODS OF TREATING DISEASECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to United States Provisional Patent Application serial number 63 / 562,764, filed March 8, 2024, the contents of which are hereby incorporated by reference in their entirety.FIELD OF THE INVENTION

[0002] The invention provides heterobifunctional compounds, pharmaceutical compositions, and their use in treating disease, such as cancer.BACKGROUND

[0003] Cancer continues to be a significant health problem despite the substantial research efforts and scientific advances reported in the literature for treating this disease. Solid tumors, including prostate cancer, breast cancer, and lung cancer remain highly prevalent among the world population. The incidence of prostate cancer increases with age, and with increasing longevity of human subjects, there continues to be a corresponding rise in the number of patients suffering from prostate cancer. Breast cancer is one of the most common cancers among women and is a leading cause of death for women between ages 50-55. Lung cancer is a leading cause of death among cancer patients, where over 85% of lung cancers are non-small cell lung cancer (NSCLC). Many lung cancers are attributed to tobacco smoking. Current treatment options for these cancers are not effective for all patients and / or can have substantial adverse side effects.

[0004] New therapies are needed to address this unmet need in cancer therapy. In particular, new therapies are needed that achieve an anti -cancer effect through a different mechanism than commonly available therapies. Exemplary mechanisms for common anti -cancer therapies include (a) alkylation of DNA which limits ability of the cell to reproduce, (b) topoisomerase inhibition, in which the therapeutic agent inhibits the activity of a topoisomerases thereby limiting separation of strands of DNA, and (c) mitotic inhibition, where the therapeutic agent reduces ability of the cell to divide. New therapies that achieve an anti-cancer effect through a different mechanism present an opportunity to treat cancers more effectively and / or to treat cancers that have become resistant to currently available medicines.

[0005] The present invention addresses the foregoing needs and provides other related advantages.SUMMARY

[0006] The invention provides heterobifunctional compounds, pharmaceutical compositions, and their use in treating disease, such as cancer. In particular, one aspect of the invention provides a collection of heterobifunctional compounds, such as a compound represented by Formula I:or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Further description of additional collections of heterobifunctional compounds are described in the detailed description. The compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0007] Another aspect of the invention provides a method of treating cancer. The method comprises administering to a patient in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, to treat the cancer.

[0008] Another aspect of the invention provides a method of causing death of a cancer cell. The method comprises contacting a cancer cell with an effective amount of a compound described herein, such as a compound of Formula I, to cause death of the cancer cell.DETAILED DESCRIPTION

[0009] The invention provides heterobifunctional compounds, pharmaceutical compositions, and their use in treating disease, such as cancer. The practice of the present invention employs, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology. Such techniques are explained in the literature, such as in “Comprehensive Organic Synthesis” (B.M. Trost & I. Fleming, eds., 1991-1992); “Handbook of experimental immunology” (D.M. Weir & C.C. Blackwell, eds.); “Current protocols in molecular biology”(F.M. Ausubel et al., eds., 1987, and periodic updates); and “Current protocols in immunology” (J.E. Coligan et al., eds., 1991), each of which is herein incorporated by reference in its entirety.

[0010] Various aspects of the invention are set forth below in sections; however, aspects of the invention described in one particular section are not to be limited to any particular section. Further, when a variable is not accompanied by a definition, the previous definition of the variable controls.Definitions

[0011] Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence, the definition of “alkyl” applies to “alkyl” as well as the “alkyl” portions of “- O-alkyl” etc. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0012] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “cycloaliphatic”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point ofattachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0013] As used herein, the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term “heterobicyclic” is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N- oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include:

[0014] Exemplary bridged bicyclics include:

[0015] The term “lower alkyl” refers to a C1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0016] The term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.

[0017] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quatemized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2 / 7-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)).

[0018] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation.

[0019] As used herein, the term “bivalent Ci-8 (or Ci-e) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0020] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., -(CH2)n- wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0021] The term “-(Co alkylene)-“ refers to a bond. Accordingly, the term “-(Co-3 alkylene)-” encompasses a bond (i.e., Co) and a -(C1.3 alkylene)- group.

[0022] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0023] The term “halogen” means F, Cl, Br, or I.

[0024] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or“aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. The term “haloaryl” refers to an aryl group that is substituted with at least one halogen. Exemplary haloaryl groups include chlorophenyl (e.g., 3 -chlorophenyl, 4-chlorophenyl), fluorophenyl, and the like. The term “phenylene” refers to a bivalent phenyl group.

[0025] The terms “heteroaryl” and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6,or 9 ring atoms; having 6, 10, or 14 z electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4 / 7-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. A heteroaryl group may be mono- or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. The term “haloheteroaryl” refers to a heteroaryl group that is substituted with at least one halogen. Exemplary haloheteroaryl groups include chloropyridine, fluoropyridine, chloropyrazole, fluoropyrazole, and the like. The term “heteroarylene” refers to a bivalent heteroaryl group. Similarly, the terms “pyrazolylene”, “imidazolylene”, and “pyrrolylene”, respectively refer to bivalent pyrazolyl, imidazolyl, and pyrrolyl groups. Similarly, the terms “pyridazinylene,” “pyrimidinylene,” “pyrazinylene,” and “pyridinylene,” respectively refer to bivalent pyridazinyl, pyrimidinyl, pyrazinyl, and pyridinyl groups.

[0026] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4- di hydro-2 / / pyrrol yl), NH (as in pyrrolidinyl), or+NR (as in / / -substituted pyrrolidinyl).

[0027] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6- azaspiro[3.3]heptane, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3 / f-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. The term “heterocyclylene” refers to a bivalent heterocyclyl group. The terms “piperidinylene,” “piperazinylene,” and “azetidinylene”, respectively refer to bivalent piperidinyl, piperazinyl, and azetidinyl groups.

[0028] As used herein, the term “heterocycloalkyl” refers to a saturated heterocyclyl. The term “heterocycloalkylene” refers to a bivalent heterocycloalkyl group.

[0029] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0030] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0031] Each optional substituent on a substitutable carbon is a monovalent substituent independently selected from halogen; -(CH2)0-4R°; -(CH2)o 4OR0; -0(CH2)o-4R°, -0-(CH2)o_ 4C(O)OR°; -(CH2)O-4CH(OR°)2; -(CH2)O 4SR0; -(CH2)O 4Ph, which may be substituted with R°; -(CH2)o-4O(CH2)o iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)o-40(CH2)o-i-pyridyl which may be substituted with R°; -NO2; -CN; - N3; -(CH2)O 4N(RO)2; -(CH2)O4N(R°)C(O)R°; -N(R°)C(S)R°; -(CH2)O- 4N(RO)C(O)NR°2; -N(RO)C(S)NR°2; (CH2)O-IN(R°)C(0)OR°; N(R°)N(R°)C(O)R°; -N(R°)N(RO)C(O)NRO2; -N(R°)N(R°)C(O)OR°; -(CH2)o4C(O)R°; -C(S)R°; -(CH2)(MC(0)0R°; -(CH2)O4C(O)SRO; -(CH2)o-iC(0)OSiR°3; -(CH2)o4OC(O)R°; -OC(0)(CH2)O-ISR-, SC(S)SR°; -(CH2)o4SC(O)R°; -(CH2)O4C(O)NRO2; -C(S)NRO2; -C(S)SR°; -SC(S)SR°, -(CH2)O 4OC(O)NR°2;-C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2)o4SSR°; -(CH2)o4S(0)2RO; -(CH2)O4S(O)2ORO; -(CH2)O ^OS(O)2R°; -S(0)2NRO2; -S(O)(NR°)R°; - S(O)2N=C(NR°2)2; -(CH2)O 4S(O)RO; -N(RO)S(O)2NRO2; -N(RO)S(O)2R°; -N(OR°)R°; - C(NH)NR°2; -P(O)2RO; -P(O)RO2; -OP(O)RO2; -OP(O)(ORO)2; SiR°3; -(Ci^ straight or branched alkylene)O-N(R°)2; or -(C1-4 straight or branched alkylene)C(O)O-N(R°)2.

[0032] Each R° is independently hydrogen, C1-6 aliphatic, -CH2PI1, -0(CH2)o 1Ph, -CH2-(5- 6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted by a divalent substituent on a saturated carbon atom of R° selected from =0 and =S; or each R° is optionally substituted with a monovalent substituent independently selected from halogen, -(CH2)o-2R*, -(haloR*), -(CH2)o2OH, -(CH2)o2OR*, - (CH2)O2CH(OR*)2; -O(haloR’), -CN, -N3, -(CH2)o2C(O)R’, -(CH2)o2C(O)OH, -(CH2)o-2C(O)OR*, -(CH2)O -2SR*, -(CH2)O 2SH, -(CH2)O2NH2, -(CH2)Q_2NHR*, -(CH2)O 2NR"2, -NO2, -SiR*3, -OSiR*3, -C(O)SR* -(Ci-4 straight or branched alkylene)C(O)OR*, or -SSR*.

[0033] Each R* is independently selected from C i 4 aliphatic, -CH2Ph, -0(CH2)o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R* is unsubstituted or where preceded by halo is substituted only with one or more halogens; or wherein an optional substituent on a saturated carbon is a divalent substituent independently selected from =0, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R\ =NR*, =N0R*, -O(C(R*2))23O-, or- S(C(R*2))2-3S-, or a divalent substituent bound to vicinal substitutable carbons of an “optionally substituted” group is -O(CR*2)23O-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0034] When R* is C1-6 aliphatic, R* is optionally substituted with halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is independently selected from C1-4 aliphatic, -CH2Ph, -0(CH2)o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R* is unsubstituted or where preceded by halo is substituted only with one or more halogens.

[0035] An optional substituent on a substitutable nitrogen is independently -R1', -NR^, - C(O)Rr, -C(O)ORr, -C(O)C(O)Rt, -C(O)CH2C(O)Rt, -S(O)2R+, -S(O)2NRT2, -C(S)NRT2, - C(NH)NR:2,wherein each R:is independently hydrogen, C1-6 aliphatic, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, two independent occurrences of R \ taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein when R:is C1-6 aliphatic, R:is optionally substituted with halogen, -R*, -(haloR*), -OH, -OR*, - O(haloR’), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is independently selected from C1-4 aliphatic, -CH2Ph, -0(CH2)o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, and wherein each R* is unsubstituted or where preceded by halo is substituted only with one or more halogens.

[0036] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge el al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenyl propionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0037] Further, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D C. on their website). These disclosures are incorporated herein by reference.

[0038] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0039] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. The invention includes compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C -enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.

[0040] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, such as, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Alternatively, a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis. Still further, where the molecule contains a basic functional group (such as amino) or an acidic functional group (such as carboxylic acid) diastereomeric salts are formed with an appropriate optically- active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers.

[0041] Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. Chiral center(s) in a compound of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. Further, to the extent a compound described herein may exist as a atropisomer (e.g., substituted biaryls), all forms of such atropisomer are considered part of this invention.

[0042] Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name, and an ambiguity exists between the structure and the name, the structure predominates. It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.

[0043] The terms “a” and “an” as used herein mean “one or more” and include the plural unless the context is inappropriate.

[0044] The term “alkyl” refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C12 alkyl, C1-C10 alkyl, and Ci-Ce alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3- methyl-1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3-methyl-l-pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l- butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.

[0045] The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “C3-C6 cycloalkyl,” derived from a cycloalkane. Exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl. The term “cycloalkylene” refers to a bivalent cycloalkyl group.

[0046] The term “haloalkyl” refers to an alkyl group that is substituted with at least one halogen. Exemplary haloalkyl groups include -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, and the like. The term “chloroalkyl” refers to an alkyl group that is substituted with at least one chloro.The term “bromoalkyl” refers to an alkyl group that is substituted with at least one bromo. The term “haloalkylene” refers to a bivalent haloalkyl group.

[0047] The term “hydroxyalkyl” refers to an alkyl group that is substituted with at least one hydroxyl. Exemplary hydroxyalkyl groups include -CH2CH2OH, -C(H)(OH)CH3, -CH2C(H)(OH)CH2CH2OH, and the like.

[0048] The term “heteroalkyl” refers to an alkyl group in which one or more carbon atoms has been replaced by a heteroatom (e.g., N, O, or S). Exemplary heteroalkyl groups include -OCH3, -CH2OCH3, -CH2CH2N(CH3)2, and -CH2CH2OH. The heteroalkyl group may contain, for example, from 2-4, 2-6, or 2-8 atoms selected from the group consisting of carbon and a heteroatom (e.g., N, O, or S). The phrase 3-8 membered heteroalkyl refers to a heteroalkyl group having from 3 to 8 atoms selected from the group consisting of carbon and a heteroatom. The term “heteroalkylene” refers to a bivalent heteroalkyl group.

[0049] The terms “alkenyl” and “alkynyl” are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively. The term “haloalkenyl” refers to an alkenyl group that is substituted with at least one halogen. The term “fluoroalkenyl” refers to an alkenyl group that is substituted with at least one fluoro. The term “nitroalkenyl” refers to an alkenyl group that is substituted with at least one nitro.

[0050] The term “carbocyclylene” refers to a bivalent cycloaliphatic group.

[0051] The terms “alkoxyl” or “alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, terZ-butoxy and the like. The term “haloalkoxyl” refers to an alkoxyl group that is substituted with at least one halogen. Exemplary haloalkoxyl groups include -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -OCF2CF3, and the like.

[0052] The term “oxo” is art-recognized and refers to a “=O” substituent. For example, a cyclopentane substituted with an oxo group is cyclopentanone.

[0053] The term “amino” is art-recognized and refers to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas:wherein R50, R51, R52and R53each independently represent a hydrogen, an alkyl, an alkenyl, -(CH2)m-R61, or R50and R51, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R61represents an aryl, a 3- 7 membered cycloalkyl, a 4-7 membered cycloalkenyl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; and m is zero or an integer in the range of 1 to 8.

[0054] The term “amido” is art-recognized and refers to both unsubstituted and substituted amides, e.g., a moiety that may be represented by the general formulas:wherein R50and R51each independently represent a hydrogen, an alkyl, an alkenyl, -(CH2)m-R61, or R?oand R51, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R61represents an aryl, a 3-7 membered cycloalkyl, a 4-7 membered cycloalkenyl, 5-10 membered heteroaryl, or 3-10 membered heterocyclyl; and m is zero or an integer in the range of 1 to 8; and R52is an alkyl, an alkenyl, or -(CH2)m-R61.

[0055] The symbol “ 'AAA / ” indicates a point of attachment.

[0056] When any substituent or variable occurs more than one time in any constituent or the compound of the invention, its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated.

[0057] One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogenbonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H2O.

[0058] As used herein, the terms “subject” and “patient” are used interchangeably and refer to organisms to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans.

[0059] The term “IC50” is art-recognized and refers to the concentration of a compound that is required to achieve 50% inhibition of the target.

[0060] As used herein, the term “effective amount” refers to the amount of a compound sufficient to effect beneficial or desired results (e.g., a therapeutic, ameliorative, inhibitory or preventative result). An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.

[0061] As used herein, the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0062] As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil / water or water / oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see e.g., Martin, Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] ,

[0063] For therapeutic use, salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0064] In addition, when a compound of the invention contains both a basic moiety (such as, but not limited to, a pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid) zwitterions (“inner salts”) may be formed. Such acidic and basic salts used within the scope of the invention are pharmaceutically acceptable (z.e., non-toxic, physiologically acceptable) salts. Such salts of the compounds of the invention may be formed, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0065] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.

[0066] As a general matter, compositions specifying a percentage are by weight unless otherwise specified.I. Heterobifunctional Compounds

[0067] One aspect of the invention provides heterobifunctional compounds. The compounds may be used in the pharmaceutical compositions and therapeutic methods described herein. Exemplary compounds are described in the following sections, along with exemplary procedures for making the compounds. Without being bound by theory, the compounds can facilitate therapeutic effects by binding to both an androgen receptor and BRD4 (bromodomain-containing protein 4).

[0068] One aspect of the invention provides a compound represented by Formula I:or a pharmaceutically acceptable salt thereof; wherein:R1is phenyl substituted by cyano, halogen, and m occurrences of R4;R2represents independently for each occurrence C1-4 alkyl;R3is hydrogen or C1-4 alkyl;R4represents independently for each occurrence C1-4 alkyl;R5represents independently for each occurrence C 1-4 alkyl or halogen;B1is (i) cyclobutylene substituted by 1, 2, 3, or 4 occurrences of R2or (ii) cyclohexylene substituted by 0, 1, or 2 occurrences of R2;A1is a pyridazinylene, pyrimidinylene, or pyrazinylene, each of which is substituted with n occurrences of R5;R2Arepresents independently for each occurrence C1.4 alkyl;R3Ais hydrogen, halo, C1.2 alkyl, or C1-2 haloalkyl;R4Ais Ci-4 alkyl or -(C1.3 alkylene)-(oxazolyl substituted by 0 or 1 occurrence of C1.2 alkyl); m and n are independently 0, 1, or 2; andL is one of the following:(i) -(piperidinylene)-(Ci-4 alkylene)-O-*** or -(piperidinylene)-O-(C2-4 alkylene)-O- ***, wherein *** is the point of attachment to A2;(ii) an 8-1 1 membered spirocyclic, saturated heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclic ring is substituted with 0, 1, or 2 occurrences of fluoro;(iii) -(8-10 membered spirocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-O-*** or -(8-10 membered spirocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(Ci-4 alkylene)-***, wherein *** is the point of attachment to A2;(iv) -(7-8 membered spirocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C2-4 alkynylene)-***, wherein *** is the point of attachment to A2;(v) a 7-9 membered fused bicyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen, wherein the heterocyclic ring is substituted by 1 or 2 occurrences of fluoro;(vi) l,2,3,5-tetrahydropyrrolo[3,4-c]pyrrolylene; or(vii) -(azetidinylene)-(Ci-4 alkylene)-(azetidinylene)-.

[0069] The definitions of variables in Formula I above encompass multiple chemical groups. The application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).

[0070] In certain embodiments, the compound is a compound of Formula I.

[0071] As defined generally above, R1is phenyl substituted by cyano, halogen, and m occurrences of R4. In certain embodiments, R1is phenyl substituted by halogen and cyano. In some embodiments, R1is. In certain embodiments, R1is selected from the groups depicted in the compounds in Tables 1 and 2 below.

[0072] As generally defined above, R2represents independently for each occurrence Ci-4 alkyl. In certain embodiments, R2is C1-3 alkyl. In certain embodiments, R2is C1-2 alkyl. In certain embodiments, R2is C2-3 alkyl. In certain embodiments, R2is C2-4 alkyl. In certainembodiments, R2is C3-4 alkyl. In certain embodiments, R2is methyl. In certain embodiments, R2is C2 alkyl. In certain embodiments, R2is C3 alkyl. In certain embodiments, R2is C4 alkyl.

[0073] In certain embodiments, R2is selected from the groups depicted in the compounds in Tables 1 and 2 below.

[0074] As generally defined above, R3hydrogen or C1-4 alkyl. In certain embodiments, R3is hydrogen. In certain embodiments, R3is C1-4 alkyl. In certain embodiments, R3is C1-3 alkyl. In certain embodiments, R3is C1-2 alkyl. In certain embodiments, R3is C2-3 alkyl. In certain embodiments, R3is C2-4 alkyl. In certain embodiments, R3is C3-4 alkyl. In certain embodiments, R3is methyl. In certain embodiments, R3is C2 alkyl. In certain embodiments, R3is C3 alkyl. In certain embodiments, R3is C4 alkyl.

[0075] In certain embodiments, R3is selected from the groups depicted in the compounds in Tables 1 and 2 below.

[0076] As generally defined above, R4represents independently for each occurrence C1.4 alkyl. In certain embodiments, R4is C1-3 alkyl. In certain embodiments, R4is C1-2 alkyl. In certain embodiments, R4is C2-3 alkyl. In certain embodiments, R4is C2-4 alkyl. In certain embodiments, R4is C3-4 alkyl. In certain embodiments, R4is methyl. In certain embodiments, R4is C2 alkyl. In certain embodiments, R4is C3 alkyl. In certain embodiments, R4is C4 alkyl.

[0077] In certain embodiments, R4is selected from the groups depicted in the compounds in Tables 1 and 2 below.

[0078] As generally defined above, R5represents independently for each occurrence C1-4 alkyl or halogen. In certain embodiments, R5is a halogen. In certain embodiments, R5is C1.4 alkyl. In certain embodiments, R3is C1-3 alkyl. In certain embodiments, R5is C1-2 alkyl. In certain embodiments, R5is C2-3 alkyl. In certain embodiments, R5is C2-4 alkyl. In certain embodiments, R5is C3-4 alkyl. In certain embodiments, R5is methyl. In certain embodiments, R5is C2 alkyl. In certain embodiments, R3is C3 alkyl. In certain embodiments, R5is C4 alkyl.

[0079] In certain embodiments, R3is selected from the groups depicted in the compounds in Tables 1 and 2 below.

[0080] As generally defined above, B1is (i) cyclobutylene substituted by 1, 2, 3, or 4 occurrences of R2or (ii) cyclohexylene substituted by 0, 1, or 2 occurrences of R2.

[0081] In certain embodiments, B1is cyclobutylene substituted by 1 occurrence of R2. In certain embodiments, B1is cyclobutylene substituted by 2 occurrences of R2. In certain embodiments, B1is cyclobutylene substituted by 3 occurrences of R2. In certain embodiments, B1is cyclobutylene substituted by 4 occurrences of R2. In certain embodiments, B1is, certain embodiments, B1is. In certain embodiments,

[0082] In certain embodiments, B1is cyclohexylene substituted by 0, 1, or 2 occurrences of R2. In certain embodiments, B1is cyclohexylene. In certain embodiments, B1is cyclohexylene substituted by 1 or 2 occurrences of R2. In certain embodiments, B1is cyclohexylene substituted by 2 occurrences of R2In certain embodiments, B1isIn certain embodiments, B1In certain embodiments, B1isIn certain embodiments, B1is selected from the groups depicted in the compounds in Tables 1 and 2 below.

[0083] As generally defined above, A1is a pyridazinylene, pyrimidinylene, or pyrazinylene, each of which is substituted with n occurrences of R5. In certain embodiments, A1is a pyridazinylene substituted with n occurrences of R5. In certain embodiments, A1is a pyrimidinylene substituted with n occurrences of R5. In certain embodiments, A1is aN-N pyrazinylene substituted with n occurrences of R5. In certain embodiments, A1isIn certain embodiments, A1is, wherein ** is the point of attachment to L. In certain embodiments, A1is, wherein ** is the point of attachment to L. In certainembodiments, A1isIn certain embodiments, A1is selected from the groups depicted in the compounds in Tables 1 and 2 below.

[0084] As defined generally above,

[0085] In certain embodiments, A2is selected from

[0087] In certain embodiments, A2is selected from the groups depicted in the compounds in Tables 1 and 2 below.

[0088] As generally defined above, R1Ais C1-4 alkyl. In certain embodiments, R1Ais C1-3 alkyl. In certain embodiments, R1Ais C1.2 alkyl. In certain embodiments, R1Ais C2-3 alkyl. In certain embodiments, R1Ais C2-4 alkyl. In certain embodiments, R1Ais C3-4 alkyl. In certain embodiments, R1Ais methyl. In certain embodiments, R1Ais C2 alkyl. In certain embodiments, R1Ais C3 alkyl. In certain embodiments, R1Ais C4 alkyl.

[0089] In certain embodiments, R1 Ais selected from the groups depicted in the compounds in Tables 1 and 2 below.

[0090] As generally defined above, R2Arepresents independently for each occurrence C1-4 alkyl. In certain embodiments, R2Ais C1.3 alkyl. In certain embodiments, R2Ais C1-2 alkyl. In certain embodiments, R2Ais C2-3 alkyl. In certain embodiments, R2Ais C2-4 alkyl. In certain embodiments, R2Ais C3-4 alkyl. In certain embodiments, R2Ais methyl. In certain embodiments, R2Ais C2 alkyl. In certain embodiments, R2Ais C3 alkyl. In certain embodiments, R2Ais C4 alkyl.

[0091] In certain embodiments, R2Ais selected from the groups depicted in the compounds in Tables 1 and 2 below.

[0092] As generally defined above, R3Ais hydrogen, halo, C1-2 alkyl, or C1.2 haloalkyl. In certain embodiments, R3Ais halo, C1.2 alkyl, or C1-2 haloalkyl. In certain embodiments, R3Ais hydrogen, halo, or C1-2 haloalkyl. In certain embodiments, R3Ais hydrogen, fluoro, or trifluoromethyl. In certain embodiments, R3Ais halo or C1-2 haloalkyl. In certain embodiments, R3Ais fluoro or trifluoromethyl. In certain embodiments, R3Ais hydrogen. In certain embodiments, R3Ais halo. In certain embodiments, R3Ais fluoro. In certain embodiments, R3Ais C1-2 alkyl. In certain embodiments, R3Ais C2 alkyl. In certain embodiments, R3Ais methyl. In certain embodiments, R3Ais C1.2 haloalkyl. In certain embodiments, R3Ais C2 haloalkyl. In certain embodiments, R3Ais Ci haloalkyl. In certain embodiments, R3Ais trifluoromethyl.

[0093] In certain embodiments, R3Ais selected from the groups depicted in the compounds in Tables 1 and 2 below.

[0094] As generally defined above, R4Ais C1-4 alkyl or -(C1-3 alkylene)-(oxazolyl substituted by 0 or 1 occurrence of C1-2 alkyl). In certain embodiments, R4Ais methyl or -(CH2)-(oxazolyl). In certain embodiments, R4Ais C1-4 alkyl. In certain embodiments, R4Ais C1-3 alkyl. In certain embodiments, R4Ais C1.2 alkyl. In certain embodiments, R4Ais C2-3 alkyl. In certain embodiments, R4Ais C2-4 alkyl. In certain embodiments, R4Ais C3-4 alkyl. In certain embodiments, R4Ais methyl. In certain embodiments, R4Ais C2 alkyl. In certain embodiments, R4Ais C3 alkyl. In certain embodiments, R4Ais C4 alkyl.

[0095] In certain embodiments, R4Ais -(C1-3 alkylene)-(oxazolyl substituted by 0 or 1 occurrence of C1.2 alkyl). In certain embodiments, R4Ais -(C1-3 alkylene)-(oxazolyl). In certain embodiments, R4Ais -(C1-2 alkylene)-(oxazolyl). In certain embodiments, R4Ais -(CH2)- (oxazolyl). In certain embodiments, R4Ais -(C1-3 alkylene)-(oxazolyl substituted by 1 occurrence of C1-2 alkyl). In certain embodiments, R4Ais -(C1-2 alkylene)-(oxazolyl substituted by 1occurrence of C1.2 alkyl). In certain embodiments, R4Ais -(CH2)-(oxazolyl substituted by 1 occurrence of C1.2 alkyl). In certain embodiments, R4Ais -(CH2)-(oxazol-2-yl).

[0096] In certain embodiments, R4Ais selected from the groups depicted in the compounds in Tables 1 and 2 below.

[0097] As defined generally above, m is 0, 1, or 2. In certain embodiments, m is 0 or 1. In certain embodiments, m is 1 or 2. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is selected from the values represented in the compounds in Tables 1 and 2 below.

[0098] As defined generally above, n is 0, 1, or 2. In certain embodiments, n is 0 or 1 . In certain embodiments, n is 1 or 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is selected from the values represented in the compounds in Tables 1 and 2 below.

[0099] As generally defined above, L is one of the following:(i) -(piperidinylene)-(Ci-4alkylene)-O-*** or -(piperidinylene)-O-(C2-4 alkylene)-O-***, wherein *** is the point of attachment to A2;(ii) an 8-11 membered spirocyclic, saturated heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclic ring is substituted with 0, 1, or 2 occurrences of fluoro;(iii) -(8-10 membered spirocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-O-*** or -(8-10 membered spirocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(Ci-4 alkylene)-***, wherein *** is the point of attachment to A2;(iv) -(7-8 membered spirocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C2-4 alkynylene)-***, wherein *** is the point of attachment to A2;(v) a 7-9 membered fused bicyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen, wherein the heterocyclic ring is substituted by 1 or 2 occurrences of fluoro;(vi) l,2,3,5-tetrahydropyrrolo[3,4-c]pyrrolylene; or(vii) -(azetidinylene)-(Ci-4 alkylene)-(azetidinylene)-.

[0100] In certain embodiments, L is -(piperidinylene)-(Ci-4 alkylene)-O-*** or - (piperidinylene)-O-(C2-4 alkylene)-O-***, wherein *** is the point of attachment to A2. In certain embodiments, L is -(piperidinylene)-(Ci-4 alkylene)-O-***, wherein *** is the point of attachment to A2. In certain embodiments, L is -(piperidinylene)-O-(C2-4 alkylene)-O-***, wherein *** 18 the point of attachment to A2.

[0101] In certain embodiments, L is one of the following:• an 8-11 membered spirocyclic, saturated heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclic ring is substituted with 0, 1, or 2 occurrences of fluoro;• -(8-10 membered spirocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-O-*** or -(8-10 membered spirocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(Ci-4 alkylene)-***, wherein *** is the point of attachment to A2; or• -(7-8 membered spirocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C2-4alkynylene)-***, wherein *** is the point of attachment to A2.

[0102] In certain embodiments, L is an 8-11 membered spirocyclic, saturated heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclic ring is substituted with 0, 1, or 2 occurrences of fluoro. In certain embodiments, L is an 8-11 membered spirocyclic, saturated heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen. In certain embodiments, L is an 8-11 membered spirocyclic, saturated heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclic ring is substituted with 1 occurrence of fluoro. In certain embodiments, L is an 8-11 membered spirocyclic, saturated heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclic ring is substituted with 2 occurrence of fluoro.

[0103] In certain embodiments, L is an 8-11 membered spirocyclic, saturated heterocyclic ring containing 2 or 3 heteroatoms independently selected from nitrogen and oxygen, wherein at least 2 of the heteroatoms are nitrogen, and wherein the heterocyclic ring is substituted with 0, 1,or 2 occurrences of fluoro. In certain embodiments, L is an 8-11 membered spirocyclic, saturated heterocyclic ring containing 2 or 3 heteroatoms independently selected from nitrogen and oxygen, wherein at least 2 of the heteroatoms are nitrogen. In certain embodiments, L is an 8-11 membered spirocyclic, saturated heterocyclic ring containing 2 or 3 heteroatoms independently selected from nitrogen and oxygen, wherein at least 2 of the heteroatoms are nitrogen, and wherein the heterocyclic ring is substituted with 1 or 2 occurrences of fluoro.[00104J In certain embodiments, L is -(8-10 membered spirocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-©-*** or -(8-10 membered spirocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(Ci-4 alkylene)- ***, wherein *** is the point of attachment to A2. In certain embodiments, L is -(8-10 membered spirocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-O- ***, wherein *** is the point of attachment to A2. In certain embodiments, L is -(8-10 membered spirocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(Ci-4 alkylene)-***, wherein *** is the point of attachment to A2.

[0105] In certain embodiments, L is -(7-8 membered spirocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C2-4 alkynylene)-***, wherein *** is the point of attachment to A2. In certain embodiments, L is -(7-membered spirocyclic saturated heterocyclic ring containing 1 heteroatom selected from nitrogen)-OC-***, wherein *** is the point of attachment to A2.

[0106] In certain embodiments, L is a 7-9 membered fused bicyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen, wherein the heterocyclic ring is substituted by 1 or 2 occurrences of fluoro. In certain embodiments, L is a 7-9 membered fused bicyclic saturated heterocyclic ring containing 2 heteroatoms selected from nitrogen, wherein the heterocyclic ring is substituted by 1 or 2 occurrences of fluoro. In certain embodiments, L is a 7- 9 membered fused bicyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen, wherein the heterocyclic ring is substituted by 2 occurrences of fluoro.

[0107] In certain embodiments, L is l,2,3,5-tetrahydropyrrolo[3,4-c]pyrrolylene.

[0108] In certain embodiments, L is -(azetidinylene)-(Ci-4alkylene)-(azetidinylene)-.

[0109] In certain embodiments, L is one of the following, wherein *** is the point of attachment to A2:

[0110] In certain embodiments, L is one of the following, wherein *** is the point of attachment to A2:

[0111] In certain embodiments, L is one of the following, wherein *** is the point of attachment to A2:

[0112] In certain embodiments, L is one of the following, wherein *** is the point of attachment to A2:

[0113] In certain embodiments, L is one of the following, wherein *** is the point of attachment to A2:

[0114] In certain embodiments, L is selected from the groups depicted in the compounds in Tables 1 and 2 below.

[0115] In certain embodiments, the compound of Formula I is a compound of Formula la or a pharmaceutically acceptable salt thereof:wherein each of R1, R2, R3, A1, L, and A2is as defined in embodiments herein. In certain embodiments, the compound is a compound of Formula la.

[0116] In certain embodiments, the compound of Formula I is a compound of Formula lb or a pharmaceutically acceptable salt thereof:wherein each of R1, R3, A1, L, and A2is as defined in embodiments herein. In certain embodiments, the compound is a compound of Formula lb.

[0117] In certain embodiments, the compound of Formula I is a compound of Formula Ic or a pharmaceutically acceptable salt thereof:wherein each of R1, R3, A1, L, and A2is as defined in embodiments herein. In certain embodiments, the compound is a compound of Formula Ic.

[0118] In certain embodiments, the compound of Formula I is a compound of Formula Id or a pharmaceutically acceptable salt thereof:wherein each of A1, L, and A2is as defined in embodiments herein. In certain embodiments, the compound is a compound of Formula Id.

[0119] In certain embodiments, the compound of Formula I is a compound of Formula le or a pharmaceutically acceptable salt thereof:wherein each of A1, L, and A2is as defined in embodiments herein. In certain embodiments, the compound is a compound of Formula le.

[0120] In certain embodiments, the compound of Formula I is a compound of Formula If or a pharmaceutically acceptable salt thereof:wherein each of R1, R2, R3, A1, L, and A2is as defined in embodiments herein. In certain embodiments, the compound is a compound of Formula If.

[0121] In certain embodiments, the compound of Formula I is a compound of Formula Ig or a pharmaceutically acceptable salt thereof:wherein each of R1, R2, R3, A1, L, and A2is as defined in embodiments herein. In certain embodiments, the compound is a compound of Formula Ig.

[0122] In certain embodiments, the compound of Formula I is a compound of Formula Ih or a pharmaceutically acceptable salt thereof:wherein each of A1, L, and A2is as defined in embodiments herein. In certain embodiments, the compound is a compound of Formula Ih.

[0123] In certain embodiments, the compound of Formula I is a compound of Formula li or a pharmaceutically acceptable salt thereof:wherein each of A1, L, and A2is as defined in embodiments herein. In certain embodiments, the compound is a compound of Formula li.

[0124] The description above describes multiple embodiments relating to compounds of Formula I. The patent application specifically contemplates all combinations of the embodiments.Exemplary Specific Compounds

[0125] In certain embodiments, the compound is a compound in Table 1 or 2, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1 or 2. In certain embodiments, the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1.TABLE 1.

[0126] In certain embodiments, the compound is a compound in Table 2, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 2.TABLE 2.Synthetic Methods

[0127] Methods for preparing compounds described herein are illustrated in the following synthetic Scheme. The Scheme is provided for the purpose of illustrating the invention, and is not intended to limit the scope or spirit of the invention. Starting materials shown in the Scheme can be obtained from commercial sources or can be prepared based on procedures described in the literature.

[0128] In the Scheme, it is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated (for example, use of protecting groups or alternative reactions). Protecting group chemistry and strategy is well known, such as described in, for example, “Protecting Groups in Organic Synthesis”, T. W.Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, the entire contents of which are hereby incorporated by reference.

[0129] The synthetic route illustrated in Scheme l is a general method for preparing compounds of Formula F. Reaction of chloride A and compound B where X is a boronic ester under palladium coupling conditions provides compound C. Removal of the protecting group (Pg) from compound C provides compound D. The Pg may be, for example, a Boc protecting group that can be removed by treating the compound with trifluoroacetic acid. Coupling of compound D with compound E (such as a nucleophilic aromatic substitution reaction, when the leaving group in compound E is chloro) provides the final compound of Formula F.SCHEME 1.

[0130] The modular synthetic route illustrated in Scheme 1 can be readily modified to provide additional compounds by conducting functional group transformations on the intermediate and / or final compounds. Such functional group transformations are well known in the art, as described in, for example, Comprehensive Organic Synthesis (B.M. Trost & I. Fleming, eds., 1991-1992); Organic Synthesis, 3rdEd. (Michael B. Smith, Wavefunction, Inc., Irvine: 2010); Modern Methods of Organic Synthesis, 4thEd. (William Carruthers and IainColdham, Cambridge University Press, Cambridge: 2004); March ’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 8thEd., (Michael B. Smith, John Wiley & Sons, New York: 2020); and Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Ed. (Richard C. Larock, ed., John Wiley & Sons, New York: 2018). Protecting group strategies may be deployed as appropriate to accommodate differing functional groups in the molecules used in the synthetic route. Protecting group chemistry and strategy is described in, for example, Protecting Groups in Organic Synthesis, 3rdEdition, T. W. Greene and P. G. M. Wuts, John Wiley & Sons, 1999 and Greene's Protective Groups in Organic Synthesis, 5th Ed., (Peter G. M. Wuts, John Wiley & Sons: 2014).II. Therapeutic Applications

[0131] The heterobifunctional compounds described herein, such as a compound of Formula I, or other compounds in Section I, provide therapeutic benefits to patients suffering from cancer. Accordingly, one aspect of the invention provides a method of treating cancer. The method comprises administering to a patient in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, or other compound in Section 1, to treat the cancer. In certain embodiments, the compound is a compound of Formula I. In certain embodiments, the particular compound of Formula I is a compound defined by one of the embodiments described above.Cancer

[0132] In certain embodiments, the cancer is ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland carcinoma, bile duct cancer, gallbladder cancer, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma, or leukemia. In certain embodiments, the cancer is prostate cancer.

[0133] In certain embodiments, the cancer is squamous cell cancer, lung cancer including small cell lung cancer, non-small cell lung cancer, vulval cancer, thyroid cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer,glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, and head and neck cancer. In certain embodiments, the cancer is at least one selected from the group consisting of ALL, T-lineage Acute lymphoblastic Leukemia (T-ALL), T-lineage lymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cell Leukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, Burkitts Lymphoma, B- cell ALL, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, lymphoma, leukemia, multiple myeloma myeloproliferative diseases, large B cell lymphoma, or B cell Lymphoma.

[0134] In certain embodiments, the cancer is a solid tumor or leukemia. In certain other embodiments, the cancer is colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, lung cancer, leukemia, bladder cancer, stomach cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, thyroid cancer, kidney cancer, uterus cancer, esophagus cancer, liver cancer, an acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, or retinoblastoma. In certain other embodiments, the cancer is small cell lung cancer, non-small cell lung cancer, melanoma, cancer of the central nervous system tissue, brain cancer, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, or diffuse large B-Cell lymphoma. In certain other embodiments, the cancer is breast cancer, colon cancer, small-cell lung cancer, non-small cell lung cancer, prostate cancer, renal cancer, ovarian cancer, leukemia, melanoma, or cancer of the central nervous system tissue. In certain other embodiments, the cancer is colon cancer, small-cell lung cancer, non-small cell lung cancer, renal cancer, ovarian cancer, renal cancer, or melanoma.

[0135] In certain embodiments, the cancer is a fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma,hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms’ tumor, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, or hemangioblastoma.

[0136] In certain embodiments, the cancer is a neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastases, glioblastoma multiforms, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, rectal adeno carcinoma, Dukes C & D colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi’s sarcoma, karotype acute myeloblastic leukemia, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma, low grade follicular lymphoma, metastatic melanoma, localized melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressive, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma, unresectable hepatocellular carcinoma, Waidenstrom’s macroglobulinemia, smoldering myeloma, indolent myeloma, fallopian tube cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, castrate resistant prostate cancer, castrate resistant metastatic prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, or leiomyoma.

[0137] In certain embodiments, the cancer is bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, non- Hodgkins's lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocorticalcancer, gall bladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers.

[0138] In certain embodiments, the cancer is hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical adenoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal / stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST); Waldenstrom's macroglobulinemia; or medulloblastoma.

[0139] In certain embodiments, the cancer is hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0140] In certain embodiments, the cancer is a solid tumor, such as a sarcoma, carcinoma, or lymphoma. In certain embodiments, the cancer is kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma, or colorectal cancer; colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical carcinoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma;gastrointestinal / stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST); Waldenstrom's macroglobulinemia; or medulloblastoma.

[0141] In certain embodiments, the cancer is renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0142] In certain embodiments, the cancer is hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0143] In certain embodiments, the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine papillary serous carcinoma (UPSC). In some embodiments, the cancer is hepatocholangiocarcinoma. In some embodiments, the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In someembodiments, the cancer is anaplastic thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer, or pancreatic ductal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumors (MPNST). In some embodiments, the cancer is neurofibromatosis- 1 associated MPNST. In some embodiments, the cancer is Waldenstrom's macroglobulinemia. In some embodiments, the cancer is medulloblastoma.Causing Death of Cancer Cell

[0144] Another aspect of the invention provides a method of causing death of a cancer cell. The method comprises contacting a cancer cell with an effective amount of a compound described herein, such as a compound of Formula I, or other compounds in Section I, to cause death of the cancer cell. In certain embodiments, the particular compound of Formula I is a compound defined by one of the embodiments described above.

[0145] In certain embodiments, the cancer cell is selected from an ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland carcinoma, bile duct cancer, gallbladder cancer, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma, or leukemia cell. In certain embodiments, the cancer cell is one or more of the cancers recited in the section above entitled “Cancer.” In certain embodiments, the cancer cell is a prostate cancer cell.Combination Therapies

[0146] The compounds useful within the methods of the invention may be used in combination with one or more additional therapeutic agents useful for treating any disease contemplated herein. These additional therapeutic agents may comprise compounds that are commercially available or synthetically accessible to those skilled in the art. These additional therapeutic agents are known to treat, prevent, or reduce the symptoms, of a disease or disorder contemplated herein.

[0147] Accordingly, in certain embodiments, the method further comprises administering to the subject an additional therapeutic agent that treats the disease contemplated herein.

[0148] In certain embodiments, administering the compound of the invention to the subject allows for administering a lower dose of the additional therapeutic agent as compared to the dose of the additional therapeutic agent alone that is required to achieve similar results in treating the disease contemplated herein. For example, in certain embodiments, the compound of the invention enhances the therapeutic activity of the additional therapeutic compound, thereby allowing for a lower dose of the additional therapeutic compound to provide the same effect.[00149J A synergistic effect may be calculated, for example, using suitable methods such as, for example, the Sigmoid-EmaXequation (Holford & Scheiner, 1981, Clin. Pharmacokinet. 6:429- 453), the equation of Loewe additivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 1 14:313-326) and the median-effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul. 22:27-55). Each equation referred to above may be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively.

[0150] In certain embodiments, the compound of the invention and the therapeutic agent are co-administered to the subject. In other embodiments, the compound of the invention and the therapeutic agent are coformulated and co-administered to the subject.

[0151] In certain embodiments, the compound is administered in combination with a second therapeutic agent having activity against cancer. In certain embodiments, the second therapeutic agent is mitomycin, tretinoin, ribomustin, gemcitabine, vincristine, etoposide, cladribine, mitobronitol, methotrexate, doxorubicin, carboquone, pentostatin, nitracrine, zinostatin, cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole, fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine, bicalutamide, vinorelbine, vesnarinone, aminoglutethimide, amsacrine, proglumide, elliptinium acetate, ketanserin, doxifluridine, etretinate, isotretinoin, streptozocin, nimustine, vindesine, flutamide, drogenil, butocin, carmofur, razoxane, sizofilan, carboplatin, mitolactol, tegafur, ifosfamide, prednimustine, picibanil, levamisole, teniposide, improsulfan, enocitabine, lisuride, oxymetholone, tamoxifen, progesterone, mepitiostane, epitiostanol, formestane, interferon-alpha, interferon-2 alpha, interferon-beta, interferon-gamma, colony stimulating factor-1, colony stimulating factor-2, denileukin diftitox, interleukin-2, and luteinizing hormone releasing factor.

[0152] In certain embodiments, the second therapeutic agent is an mTOR inhibitor, which inhibits cell proliferation, angiogenesis and glucose uptake. Approved mTOR inhibitors useful in the present invention include everolimus (Afinitor®, Novartis); temsirolimus (Torisel®, Pfizer); and sirolimus (Rapamune®, Pfizer).

[0153] In certain embodiments, the second therapeutic agent is a Poly ADP ribose polymerase (PARP) inhibitor. Approved PARP inhibitors useful in the present invention include olaparib (Lynparza®, AstraZeneca); rucaparib (Rubraca®, Clovis Oncology); and niraparib (Zejula®, Tesaro). Other PARP inhibitors being studied which may be used in the present invention include talazoparib (MDV3800 / BMN 673 / LT00673, Medivation / Pfizer / Biomarin); veliparib (ABT-888, Abb Vie); and BGB-290 (BeiGene, Inc.).

[0154] In certain embodiments, the second therapeutic agent is a phosphatidylinositol 3 kinase (PI3K) inhibitor. Approved PI3K inhibitors useful in the present invention include idelalisib (Zydelig®, Gilead). Other PI3K inhibitors being studied which may be used in the present invention include alpelisib (BYL719, Novartis); taselisib (GDC-0032, Genentech / Roche); pictilisib (GDC-0941, Genentech / Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics).

[0155] In certain embodiments, the second therapeutic agent is a proteasome inhibitor. Approved proteasome inhibitors useful in the present invention include bortezomib (Velcade®, Takeda); carfilzomib (Kyprolis®, Amgen); and ixazomib (Ninlaro®, Takeda).

[0156] In certain embodiments, the second therapeutic agent is a histone deacetylase (HD AC) inhibitor. Approved HD AC inhibitors useful in the present invention include vorinostat (Zolinza®, Merck); romidepsin (Istodax®, Celgene); panobinostat (Farydak®, Novartis); and belinostat (Beleodaq®, Spectrum Pharmaceuticals). Other HDAC inhibitors being studied which may be used in the present invention include entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide (Epidaza®, HBI-8000, Chipscreen Biosciences, China).

[0157] In certain embodiments, the second therapeutic agent is a CDK inhibitor, such as a CDK 4 / 6 inhibitor. Approved CDK 4 / 6 inhibitors useful in the present invention include palbociclib (Ibrance®, Pfizer); and ribociclib (Kisqali®, Novartis). Other CDK 4 / 6 inhibitorsbeing studied which may be used in the present invention include abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics).

[0158] In certain embodiments, the second therapeutic agent is an indoleamine (2,3)- dioxygenase (IDO) inhibitor. IDO inhibitors being studied which may be used in the present invention include epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis); GDC-0919 (Genentech / Roche); PF- 06840003 (Pfizer); BMS:F001287 (Bristol-Myers Squibb); Phy906 / KD108 (Phytoceutica); and an enzyme that breaks down kynurenine (Kynase, Kyn Therapeutics).

[0159] In certain embodiments, the second therapeutic agent is a growth factor antagonist, such as an antagonist of platelet-derived growth factor (PDGF), or epidermal growth factor (EGF) or its receptor (EGFR). Approved PDGF antagonists which may be used in the present invention include olaratumab (Lartruvo®; Eli Lilly). Approved EGFR antagonists which may be used in the present invention include cetuximab (Erbitux®, Eli Lilly); necitumumab (Portrazza®, Eli Lilly), panitumumab (Vectibix®, Amgen); and osimertinib (targeting activated EGFR, Tagrisso®, AstraZeneca).

[0160] In certain embodiments, the second therapeutic agent is an aromatase inhibitor. Approved aromatase inhibitors which may be used in the present invention include exemestane (Aromasin®, Pfizer); anastazole (Arimidex®, AstraZeneca) and letrozole (Femara®, Novartis).

[0161] In certain embodiments, the second therapeutic agent is an antagonist of the hedgehog pathway. Approved hedgehog pathway inhibitors which may be used in the present invention include sonidegib (Odomzo®, Sun Pharmaceuticals); and vismodegib (Erivedge®, Genentech), both for treatment of basal cell carcinoma.

[0162] In certain embodiments, the second therapeutic agent is a folic acid inhibitor. Approved folic acid inhibitors useful in the present invention include pemetrexed (Alimta®, Eli Lilly).

[0163] In certain embodiments, the second therapeutic agent is a CC chemokine receptor 4 (CCR4) inhibitor. CCR4 inhibitors being studied that may be useful in the present invention include mogamulizumab (Poteligeo®, Kyowa Hakko Kirin, Japan).

[0164] In certain embodiments, the second therapeutic agent is an isocitrate dehydrogenase (IDH) inhibitor. IDH inhibitors being studied which may be used in the present invention include AG120 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).

[0165] In certain embodiments, the second therapeutic agent is an arginase inhibitor. Arginase inhibitors being studied which may be used in the present invention include AEB1102 (pegylated recombinant arginase, Aeglea Biotherapeutics), which is being studied in Phase 1 clinical trials for acute myeloid leukemia and myelodysplastic syndrome (NCT02732184) and solid tumors (NCT02561234); and CB-1158 (Calithera Biosciences).

[0166] In certain embodiments, the second therapeutic agent is a glutaminase inhibitor. Glutaminase inhibitors being studied which may be used in the present invention include CB-839 (Calithera Biosciences).

[0167] In certain embodiments, the second therapeutic agent is an antibody that binds to tumor antigens, that is, proteins expressed on the cell surface of tumor cells. Approved antibodies that bind to tumor antigens which may be used in the present invention include rituximab (Rituxan®, Genentech / Biogenldec); ofatumumab (anti-CD20, Arzerra®, GlaxoSmithKline); obinutuzumab (anti-CD20, Gazyva®, Genentech), ibritumomab (anti-CD20 and Yttrium-90, Zevalin®, Spectrum Pharmaceuticals); daratumumab (anti-CD38, Darzalex®, Janssen Biotech), dinutuximab (anti-glycolipid GD2, Unituxin®, United Therapeutics); trastuzumab (anti-HER2, Herceptin®, Genentech); ado-trastuzumab emtansine (anti-HER2, fused to emtansine, Kadcyla®, Genentech); and pertuzumab (anti-HER2, Perjeta®, Genentech); and brentuximab vedotin (anti-CD30-drug conjugate, Adcetris®, Seattle Genetics).

[0168] In certain embodiments, the second therapeutic agent is a topoisomerase inhibitor. Approved topoisomerase inhibitors useful in the present invention include irinotecan (Onivyde®, Merrimack Pharmaceuticals); topotecan (Hycamtin®, GlaxoSmithKline). Topoisomerase inhibitors being studied which may be used in the present invention include pixantrone (Pixuvri®, CTI Biopharma).

[0169] In certain embodiments, the second therapeutic agent is a nucleoside inhibitor, or other therapeutic that interfere with normal DNA synthesis, protein synthesis, cell replication, or will otherwise inhibit rapidly proliferating cells. Such nucleoside inhibitors or other therapeuticsinclude trabectedin (guanidine alkylating agent, Yondelis®, Janssen Oncology), mechlorethamine (alkylating agent, Valchlor®, Aktelion Pharmaceuticals); vincristine (Oncovin®, Eli Lilly; Vincasar®, Teva Pharmaceuticals; Marqibo®, Talon Therapeutics); temozolomide (prodrug to alkylating agent 5-(3-methyltriazen-l-yl)-imidazole-4-carboxamide (MTIC) Temodar®, Merck); cytarabine injection (ara-C, antimetabolic cytidine analog, Pfizer); lomustine (alkylating agent, CeeNU®, Bristol-Myers Squibb; Gleostine®, NextSource Biotechnology); azacitidine (pyrimidine nucleoside analog of cytidine, Vidaza®, Celgene); omacetaxine mepesuccinate (cephalotaxine ester) (protein synthesis inhibitor, Synribo®; Teva Pharmaceuticals); asparaginase Erwinia chiysanthemi (enzyme for depletion of asparagine, Elspar®, Lundbeck; Erwinaze®, ELISA Pharma); eribulin mesylate (microtubule inhibitor, tubulin-based antimitotic, Halaven®, Eisai); cabazitaxel (microtubule inhibitor, tubulin-based antimitotic, Jevtana®, Sanofi -Aventis); capacetrine (thymidylate synthase inhibitor, Xeloda®, Genentech); bendamustine (bifunctional mechlorethamine derivative, believed to form interstrand DNA cross-links, Treanda®, Cephalon / Teva); ixabepilone (semi-synthetic analog of epothilone B, microtubule inhibitor, tubulin-based antimitotic, Ixempra®, Bristol-Myers Squibb); nelarabine (prodrug of deoxyguanosine analog, nucleoside metabolic inhibitor, Arranon®, Novartis); clorafabine (prodrug of ribonucleotide reductase inhibitor, competitive inhibitor of deoxycytidine, Clolar®, Sanofi-Aventis); and trifluridine and tipiracil (thymidine- based nucleoside analog and thymidine phosphorylase inhibitor, Lonsurf®, Taiho Oncology).

[0170] In certain embodiments, the second therapeutic agent is a platinum-based therapeutic, also referred to as platins. Platins cause cross-linking of DNA, such that they inhibit DNA repair and / or DNA synthesis, mostly in rapidly reproducing cells, such as cancer cells. Approved platinum-based therapeutics which may be used in the present invention include cisplatin (Platinol®, Bristol-Myers Squibb); carboplatin (Paraplatin®, Bristol-Myers Squibb; also, Teva; Pfizer); oxaliplatin (Eloxitin® Sanofi -Aventis); and nedaplatin (Aqupla®, Shionogi). Other platinum-based therapeutics which have undergone clinical testing and may be used in the present invention include picoplatin (Poniard Pharmaceuticals); and satraplatin (JM-216, Agennix).

[0171] In certain embodiments, the second therapeutic agent is a taxane compound, which causes disruption of microtubules, which are essential for cell division. Approved taxane compounds which may be used in the present invention include paclitaxel (Taxol®, Bristol-Myers Squibb), docetaxel (Taxotere®, Sanofi -Aventis; Docefrez®, Sun Pharmaceutical), albumin-bound paclitaxel (Abraxane®; Abraxis / Celgene), and cabazitaxel (Jevtana®, Sanofi- Aventis). Other taxane compounds which have undergone clinical testing and may be used in the present invention include SID530 (SK Chemicals, Co.) (NCT00931008).

[0172] In certain embodiments, the second therapeutic agent is an inhibitor of anti-apoptotic proteins, such as BCL-2. Approved anti-apoptotics which may be used in the present invention include venetoclax (Venclexta®, AbbVie / Genentech); and blinatumomab (Blincyto®, Amgen). Other therapeutic agents targeting apoptotic proteins which have undergone clinical testing and may be used in the present invention include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

[0173] In certain embodiments, the second therapeutic agent is a selective estrogen receptor modulator (SERM), which interferes with the synthesis or activity of estrogens. Approved SERMs useful in the present invention include raloxifene (Evista®, Eli Lilly).

[0174] In certain embodiments, the second therapeutic agent is an inhibitor of interaction between the two primary p53 suppressor proteins, MDMX and MDM2. Inhibitors of p53 suppression proteins being studied which may be used in the present invention include ALRN- 6924 (Aileron), a stapled peptide that equipotently binds to and disrupts the interaction of MDMX and MDM2 with p53. ALRN-6924 is currently being evaluated in clinical trials for the treatment of AML, advanced myelodysplastic syndrome (MDS) and peripheral T-cell lymphoma (PTCL) (NCT02909972; NCT02264613).

[0175] In certain embodiments, the second therapeutic agent is an inhibitor of transforming growth factor-beta (TGF-beta or TGFP). Inhibitors of TGF-beta proteins being studied which may be used in the present invention include NIS793 (Novartis), an anti-TGF-beta antibody being tested in the clinic for treatment of various cancers, including breast, lung, hepatocellular, colorectal, pancreatic, prostate and renal cancer (NCT 02947165). In some embodiments, the inhibitor of TGF-beta proteins is fresolimumab (GC1008; Sanofi-Genzyme), which is being studied for melanoma (NCT00923169); renal cell carcinoma (NCT00356460); and non-small cell lung cancer (NCT02581787). Additionally, in some embodiments, the additional therapeutic agent is a TGF-beta trap, such as described in Connolly et al. (2012) Infl J. Biological Sciences 8:964-978. One therapeutic compound currently in clinical trials for treatment of solid tumors isM7824 (Merck KGaA — formerly MSB0011459X), which is a bispecific, anti-PD-Ll / TGFp trap compound (NCT02699515); and (NCT02517398). M7824 is comprised of a fully human IgGl antibody against PD-L1 fused to the extracellular domain of human TGF-beta receptor II, which functions as a TGFp “trap.”

[0176] In certain embodiments, the second therapeutic agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from sipuleucel-T (Provenge®, Dendreon / Valeant Pharmaceuticals), which has been approved for treatment of asymptomatic, or minimally symptomatic metastatic castrate-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec (Imlygic®, BioVex / Amgen, previously known as T-VEC), a genetically modified oncolytic viral therapy approved for treatment of unresectable cutaneous, subcutaneous and nodal lesions in melanoma. In some embodiments, the additional therapeutic agent is selected from an oncolytic viral therapy such as pexastimogene devacirepvec (PexaVec / JX-594, SillaJen / formerly Jennerex Biotherapeutics), a thymidine kinase- (TK-) deficient vaccinia virus engineered to express GM-CSF, for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); pelareorep (Reolysin®, Oncolytics Biotech), a variant of respiratory enteric orphan virus (reovirus) which does not replicate in cells that are not RAS-activated, in numerous cancers, including colorectal cancer (NCTO 1622543); prostate cancer (NCT01619813); head and neck squamous cell cancer (NCTO 1166542); pancreatic adenocarcinoma (NCT00998322); and non-small cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev (NG-348, PsiOxus, formerly known as ColoAdl), an adenovirus engineered to express a full length CD80 and an antibody fragment specific for the T-cell receptor CD3 protein, in ovarian cancer (NCT02028117); metastatic or advanced epithelial tumors such as in colorectal cancer, bladder cancer, head and neck squamous cell carcinoma and salivary gland cancer (NCT02636036); ONCOS-102 (Targovax / formerly Oncos), an adenovirus engineered to express GM-CSF, in melanoma (NCT03003676); and peritoneal disease, colorectal cancer or ovarian cancer (NCT02963831); GL-ONC1 (GLV-lh68 / GLV-lhl53, Genelux GmbH), vaccinia viruses engineered to express beta-galactosidase (beta-gal) / beta-glucoronidase or beta-gal / human sodium iodide symporter (hNIS), respectively, were studied in peritoneal carcinomatosis (NCT01443260); fallopian tube cancer, ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF, in bladder cancer (NCT02365818).

[0177] In certain embodiments, the second therapeutic agent is an immune checkpoint inhibitor selected from a PD-1 antagonist, a PD-L1 antagonist, or a CTLA-4 antagonist. In some embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is administered in combination with nivolumab (anti-PD-1 antibody, Opdivo®, Bristol-Myers Squibb); pembrolizumab (anti-PD-1 antibody, Keytruda®, Merck); ipilimumab (anti-CTLA-4 antibody, Yervoy®, Bristol-Myers Squibb); durvalumab (anti-PD-Ll antibody, Imfinzi®, AstraZeneca); or atezolizumab (anti-PD-Ll antibody, Tecentriq®, Genentech). Other immune checkpoint inhibitors suitable for use in the present invention include REGN2810 (Regeneron), an anti-PD-1 antibody tested in patients with basal cell carcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cell carcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma (NCT03002376); pidilizumab (CureTech), also known as CT- 011, an antibody that binds to PD-1, in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab (Bavencio®, Pfizer / Merck KGaA), also known as MSB0010718C), a fully human IgGl anti-PD-Ll antibody, in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, renal cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer; and PDR001 (Novartis), an inhibitory antibody that binds to PD-1, in clinical trials for non-small cell lung cancer, melanoma, triple negative breast cancer and advanced or metastatic solid tumors. Tremelimumab (CP-675,206; Astrazeneca) is a fully human monoclonal antibody against CTLA-4 that has been in studied in clinical trials for a number of indications, including: mesothelioma, colorectal cancer, kidney cancer, breast cancer, lung cancer and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, squamous cell cancer of the head and neck, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic cancer in the liver, liver cancer, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplastic thyroid cancer, urothelial cancer, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody that is being studied in Phase 1 clinical trials for advanced solid tumors (NCT02694822).

[0178] Another aspect of the invention provides for the use of a compound described herein(such as a compound of Formula I, or other compounds in Section I) in the manufacture of a medicament. In certain embodiments, the medicament is for treating a disease described herein, such as cancer.

[0179] Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, or other compounds in Section I) for treating a medical disease, such a disease described herein (e.g., cancer).Evaluation of Cellular Growth Inhibition ofHEK293 cells and HeLa cells

[0180] Compounds can be evaluated for ability to inhibit the proliferation of HEK293 cells or HeLa cells according to the following procedure. HEK293 and HeLa cells are cultured in DMEM medium supplemented with 10% fetal bovine serum and 1% Penn / Strep. Cells are seeded in white 384-well plates at 500 cells / well in 25 μL complete medium. Following seeding, plates are spun at 300 x g for three minutes and cultured at 37 °C with 5% CO2 in a humidified tissue culture incubator. After 24 hours, compounds are titrated in 100% DMSO and diluted in complete cell culture medium. A 25 μL aliquot of compound / media mixture is added to cells to bring total volume in well to 50 pL. DMSO alone is used as a negative control. Plates are then spun at 300*g for three minutes and stored at 37 °C with 5% CO2 for three days. On Day 0 and Day 3 of compound treatment, cell viability is quantified with CellTiter-Glo 2.0 reagent (Promega). After equilibrating microplates at room temperature for 30 minutes, 25 μL CellTiter- Glo 2.0 reagent is dispensed into each well to bring total volume to 75 pL. Plates are mixed on shaker for 2 minutes at 500rpm, followed by a 10-minute incubation at room temperature. Following a quick spin, luminescence readings are measured with an EnVision Plate Reader. Data is normalized to DMSO treated Day 0 and Day 3 readings. A four-parameter non-linear regression curve fit is applied to dose-response data in GraphPad Prism data analysis software to determine the half maximal growth inhibitory concentration (GI50) for each compound.III. Pharmaceutical Compositions and Dosing Considerations

[0181] As indicated above, the invention provides pharmaceutical compositions, which comprise a therapeutically-effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and / or diluents. The pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes forapplication to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally. In certain embodiments, the invention provides a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula I) and a pharmaceutically acceptable carrier.

[0182] The phrase “therapeutically effective amount” as used herein means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit / risk ratio applicable to any medical treatment.

[0183] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0184] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0185] Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0186] Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by anymethods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

[0187] In certain embodiments, a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and poly anhydrides; and a compound of the present invention. In certain embodiments, an aforementioned formulation renders orally bioavailable a compound of the present invention.

[0188] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0189] Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste.

[0190] In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, trouches and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fdlers or extenders, such as starches, lactose, sucrose, glucose,mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0191] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0192] The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They may be formulated for rapid release, e.g, freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release theactive ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro- encapsulated form, if appropriate, with one or more of the above-described excipients.

[0193] Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0194] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0195] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0196] Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.

[0197] Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0198] Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0199] The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0200] Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0201] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[0202] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.

[0203] Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0204] Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.[00205J These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

[0206] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0207] Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.

[0208] When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, forexample, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0209] The preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.

[0210] The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0211] The phrases “systemic administration,” “administered systemically,” “peripheral administration” and “administered peripherally” as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient’s system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.

[0212] These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intraci sternally and topically, as by powders, ointments or drops, including buccally and sublingually.

[0213] Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.

[0214] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effectiveto achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0215] The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0216] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0217] In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Preferably, the compounds are administered at about 0.01 mg / kg to about 200 mg / kg, more preferably at about 0.1 mg / kg to about 100 mg / kg, even more preferably at about 0.5 mg / kg to about 50 mg / kg. When the compounds described herein are co-administered with another agent (e.g., as sensitizing agents), the effective amount may be less than when the agent is used alone.

[0218] If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day.

[0219] The invention further provides a unit dosage form (such as a tablet or capsule) comprising a heterobifunctional substituted compound described herein in a therapeutically effective amount for the treatment of a medical disorder described herein.IV. MEDICAL KITS

[0220] Another aspect of this invention is a kit comprising (i) a compound described herein, such as a compound of Formula I, and (ii) instructions for use, such as treating cancer.V. EXAMPLES

[0221] The invention now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and is not intended to limit the invention.General Methods

[0222] All reactions were carried out under an atmosphere of dry nitrogen or argon. Glassware was oven-dried prior to use. Unless otherwise indicated, common reagents or materials were obtained from commercial sources and used without further purification. N,N- Diisopropylethylamine (DIPEA) was obtained anhydrous by distillation over potassium hydroxide. Tetrahydrofuran (THF), di chloromethane (CH2Q2), and dimethylformamide (DMF) was dried by a PureSolv™ solvent drying system. PTLC refers to preparatory thin layer chromatographic separation. Abbreviations: HFIP (hexafluoroisopropanol), HEPES (4-(2- hydroxyethyl)-l-piperazineethanesulfonic acid. Flash column chromatography was performed using silica gel 60 (230-400 mesh). Analytical thin layer chromatography (TLC) was carried out on Merck silica gel plates with QF-254 indicator and visualized by UV or KMnCU.

[0223] rH and13C NMR spectra were recorded on an Agilent DD2 500 (500 MHz1H; 125 MHz13C) or Agilent DD2600 (600 MHz ’H; 150 MHz13C) or Agilent DD2400 (400 MHz1H; 100 MHz13C) spectrometer at room temperature. Chemical shifts were reported in ppm relative to the residual CDCI3 (8 7.26 ppm 'H, 8 77.0 ppm13C), CD3OD (8 3.31 ppm1H; 849.00 ppm13C), or t / <-DMSO (8 2.50 ppm 'H; 839.52 ppm13C). NMR chemical shifts were expressed in ppm relative to internal solvent peaks, and coupling constants were measured in Hz. (bs = broad signal). In most cases, only peaks of the major rotamer are reported.

[0224] Mass spectra were obtained using Agilent 1100 series LC / MSD spectrometers. Analytical HPLC analyses were carried out on 250 x 4.6 mm C-18 column using gradientconditions (10-100% B, flow rate = 1 .0 mL / min, 20 min), or as described in the LC-MS Method tables.

[0225] Unless indicated otherwise, preparative HPLC was carried out on 250 x 21.2 mm C- 18 column using gradient conditions (10-100% B, flow rate = 10.0 mL / min, 20 min). The eluents used were: solvent A (H2O with 0.1% TFA) and solvent B (CH3CN with 0.1% TFA). Final products were typically purified via reversed-phase HPLC, PTLC, or flash column chromatography.

[0226] The following abbreviations are used herein: ACN: acetonitrile; Bn: benzyl; Boc: tert-butoxy carbonyl; DCM: dichloromethane; DIEA: diisopropylethylamine; DMAP: 4- dimethylaminopyridine; DMF: dimethylformamide; DMSO: dimethylsulfoxide; EtOH: ethanol; EA or EtOAc: ethyl acetate; equiv. or eq.: molar equivalents; FA: formic acid; h: hour or hours; HATU: l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HPLC: high-pressure liquid chromatography; JQ1 : 2-[(9S)-7-(4- chlorophenyl)-4,5,13-trimethyl-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7,10,12- pentaen-9-yl]acetic acid; LCMS or LC-MS: liquid chromatography-mass spectrometry; MeOH: methanol; MS: mass spectrometry; NMP: N-methylpyrrolidone; NMR: nuclear magneticresonance; PE: petroleum ether; rt: room temperature; TEA: triethylamine; TFA: tri fluoroacetic acid; THF: tetrahydrofuran; and Tos or Ts: p-toluenesulfonyl.EXAMPLE 1 - Synthesis of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[6-[2-[3-fluoro-4-[4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]ethynyI]-2-azaspiro[3.3]heptan-2-yl]pyridazine-3- carboxamide (1-4)

[0227] Step 1 : Preparation of 3-(4-chloro-2-fluoro-phenyl)-3-oxo-propanenitrile. A solution of acetonitrile (9.3 g, 225.3 mmol, 11.9 mL, 1.7 equiv) in THF (200 mL) was stirred at - 78°C under N2 protection. Then n-BuLi (2.5 M, 106.0 mL, 2.0 equiv) was added to the mixture and stirred for 0.5 h. Then methyl 4-chloro-2-fluoro-benzoate (25.0 g, 132.5 mmol, 1.0 equiv) in THF (20 mL) was added dropwise, and the mixture was stirred for 1.5 h under N2 protection. The reaction mixture was quenched with a saturated aqueous NH4CI (200 ml) solution at 0 °C.The resulting mixture was extracted with ethyl acetate (100 mL x 4). The combined organic layers were dried over anhydrous NazSCh, fdtered and concentrated under vacuum. The crude product was triturated with petroleum ether / ethyl acetate = 20 / 1 at 25 °C for 30 min to give 3-(4- chloro-2-fluoro-phenyl)-3-oxo-propanenitrile (23.0 g, 116.4 mmol, 87.80% yield) as a yellow solid.

[0228] Step 2: Preparation of (2-amino-4,5-dimethyl-3-thienyl)-(4-chloro-2-fluoro- phenyl)methanone. To a solution of 3-(4-chloro-2-fluoro-phenyl)-3-oxo-propanenitrile (23.0 g, 116.4 mmol, 1.0 equiv) and butan-2-one (8.4 g, 116.4 mmol, 10.4 mL, 1.0 equiv) in EtOH (200 mL) was added TEA (23.6 g, 232.8 mmol, 32.4 mL, 2.0 equiv) and sulfur (4.4 g, 138.5 mmol, 1 .2 equiv). The mixture was stirred at 50 °C for 12 h. To the reaction mixture was added water (500 mL), and the mixture was extracted with ethyl acetate (500 mL x 3). The combined organic phase was washed with brine (500 mL), dried over anhydrous Na2SO4 , fdtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=35 / l to 30 / 1) to give (2-amino-4,5-dimethyl-3-thienyl)-(4-chloro-2-fluoro- phenyl)methanone (10.0 g, 35.2 mmol, 30% yield) as a yellow oil.[00229J Step 3: Preparation of tert-butyl 4-[[3-(4-chloro-2-fluoro-benzoyl)-4,5-dimethyl- 2-thienyl]amino]-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxo-butanoate. To a solution of (2-amino-4,5-dimethyl-3-thienyl)-(4-chloro-2-fluoro-phenyl)methanone (8.8 g, 31.0 mmol, 1.0 equiv) and (2S)-4-tert-butoxy-2-(9EI-fluoren-9-ylmethoxycarbonylamino)-4-oxo- butanoic acid (19.1 g, 46.5 mmol, 1.5 equiv) in EtOAc (40 mL) was added pyridine (9.8 g, 124.0 mmol, 10.0 mL, 4.0 equiv) and T4P (44.7 g, 62.0 mmol, 50% purity, 2.0 equiv). The mixture was stirred at 25 °C for 12 h. To the reaction mixture was added water (300 mL), and the mixture was extracted with ethyl acetate (80 mL x 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4 , fdtered and concentrated in vacuo. The residue was purified by column chromatography (Si O2, petroleum ether / ethyl acetate=8 / l to 6 / 1) to give the tert-butyl 4-[[3-(4-chloro-2-fluoro-benzoyl)-4,5-dimethyl-2-thienyl]amino]-3-(9H-fluoren-9- ylmethoxycarbonylamino)-4-oxo-butanoate (15.5 g, 22.9 mmol, 73% yield) as a mixture of stereoisomers that was a yellow oil.

[0230] Step 4: Preparation of tert-butyl 3-amino-4-[[3-(4-chloro-2-fluoro-benzoyl)-4,5- dimethyl-2-thienyl]amino]-4-oxo-butanoate. To a solution of tert-butyl 4-[[3-(4-chloro-2-fluoro-benzoyl )-4,5-dimethyl-2-thienyl]amino]-3-(9H-fluoren-9-ylmethoxy-carbonylamino)-4- oxo-butanoate (14.0 g, 20.7 mmol, 1.0 equiv) in DCM (280 mb) was added piperidine (5.3 g, 62.0 mmol, 6.1 mL, 3.0 equiv). The mixture was stirred at 25 °C for 2 h. To the reaction mixture was added water (300 mL), and the mixture was extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with brine (350 mL), dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=10 / l to 8 / 1) to give tert-butyl 3-amino-4-[[3-(4-chloro-2-fluoro- benzoyl)-4,5-dimethyl-2-thienyl]amino]-4-oxo-butanoate (9.4 g, 20.7 mmol, 99 % yield) as a mixture of stereoisomers that was a yellow oil.

[0231] Step 5: Preparation of tert-butyl 2-[5-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2- oxo-l,3-dihydrothieno[2,3-e][l,4]diazepin-3-yl]acetate. To a solution of tert-butyl 3-amino-4- [[3-(4-chloro-2-fluoro-benzoyl)-4,5-dimethyl-2-thienyl]amino]-4-oxo-butanoate (9.4 g, 20.6 mmol, 1.0 equiv) in EtOH (90 mL) was added AcOH (31.5 g, 524.0 mmol, 30.0 mL, 25.4 equiv). The mixture was stirred at 90 °C for 3 h. To the reaction mixture was added water (100 mL), and the mixture was extracted with ethyl acetate (150 mL x 3). The combined organic phase was washed with brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=8 / l to 6 / 1) to give tert-butyl 2-[5-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-oxo-l,3-dihydrothieno [2,3-e][l,4]diazepin-3-yl]acetate (8.9 g, 20.4 mmol, 98% yield) as a mixture of stereoisomers that was a yellow oil.

[0232] Step 6: Preparation of tert-butyl 2-[7-(4-chloro-2-fluoro-phenyl)-4,5,13- trimethyl-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9- yl]acetate. t-BuOK in tetrahydrofuran (1.0 M, 22.4 mL, 1.1 equiv) was added to tert-butyl 2-[5- (4-chloro-2-fluoro-phenyl)-6,7-dimethyl -2-oxo- 1,3-dihy drothieno[2,3-e][ l,4]diazepin-3- yl]acetate (8.9 g, 20.4 mmol, 1.0 equiv) in THF (90 mL) at -78 °C and stirred at 25 °C for 30 min. The reaction mixture was cooled back down to -78 °C. [Chloro(phenoxy)phosphoryl] oxybenzene (6.6 g, 24.4 mmol, 5.1 mL, 1.2 equiv) was added to the reaction mixture. The resulting mixture was warmed to 25 °C over 45 min, and then acetohydrazide (2.3 g, 30.6 mmol, 1.5 equiv) was added to the reaction mixture. The reaction mixture was stirred at 25°C, n-BuOH (90 mL) was added to the reaction mixture and heated to 90 °C for 1 h. The reaction mixture was quenched with a saturated aqueous NH4CI (100 ml) solution at 0 °C by dropwise addition, andthe resulting mixture was extracted with ethyl acetate (100 mL x 2). The combined organic layers were dried over anhydrous NazSCL, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=8 / l to 6 / 1) to give tert- butyl 2-[7-(4-chloro-2-fluoro-phenyl)-4,5,13-trimethyl-3-thia-l,8,l 1,12-tetrazatri cyclo [8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate (8.9 g, 18.74 mmol, 91% yield) as a mixture of stereoisomers that was a yellow oil.[00233J Step 7: Preparation of 2-[7-(4-chloro-2-fluoro-phenyl)-4,5,13-trimethyl-3-thia-1.8.11.12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid. To a solution of tert-butyl 2-[7-(4-chloro-2-fluoro-phenyl)-4,5,13-trimethyl-3-thia-l, 8,11,12- tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate (8.9 g, 18.7 mmol, 1.0 equiv) in DCM (40 mL) was added TFA (20.0 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was used in the next step directly. 2-[7-(4-Chloro-2-fluoro-phenyl)-4,5,13-trimethyl-3- thia-l,8,l l,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (7.8 g, 18.6 mmol) was obtained as a mixture of stereoisomers that was a yellow oil.[00234J Step 8: Preparation of 2-[7-(4-chloro-2-fluoro-phenyl)-4,5,13-trimethyl-3-thia-1.8.11.12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-(2,2- dimethoxyethyl)acetamide. To a solution of 2-[7-(4-chloro-2-fluoro-phenyl)-4,5,13-trimethyl- 3-thia-l ,8, 1 l ,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (7.8 g, 18.6 mmol, 1.0 equiv) and 2,2-dimethoxyethanamine (5.8 g, 55.8 mmol, 6.09 mL, 3.0 equiv) in DMF (70 mL) was added HATU (7.8 g, 20.5 mmol, 1.1 equiv) and DIEA (7.2 g, 55.8 mmol, 9.73 mL, 3.0 equiv). The mixture was stirred at 25 °C for 0.5 h. To the reaction mixture was added water (20 mL), and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, DCM / MeOH=40 / l to 20 / 1) to give 2-[7-(4-chloro-2-fluoro-phenyl)-4,5,13-trimethyl-3-thia-1.8.11.12-tetrazatri cyclo[8.3.0.02, 6]trideca-2(6), 4, 7, 10,12-pentaen-9-yl]-N-(2,2-dimethoxy ethyl) acetamide (6.3 g, 12.5 mmol, 66% yield) as a mixture of stereoisomers that was a yellow oil.

[0235] Step 9: Preparation of 2-[[7-(4-chloro-2-fluoro-phenyI)-4,5,13-trimethyl-3-thia- l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole. Asolution of 2-[7-(4-chloro-2-fluoro-phenyl)-4,5, 13-trimethyl-3-thia-l ,8, 11,12 -tetrazatri cyclo [8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-(2,2-dimethoxyethyl)acetamide (2.0 g, 3.9 mmol, 1.0 equiv) in phosphorus pentoxide solution in methanesulfonic acid (20 mL) was stirred at 100 °C for 12 h. The reaction mixture was quenched with a saturated aqueous NaHCCL (200 ml) solution at 0 °C by dropwise addition. The resulting mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiCL, DCM: MeOH =30 / 1 to 20 / 1). The residue was further purified by prep-HPLC (column: Phenomenex luna C18 (250*70mm,10 um); mobile phase: [water(FA)-ACN]; gradient: 40%-70% B over 20 min) to give 2-[[7-(4-chloro-2-fluoro-phenyl)-4,5,13-trimethyl-3-thia-l,8,l l,12-tetrazatricyclo [8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (1 g, 2.26 mmol, 57% yield) as a mixture of stereoisomers that was a white solid.

[0236] Step 10: Preparation of tert-butyl (S)-6-((3-fluoro-4-(2,3?9-trimethyl-6-(oxazol- 2-ylmethyl)-6H-thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepin-4-yl)phenyl)ethynyl)-2- azaspiro[3.3]heptane-2-carboxylate. A mixture of tert-butyl 6-ethynyl-2-azaspiro[3.3]heptane-2-carboxylate (500 mg, 2.3 mmol, 2.5 equiv), 2-[[7-(4-chloro-2-fluoro-phenyl)-4,5,13-trimethyl-3-thia-l,8, 1 l,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (400 mg, 905 μmol, 1.0 equiv), [2-(2-aminophenyl) phenyl]-methylsulfonyloxy-palladium;2-(2- dicyclohexylphosphanylphenyl)-N,N-dimethyl-aniline (69 mg, 90 μmol, 0.1 equiv), and CS2CO3 (589 mg, 1.8 mmol, 2.0 equiv) in MeCN (10 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 90 °C for 2 h under N2 atmosphere. To the reaction mixture was added water (20 mL) and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*40mm* 15um; mobile phase: [water(FA)-ACN]; gradient:55%-85% B over 15 min). The residue was further purified by prep-SFC (column: DA1CEL CHIRALPAK AS(250mm *30mm,10um);mobile phase: [CC>2-MeOH];B%:50%, isocratic elution mode) to give tert-butyl (R)-6-((3-fluoro-4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][l,2,4]triazolo[4,3- a][l ,4]diazepin-4-yl)phenyl)ethynyl)-2-azaspiro[3.3]heptane-2-carboxylate (140 mg, 223.38 μmol, 24.68% yield) as a yellow oil and tert-butyl (S)-6-((3-fluoro-4-(2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][l ,2,4]triazolo[4,3-a][l,4]diazepin-4-yl)phenyl)ethynyl)-2- azaspiro[3.3]heptane-2-carboxylate (140 mg, 223.38 μmol, 24.68% yield) as a yellow oil.

[0237] Step 11: Preparation of (S)-2-((4-(4-((2-azaspiro[3.3]heptan-6-yl)ethynyl)-2- fluorophenyl)-2,3,9-triinethyl-6H-thieno[3,2-f|[l,2,4]triazolo[4,3-a][l,4]diazepin-6- yl)methyl)oxazole. To a solution of tert-butyl (S)-6-((3-fluoro-4-(2,3,9-trimethyl-6-(oxazol-2- ylmethyl)-6H-thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepin-4-yl)phenyl)ethynyl)-2- azaspiro[3.3]heptane-2-carboxylate (140 mg, 223 μmol, 1.0 equiv) in DCM (3 mL) was added TFA (1.0 mL) .The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was quenched with a saturated aqueous NaHCOi (10 ml) solution at 0 °C by dropwise addition. The resulting mixture was extracted with ethyl acetate (10 mL x 2). The combined organic layers were dried over anhydrous Na2SO4 , filtered and concentrated in vacuum. The residue was used for the next step directly. (S)-2-((4-(4-((2-azaspiro[3.3]heptan-6-yl)ethynyl)-2-fluorophenyl)-2,3,9-trimethyl- 6H-thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)methyl)oxazole (120 mg, crude) was obtained as a yellow oil.

[0238] Step 12: Preparation of N-((lr,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(6- ((3-fluoro-4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][l,2,4]triazolo[4,3- a][l,4]diazepin-4-yl)phenyl)ethynyl)-2-azaspiro[3.3]heptan-2-yl)pyridazine-3-carboxamide (1-4). To a solution of (S)-2-((4-(4-((2-azaspiro[3.3]heptan-6-yl)ethynyl)-2-fluorophenyl)-2,3,9- trimethyl-6H-thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)methyl)oxazole (60 mg, 113 μmol, 1.0 equiv) and 6-chloro-N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]pyridazine-3- carboxamide (44 mg, 113 μmol, 1.0 equiv) in NMP (1 mL) was added DIEA (29 mg, 227 μmol, 39μL, 2.0 equiv). The mixture was stirred at 70 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Phenom enex luna C 18 150*25mm* 10um;mobile phase: [water(FA)-ACN]; gradient: 57%-87% B over 10 min). N-((lr,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(6- ((3-fluoro-4-((S)-2,3,9-trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][l,2,4]triazolo[4,3- a][l,4]diazepin-4-yl)phenyl)ethynyl)-2-azaspiro[3.3]heptan-2-yl)pyridazine-3-carboxamide (1-4, 35 mg, 39 μmol, 34% yield, 98.46% purity) was obtained as a white solid.1H NMR: (400 MHz, DMSO-d6) δ = 8.57-5.50 (m, 1H), 8.03-7.86 (m, 1H), 7.86 - 7.80 (m, H), 7.38 - 7.30 (m, 4H), 7.29-7.20 (m, 2H), 6.85 - 6.82 (m, 1H), 4.76 - 4.73 (m, 1H), 4.56 - 4.53 (m, 2H), 4.18 - 4.12 (m, 4H), 3.88 - 3.82 (m, 4H), 2.67-2.64 (m, 6H), 2.62-2.59 (m, 4H), 2.41 -2.38 (m, 2H), 2.11 - 1.91(m, 2H), 1.63 - 1 .60 (m, 4H), 1 .60 - 1.58 (m, 2H). LC-MS: MS (ES+): RT = 2.599 min, m / z = 881.2 [M + H+],EXAMPLE 2 - Synthesis of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[5-[4-[(9S)- 4,5,9,13-tetramethyl-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-7-yl] phenyl]-4,6-dihydropyrrolo [3,4-c] pyrrol-2-yl] pyridazine-3-carboxamide (1-1)

[0239] Step 1: Preparation of tert-butyl 2-[4-[(9S)-4,5,9,13-tetramethyl-3-thia-l,8,ll,12- tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-l,3,4,6-tetrahydro- pyrrolo[3,4-c]pyrrole-5-carboxylate. A mixture of tert-butyl 2,3,4,6-tetrahydro-lH-pyrrolo [3, 4-c]pyrrole-5 -carboxylate (246 mg, 644 μmol, 1.0 equiv, p-TSA salt), (9S)-7-(4-chloro- phenyl)-4,5,9,13-tetramethyl-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaene (230 mg, 644 μmol, 1.0 equiv), CS2CO3 (629 mg, 1.93 mmol, 3.0 equiv), and SPhos Pd G3 (50 mg, 64 prnol, 0.1 equiv) in dioxane (5 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 90 °C for 2 h under N2 atmosphere. The reaction was filtered and the filtrate was concentrated in vacuo to give the crude product. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 0 / 1). Tert-butyl 2-[4-[(9S)-4,5,9,13-tetramethyl-3-thia-l,8,l 1,12-tetrazatri cyclo [8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-7-yl]phenyl]-l,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylate (300 mg, 565 μmol, 87% yield) was obtained as a white solid.

[0240] Step 2: Preparation of (9S)-4,5,9,13-tetramethyl-7-[4-(2,3,4,6-tetrahydro-lH- pyrrolo[3,4-c]pyrroI-5-yl)phenyl]-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaene. To a solution of tert-butyl 2-[4-[(9S)-4,5,9,13-tetramethyl-3-thia- 1,8,11,12-tetrazatri cyclo[8.3.0.02, 6]trideca-2(6), 4, 7, 10,12-pentaen-7-yl]phenyl]-l, 3,4,6- tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylate (300 mg, 565 μmol, 1.0 equiv) in DCM (4 mb) was added TFA (3.07 g, 26.9 mmol, 2.00 mL, 47.6 equiv). The mixture was stirred at 25 °C for 0.5 h. To the reaction mixture was added NaHCO3 (10 mL) and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. Compound (9S)-4,5,9,13- tetramethyl-7-[4-(2,3,4,6-tetrahydro-lH-pyrrolo[3,4-c]pyrrol-5-yl)phenyl]-3-thia-l,8,l 1,12- tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaene (240 mg, crude) was obtained as a white solid.[00241J Step 3: Preparation of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[5-[4-[(9S)- 4,5,9,13-tetramethyI-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-7-yl]phenyl]-4,6-dihydropyrrolo[3,4-c]pyrrol-2-yl]pyridazine-3-carboxamide (1-1). To a solution of (9S)-4,5,9,13-tetramethyl-7-[4-(2,3,4,6-tetrahydro-lH-pyrrolo[3,4-c]pyrrol-5- yl)phenyl]-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaene (120 mg, 278 μmol, 1.0 equiv) in NMP (2 mL) was added DIEA (180 mg, 1.39 mmol, 242μL, 5.0 equiv) and 6-chloro-N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]pyridazine-3-carboxamide (109 mg, 278 μmol, 1.0 equiv). The mixture was stirred at 60 °C for 3 h. To the reaction mixture was added water (10 mL) and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [water(FA)-ACN]; gradient:32%-62% B over 10 min) to yield N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[5-[4-[(9S)-4,5,9,13- tetramethyl-3-thia- 1,8, 11,12-tetrazatri cyclo[8.3.0.02, 6]trideca-2(6), 4, 7, 10, 12-pentaen-7-yl] phenyl]-4,6-dihydropyrrolo[3,4-c]pyrrol-2-yl]pyridazine-3-carboxamide (1-1, 13 mg, 15 μmol, 5% yield, 91% purity) as a white solid.!H NMR (400 MHz, methanol-^) δ 7.99 (d, J= 9.6 Hz,1H), 7.69 (d, J= 8.8 Hz, 1H), 7.57 (s, 4H), 7.23 - 7.17 (m, 3H), 7.11 (d, J= 9.6 Hz, 1H), 7.08 - 7.02 (m, 1H), 4.78 - 4.68 (m, 3H), 4.58 (s, 2H), 4.54 - 4.48 (m, 1H), 4.36 - 4.28 (m, 1H), 4.05 - 3.91 (m, 1H), 2.71 (s, 3H), 2.46 (s, 3H), 2.25 - 2.18 (m, 2H), 2.14 - 2.08 (m, 2H), 2.02 (d, J= 6.8 Hz, 3H), 1.75 (s, 3H), 1.70 - 1.62 (m, 4H). LC-MS: MS (ES+): RT = 2.539 min, m / z = 783.4 [M + H+]; LCMS method: 25.EXAMPLE 3 - Synthesis of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[4-[(9S)- 4,5,9,13-tetramethyl-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-7-yl]phenyI]-l-oxa-4,9-diazaspiro[5.5]undecan-9-yl]pyridazine-3-carboxamide (I-

[0242] Step 1: Preparation of tert-butyl 4-[[(2-chloroacetyl)amino]methyl]-4-hydroxy- piperidine-l-carboxylate. To a solution of K2CO3 (2.40 g, 17.4 mmol, 2.0 equiv) in H2O (15 mL) was added tert-butyl 4-(aminomethyl)-4-hydroxy-piperidine-l -carboxylate (2.00 g, 8.68 mmol, 1.0 equiv) in EtOAc (15 mL) at 0 °C, and then 2-chloroacetyl chloride (1.23 g, 10.9 mmol, 865μL, 1.3 equiv) was added slowly. The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with H2O (10 mL), and then extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by p / cp-HPLC (column: Phenomenex luna Cl 8 150*25 mm* lOum; mobile phase: [water(FA)-ACN]; gradient: 18%-48% B over 9 min) to give tert-butyl 4-[[(2-chloroacetyl) amino]methyl]-4-hydroxy-piperidine-l-carboxylate (1.51 g, 4.89 mmol, 60% yield) as a white solid.

[0243] Step 2: Preparation of tert-butyl 3-oxo-l-oxa-4,9-diazaspiro[5.5]undecane-9- carboxylate. To a solution of tert-butyl 4-[[(2-chloroacetyl)amino]methyl]-4-hydroxy- piperidine-1 -carboxylate (1.30 g, 4.20 mmol, 1.0 equiv) in IPA (10 mL) was added t-BuOK (1 M, 42.4 mL, 10 equiv). The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched by the addition of AcOH at 0 °C, and then it was concentrated under reduced pressure to afford the crude product. The residue was purified by p / ep-HPLC (column: Phenomenex luna Cl 8 150*25 mm* 10 um; mobile phase: [water (FA)-ACN]; gradient: 22%-52% B over 9 min) to give tert-butyl 3-oxo-l-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (790 mg, 2.92 mmol, 69% yield) as a white solid.

[0244] Step 3: Preparation of tert-butyl l-oxa-4,9-diazaspiro[5.5]undecane-9- carboxylate. To a solution of tert-butyl 3-oxo-l-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (490 mg, 1.81 mmol, 1.0 equiv) in THF (5 mL) was slowly added BH3.THF (1 M, 7.25 mL, 4.0 equiv) dropwise at 0 °C. The mixture was stirred at 55 °C for 2 h. The reaction mixture was quenched slowly by the addition of MeOH (10 mL) dropwise at 0 °C. The reaction mixture was concentrated under reduced pressure to remove THF. Then MeOH (5 mL) and N,N,N',N' -tetra methylethane-l,2-diamine (843 mg, 7.25 mmol, 1.09 mL, 4.0 equiv) were added to the reaction mixture. The mixture was stirred at 70 °C for 6 h. Then the reaction mixture was concentrated under reduced pressure to give the crude compound tert-butyl l-oxa-4,9-diazaspiro[5.5] undecane-9-carboxylate (464 mg, 1.81 mmol) as a colorless oil.

[0245] Step 4: Preparation of O4-benzyl O9-tert-butyl l-oxa-4,9-diazaspiro[5.5] undecane-4,9-dicarboxylate. To a solution of tert-butyl l-oxa-4,9-diazaspiro[5.5]undecane-9- carboxylate (464 mg, 1.81 mmol, 1.0 equiv) in DCM (1 mL) was added TEA (549 mg, 5.43 mmol, 756 μL, 3.0 equiv) and CbzCl (371 mg, 2.17 mmol, 310μL, 1.2 equiv). The mixture was stirred at 25 °C for 8 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm* 10 um; mobile phase: [water(FA)-ACN];gradient:50%-80% B over 10 min) to give O4-benzyl 09-tert-butyl l-oxa-4,9-diazaspiro[5.5]undecane-4,9-dicarboxylate (290 mg, 743 μmol, 41% yield) as a colorless oil.

[0246] Step 5: Preparation of tert-butyl l-oxa-4,9-diazaspiro[5.5]undecane-9- carboxylate. To a solution of O4-benzyl 09-tert-butyl l-oxa-4,9-diazaspiro[5.5]undecane-4,9- dicarboxylate (290 mg, 743 μmol, 1.0 equiv) in THF (3 mL) was added Pd / C (300 mg, 282 μmol, 10% purity) and Pd(OH)2 (200 mg, 142 μmol, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H2 3 times. The mixture was stirred under H2 (15 psi) at 25 °C for 8 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give crude tert-butyl l-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (190 mg, 741 pmol) as a colorless oil.

[0247] Step 6: Preparation of tert-butyl 4-[4-[(9S)-4,5,9,13-tetramethyl-3-thia-l,8,ll,12- tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-1-oxa-4,9-diazaspiro [5.5]undecane-9-carboxylate. To a solution of (95)-7-(4-chlorophenyl)-4,5,9,13-tetramethyl-3- thia-1,8, 1 l,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaene (250 mg, 701 μmol, 1.0 equiv) in dioxane (2 mL) was added tert-butyl l-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (189 mg, 736 μmol, 1.1 equiv), SPhos Pd G3 (54.7 mg, 70.1 μmol, 0.1 equiv) and CS2CO3 (456 mg, 1.40 mmol, 2.0 equiv). The mixture was stirred at 90 °C for 3 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by prep-UPLC (column: Phenomenex luna C18 150*25 mm* 10 um; mobile phase: [water(FA)-ACN]; gradient:30%- 50% B over 10 min column: Phenomenex luna C18 150*25 mm* 10 um; mobile phase: [water(FA)-ACN];gradient:30%-50% B over 10 min) to give tert-butyl 4-[4-[(9S)-4,5,9,13- tetramethyl-3-thia- 1,8, 1 l,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7- yl]phenyl]-l-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (190 mg, 329 μmol, 47% yield) as a light yellow solid.

[0248] Step 7: Preparation of 4-[4-[(9S)-4,5,9,13-tetramethyl-3-thia-l,8,ll,12- tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-l-oxa-4,9- diazaspiro [5.5] undecane. To a solution of tert-butyl 4-[4-[(9.S')-4,5,9,13-tetramethyl-3-thia- 1,8,1 l,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-l-oxa-4,9- diazaspiro[5.5]undecane-9-carboxylate (190 mg, 329 μmol, 1.0 equiv) in DCM (1 mL) was added TFA (0.5 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated and basified with saturated NaHCO3 at 0°C. The mixture was extracted with DCM / MeOH (10: 1, 50 mL x 2), dried over Na2SO4 , filtered and concentrated to give 4-[4-[(9S)-4.5.9.13-tetramethyl-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7- yl]phenyl]-l-oxa-4,9-diazaspiro[5.5]undecane (150 mg, 315 pmol) as a white solid.

[0249] Step 8: Preparation of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[4-[(9S)-4.5.9.13-tetramethyl-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-7-yl]phenyl]-l-oxa-4,9-diazaspiro[5.5]undecan-9-yI]pyridazine-3-carboxamide (I- 2). To a solution of 4-[4-[(9S)-4,5,9,13-tetramethyl-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02,6] trideca-2(6),4,7, 10,12-pentaen-7-yl]phenyl]-l-oxa-4,9-diazaspiro[5.5]undecane (75.0 mg, 157 μmol, 1.0 equiv)' in NMP (0.5 mL) was added DIEA (61.0 mg, 472 μmol, 82.2 3.0 equiv) andμL, 6-chloro-N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]pyridazine-3-carboxamide (73.9 mg, 189 μmol, 1.2 equiv). The mixture was stirred at 65 °C for 12 h. The residue was purified by prep- HPLC (column: Waters xbridge 150*25 mm 10 um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 56%-76% B over 8 min) to give compound N-[4-(3-chloro-4-cyano-phenoxy) cyclohexyl]-6-[4-[4-[(95)-4, 5, 9,13-tetramethyl-3 -thia- 1,8,1 l,12-tetrazatricyclo[8.3.0.02,6] trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-l-oxa-4,9-diazaspiro[5.5]undecan-9-yl]pyridazine- 3-carboxamide (1-2, 61.1 mg, 73.5 μmol, 47% yield) as a yellow solid.1H NMR (:400 MHz, CD3OD) δ 8.48 (d, J= 8.3 Hz, 1H), 7.92 (d, J= 9.7 Hz, 1H), 7.71 (d, J= 8.8 Hz, 1H), 7.41 - 7.30 (m, 3H), 7.22 (d, J= 2.4 Hz, 1H), 7.10 - 7.04 (m, 1H), 6.97 (d, J= 9.0 Hz, 2H), 4.56 - 4.51 (m, 2H), 4.32 - 4.19 (m, 3H), 4.04 - 3.99 (m, 1H), 3.96 - 3.91 (m, 2H), 3.56 - 3.45 (m, 2H), 3.37 (s, 1H), 3.23 (s, 2H), 2.71 (s, 3H), 2.46 (s, 3H), 2.22 (d, J= 2.3 Hz, 2H), 2.17 - 2.07 (m, 4H), 2.00 (d, J= 6.8 Hz, 3H), 1.78 - 1.71 (m, 5H), 1.66 (t, J= 9.5 Hz, 4H). LC-MS: MS (ES+): RT =2.143 min, m / z = 831 .4 [M + H+]; LCMS method: 10.EXAMPLE 4 - Synthesis of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[[3-[(9S)- 4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-7-yllphenoxy]methyl]-l-piperidyl]pyridazine-3-carboxamide (1-6)23% yieldStep 12

[0250] Step 1: Preparation of (2-amino-4,5-dimethyl-3-thienyl)-(3-chlorophenyl) methanone. To a solution of 3-(3-chlorophenyl)-3-oxo-propanenitrile (50.0 g, 278.4 mmol, 1.0 equiv) and butan-2-one (20 g, 278.4 mmol, 25.0 mL, 1.0 equiv) in EtOH (500.0 mL) was added sulfur (10.6 g, 331 .3 mmol, 1 .2 equiv) and TEA (56.4 g, 556.8 mmol, 77.5 mL, 2.0 equiv). The mixture was stirred at 50 °C for 12 h. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=l / O to 20 / 1) to give (2-amino-4,5-dimethyl-3-thienyl)-(3- chlorophenyl)methanone (40.0 g, 150.5 mmol, 54% yield) as a yellow solid.

[0251] Step 2: Preparation of tert-butyl (3S)-4-[[3-(3-chlorobenzoyl)-4,5-dimethyl-2- thienyl]amino]-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxo-butanoate. To a solution of (2-amino-4,5-dimethyl-3-thienyl)-(3-chlorophenyl)methanone (17.0 g, 63.9 mmol, 1.0 equiv), (2S)-4-tert-butoxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxo-butanoic acid (39.5 g, 96.0 mmol, 1.5 equiv), and pyridine (20.2 g, 255.9 mmol, 20.7 mL, 4.0 equiv) in EtOAc (85.0 mL) was added T4P (92.2 g, 127.9 mmol, 50% purity, 2.0 equiv). The mixture was stirred at 25 °C for 12 h. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=10 / l to 5 / 1) to give tert-butyl (3 S)-4-[[3-(3-chlorobenzoyl)-4,5-dimethyl-2 -thienyl] amino]-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxo-butanoate (42.0 g, 63.7 mmol, 99 % yield) as a yellow oil.

[0252] Step 3: Preparation of tert-butyl (3S)-3-amino-4-[[3-(3-chlorobenzoyl)-4,5- dimethyl-2-thienyl]amino]-4-oxo-butanoate. To a solution of tert-butyl (3S)-4-[[3-(3- chlorobenzoyl)-4,5-dimethyl-2-thienyl]amino]-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4- oxo-butanoate (15.0 g, 22.8 mmol, 1.0 equiv) in DCM (150.0 mL) was added piperidine (50.0 mL) dropwise. The resulting mixture was stirred at 25 °C for 3 h. The residue was purified by column chromatography (S1O2, petroleum ether / ethyl acetate=15 / l to 5 / 1) to give tert-butyl (3S)- 3-amino-4-[[3-(3-chlorobenzoyl)-4,5-dimethyl-2-thienyl]amino]-4-oxo-butanoate (9.4 g, 21.5 mmol, 95% yield) as a yellow oil.

[0253] Step 4: Preparation of tert-butyl 2-[(3S)-5-(3-chlorophenyl)-6,7-dimethyl-2-oxo- l,3-dihydrothieno[2,3-e][l,4]diazepin-3-yl]acetate. A mixture of tert-butyl (3S)-3-amino-4- [[3-(3-chlorobenzoyl)-4,5-dimethyl-2-thienyl]amino]-4-oxo-butanoate (9.0 g, 20.6 mmol, 1.0 equiv) in EtOH (60.0 mL) and AcOH (20.0 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 25 °C for 12 h under N2 atmosphere. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=10 / l to 5 / 1) to give tert-butyl 2- [(3S)-5-(3-chlorophenyl)-6,7-dimethyl-2-oxo-l,3-dihydrothieno[2,3-e][l,4]diazepin-3-yl]acetate (6.6 g, 15.8 mmol, 76% yield) as a yellow solid.

[0254] Step 5: Preparation of tert-butyl 2-[(9R)-7-(3-chlorophenyl)-4,5,13-trimethyl-3- thia-l,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate. t-BuOK(1.00 M, 17.3 mL, 1.1 equiv) was added to tert-butyl 2-[(3S)-5-(3-chlorophenyl)-6,7-dimethyl-2- oxo-1, 3-dihydrothieno[2,3-e][l,4]diazepin-3-yl]acetate (6.6 g, 15.8 mmol, 1.0 equiv) in THF (66.0 mL) at -78 °C and stirred at 25 °C for 30 min. The reaction mixture was cooled back down to -78 °C. [chloro(phenoxy)phosphoryl]oxybenzene (5.1 g, 18.9 mmol, 3.9 mL, 1.2 equiv) was added to reaction mixture. The resulting mixture was warmed to 25 °C over 45 min. Then acetohydrazide (1.8 g, 23.6 mmol, 1.5 equiv) was added to reaction mixture. The reaction mixture was stirred at 25 °C, and n-BuOH (66.0 mL) was added to reaction mixture and heated to 90 °C for 1 h. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=5 / l to 1 / 1) to give tert-butyl 2-[(9R)-7-(3-chlorophenyl)-4,5,13-trimethyl-3- thia-l,8,l l,12-tetrazatricyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate (3.9 g, 8.5 mmol, 54% yield) as a yellow solid.

[0255] Step 6: Preparation of 2-[(9S)-7-(3-chlorophenyl)-4,5,13-trimethyl-3-thia- l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid. A mixture of tert-butyl 2-[(9R)-7-(3-chlorophenyl)-4,5,13-trimethyl-3-thia-l,8,l 1,12-tetrazatri cyclo [8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate (3.9g, 8.5 mmol, 1.0 equiv) in DCM (26.0 mL) and TFA (13.0 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 25 °C for 2 h under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give 2-[(9S)-7-(3-chlorophenyl)-4,5,13-trimethyl-3-thia-l, 8,11,12- tetrazatri cyclo [8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (3.4 g, 8.5 mmol, 99% yield) as a yellow oil.

[0256] Step 7 : Preparation of 2-[(9S)-7-(3-chlorophenyl)-4,5,l 3-trimethyl-3-thia-l ,8,11 , 12-tetrazatricydo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-(2,2-dimethoxyethyl) acetamide. To a solution of 2-[(9S)-7-(3-chlorophenyl)-4,5,13-trimethyl-3-thia-l,8,l l,12- tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (3.3 g, 8.2 mmol, 1.0 equiv), 2,2-dimethoxyethanamine (2.6 g, 24.7 mmol, 2.7 mL, 3.0 equiv), and DIEA (2.1 g, 16.5 mmol, 2.9 mL, 2.0 equiv) in DMF (33.0 mL) was added HATU (3.4 g, 9.1 mmol, 1.1 equiv). The mixture was stirred at 25 °C for 1 h. The residue was purified by column chromatography (SiO2, DCM: MeOH = 10: 1) to give 2-[(9S)-7-(3-chlorophenyl)-4,5,13-trimethyl-3-thia-l, 8,11,12- tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-(2,2-dimethoxyethyl)acetamide (3.9 g, 7.9 mmol, 97% yield) as a yellow oil.

[0257] Step 8: Preparation of 2-[[(9S)-7-(3-chlorophenyl)-4,5,13-trimethyl-3-thia-1.8.11.12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole. A mixture of 2-[(9S)-7-(3-chlorophenyl)-4,5,13-trimethyl-3-thia-l,8,l 1,12-tetrazatricyclo [8.3.0.02, 6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-(2,2-dimethoxyethyl)acetamide (930 mg, 1.9 mmol, 1.0 equiv)' in phosphorus pentoxide solution in methanesulfonic acid (10.0 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 100 °C for 12 h under N2 atmosphere. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=0 / l to DCM: MeOH = 15: 1 ) to give 2-[[(9S)-7-(3-chlorophenyl)-4,5,13-trimethyl-3- thia-l,8,l l,12-tetrazatricyclo[8.3.0.02,6] trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (2.3 g, 5.4 mmol, 71% yield) as a black oil.

[0258] Step 9: Preparation of 3-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1.8.11.12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenol. A mixture of 2-[[(9S)-7-(3-chlorophenyl)-4,5,13-trimethyl-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02,6]trideca- 2(6), 4, 7, 10, 12-pentaen-9-yl]methyl]oxazole (1.0 g, 2.4 mmol, 1.0 equiv), BrettPhos Pd G3 (213.8 mg, 235 μmol, 0.1 equiv), and KOH (397 mg, 7.1 mmol, 3.0 equiv) in dioxane (10.0 mL) and H2O (1.0 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 90 °C for 2 h under N2 atmosphere. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=l / l to ethyl acetate / MeOH = 20 / 1 ). The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [water(FA)- ACN]; gradients 1 %-61 % B over 10 min) to give the desired compound (300 mg, 31% yield, purity 99%) as a white solid, which was further separated by SFC (column: DAICELCHIRALPAK AD (250mm*30mm,10um); mobile phase: [CO2-EtOH / ACN]; B%:50%, isocratic elution mode) to give 3-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l, 8,11,12- tetrazatricyclo[8.3.0.02,6] trideca-2(6),4,7,10,12-pentaen-7-yl]phenol (300 mg, 739 μmol, 31% yield) as a white solid.

[0259] Step 10: Preparation of tert-butyl 4-[[3-[(9S)-4,5,13-trimethyl-9-(oxazoI-2-yl methyl)-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7- yljphenoxy] methyl]piperidine-l-carboxylate. A mixture of 3-[(9S)-4,5,13-trimethyl-9- (oxazol-2-ylmethyl)-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7- yl]phenol (60 mg, 147 μmol, 1.0 eqiuv). tert-butyl 4-(p-tolylsulfonyloxymethyl)piperidine-l- carboxylate (109 mg, 296 μmol, 2.0 equiv\ and CS2CO3 (145 mg, 444 μmol, 3.0 equiv) in DMF (1.0 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 70 °C for 12 h under N2 atmosphere. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [water(FA)-ACN]; gradient:58%-88% B over 10 min) to give tert-butyl 4-[[3-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l, 8,11,12- tetrazatricyclo [8.3.0.02,6]trideca-2(6),4,7, 10,12-pentaen-7-yl]phenoxy]methyl]piperidine-l- carboxylate (60 mg, 99 μmol, 67% yield) as yellow oil.

[0260] Step 11: Preparation of 2-[[(9S)-4,5,13-trimethyl-7-[3-(4-piperidylmethoxy) phenyl]-3-thia-l,8,ll,12-tetrazatricydo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl] methyljoxazole. A mixture of tert -butyl 4-[[3-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3- thia-l,8,l l,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]methyl] piperidine-l-carboxylate (60 mg, 99 μmol, 1.0 equiv) in TFA (1.0 mL) and DCM (3.0 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 25 °C for 0.5 h under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give 2-[[(9S)-4, 5, 13-trimethyl-7-[3-(4-piperidylmethoxy)phenyl]-3 -thia- 1,8,11,12-tetrazatri cyclo [8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (60 mg, 97 μmol, 98% yield, TFA) as a yellow oil.

[0261] Step 12: Preparation of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[4-[[3- [(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6] trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]methyl]-l-piperidyl]pyridazine-3-carboxamide (1-6). A mixture of 2-[[(9S)-4,5,13-trimethyl-7-[3-(4-piperidylmethoxy)phenyl]-3-thia-l, 8,11,12-tetrazatri cyclo[8.3.0.02, 6]trideca-2(6), 4, 7, 10,12-pentaen-9-yl]methyl]oxazole (60 mg, 1 19 μmol, 1.0 equiv\ 6-chloro-N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]pyridazine-3-carboxamide (47 mg, 119 μmol, 1.0 equiv), and K2CO3 (17 mg, 119 μmol, 1.0 equiv) in NMP (1.0 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 70 °C for 12 h under N2 atmosphere. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [water(FA)-ACN]; gradient: 58%-88% B over 10 min) and purified by prep-TLC (SiO2, DCM: MeOH = 10: 1) to give N-[4-(3-chloro-4-cyano-phenoxy) cyclohexyl]-6-[4-[[3-[(9S)-4,5,13-trimethyl-9-(oxazol-2-yhnethyl)-3-thia-l,8,l 1,12-tetraza tricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]methyl]-l-piperidyl]pyridazine- 3-carboxamide (1-6, 23.87 mg, 27.56 μmol, 23.09% yield, 99% purity) as a white solid.JH NMR: (400 MHz, CD3OD) δ = 7.94 - 7.88 (m, 2H), 7.73 - 7.66 (m, 1H), 7.34 - 7.25 (m, 2H), 7.21 (d, J = 2.4 Hz, 1H), 7.13 (s, 1H), 7.08 - 7.03 (m, 2H), 7.00 - 6.95 (m, 1H), 6.91 - 6.85 (m, 1H), 4.80 - 4.74 (m, .7 = 6.4, 8.5 Hz, 1H), 4.61 - 4.55 (m, J= 1.2, 12.1 Hz, 4H), 4.06 - 3.91 (m, 3H), 3.88 (d, J = 6.4 Hz, 2H), 3.17 - 3.08 (m, 2H), 2.72 (s, 3H), 2.45 (s, 3H), 2.24 - 2.19 (m, 2H), 2.14 - 2.08 (m, 2H), 2.03 - 1.94 (m, 2H), 1.69 - 1.67 (m, 3H), 1.66 - 1.61 (m, 3H), 1.51 - 1.40 (m, 2H), 1.37 - 1.26 (m, 2H). LC-MS: MS (ES+): RT = 2.742 min, m / z = 857.4 [M +H+] .EXAMPLE 5 - Synthesis of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[2-[2-[(9S)- 4,5,9,13-tetramethyl-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-7-yl]phenyI]-2,8-diazaspiro[3.5]nonan-8-yl]pyridazine-3-carboxamide (1-13)Step 4

[0262] Step 1: Preparation of tert-butyl 2,6-diazaspiro[3.5]nonane-6-carboxylate. To a solution of tert-butyl 2-benzhydryl-2,8-diazaspiro[3.5]nonane-8-carboxylate (4.3 g, 11.0 mmol, 1.0 equiv) in EtOH (60.0 mL) was added Pd / C (1.6 g, 1.5 mmol, 10% purity, 1.3 equiv) and AcOH (1.9 g, 32.2 mmol, 1.8 mL, 2.9 equiv) under H2 atmosphere. The suspension was degassed and purged with H2 3 times. The mixture was stirred under H2 (50 psi) at 50 °C for 16 h. The residue was purified by column chromatography (SiCL, DCM: MeOH = 20: 1) to give tert-butyl 2,6-diazaspiro[3.5]nonane-6-carboxylate (1.1 g, 4.9 mmol, 44% yield) as a yellow oil.

[0263] Step 2: Preparation of tert-butyl 2-(2-bromophenyl)-2,8-diazaspiro[3.5]nonane- 8-carboxylate. A mixture of tert-butyl 2,6-diazaspiro[3.5]nonane-6-carboxylate (1.0 g, 4.4 mmol, 1.0 equiv), 1,2-dibromobenzene (2.1 g, 8.8 mmol, 1.1 mL, 2.0 equiv), CS2CO3 (4.3 g, 13.3 mmol, 3.0 equiv), Xantphos (511 .3 mg, 883 μmol, 0.2 equiv) and Pd(dba)2 (254 mg, 442 μmol, 0.1 equiv) in dioxane (10.0 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 110 °C for 12 h under N2 atmosphere. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*40mm* 15um; mobile phase: [water(FA)-ACN]; gradient: 80%- 100% B over 10 min) to give tert-butyl 2-(2-bromophenyl)-2,8-diazaspiro [3.5]nonane-8-carboxylate (970 mg, 2.5 mmol, 58% yield) as a yellow oil.

[0264] Step 3: Preparation of tert-butyl 2-[2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]-2,8-diazaspiro[3.5]nonane-8-carboxylate. To a solution of tert-butyl 2-(2- bromophenyl)-2,8-diazaspiro[3.5]nonane-8-carboxylate (700 mg, 1.8 mmol, 1.0 equiv) and 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1 .7 g, 9.2 mmol, 1 .9 mL, 5.0 equiv) in THF (7.0 mL) was added n-BuLi (2.5 M, 3.7 mL, 5.0 equiv} at -78 °C under N2 protection. The mixture was allowed to slowly warm to 25 °C over 12 h. The residue was purified by prep- HPLC (column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [water(FA)-ACN]; gradient:33%-63% B over 10 min) to give tert-butyl 2-[2-(4,4,5,5-tetramethyl-l,3,2-dioxa borolan-2-yl)phenyl]-2,8-diazaspiro[3.5]nonane-8-carboxylate (190 mg, 443 μmol, 24.16% yield) as a white solid.

[0265] Step 4: Preparation of tert-butyl 2-[2-[(9S)-4,5,9,13-tetramethyl-3-thia-l,8,ll,12- tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-2,8-diazaspiro [3.5] nonane-8-carboxylate. A mixture of tert-butyl 2-[2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]-2,8-diazaspiro[3.5]nonane-8-carboxylate (150 mg, 350 μmol, 1.0 equiv), (9S)-7- chloro-4,5,9,13-tetramethyl-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7, 10,12- pentaene (197 mg, 700 μmol, 2.0 equiv), Pd(dppf)C12 (26 mg, 35 μmol, 0.1 equiv), and CS2CO3 (342 mg, 1.1 mmol, 3.0 equiv) in THF (0.9 mL) and H2O (0.3 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 50 °C for 2 h under N2 atmosphere. The residue was purified by prep-HPLC (column: Phenomenex luna Cl 8 150*25mm* lOum; mobile phase: [water(FA)-ACN]; gradient:45%-75% B over 10 min) to give tert-butyl 2-[2-[(9S)-4,5,9, 13-tetramethyl-3-thia- 1,8,1 l,12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl] phenyl]-2,8-diazaspiro[3.5]nonane-8-carboxylate (150 mg, 274 μmol, 78% yield) as a brown solid.

[0266] Step 5: Preparation of (9S)-7-[2-(2,8-diazaspiro[3.5]nonan-2-yl)phenyl]-4,5,9,13- tetramethyl-3-thia-l, 8, ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6), 4, 7, 10,12-pentaene. A mixture of tert-butyl 2-[2-[(9S)-4,5,9,13-tetramethyl-3-thia-l,8,l 1,12-tetrazatricyclo [8.3.0.026] trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-2,8-diazaspiro[3.5]nonane-8-carboxylate (150 mg, 274 μmol, 1.0 equiv) in TFA (1.0 mL) and DCM (3.0 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 25 °C for 0.5 h under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give (9S)-7-[2-(2,8-diazaspiro [3.5]nonan-2-yl)phenyl]-4,5,9,13-tetramethyl-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02'6]trideca- 2(6), 4, 7, 10,12-pentaene (150 mg, 268 μmol, 98% yield, TFA) as a yellow oil.

[0267] Step 6: Preparation of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[2-[2-[(9S)-4.5.9.13-tetramethyl-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-7-yl] phenyl]-2,8-diazaspiro [3.5] nonan-8-yl] pyridazine-3-carboxamide (1-13). A mixture of (9S)-7-[2-(2,8-diazaspiro[3.5]nonan-2-yl)phenyl]-4,5,9,13-tetramethyl-3-thia-l,8,l 1, 12-tetrazatricyclo[8.3.0.02'6]trideca-2(6),4,7,10,12-pentaene (150 mg, 336 μmol, 1.0 equiv), 6- chloro-N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]pyridazine-3-carboxamide (169 mg, 336 μmol, 1.0 equiv, TFA), and K2CO3 (232 mg, 1.7 mmol, 5.0 equiv) in NMP (3.0 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 70 °C for 12 h under N2 atmosphere. The residue was purified by prep-TLC (SiO2, DCM: MeOH = 15: 1). The residue was further purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [water(TFA)-ACN]; gradient:39%-69% B over 10 min), and again with prep-HPLC (column: Waters xbridge 150*25mm lOum; mobile phase: [water( NFLHCCX^-ACN]; gradient: 57%-77% B over 8 min) to give N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[2-[2-[(9S)-4.5.9.13-tetramethyl-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7, 10,12-pentaen-7- yl]phenyl]-2,8-diazaspiro[3.5]nonan-8-yl]pyridazine-3-carboxamide (1-13, 60 mg, 72 μmol, 22% yield, 97% purity) as a white solid.1H NMR: (400 MHz, MeOD) δ = 7.98 - 7.89 (m, 1H), 7.74 - 7.65 (m, 1H), 7.42 - 7.25 (m, 2H), 7.21 (d, J = 1.6 Hz, 1H), 7.10 - 7.01 (m, 1H), 6.80 - 6.68 (m, 1H), 6.63 - 6.54 (m, 1H), 4.62 - 4.49 (m, 8H), 4.36 - 4.22 (m, 1H), 4.03 (s, 2H), 3.79 - 3.73 (m, 1H), 3.46 (d, J= 2.8 Hz, 3H), 2.68 - 2.55 (m, 3H), 2.46 (s, 1H), 2.24 - 2.18 (m, 2H), 2.15 - 2.08 (m, 2H), 1.94 (d, .7= 6.8 Hz, 3H), 1.88 - 1.77 (m, 2H), 1.66 (s, 9H). LC-MS: MS (ES+): RT = 1.973 min, m / z = 801.3 [M +H+],EXAMPLE 6 - Synthesis of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[2-[[3-fluoro-4- [(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6] trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]methyl]-7-azaspiro[3.5]nonan-7-yl]pyridazine-3- carboxamide (1-18)

[0268] Step 1: Preparation of tert-butyl 2-[(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)methylene]-7-azaspiro[3.5]nonane-7-carboxylate. To the solution of TMP (2.4 g, 16.7 mmol, 2.8 mL, 2.0 equiv) in THF (20.0 mL) was added zz-BuLi (2.5 M, 6.7 mL, 2.0 equiv) at -30 °C, then the solution was stirred at -30 °C for 0.5 h. A solution of 4,4,5,5-tetramethyl-2-[(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methyl]-l,3,2-dioxaborolane (3.36 g, 12.5 mmol, 1.5 equiv) in THF (5.0 mL) was added to the TMP solution at -78 °C and stirred for 0.5 h. Then tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (2.0 g, 8.4 mmol, 1.0 equiv) in THF (5.0 mL) was added to the mixture at -78 °C and stirred for 2 h. The mixture was then stirred at 25 °C for 9 h. The reaction mixture was quenched with a saturated aqueous NH4CI (60 mL) solution at 0 °C dropwise. The resulting mixture was extracted with ethyl acetate (40 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (Si O2, petroleum ether / ethyl acetate=8 / l to 5 / 1). Tert-butyl 2-[(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methylene]-7-azaspiro[3.5]nonane-7- carboxylate (1.8 g, 5.0 mmol, 59% yield) was obtained as a yellow oil.

[0269] Step 2: Preparation of tert-butyl 2-[[3-fluoro-4-[(9S)-4,5,13-trimethyl-9-(oxazol- 2-ylmethyl)-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7- yl]phenyl]methylene]-7-azaspiro[3.5]nonane-7-carboxylate. A mixture of tert-butyl 2- [(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methylene]-7-azaspiro[3.5]nonane-7-carboxylate (370 mg, 1.0 mmol, 1.8 equiv), 2-[[(9S)-7-(4-chloro-2-fhioro-phenyl)-4,5,13-trimethyl-3-thia- 1,8,1 l,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (250 mg, 566 μmol, 1.0 equiv), Xphos Pd G4 (49 mg, 57 μmol, 0.1 equiv), and K3PO4 (360 mg, 1.7 mmol, 3.0 equiv) in THF (6.0 mL) and H2O (1.0 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 60 °C for 7 h under N2 atmosphere. To the reaction mixture was added water (30 mL) and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=O / l). Tert-butyl 2-[[3-fhioro-4-[(9S)-4,5,13-trimethyl-9-(oxazol-2- ylmethyl)-3 -thia- 1,8,1 l,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl] methylene]-7-azaspiro[3.5]nonane-7-carboxylate (360 mg, 560 μmol, 99% yield) was obtained as a yellow solid.

[0270] Step 3: Preparation of tert-butyl 2-(3-fluoro-4-(2,3,9-trimethyl-6-(oxazol-2- ylmethyl)-6H-thieno[3,2-f|[l,2,4]triazolo[4,3-a][l,4]diazepin-4-yl)benzyl)-7-azaspiro[3.5] nonane-7-carboxylate. Pd / C (500 mg, 470 μmol, 10% purity, 0.8 equiv) was added into a 100 mL single-necked round bottom flask under N2. CF3CH2OH (5.0 mL) was added at 25 °C under N2 atmosphere. After the addition, tert-butyl 2-[[3-fluoro-4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l ,8, 1 l,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl] methylene]-7-azaspiro[3.5]nonane-7-carboxylate (360 mg, 560 μmol, 1.0 equiv) was added under N2 atmosphere. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 atmosphere at 25 °C for 5 h. The reaction mixture was filtered and the filtrate was concentrated. Tert-butyl 2-(3-fluoro-4-(2,3,9-trimethyl-6-(oxazol-2- ylmethyl)-6H-thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepin-4-yl)benzyl)-7-azaspiro[3.5] nonane-7- carb oxy late (300 mg, 489 μmol, 83% yield, 99% purity) was obtained as a colorless oil and used in the next step without further purification.

[0271] Step 4: Preparation of tert-butyl 2-[[3-fluoro-4-[(9S)-4,5,13-trimethyl-9-(oxazol- 2-ylmethyl)-3-thia-l ,8,11 ,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,l 0,12-pentaen-7- yl] phenyl] methyl]-7-azaspiro [3.5]nonane-7-carboxylate. Tert-butyl 2-(3 -fluoro-4-(2,3 ,9- trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepin-4-yl)benzyl) -7-azaspiro[3.5]nonane-7-carboxylate (300 mg, 489 μmol, 83% yield, 99% purity) was separated by SFC (column: DAICEL CHIRALPAK AS (250mm*30mm,10um); mobile phase: [CO2- ACN / i-PrOH (0.1% NH3H2O)]; B%:50%, isocratic elution mode). Tert-butyl 2-[[3-fluoro-4- [(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,l 1,12-tetrazatri cyclo [8.3.0.02,6] trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]methyl]-7-azaspiro[3.5]nonane-7-carboxylate (236 mg, 361 μmol, 64% yield, 99% purity) was obtained as a colorless oil.

[0272] Step 5: Preparation of 2-[[(9S)-7-[4-(7-azaspiro[3.5]nonan-2-ylmethyl)-2-fluoro- phenyl]-4,5,13-trimethyl-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-9-yl]methyl]oxazole. To a solution of tert-butyl 2-[[3-fluoro-4-[(9S)-4,5,13-trimethyl- 9-(oxazol-2-ylmethyl)-3-thia-l,8,l 1,12-tetrazatri cyclo[8.3.0.02, 6]trideca-2(6), 4, 7, 10,12-pentaen- 7-yl]phenyl]methyl]-7-azaspiro[3.5]nonane-7-carboxylate (230 mg, 357 μmol, 1.0 equiv) in DCM (3.0 mL) was added TFA (1.5 mL). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The pH of the aqueous phase was adjusted to 8-9 by the addition of a saturated aqueous NaHCCh solution, and then diluted with DCM (20 mL), and extracted with DCM (20 mL x 2). The combined organic layers were washed with water, dried over anhydrous Na2SO4 , filtered and concentrated under reduced pressure to give a residue. 2-[[(9S)-7-[4-(7-azaspiro[3.5]nonan-2-ylmethyl)-2-fluoro-phenyl]- 4, 5, 13-trimethyl -3-thia-l, 8,11,12-tetrazatri cyclo[8.3.0.02, 6]trideca-2(6), 4, 7, 10,12-pentaen-9-yl]methyl]oxazole (200 mg, crude) was obtained as a yellow oil and used for the next step without further purification.

[0273] Step 6: Preparation of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[2-[[3- fluoro-4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,ll,12-tetrazatricyclo [8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]methyl]-7-azaspiro[3.5]nonan-7- yl]pyridazine-3-carboxamide (1-18). To a solution of2-[[(9S)-7-[4-(7-azaspiro[3.5]nonan-2- ylmethyl)-2-fluoro-phenyl]-4,5,13-trimethyl-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (50 mg, 92 μmol, 1.0 equiv) in NMP (1.0 mL) was added DIEA (24 mg, 184 μmol, 32 2.0 μ eLqu, iv) and 6-chloro-N-[4-(3-chloro-4-cyano- phenoxy)cyclohexyl]pyridazine-3-carboxamide (43 mg, 110 μmol, 1 .2 equiv). The mixture was stirred at 70 °C for 8 h. The residue mixture was filtered. The filtrate was purified by prep-HPLC (column: Phenom enex luna C 18 150*25mm* lOum; mobile phase: [water(FA)-ACN]; gradient: 65%-95% B over 10 min). N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[2-[[3-fluoro-4-[(9S)- 4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6), 4,7,10,12-pentaen-7-yl]phenyl]methyl]-7-azaspiro[3.5]nonan-7-yl]pyridazine-3-carboxamide (I- 18, 27.6 mg, 30 μmol, 33% yield, 99% purity) was obtained as a white solid.1H NMR: (400 MHz, CD3OD) δ = 7.93 - 7.83 (m, 2H), 7.72 - 7.66 (m, 1H), 7.30 - 7.23 (m, 2H), 7.22 - 7.18 (m, 1H), 7.17 - 7.09 (m, 1H), 7.08 - 7.01 (m, 2H), 6.96 - 6.90 (m, 1H), 4.81 - 4.75 (m, 1H), 4.51 (s, 1H), 4.06 - 3.90 (m, 3H), 3.75 - 3.68 (m, 2H), 3.68 - 3.61 (m, 2H), 2.81 - 2.76 (m, 2H), 2.73 - 2.68 (m, 3H), 2.65 - 2.55 (m, 1H), 2.45 - 2.39 (m, 3H), 2.26 - 2.14 (m, 2H), 2.14 - 2.06 (m, 2H), 2.05 - 1.98 (m, 2H), 1.77 - 1.69 (m, 2H), 1.68 - 1.54 (m, 11H). LC-MS: MS (ES+): RT = 2.621 min, m / z = 899.5 [M+H]+; LCMS method: 25.EXAMPLE 7 - Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-5-[3-[[l-[4-[(9S)-4,5,9,13-tetramethyl-3-thia-l,8,ll,12-tetrazatricyclo [8.3.0.02, 6] trideca-2(6), 4, 7,10, 12-pentaen-7-yl]phenyl]azetidin-3-yl]methyl]azetidin-l- yl]pyrazine-2-carboxamide (II-l)

[0274] Step 1: Preparation of tert-butyl 3-[[l-[4-[(9S)-4,5,9,13-tetramethyl-3-thia-l,8,ll, 12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]azetidin-3-yl] methyl]azetidine-l-carboxylate. A mixture of (9S)-7-(4-chlorophenyl)-4,5,9,13-tetramethyl-3- thia-l,8,l l,12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7,10,12-pentaene (600 mg, 1.7 mmol, 1 equiv), tert-butyl 3-(azetidin-3-ylmethyl)azetidine-l-carboxylate (570 mg, 2.5 mmol, 1.5 equiv), CS2CO3 (1.65 g, 5.0 mmol, 3.0 equiv), and SPhos Pd G3 (270 mg, 0.3 mmol, 0.2 equiv) in dioxane (10 mL) was stirred at 90 °C for 3 h under N2 atmosphere. The crude mixture was fdtered through a pad of celite. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate = 1 / 1 to 0 / 1 to CLLCh / MeOH = 20 / 1) to afford tert-butyl 3-[[l-[4- [(9S)-4,5,9,13-tetramethyl-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7,10, 12-pentaen-7-yl]phenyl]azetidin-3-yl]methyl]azetidine-l -carboxylate (400 mg, 0.73 mmol, 44% yield) as a yellow solid.

[0275] Step 2: Preparation of (9S)-7-[4-[3-(azetidin-3-ylmethyl)azetidin-l-yl]phenylJ-4.5.9.13-tetramethyl-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaene. To a solution of tert-butyl 3-[[l-[4-[(9S)-4,5,9,13-tetramethyl-3-thia-l,8,l 1,12- tetrazatri cyclo [8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]azetidin-3-yl]methyl] azetidine- 1 -carboxylate (50 mg, 92 μmol, 1 equiv) in CH2CI2 (1 mL) was added TFA (0.3 mL) at 20 °C. The mixture was stirred at 20 °C for 1 h. The mixture was concentrated in vacuo to afford (9S)-7-[4-[3-(azetidin-3-ylmethyl)azetidin-l-yl]phenyl]-4,5,9,13-tetramethyl-3-thia-1,8,1 l,12-tetrazatricyclo[8.3.0.02-6]trideca-2(6),4,7,10,12-pentaene (42 mg, crude, TFA salt) as a yellow oil.

[0276] Step 3: Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-5-[3-[[l-[4-[(9S)-4,5,9,13-tetramethyl-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6] trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]azetidin-3-yl]methyI]azetidin-l-yl]pyrazine-2- carboxamide (II-l). To a solution of (9S)-7-[4-[3-(azetidin-3-ylmethyl)azetidin-l-yl]phenyl]-4.5.9.13-tetramethyl-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7, 10, 12-pentaene (60 mg, 0.11 mmol, 1 equiv, TFA salt) in DMSO (2 mL) was added DIEA (69 mg, 0.54 mmol, 5 equiv} and 5-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclo butyl]pyrazine- 2-carboxamide (36 mg, 0.09 mmol, 0.8 equiv). The mixture was stirred at 80 °C for 2 h. To the reaction mixture was added EtOAc (10 mL) and water (20 mL) and the layers were separated.The aqueous phase was extracted with EtOAc (10 mL x 2). The combined extracts were washed with brine (20 mL), dried over Na2SO4, fdtered and concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [water(FA)-ACN]; gradient: 39%-69% B over 10 min ) to afford N-[3-(3- chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-5-[3-[[l-[4-[(9S)-4,5,9, 13- tetramethyl-3-thia- 1,8,1 l,12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl] phenyl]azetidin-3-yl]methyl]azetidin-l-yl]pyrazine-2-carboxamide (II-l, 16.49 mg, 19.27 μmol, 18% yield, 97% purity) as a yellow solid. 'H NMR (400 MHz, CD3OD) δ 8.61 (1H, s), 7.80 (1H, s), 7.72 (d, 1H, J= 8.8 Hz), 7.33-7.26 (m, 2H), 7.14 (d, 1H, J= 2.0 Hz), 7.06-6.92 (m, 1H), 6.42 (2H, d, J= 8.8 Hz), 4.38-4.28 (3H, m), 4.32-4.18 (m, 1H), 4.10-4.01 (3H, m), 3.96-3.85 (m, 2H), 3.72-3.55 (m, 2H), 2.98-2.76 (2H, m), 2.69 (3H, s), 2.44 (3H, s), 2.12-2.04 (2H, m), 1.96 (d, 3H,J= 6.8 Hz), 1.72 (3 H, s), 1.27 (6H, s), 1.20 (6H, s). LC-MS: MS (ES+): RT = 2.197 min, m / z = 829.5 [M + H+]; LCMS method: 25.EXAMPLE 8 - Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[2-[[3-fluoro-4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,ll,12- tetrazatricycIo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]methyl]-7-azaspiro [3.5]nonan-7-yl]pyrimidine-5-carboxamide (II-3)

[0277] Step 1: Preparation of 2-chloropyrimidine-5-carbonyl chloride. To a solution of2-chloropyrimidine-5-carboxylic acid (1.30 g, 8.20 mmol, 1.0 equiv) in DCM (30 mL) was added DMF (59.9 mg, 819 umol, 63.1 uL, 0.1 equiv) and (COC1)2 (3.12 g, 24.6 mmol, 2.15 mL,3.0 equiv). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give 2-chloropyrimidine-5-carbonyl chloride (1.02 g, 5.76 mmol, 70% yield) as a white solid.

[0278] Step 2: Preparation of tert-butyl N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4- tetramethyl-cyclobutyljcarbamate. To a solution of tert-butyl N-(3 -hydroxy-2, 2,4,4- tetramethyl-cyclobutyl)carbamate (840 mg, 3.45 mmol, 1.0 equiv) in DMF (15 mL) was added NaH (207 mg, 5.18 mmol, 60% purity, 1.5 equiv) at 0 °C . After addition, the mixture was stirred at 0 °C for 1.0 h, and then 2-chloro-4-fluoro-benzonitrile (537 mg, 3.45 mmol, 1.0 equiv) was added at 0 °C. The resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by addition of a saturated aqueous solution of NH4CI (20 mL) at 0 °C, and then diluted with ethyl acetate (20 mL). The aqueous phase was extracted with ethyl acetate (10 mL * 2). The residue was purified by flash silica gel chromatography (ISCO; 12 g SepaFlash Silica Flash column, eluent: 0-10% ethyl acetate / petroleum ether gradient) to afford tert-butyl N-[3-(3- chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]carbamate (1.19 g, 3.14 mmol, 91% yield) as a white solid.[00279J Step 3: Preparation of give 4-(3-amino-2,2,4,4-tetramethyl-cyclobutoxy)-2- chloro-benzonitrile. To a solution of tert-butyl N-[3-(3 -chi oro-4-cyano-phenoxy)-2, 2,4,4- tetramethyl-cyclobutyl]carbamate (1.19 g, 3.14 mmol, 1.0 equiv) in DCM (9.0 mL) was added TFA (3.79 g, 33.3 mmol, 2.5 mL, 10.6 equiv). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove solvent to give 4-(3-amino- 2,2,4,4-tetramethyl-cyclobutoxy)-2-chloro-benzonitrile (1.15 g, 2.9 mmol, 92% yield, 99% purity, TFA salt) as a white solid.

[0280] Step 4: Preparation of 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetra methyl-cyclobutyl]pyrimidine-5-carboxamide. To a mixture of 4-(3-amino-2, 2,4,4- tetramethyl-cyclobutoxy)-2-chloro-benzonitrile (1.40 g, 3.56 mmol, 1.0 equiv, TFA salt) in DCM (30 mL) was added TEA (1.80 g, 17.8 mmol, 2.48 mL, 5.0 equiv) dropwise into the mixture at 0 °C and stirred for 30 min. Then 2-chloropyrimidine-5-carbonyl chloride (756 mg, 4.28 mmol, 1.2 equiv) in DCM (30 mL) was added dropwise into the mixture at 0 °C and stirred for 10 min. Then the mixture was stirred at 0 °C for 20 min under N2 atmosphere. The reaction mixture was quenched by the addition of water (20 mL) at 0 °C, and then extracted with ethyl acetate (20 mLx 2). The combined organic layers were washed with water (10 mL), dried over Na2SO4, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=5 / l to 2 / 1) to give 2-chloro-N-[3-(3- chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]pyrimidine-5-carboxamide (1.16 g, 2.77 mmol, 77% yield) as a white solid.

[0281] Step 5: Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutylJ-2-[2-[[3-fluoro-4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,ll,12- tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]methyl]-7-azaspiro [3.5]nonan-7-yl]pyrimidine-5-carboxamide (II-3). To a solution of 2-[[(9S)-7-[4-(7-azaspiro

[0035] nonan-2-ylmethyl)-2-fluoro-phenyl]-4,5, 13 -tri methyl -3 -thi a- 1 ,8, 11,12 -tetrazatri cyclo [8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (50 mg, 92 μmol, 1.0 equiv) in NMP (1.0 mL) was added DIEA (24 mg, 184 μmol, 32 2.0 equiμv)L a,nd 2-chloro-N-[3-(3- chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]pyrimidine-5-carboxamide (46 mg, 110 μmol, 1.2 equiv). The mixture was stirred at 25 °C for 2 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by prep-TLC (SiO2, PE:EA =0: 1). N-[3-(3- chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[[3-fluoro-4-[(9S)-4,5,13-tri methyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7, 10,12- pentaen-7-yl]phenyl]methyl]-7-azaspiro[3.5]nonan-7-yl]pyrimidine-5-carboxamide (II-3, 48.6 mg, 52 μmol, 57% yield, 99% purity) was obtained as a white solid.(400 MHz, CD3OD) δ = 8.72 - 8.68 (m, 2H), 7.91 - 7.88 (m, 1H), 7.75 - 7.70 (m, 1H), 7.30 - 7.24 (m, 1H), 7.14 - 7.10 (m, 2H), 7.08 - 7.03 (m, 1H), 7.00 - 6.90 (m, 2H), 4.81 - 4.77 (m, 1H), 4.28 - 4.25 (m,1H), 4.14 - 4.10 (m, 1H), 4.06 - 3.91 (m, 2H), 3.88 - 3.82 (m, 2H), 3.81 - 3.76 (m, 2H), 3.49 -3.42 (m, 1H), 2.84 - 2.82 (m, 1H), 2.81 - 2.76 (m, 2H), 2.73 - 2.68 (m, 3H), 2.65 - 2.53 (m, 1H),2.45 - 2.40 (m, 3H), 2.39 - 2.33 (m, 1H), 2.03 - 1.96 (m, 2H), 1.69 - 1.63 (m, 5H), 1.62 - 1.52 (m,4H), 1.29 - 1.24 (m, 6H), 1.23 - 1.19 (m, 6H). LC-MS: MS (ES+): RT = 3.112 min, m / z = 927.6[M+H]+; LCMS method: 25.EXAMPLE 9 - Synthesis of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[6-[2-[2-fluoro- 4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6] trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]ethynyl]-2-azaspiro[3.31heptan-2-yl]pyridazine- 3-carboxamide (1-17)

[0282] Step 1: Preparation of 3-(4-chloro-3-fluoro-phenyl)-3-oxo-propanenitriIe. To a solution of acetonitrile (11.9 g, 291 mmol, 15.3 mL, 2.2 equiv) in THF (200 mL) was added a solution of w-BuLi (2.5 M, 106 mL, 2.0 equiv) dropwise at -78 °C under N2 and stirred at -78 °C for 1 h. Then methyl 4-chl oro-3 -fluoro-benzoate (25.0 g, 132 mmol, 1.0 equiv) in THF (100 mL) was added at -78 °C dropwise. The reaction mixture was warmed to 25° C and stirred at 25 °C for 11 h. The reaction mixture was quenched with a saturated aqueous NH4CI (50 mL) solution at 0 °C dropwise. The resulting mixture was extracted with ethyl acetate (200 mL x 3). The combined organic layers were dried over anhydrous ISfeSCL, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 1 / 1). Compound 3 -(4-chl oro-3 -fluoro-phenyl)-3-oxo-propanenitrile (15 g, 75 mmol, 57 % yield) was obtained as a white solid.

[0283] Step 2: Preparation of (2-amino-4,5-dimethyl-3-thienyl)-(4-chloro-3-fluoro- phenyl)methanone. To a solution of 3-(4-chloro-3-fluoro-phenyl)-3-oxo-propanenitrile (15 g, 75 mmol, 1.0 equiv), butan-2-one (5.47 g, 75.9 mmol, 6.79 mL, 1.0 equiv) in EtOH (200 mL) was added morpholine (6.61 g, 75.9 mmol, 6.68 mL, 1.0 equiv) and S (2.59 g, 80.7 mmol, 1.1 equiv). The mixture was stirred at 70 °C for 12 h. To the reaction mixture was added water (500mL) and the mixture was extracted with ethyl acetate (500 mL x 3). The combined organic phase was washed with brine (500 mL), dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 5 / 1). The crude was further purified by trituration (petroleum ether / ethyl acetate = 3 / 1, 300 mL). Compound (2-amino-4,5-dimethyl-3-thienyl)-(4-chloro-3-fluoro-phenyl) methanone (9.0 g, 31 mmol, 41 % yield) was obtained as a yellow solid.

[0284] Step 3: Preparation of tert-butyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)- 4-((3-(4-chloro-3-fluorobenzoyl)-4,5-dimethylthiophen-2-yl)amino)-4-oxobutanoate. To a solution of (2S)-4-tert-butoxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxo-butanoic acid (18.7 g, 45.4 mmol, 1.5 equiv) in EtOAc (86 mL) was added pyridine (9.59 g, 121 mmol, 9.79 mL, 4.0 equiv') and T4P (43.6 g, 60.6 mmol, 50% purity, 2.0 equiv) at 0 °C. The mixture was stirred at 25 °C for 1 h, then (2-amino-4,5-dimethyl-3-thienyl)-(4-chloro-3-fluoro-phenyl) methanone (8.6 g, 30 mmol, 1.0 equiv) was added at 0 °C, and then the reaction mixture was stirred at 25 °C for another 1 h. To the reaction mixture was added water (200 mL) and the mixture was extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1). Compound tert-butyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-((3-(4-chloro-3- fluorobenzoyl)-4,5-dimethylthiophen-2-yl)amino)-4-oxobutanoate (20 g, 29 mmol, 97 % yield) was obtained as a white solid.

[0285] Step 4: Preparation of tert-butyl 3-amino-4-((3-(4-chloro-3-fluorobenzoyl)-4,5- dimethylthiophen-2-yl)amino)-4-oxobutanoate. To a solution of tert-butyl 3-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-4-((3-(4-chloro-3-fluorobenzoyl)-4,5-dimethylthiophen-2-yl) amino)-4-oxobutanoate (20 g, 29 mmol, 1.0 equiv) in DCM (100 mL) was added piperidine (12.5 g, 147 mmol, 14.5 mL, 5.0 equiv). The mixture was stirred at 25 °C for 2 h. To the reaction mixture was added water (200 mL) and the mixture was extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1). Compound tert-butyl 3-amino-4-((3-(4-chloro-3- fluorobenzoyl)-4, 5-dimethylthi ophen-2 -yl)amino)-4-oxobutanoate (13 g, 28 mmol, 96 % yield) was obtained as a white solid.

[0286] Step 5: Preparation of tert-butyl 2-(5-(4-chloro-3-fluorophenyl)-6,7-dimethyl-2- oxo-2, 3-dihydro-lH-thieno[2,3-e][l,4]diazepin-3-yl)acetate. To a solution of tert-butyl 3- amino-4-((3-(4-chloro-3-fluorobenzoyl)-4,5-dimethylthiophen-2-yl)amino)-4-oxobutanoate (13 g, 28 mmol, 1.0 equiv) in EtOH (130 mL) was added AcOH (8.58 g, 142 mmol, 8.18 mL, 5.0 equiv). The mixture was stirred at 25 °C for 2 h. To the reaction mixture was added a saturated solution of aqueous NaHCCL (200 mL) and the mixture was extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1). Compound tert-butyl 2-(5-(4-chloro-3- fluorophenyl)-6,7-dimethyl-2-oxo-2,3-dihydro-lH-thieno[2,3-e][l,4]diazepin-3-yl)acetate (11 g, 25 mmol, 88% yield) was obtained as a yellow solid.

[0287] Step 6: Preparation of tert-butyl 2-(4-(4-chloro-3-fluorophenyl)-2,3,9-trimethyl- 6H-thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetate. Potassium terLbutoxide (1 M, 7.55 mL, 1.1 equiv) was added to a solution tert-butyl 2-(5-(4-chloro-3-fluoro phenyl)-6,7- dimethyl-2-oxo-2,3-dihydro-lH-thieno[2,3-e][l,4]diazepin-3-yl)acetate (3.0 g, 6.8 mmol, 1.0 equiv) in THF (30 mL) at -78 °C. The reaction mixture was warmed to 25 °C, and stirred at 25 °C for 30 min. The reaction mixture was cooled to -78 °C. [chloro(phenoxy) phosphoryl] oxybenzene (2.21 g, 8.24 mmol, 1.71 mL, 1.2 equiv) was added to reaction mixture. The resulting mixture was warmed to 25 °C over 30 min. Then acetohydrazide (762 mg, 10.3 mmol, 1.5 equiv) was added to the reaction mixture. The reaction mixture was stirred at 25 °C, «-BuOH (30 mL) was added to the reaction mixture and it was heated to 90 °C for 1 h. To the reaction mixture was added water (200 mL) and the mixture was extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1). Compound tert-butyl 2-(4-(4-chloro-3- fhiorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetate (2.0 g, 4.2 mmol, 61 % yield) was obtained as a yellow solid.

[0288] Step 7: Preparation of 2-(4-(4-chloro-3-fluorophenyl)-2,3,9-trimethyl-6H- thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetic acid. To a solution of tert-butyl 2- (4-(4-chloro-3-fhiorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepin- 6-yl)acetate (2.0 g, 4.2 mmol, 1.0 equiv) in DCM (20 mL) was added TFA (15.3 g, 134 mmol, 10mL, 31 .9 equiv). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated in vacuo to give the crude product. Compound 2-(4-(4-chl oro-3 -fluorophenyl)- 2,3,9-trimethyl-6H-thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetic acid (2.2 g, crude, TFA salt) was obtained as a brown solid.

[0289] Step 8: Preparation of 2-(4-(4-chloro-3-fluorophenyl)-2,3,9-trimethyl-6H- thieno [3,2-f] [ 1 ,2,4 ] t riazolo [4,3-a] [1,4] diazepin-6-yl)-N-(2,2-dimethoxyethyl)acetamide. To a solution of 2-(4-(4-chloro-3-fluorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][l,2,4]triazolo[4,3- a][l,4]diazepin-6-yl)acetic acid (2.2 g, 4.1 mmol, 1.0 equiv, TFA salt), 2,2-dimethoxy ethanamine (520 mg, 4.95 mmol, 539 1.2 equμiLv,) in DCM (20 mL) was added DIEA (2.67 g, 20.6 mmol, 3.60 mL, 5.0 equiv and HATU (2.35 g, 6.19 mmol, 1.5 equiv). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuo to give the crude product. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1). Compound 2-(4-(4-chloro-3-fluorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][l ,2,4] triazolo[4,3-a][l,4]diazepin-6-yl)-N-(2,2-dimethoxyethyl)acetamide (2.0 g, 3.9 mmol, 95 % yield) was obtained as a yellow solid.

[0290] Step 9: Preparation of 2-((4-(4-chloro-3-fluorophenyl)-2,3,9-trimethyl-6H- thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)methyl)oxazole. A mixture of 2-(4-(4- chloro-3-fhjorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f [l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)- N-(2,2-dimethoxyethyl)acetamide (2.0 g, 3.9 mmol, 1.0 equiv) in Eaton’s reagent (20 mL) was stirred at 100 °C for 12 h. The reaction mixture was added to ice / saturated aqueous NaHCCE (200 mL) dropwise and the mixture was extracted with DCM (100 mL x 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiCE, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1). Compound 2-((4-(4-chloro-3-fluorophenyl)-2,3,9-trimethyl- 6H-thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)methyl)oxazole (0.5 g, 1.1 mmol, 28 % yield) was obtained as a yellow solid.

[0291] Step 10: Preparation of tert-butyl 6-((2-fluoro-4-(2,3,9-trimethyl-6-(oxazol-2- ylmethyl)-6H-thieno[3, 2-1] [1,2, 4]triazolo [4,3-a] [1, 4]diazepin-4-yl)phenyl)ethynyl)-2- azaspiro[3.3]heptane-2-carboxylate. A mixture of 2-((4-(4-chloro-3-fluorophenyl)-2,3,9- trimethyl-6H-thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)methyl)oxazole (400 mg, 905μmol, 1.0 equiv), tert-butyl 6-ethynyl-2-azaspiro[3.3]heptane-2-carboxylate (500 mg, 2.26 mmol, 2.5 equiv), [2-(2-aminophenyl)phenyl]-methylsulfbnyloxy-palladium;2-(2-di cyclohexyl- phosphanylphenyl)-N,N-dimethyl-aniline (69.0 mg, 90.5 μmol, 0.1 equiv), CS2CO3 (589 mg, 1.81 mmol, 2.0 equiv) in MeCN (16 mb) was degassed and purged with N2 3 times, and then the mixture was stirred at 90 °C for 2 h under N2 atmosphere. The reaction mixture was concentrated in vacuo to give the crude product. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1). Compound tert-butyl 6-((2-fluoro-4-(2,3,9- trimethyl-6-(oxazol-2-ylmethyl)-6H-thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4] diazepin-4- yl)phenyl)ethynyl)-2-azaspiro [3.3]heptane-2-carboxylate (500 mg, 797 μmol, 88 % yield) was obtained as a white solid.

[0292] Step 11: Preparation of 2-((4-(4-((2-azaspiro[3.3]heptan-6-yl)ethynyl)-3- fluorophenyl)-2,3,9-trimethyl-6H-thieno [3,2-f] [1 ,2,4] triazolo [4,3-a] [1 ,4] diazepin-6-yl) methyl)oxazole. To a solution of tert-butyl 6-((2-fluoro-4-(2,3,9-trimethyl-6-(oxazol-2-yl methyl)-6H-thieno[3 ,2-f] [1 ,2,4]triazolo[4,3 -a] [ 1 ,4]diazepin-4-yl)phenyl)ethynyl)-2-aza spiro[3.3]heptane-2-carboxylate (500 mg, 797 μmol, 1.0 equiv) in DCM (5 mL) was added TFA (3.07 g, 26.9 mmol, 2 mL, 33.7 equiv). The mixture was stirred at 25 °C for 2 h. To the reaction mixture was added water (20 mL) and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4 , filtered and concentrated in vacuo, The crude product was purified by preparative HPLC (column: Phenom enex luna C18 150*25mm* 10um;mobile phase: [water(FA)- ACN];gradient:12%-42% B over 10 min as additive) to yield. The product was purified by SFC (column: DAICEL CHIRALPAK AS(250mm*30mm,10um);mobile phase: [CO2- ACN / EtOH(0.1% NH3H2O)];B%:50%, isocratic elution mode as additive) to yield. The crude product was purified by preparative HPLC (column: REGIS(S,S)WHELK-O1 (250mm*25mm, 10um);mobile phase: [CO2-ACN / EtOH(0.1% NH3H2O)];B%:55%, isocratic elution mode as additive). Compound 2-((4-(4-((2-azaspiro[3.3]heptan-6-yl)ethynyl)-3-fluorophenyl)-2,3,9- trimethyl-6H-thieno[3,2-f][l,2,4] triazolo[4,3-a][l,4]diazepin-6-yl)methyl)oxazole (80 mg, 0.15 mmol, 40 % yield) was obtained as a white solid.

[0293] Step 12: Preparation of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[6-[2-[2- fluoro-4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,ll,12-tetrazatricyclo [8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]heptan-2-yl]pyridazine-3-carboxamide (T-17). To a solution of 2-((4-(4-((2-azaspiro[3.3]heptan-6- yl)ethynyl)-3-fluorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepin- 6-yl)methyl)oxazole (40 mg, 75 μmol, 1.0 equiv) in NMP (0.5 mL) was added DIEA (29 mg, 0.22 mmol, 39 μ 3L.0, equiv) and 6-chloro-N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl] pyridazine-3 -carboxamide (29 mg, 75 μmol, 1.0 equiv). The mixture was stirred at 60 °C for 12 h. To the reaction mixture was added water (10 mL) and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (column: Waters xbridge 150*25mm lOum; mobile phase: [water (NH4HCO3) -ACN]; gradient: 59%-79% B over 8 min) to yield N-[4-(3-chloro-4-cyano-phenoxy)cyclo hexyl]-6-[6-[2-[2-fluoro-4-[(9S)-4, 5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia- 1,8,11,12-tetraza tricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]ethynyl]-2-azaspiro[3.3]heptan-2- yl]pyridazine-3 -carboxamide (1-17, 12 mg, 14 μmol, 18 % yield, 98 % purity) as a white solid. 'HNMR (400 MHz, methanol-d4) δ 7.94 - 7.86 (m, 2H), 7.69 (d, J= 8.8 Hz, 1H), 7.42 (t, J= 7.6 Hz, 1H), 7.22 - 7.12 (m, 4H), 7.07 - 7.02 (m, 1H), 6.84 (d, J= 9.6 Hz, 1H), 4.82 - 4.76 (m, 2H), 4.24 (d, J= 4.8 Hz, 4H), 4.08 - 3.91 (m, 3H), 3.30 - 3.26 (m, 1H), 2.80 - 2.68 (m, 5H), 2.53 - 2.44 (m, 5H), 2.25 - 2.16 (m, 2H), 2.14 - 2.05 (m, 2H), 1.73 (s, 3H), 1.70 - 1.58 (m, 4H). LC- MS: MS (ES+): RT = 2.354 min, m / z = 881.4 [M + H+]; LCMS Method: 25.EXAMPLE 10 - Synthesis of N-[4-(3-chloro-4-cyano-phenoxy)cycIohexyl]-6-[2-[3-fluoro-4- [(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6] trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonan-7-yl]pyridazine-3- carboxamide (1-20)

[0294] Step 1 : Preparation of 3-(4-chloro-2-fluoro-phenyl)-3-oxo-propanenitrile. A solution of acetonitrile (9.3 g, 225.3 mmol, 11.9 mL, 1.7 equiv) in THF (200 mL) was stirred at - 78°C under N2 protection. Then n-BuLi (2.5 M, 106.0 mL, 2.0 equiv) was added to the mixture and stirred for 0.5 h. Then the methyl 4-chloro-2-fluoro-benzoate (25.0 g, 132.5 mmol, 1.0 equiv) in THF (20 mL) was added dropwise and the mixture was stirred for 1.5 h under N2 protection. The reaction mixture was quenched with a saturated aqueous NH4CI (200 ml) solution at 0 °C. And the resulting mixture was extracted with ethyl acetate (100 mL x 4). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was triturated with petroleum ether / ethyl acetate = 20 / 1 at 25 °C for 30 min to give 3-(4-chloro-2-fluoro-phenyl)-3-oxo-propanenitrile (23.0 g, 116.4 mmol, 87.80% yield) as a yellow solid.

[0295] Step 2: Preparation of (2-amino-4,5-dimethyl-3-thienyl)-(4-chloro-2-fluoro- phenyl)methanone. To a solution of 3-(4-chloro-2-fluoro-phenyl)-3-oxo-propanenitrile (23.0 g, 116.4 mmol, 1.0 equiv) and butan-2-one (8.4 g, 116.4 mmol, 10.4 mL, 1.0 equiv) in EtOH (200 mL) was added TEA (23.6 g, 232.8 mmol, 32.4 mL, 2.0 equiv) and S (4.4 g, 138.5 mmol, 1.2 equiv). The mixture was stirred at 50 °C for 12 h. To the reaction mixture was added water (500 mL) and the mixture was extracted with ethyl acetate (500 mL x 3). The combined organic phase was washed with brine (500 mL), dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethylacetate=35 / l to 30 / 1) to give (2-amino-4,5-dirnethyl-3-thienyl)-(4-chloro-2-fluoro-phenyl) methanone (10.0 g, 35.2 mmol, 30% yield) as a yellow oil.

[0296] Step 3: Preparation of tert-butyl (3S)-4-[[3-(4-chloro-2-fluoro-benzoyl)-4,5- dimethyl-2-thienyl]amino]-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxo-butanoate. To a solution of (2-amino-4,5-dimethyl-3-thienyl)-(4-chloro-2-fluoro-phenyl)methanone (8.8 g, 31.0 mmol, 1.0 equiv) and (2S)-4-tert-butoxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxo- butanoic acid (19.1 g, 46.5 mmol, 1.5 equiv) in EtOAc (40 mL) was added pyridine (9.8 g, 124.0 mmol, 10.0 mL, 4.0 equiv) and T4P (44.7 g, 62.0 mmol, 50% purity, 2.0 equiv). The mixture was stirred at 25 °C for 12 h. To the reaction mixture was added water (300 mL) and the mixture was extracted with ethyl acetate (80 mL x 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous ISfeSCL, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=8 / l to 6 / 1) to give the tert-butyl (3S)-4-[[3-(4-chloro-2-fluoro-benzoyl)-4,5-dimethyl-2-thienyl]amino]-3-(9H-fluoren- 9-ylmethoxycarbonylamino)-4-oxo-butanoate (15.5 g, 22.9 mmol, 73% yield) as a yellow oil.

[0297] Step 4: Preparation of tert-butyl (3S)-3-amino-4-[[3-(4-chloro-2-fluoro-benzoyl)- 4,5-dimethyl-2-thienyl]amino]-4-oxo-butanoate. To a solution of tert-butyl (3S)-4-[[3-(4- chloro-2-fluoro-benzoyl)-4,5-dimethyl-2-thienyl]amino]-3-(9H-fluoren-9-ylmethoxy-carbonyl amino)-4-oxo-butanoate (14.0 g, 20.7 mmol, 1.0 equiv) in DCM (280 mL) was added piperidine (5.3 g, 62.0 mmol, 6.1 mL, 3.0 equiv). The mixture was stirred at 25 °C for 2 h. To the reaction mixture was added water (300 mL) and the mixture was extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with brine (350 mL), dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=10 / l to 8 / 1) to give the compound tert-butyl (3S)-3-amino-4-[[3- (4-chloro-2-fluoro-benzoyl)-4,5-dimethyl-2-thienyl]amino]-4-oxo-butanoate (9.4 g, 20.7 mmol, 99 % yield) as a yellow oil.

[0298] Step 5: Preparation of tert-butyl 2-[(3S)-5-(4-chloro-2-fluoro-phenyl)-6,7- dimethyl-2-oxo-l,3-dihydrothieno[2,3-e][l,4]diazepin-3-yl]acetate. To a solution of tert-butyl (3 S)-3-amino-4-[[3-(4-chloro-2-fluoro-benzoyl)-4,5-dimethyl-2-thienyl]amino]-4-oxo-butanoate (9.4 g, 20.6 mmol, 1.0 equiv) in EtOH (90 mL) was added AcOH (31.5 g, 524.0 mmol, 30.0 mL, 25.4 equiv'). The mixture was stirred at 90 °C for 3 h. To the reaction mixture was added water(100 mL) and the mixture was extracted with ethyl acetate (150 mL x 3). The combined organic phase was washed with brine (150 mL), dried over anhydrous Na2SO4, fdtered and concentrated in vacuo. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=8 / l to 6 / 1) to give the tert-butyl 2-[(3S)-5-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2- oxo-1, 3-dihydrothieno[2,3-e][l,4]diazepin-3-yl]acetate (8.9 g, 20.4 mmol, 98% yield) as a yellow oil.

[0299] Step 6: Preparation of tert-butyl 2-[(9S)-7-(4-chloro-2-fluoro-phenyl)-4,5,13- trimethyl-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9- yljacetate. t-BuOK (1.0 M, 22.4 mL, 1.1 equiv) was added to tert-butyl 2-[(3S)-5-(4-chloro-2- fluoro-phenyl)-6,7-dimethyl-2-oxo-l,3-dihydrothieno[2,3-e][l,4]diazepin-3-yl]acetate (8.9 g, 20.4 mmol, 1.0 equiv) in THF (90 mL) at -78 °C, and stirred at 25 °C for 30 min. The reaction mixture was cooled to -78 °C. [chloro(phenoxy)phosphoryl]oxybenzene (6.6 g, 24.4 mmol, 5.1 mL, 1.2 equiv) was added to reaction mixture. The resulting mixture was warmed to 25 °C over 45 min. Then acetohydrazide (2.3 g, 30.6 mmol, 1.5 equiv) was added to the reaction mixture. The reaction mixture was stirred at 25 °C, n-BuOH (90 mL) was then added to the reaction mixture and it was heated to 90 °C for 1 h. The reaction mixture was quenched with a saturated aqueous NH4CI (100 ml) solution at 0 °C dropwise. And the resulting mixture was extracted with ethyl acetate (100 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, fdtered and concentrated in vacuum. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate=8 / l to 6 / 1) to give the tert-butyl 2-[(9S)-7-(4-chloro-2-fluoro- phenyl)-4,5,13-trimethyl-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-9-yl]acetate (8.9 g, 18.74 mmol, 91% yield) as a yellow oil.

[0300] Step 7: Preparation of 2-[(9S)-7-(4-chloro-2-fluoro-phenyl)-4,5,13-trimethyI-3- thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid. To a solution of tert-butyl 2-[(9S)-7-(4-chloro-2-fluoro-phenyl)-4,5,13-trimethyl-3-thia-l, 8,11,12- tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate (8.9 g, 18.7 mmol, 1.0 equiv) in DCM (40 mL) was added TFA (20.0 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was used for next step directly. Compound 2-[(9S)-7-(4-chloro-2-fluoro-phenyl)-4,5,13- trimethyl-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (7.8 g, 18.6 mmol) was obtained as a yellow oil.

[0301] Step 8: Preparation of 2-[(9S)-7-(4-chloro-2-fluoro-phenyl)-4,5,13-trimethyl-3- thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-(2,2- dimethoxyethyl)acetamide. To a solution of 2-[(9S)-7-(4-chloro-2-fluoro-phenyl)-4,5,13- trimethyl-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid (7.8 g, 18.6 mmol, 1.0 equiv) and 2,2-dimethoxyethanamine (5.8 g, 55.8 mmol, 6.09 mL, 3.0 equiv) in DMF (70 mL) was added HATU (7.8 g, 20.5 mmol, 1.1 equiv) and DIEA (7.2 g, 55.8 mmol, 9.73 mL, 3.0 equiv). The mixture was stirred at 25 °C for 0.5 h. To the reaction mixture was added water (20 mL) and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous NazSCL, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, DCM / MeOH=40 / l to 20 / 1) to give 2-[(9S)-7-(4-chloro-2-fluoro-phenyl)-4,5,13-trimethyl-3-thia- 1,8,1 l,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-(2,2-dimethoxyethyl) acetamide (6.3 g, 12.5 mmol, 66% yield) as a yellow oil.

[0302] Step 9: Preparation of 2-[[(9S)-7-(4-chloro-2-fluoro-phenyl)-4,5,13-trimethyl-3- thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole. A solution of 2-[(9S)-7-(4-chloro-2-fluoro-phenyl)-4,5,13-trimethyl-3-thia-l,8,l 1,12-tetraza tricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-(2,2-dimethoxyethyl)acetamide (2.0 g, 3.9 mmol, 1.0 equiv) in Eaton’s reagent (20 mL) was stirred at 100 °C for 12 h. The reaction mixture was quenched with a saturated aqueous NaHCO3 (200 ml) solution at 0 °C dropwise. The resulting mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous Na?SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO2, DCM: MeOH =30 / 1 to 20 / 1). The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250*70mm, 10 um); mobile phase: [water(FA)-ACN]; gradient:40%-70% B over 20 min) to give 2-[[(9S)-7-(4-chloro-2-fluoro- phenyl)-4, 5,13-trimethyl-3-thia- 1,8,1 l,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-9-yl]methyl]oxazole (3.0 g, 6.79 mmol, 57% yield) as a white solid.

[0303] Step 10: Preparation of 2-[[(9S)-7-[2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxa borolan-2-yl)phenyl]-4,5,13-trimethyl-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6] trideca- 2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole. A mixture of 2-[[(9S)-7-(4-chloro-2-fluoro- phenyl)-4, 5,13-trimethyl-3-thia- 1,8,1 l,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4, 7,10,12- pentaen-9-yl]methyl]oxazole (550 mg, 1.2 mmol, 1.0 equiv), BPD (1.0 g, 3.9 mmol, 3.1 equiv),dichloropalladium;tricyclohexylphosphane (184 mg, 249 μmol, 0.2 equiv) and KOAc (269 mg, 2.7 mmol, 2.2 equiv) in THF (5 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 70 °C for 12 h under N2 atmosphere. The reaction mixture was partitioned between H2O (50 mL) and ethyl acetate (50 mL x 3). The organic phase was separated, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the 2-[[(9S)-7-[2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) phenyl]-4, 5,13-trimethyl-3-thia- 1,8,1 l,12-tetrazatricyclo[8.3.0.02,6] trideca-2(6),4,7,10,12- pentaen-9-yl]methyl]oxazole (660 mg, 1.2 mmol, 99% yield) as a yellow oil.

[0304] Step 11: Preparation of 3-fluoro-4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3- thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenol. A mixture of 2-[[(9S)-7-[2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-4,5,13- trimethyl -3-thia-l, 8,11,12-tetrazatri cyclo[8.3.0.02, 6]trideca-2(6), 4, 7,10, 12-pentaen-9-yl]methyl] oxazole (360 mg, 674 μmol, 1.0 equiv), sodium;3-oxidodioxaborirane;tetrahydrate (200 mg, 1.3 mmol, 1.9 equiv) in THF (3 mL) and H2O (1 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 25 °C for 12 h under N2 atmosphere. The reaction mixture was partitioned between water (20 mL) and ethyl acetate (20 mL x 3). The organic phase was separated, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [water(FA)-ACN]; gradient:22%-52% B over 10 min) to give 3-fluoro-4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-yl methyl)-3-thia- 1,8, 11,12-tetrazatri cyclo[8.3.0.02, 6]trideca-2(6), 4, 7, 10,12-pentaen-7-yl]phenol (150 mg, 354 μmol, 52% yield) as a yellow oil.

[0305] Step 12: Preparation of tert-butyl 2-[3-fluoro-4-[(9S)-4,5,13-trimethyl-9-(oxazol- 2-ylmethyl)-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7- yl]phenoxy]-7-azaspiro[3.5]nonane-7-carboxylate. To a solution of Pl’ln (0.35 M, 2.0 mL, 2.1 equiv) in THF (2.0 mL) under N2 protection was added DIAD (143 mg, 708 μmol, 2 equiv) at 0 °C. After addition, the mixture was stirred at this temperature for 0.5 h. Then tert-butyl 2- hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (170 mg, 708 μmol, 2.0 equiv) and 3-fluoro-4- [(9S)-4, 5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia- 1,8,11, 12-tetrazatricyclo[8.3.0.02, 6]trideca- 2(6),4,7,10,12-pentaen-7-yl]phenol (1 M, 354 1.0 equiμvL), in THF (2 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 50 °C for 11.5 h. The reaction mixture concentratedunder reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenom enex Luna C 18 150*25mm*10um; mobile phase: [water(TFA)-ACN]; gradient:53%- 83% B over 10 min) to give the tert-butyl 2-[3-fluoro-4-[(9S)-4,5,13-trimethyl-9-(oxazol-2- ylmethyl)-3 -thia- 1,8,1 l,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl] phenoxy]-7-azaspiro[3.5]nonane-7-carboxylate (110 mg, 170 μmol, 48% yield) as a white solid.

[0306] Step 13: Preparation of 2-[[(9S)-7-[4-(7-azaspiro[3.5]nonan-2-yloxy)-2-fluoro- phenyl]-4,5,13-trimethyl-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12- pentaen-9-yl]methyl]oxazole. To a solution of tert-butyl 2-[3-fluoro-4-[(9S)-4,5,13-trimethyl- 9-(oxazol-2-ylmethyl)-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen- 7-yl]phenoxy]-7-azaspiro[3.5]nonane-7-carboxylate (110 mg, 170 μmol, 1.0 equiv) in DCM (3 mb) was added TFA (1.0 mb). The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give the 2-[[(9S)-7-[4-(7-azaspiro[3.5]nonan-2- yloxy)-2-fluoro-phenyl]-4,5,13-trimethyl-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (100 mg, crude) as a yellow oil.

[0307] Step 14: Preparation of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[2-[3- fluoro-4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,ll,12-tetrazatricyclo [8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenoxy]-7-azaspiro[3.5]nonan-7-yl ]pyridazine-3-carboxamide (1-20). To a solution of 2-[[(9S)-7-[4-(7-azaspiro[3.5]nonan-2- yloxy)-2-fluoro-phenyl]-4,5,13-trimethyl-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (50 mg, 91 μmol, 1.0 equiv) in NMP (2.0 mL) was added DIEA (23 mg, 182 μmol, 2.0 equiv) and 6-chloro-N-[4-(3-chloro-4-cyano-phenoxy) cyclohexyl]pyridazine-3-carboxamide (40 mg, 102 μmol, 1.1 equiv). The mixture was stirred at 70 °C for 12 h. The reaction mixture was fdtered and the filtrate was concentrated. The crude product was purified by reversed-phase HPLC (column: Phenomenex luna C18 150*25mm* lOum; mobile phase: [water(FA)-ACN]; gradient: 58%-88% B over 10 min) to give N-[4-(3- chloro-4-cyano-phenoxy)cyclohexyl]-6-[2-[3-fluoro-4-[(9S)-4,5,13-trimethyl-9-(oxazol-2- ylmethyl)-3 -thia- 1,8,1 l,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl] phenoxy]-7-azaspiro[3.5]nonan-7-yl]pyridazine-3-carboxamide (1-20, 22 mg, 24 μmol, 26% yield, 99% purity) as a white solid. 'H NMR: (400 MHz, methanol-rL) δ = 7.94 - 7.88 (m, 2H), 7.71 (d, J= 8.8 Hz, 1H), 7.35 - 7.28 (m, 2H), 7.22 (d, J= 2.4 Hz, 1H), 7.15 (s, 1H), 7.10 - 7.03 (m, 1H), 6.78 - 6.70 (m, 1H), 6.64 - 6.55 (m, 1H), 4.81 - 4.75 (m, 2H), 4.55 - 4.48 (m, 1H), 4.04 -3.94 (tn, 3H), 3.82 - 3.70 (m, 4H), 2.71 (s, 3H), 2.60 - 2.51 (tn, 2H), 2.45 (s, 3H), 2.22 (s, 2H), 2.12 (d, J= 4.0 Hz, 2H), 2.05 - 1.95 (m, 2H), 1.83 - 1.61 (m, 12H). LC-MS: MS (ES+): RT = 2.513 min, m / z = 901.6 [M +H+],EXAMPLE 11 - Synthesis of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[8-[2-fluoro-4- [4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca- 2(6),4,7,10,12-pentaen-7-yl]phenyl]-2,8-diazaspiro[4.5]decan-2-yl]pyridazine-3- carboxamide (1-26)

[0308] Step 1: Preparation of 3-(4-chloro-3-fluoro-phenyl)-3-oxo-propanenitrile. To a solution of acetonitrile (11.9 g, 291 mmol, 15.3 mL, 2.2 equiv) in THF (200 mL) was added a solution of w-BuLi (2.5 M, 106 mL, 2.0 equiv) dropwise at -78 °C under N2 and stirred at -78 °C for 1 h. Then methyl 4-chl oro-3 -fluoro-benzoate (25.0 g, 132 mmol, 1.0 equiv) in THF (100 mL) was added at -78 °C dropwise. The reaction mixture was warmed to 25° C and stirred at 25 °C for 11 h. The reaction mixture was quenched with a saturated aqueous NH4CI (50 mL) solution at 0 °C dropwise. The resulting mixture was extracted with ethyl acetate (200 mL x 3). The combined organic layers were dried over anhydrous ISfeSCL, fdtered and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 1 / 1). Compound 3-(4-chloro-3-fluoro-phenyl)-3-oxo-propanenitrile (15 g, 75 mmol, 57 % yield) was obtained as a white solid.

[0309] Step 2: Preparation of (2-amino-4,5-dimethyl-3-thienyl)-(4-chloro-3-fluoro- phenyl)methanone. To a solution of 3-(4-chloro-3-fluoro-phenyl)-3-oxo-propanenitrile (15 g, 75 mmol, 1.0 equiv) and butan-2-one (5.47 g, 75.9 mmol, 6.79 mL, 1.0 equiv) in EtOH (200 mL) was added morpholine (6.61 g, 75.9 mmol, 6.68 mL, 1.0 equiv) and S (2.59 g, 80.7 mmol, 1.1 equiv). The mixture was stirred at 70 °C for 12 h. To the reaction mixture was added water (500 mL) and the mixture was extracted with ethyl acetate (500 mL x 3). The combined organic phase was washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 5 / 1). The crude was further purified by trituration (petroleum ether / ethyl acetate = 3 / 1, 300 mL). Compound (2-amino-4,5-dimethyl-3-thienyl)-(4-chloro-3-fluoro-phenyl) methanone (9.0 g, 31 mmol, 41 % yield) was obtained as a yellow solid.

[0310] Step 3: Preparation of tert-butyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)- 4-((3-(4-chloro-3-fluorobenzoyl)-4,5-dimethylthiophen-2-yl)amino)-4-oxobutanoate. To a solution of (2S)-4-tert-butoxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxo-butanoic acid (18.7 g, 45.4 mmol, 1.5 equiv) in EtOAc (86 mL) was added pyridine (9.59 g, 121 mmol, 9.79 mL, 4.0 equiv) and T4P (43.6 g, 60.6 mmol, 50% purity, 2.0 equiv) at 0 °C. The mixture was stirred at 25 °C for 1 h, then (2-amino-4,5-dimethyl-3-thienyl)-(4-chloro-3-fluoro-phenyl) methanone (8.6 g, 30 mmol, 1.0 equiv) was added at 0 °C. The reaction mixture was then stirred at 25 °C for another 1 h. To the reaction mixture was added water (200 mL) and the mixture was extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1).Compound tert-butyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-((3-(4-chloro-3- fluorobenzoyl)-4,5-dimethyl thiophen-2-yl)amino)-4-oxobutanoate (20 g, 29 mmol, 97 % yield) was obtained as a white solid.

[0311] Step 4: Preparation of tert-butyl 3-amino-4-((3-(4-chloro-3-fluorobenzoyl)-4,5- dimethylthiophen-2-yl)amino)-4-oxobutanoate. To a solution of tert-butyl 3-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-4-((3-(4-chloro-3-fluorobenzoyl)-4,5-dimethylthiophen-2-yl) amino)-4-oxobutanoate (20 g, 29 mmol, 1.0 equiv) in DCM (100 mL) was added piperidine (12.5 g, 147 mmol, 14.5 mL, 5.0 equiv). The mixture was stirred at 25 °C for 2 h. To the reaction mixture was added water (200 mL) and the mixture was extracted with ethyl acetate (200 mL x3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4 , fdtered and concentrated in vacuo. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1). Compound tert-butyl 3-amino-4-((3-(4-chloro-3- fluorobenzoyl)-4,5-dimethylthiophen-2-yl)amino)-4-oxobutanoate (13 g, 28 mmol, 96 % yield) was obtained as a white solid.

[0312] Step 5: Preparation of tert-butyl 2-(5-(4-chloro-3-fluorophenyl)-6,7-dimethyl-2- oxo-2, 3-dihydro-lH-thieno[2,3-e][l,4]diazepin-3-yl)acetate. To a solution of tert-butyl 3- amino-4-((3-(4-chloro-3-fluorobenzoyl)-4,5-dimethylthiophen-2-yl)amino)-4-oxobutanoate (13 g, 28 mmol, 1.0 equiv) in EtOH (130 mL) was added AcOH (8.58 g, 142 mmol, 8.18 mL, 5.0 equiv). The mixture was stirred at 25 °C for 2 h. To the reaction mixture was added a saturated solution of NaHCO3 (200 mL) and the mixture was extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiCh, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1). Compound tert-butyl 2-(5-(4-chloro-3- fluorophenyl)-6,7-dimethyl-2-oxo-2,3-dihydro-lH-thieno[2,3-e][l,4]diazepin-3-yl)acetate (11 g, 25 mmol, 88% yield) was obtained as a yellow solid.

[0313] Step 6: Preparation of tert-butyl 2-(4-(4-chloro-3-fluorophenyl)-2,3,9-trimethyl- 6H-thieno[3,2-f|[l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetate. Potassium tert-butoxide (1 M, 7.55 mL, 1.1 equiv) was added to a solution tert-butyl 2-(5-(4-chloro-3-fluoro phenyl)-6,7- dimethyl-2-oxo-2,3-dihydro-lH-thieno[2,3-e][l,4]diazepin-3-yl)acetate (3.0 g, 6.8 mmol, 1.0 equiv) in THF (30 mL) at -78 °C. The reaction mixture was warmed to 25 °C, and stirred at 25 °C for 30 min. The reaction mixture was cooled to -78 °C. Chloro(phenoxy)phosphoiyl] oxybenzene (2.21 g, 8.24 mmol, 1.71 mL, 1.2 equiv) was added to reaction mixture. The resulting mixture was warmed to 25 °C over 30 min. Then acetohydrazide (762 mg, 10.3 mmol, 1.5 equiv) was added to reaction mixture. The reaction mixture was stirred at 25 °C, w-BuOH (30 mL) was added to reaction mixture, and it was heated to 90 °C for 1 h. To the reaction mixture was added water (200 mL) and the mixture was extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na?SO4, filtered and concentrated in vacuo, The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1). Compound tert-butyl 2-(4-(4-chloro-3-fluorophenyl )-2, 3, 9-trimethyl-6H-thieno[3,2-f][l, 2, 4]triazolo[4,3-a][l,4]diazepin-6-yl)acetate (2.0 g, 4.2 mmol, 61 % yield) was obtained as a yellow solid.

[0314] Step 7: Preparation of 2-(4-(4-chloro-3-fluorophenyl)-2,3,9-trimethyl-6H-thieno [3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetic acid. To a solution of tert-butyl 2-(4-(4- chloro-3-fluorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl) acetate (2.0 g, 4.2 mmol, 1.0 equiv) in DCM (20 mL) was added TFA (15.3 g, 134 mmol, 10 mb, 31.9 equiv}. The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated in vacuo to give the crude product. Compound 2-(4-(4-chloro-3-fluorophenyl)-2,3,9-trimethyl-6H- thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetic acid (2.2 g, crude, TFA salt) was obtained as a brown solid.

[0315] Step 8: Preparation of 2-(4-(4-chloro-3-fluorophenyl)-2,3,9-trimethyl-6H-thieno [3 ,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-6-yl)-N -(2,2-dim ethoxy ethyl)acetamide. To a solution of 2-(4-(4-chloro-3-fluorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][l,2,4]triazolo[4,3- a][l,4]diazepin-6-yl)acetic acid (2.2 g, 4.1 mmol, 1.0 equiv, TFA salt), 2,2-dimethoxy ethanamine (520 mg, 4.95 mmol, 539 1.2 equμiLv}, in DCM (20 mL) was added DIEA (2.67 g, 20.6 mmol, 3.60 mL, 5.0 equiv} and HATU (2.35 g, 6.19 mmol, 1.5 equiv). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuo to give the crude product. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1). Compound 2-(4-(4-chloro-3-fluorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][l ,2,4] triazolo[4,3-a][l,4]diazepin-6-yl)-N-(2,2-dimethoxyethyl)acetamide (2.0 g, 3.9 mmol, 95 % yield) was obtained as a yellow solid.

[0316] Step 9: Preparation of 2-((4-(4-chloro-3-fluorophenyl)-2,3,9-trimethyl-6H-thieno [3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)methyl)oxazole. A mixture of 2-(4-(4-chl oro-3 - fluorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)-N-(2,2- dimethoxyethyl)acetamide (2.0 g, 3.9 mmol, 1.0 equiv} in Eaton’s reagent (20 mL) was stirred at 100 °C for 12 h. The reaction mixture was added to ice / saturated aqueous NaHCO3 (200 mL) dropwise and the mixture was extracted with DCM (100 mL x 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1). Compound 2-((4-(4-chloro-3-fluorophenyl)-2, 3, 9-trimethyl-6H-thieno[3, 2-f] [1 ,2, 4]tri azol o [4,3-a][l,4]diazepin-6-yl)methyl)oxazole (0.5 g, 1 .1 mmol, 28 % yield) was obtained as a yellow solid.

[0317] Step 10: Preparation of tert-butyl 8-[2-fluoro-4-[(9S)-4,5,13-trimethyl-9-(oxazol- 2-ylmethyl)-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7- yl]phenyl]-2,8-diazaspiro[4.5]decane-2-carboxylate. A solution of 2-((4-(4-chloro-3 -fluoro phenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)methyl) oxazole (300 mg, 679 μmol, 1.0 equiv), tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (245 mg, 1.02 mmol, 1.5 equiv), SPhos Pd G3 (106 mg, 136 μmol, 0.20 equiv), and CS2CO3 (664 mg, 2.04 mmol, 3.0 equiv) in dioxane (5.0 mb) was stirred at 90 °C for 4 h under N2. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by / vcyj-HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; gradient: 56%-86% B over 10 min) to give the product tert-butyl 8-[2-fluoro -4-[(9S)-4, 5,13-trimethyl-9-(oxazol-2-ylmethyl)-3 -thia- 1,8,11,12-tetrazatri cyclo[8.3.0.02,6] tri deca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-2,8-diazaspiro[4.5]decane-2-carboxylate (250 mg, 387 μmol, 57% yield) as a yellow solid.

[0318] Step 11: Preparation of tert-butyl 8-[2-fluoro-4-[4,5,13-trimethyl-9-(oxazol-2- ylmethyl)-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7- yl]phenyl]-2,8-diazaspiro[4.5]decane-2-carboxylate. te / 7-butyl 8-[2-fluoro-4-[(9S)-4,5,13- trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7,10,12- pentaen-7-yl]phenyl]-2,8-diazaspiro[4.5]decane-2-carboxylate (260 mg, 301 pmol) was purified by SFC (column: DAICEL CHIRALPAK AS (250mm*30mm,10um); mobile phase: [CCh-EtOH (0.1% NH3 in H2O)]; B%: 45%, isocratic elution mode) to afford tert-butyl 8-[2-fluoro-4-[4,5,13- trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02’6] trideca-2(6),4,7,10, 12-pentaen-7-yl]phenyl]-2,8-diazaspiro[4.5]decane-2-carboxylate (130 mg, 201 μmol, 52% yield) stereoisomer 1 as a yellow gum, and tert-butyl 8-[2-fluoro-4-[4,5,13-trimethyl-9-(oxazol- 2-ylmethyl)-3 -thia- 1,8,11,12-tetrazatri cyclo[8.3.0.02,6]trideca-2(6), 4, 7, 10,12-pentaen-7- yl]phenyl]-2,8-diazaspiro[4.5]decane-2-carboxylate (100 mg, 155 μmol, 40% yield) stereoisomer 2 as a yellow gum.

[0319] Step 12: Preparation of 2-[[7-[4-(2,8-diazaspiro[4.5]decan-8-yl)-3-fluoro-phenyl]- 4,5,13-trimethyl-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl] methyl] oxazole. To a solution of Zc / 7-butyl 8-[2-fluoro-4-[4,5,13-trimethyl-9-(oxazol-2- ylmethyl)-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]- 2,8-diazaspiro[4.5]decane-2-carboxylate (100 mg, 155 μmol, 1.0 equiv) in DCM (2.0 mb) was added TFA (768 mg, 6.73 mmol, 0.50 mb, 43.5 equiv). The mixture was stirred at 25 °C for 1 h under N2. The pH was adjusted with an aqueous NaHCOa solution to neutral, then the mixture was extracted with methanol / dichloromethane (1 / 10) (60 mb x 3). The organic phase was dried over anhydrous Na2SO4, and concentrated under vacuum to afford 2-[[7-[4-(2,8-diazaspiro [4.5]decan-8-yl)-3-fluoro-phenyl]-4,5,13-trimethyl-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02-6] trideca-2(6),4,7,10,12-pentaen-9-yl]methyl]oxazole (85.0 mg, crude) as a yellow gum.

[0320] Step 13: Preparation of N-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[8-[2- fluoro-4-[4,5,13-trimethyl-9-(oxazoI-2-ylmethyl)-3-thia-l,8,ll,12-tetrazatricycIo [8.3.0.02,6] trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]-2,8-diazaspiro[4.5]decan-2-yl] pyridazine-3- carboxamide (1-26). To a solution of 2-[[7-[4-(2,8-diazaspiro[4.5]decan-8-yl)-3-fluoro-phenyl]- 4,5,13-trimethyl-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02'6]trideca-2(6),4,7,10,12-pentaen-9-yl] methyl]oxazole (42.0 mg, 77.0 μmol, 1.0 equiv) and 6-chloro-A-[4-(3-chloro-4-cyano-phenoxy) cyclohexyl]pyridazine-3-carboxamide (30.1 mg, 77.0 μmol, 1.0 equiv) in NMP (0.75 mb) was added DIEA (99.5 mg, 770 μmol, 134 10.0μ eLq,uiv). The mixture was stirred at 80 °C for 12 h under N2. The reaction mixture was purified by p / ep-HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; gradient: 54%-84% B over 10 min) to afford the productA-[4-(3-chloro-4-cyano-phenoxy)cyclohexyl]-6-[8-[2-fluoro-4-[4,5,13- trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,l l,12-tetrazatricyclo[8.3.0.02’6]trideca-2(6),4,7,10,12- pentaen-7-yl]phenyl]-2,8-diazaspiro[4.5]decan-2-yl]pyridazine-3-carboxamide (1-26, 23.9 mg, 26.5 μmol, 34% yield, 99.82% purity) as a white solid. (400 M1HH NzM, DRM: SO-d6) δ = 8.51 (br d, , / = 8.4 Hz, 1H), 8.04 (s, 1H), 7.84 (dd, J= 92, 14.2 Hz, 2H), 7.39 (d, J= 2.4 Hz, 1H), 7.16 - 7.02 (m, 5H), 6.97 (d, . / - 9.2 Hz, 1H), 4.63 (t, J= 7.2 Hz, 1H), 4.58 - 4.48 (m, 1H), 3.94 - 3.76 (m, 3H), 3.62 (br d, J= 2.8 Hz, 2H), 3.53 - 3.41 (m, 2H), 3.22 - 3.11 (m, 2H), 3.10 - 2.99 (m, 2H), 2.60 (s, 3H), 2.43 (s, 3H), 2.15 - 2.05 (m, 2H), 1.96 (br t, J= 6.8 Hz, 2H), 1.90 (br d, J = 11.8 Hz, 2H), 1.78 - 1.70 (m, 4H), 1.69 (s, 3H), 1.66 - 1.58 (m, 2H), 1.57 - 1.46 (m, 2H). LC- MS: MS (ESl): RT = 2.193 min, m / z = 900.6 [M+H] ; LCMS method: 25.EXAMPLE 12 - Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclo butyl]-2-[2-[[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,ll,12-tetrazatricyclo [8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]methyl]-7-azaspiro[3.5]nonan-7-yl] pyrimidine-5-carboxamide (II-4)

[0321] Step 1: Preparation of 2-chloropyrimidine-5-carbonyl chloride. To a solution of 2-chloropyrimidine-5-carboxylic acid (1.30 g, 8.20 mmol, 1.0 equiv) in DCM (30 mL) was added DMF (59.9 mg, 819 umol, 63.1 uL, 0.1 equiv) and (COC1)2 (3.12 g, 24.6 mmol, 2.15 mL, 3.0 equiv). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give 2-chloropyrimidine-5-carbonyl chloride (1.02 g, 5.76 mmol, 70% yield) as a white solid.

[0322] Step 2: Preparation of tert-butyl N-[3-(3-chloro-4-cyano-phenoxy)-2, 2,4,4- tetramethyl-cyclobutyljcarbamate. To a solution of tert-butyl N-(3 -hydroxy-2, 2,4,4- tetramethyl-cyclobutyl)carbamate (840 mg, 3.45 mmol, 1.0 equiv) in DMF (15 mL) was added NaH (207 mg, 5.18 mmol, 60% purity, 1.5 equiv) in portions at 0 °C . After the addition, the mixture was stirred at 0 °C for 1.0 h, and then 2-chloro-4-fluoro-benzonitrile (537 mg, 3.45 mmol, 1.0 equiv) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by addition of a saturated solution of aqueous NH4CI (20 mL) at 0 °C, and then diluted with ethyl acetate (20 mL). The resulting mixture was and extracted with ethyl acetate (10 mL x 2). The residue was purified by flash silica gel chromatography (ISCO; 12g SepaFlash Silica Flash Column, eluent of 0-10% ethyl acetate in petroleum ether ) to afford tert-butyl N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclo butyl]carbamate (1.19 g, 3.14 mmol, 91% yield) as a white solid.

[0323] Step 3: Preparation of 4-(3-amino-2,2,4,4-tetramethyl-cyclobutoxy)-2-chloro- benzonitrile. To a solution of tert-butyl N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]carbamate (1.19 g, 3.14 mmol, 1.0 equiv) in DCM (9.0 mL) was added TFA (3.79 g, 33.3 mmol, 2.5 mL, 10.6 equiv). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give 4-(3-amino-2,2,4,4-tetramethyl-cyclobutoxy)-2- chloro-benzonitrile (1.15 g, 2.9 mmol, 92% yield, 99% purity, TFA salt) as a white solid.[00324J Step 4: Preparation of 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2, 2,4,4- tetramethyl-cyclobutyl]pyrimidine-5-carboxamide. To a mixture of 4-(3-amino-2, 2,4,4- tetramethyl-cyclobutoxy)-2-chloro-benzonitrile (1.40 g, 3.56 mmol, 1.0 equiv, TFA salt) in DCM (30 mL) was added TEA (1 .80 g, 17.8 mmol, 2.48 mL, 5.0 equiv) dropwise into the mixture at 0 °C. The reaction mixture was stirred for 30 min, then 2-chloropyrimidine-5-carbonyl chloride (756 mg, 4.28 mmol, 1.2 equiv) in DCM (30 mL) was added dropwise into the mixture at 0 °C. The reaction mixture was stirred for 10 min, and then the mixture was stirred at 0 °C for 20 min under N2 atmosphere. The reaction mixture was quenched by the addition of water (20 mL) at 0 °C, and then extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with water (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate =5 / 1 to 2 / 1) to give 2-chloro-N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclo butyl]pyrimidine-5-carboxamide (1.16 g, 2.77 mmol, 77% yield) as a white solid.

[0325] Step 5: Preparation of tert-butyl 2-[(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)methylene]-7-azaspiro [3.5] nonane-7-carboxylate. To a solution of TMP (885 mg, 6.2 mmol, 1.0 mL, 1.5 equiv) in THF (4 mL) was added n-BuLi (2.5 M, 2.5mL, 1.5 equiv) at -30 °C under N2 atmosphere. After addition, the mixture was stirred at this temperature for 30 min, and then 4,4,5,5-tetramethyl-2-[(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methyl]-l,3,2-dioxa borolane (1.4 g, 5.0 mmol, 1.2 equiv) in THF (3 mL) was added dropwise at -78 °C. After addition, the mixture was stirred at this temperature for 30 min, and then tert-butyl 2-oxo-7-aza spiro [3.5] nonane-7-carboxylate (1.0 g, 4.18 mmol, 1.0 equiv) in THF (3 mL) was added dropwise at -78 °C. The resulting mixture was stirred at 25 °C for 12 h. The obtained mixture was then cooled to 0 °C, and a saturated solution of aqueous NH4CI (15 mL) was added dropwise. After additional stirring for 1 h, the resulting mixture was filtered and the solvent was removed under reduced pressure. H2O (20 mL) was added to the obtained residue, and theaqueous layer was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SC>4 and concentrated under vacuum to give tert- butyl 2-[(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) methylene] -7-azaspiro [3.5] nonane-7- carboxylate (1.3 g, 86 % yield) as a colorless oil.

[0326] Step 6: Preparation of tert-butyl 2-[[4-[4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3- thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl] methylene]-7-azaspiro[3.5]nonane-7-carboxylate. To a solution of 2-[[7-(4-chlorophenyl)-4, 5, 13-trimethyl-3-thia-l, 8, 11, 12-tetrazatri cyclo [8.3.0.02, 6] trideca-2(6),4,7,10,12-pentaen-9- yl]methyl]oxazole (400 mg, 943.8 μmol, 1.0 equiv) and tert-butyl 2-[(4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl)methylene]-7-azaspiro[3.5]nonane-7-carboxylate (530 mg, 1.6 mmol, 1.5 equiv) in DMF (6 mL) was added SPhos Pd G3 (73 mg, 94 μmol, 0.1 equiv) and CS2CO3 (307 mg, 943 μmol, 1.0 equiv). The mixture was stirred at 90 °C for 12 h. The reaction mixture was fdtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenom enex Luna C18 150*25mm*10um; mobile phase: [water (FA)- ACN]; B%: 62%-92%, lOmin) to give tert-butyl 2-[[4-[4,5,13-trimethyl-9-(oxazol-2-ylmethyl)- 3-thia-l ,8, 11, 12-tetrazatri cyclo[8.3.0.02, 6]trideca-2(6), 4, 7, 10, 12-pentaen-7-yl]phenyl] methylene]-7-azaspiro[3.5]nonane-7-carboxylate (400 mg, 61 %yield ) as a yellow solid.

[0327] Step 7: Preparation of tert-butyl 2-[[4-[4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3- thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]methyl]- 7-azaspiro[3.5]nonane-7-carboxylate. To a solution of tert-butyl 2-[[4-[4,5,13-trimethyl-9- (oxazol-2-ylmethyl)-3-thia-l,8,l 1, 12-tetrazatri cyclo[8.3.0.02, 6]trideca-2(6), 4, 7, 10,12-pentaen-7- yl]phenyl]methylene]-7-azaspiro[3.5]nonane-7-carboxylate (0.4 g, 642 μmol, 1.0 equiv) in THF (8 mL) was added Pd / C (0.45 g, 10% purity) under H2 (15 psi). The mixture was stirred at 25 °C for 12 h under H2 (15 psi). The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl 2-[[4-[4, 5, 13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l, 8,11, 12- tetrazatri cyclo[8.3.0.02, 6]trideca-2(6), 4, 7, 10, 12-pentaen-7-yl]phenyl]methyl]-7-azaspiro [3.5]nonane-7-carboxylate (0.4 g, 99 % yield) as a white solid.

[0328] Step 8: Preparation of 2-[[7-[4-(7-azaspiro[3.5]nonan-2-ylmethyl)phenyl]-4,5,13- trimethyl-3-thia-l,8,ll,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl] methyl] oxazole. To a solution of tert-butyl 2-[[4-[4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia- 1 ,8,1 l,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]methyl]-7- azaspiro[3.5]nonane-7-carboxylate (0.4 g, 638 μmol, 1.0 equiv) in DCM (1 mL) was added TFA (1.2 g, 10.7 mmol, 800 16μ.L8, equiv). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was fdtered and concentrated under reduced pressure to give 2-[[7-[4-(7-azaspiro [3.5] nonan-2 -ylmethyl)phenyl]-4, 5, 13-trimethyl-3-thia- 1,8,11,12-tetrazatri cyclo [8.3.0.02,6] trideca- 2(6),4,7,10, 12-pentaen-9-yl]methyl]oxazole (0.407 g, 99 % yield) as a colourless oil.[00329J Step 9: Preparation of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl- cyclobutyl]-2-[2-[[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-l,8,ll,12-tetraza tricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-7-yl]phenyl]methyl]-7-azaspiro [3.5] nonan-7-yl]pyrimidine-5-carboxamide (II-4). To a solution of 2-[[7-[4-(7-azaspiro[3.5]nonan- 2-ylmethyl)phenyl]-4,5,13-trimethyl-3-thia-l,8,l 1,12-tetrazatri cyclo [8.3.0. 02,6] trideca-2(6),4,7.10.12-pentaen-9-yl]methyl]oxazole (0.2 g, 312 μmol, 1.0 equiv, TFA salt), 2-chloro-N-[3-(3- chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]pyrimidine-5-carboxamide (143 mg, 343 μmol, 1.1 equiv) in NMP (3 mL) was added K2CO3 (129 mg, 936 μmol, 3.0 equiv). The mixture was stirred at 50 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenom enex luna C 18 150*25mm* lOum; mobile phase: [water(FA)-ACN]; gradient: 70%- 100% B over 10 min) to give the desired compound, which was further separated by SFC (column: REGIS(S,S)WHELK-01(250mm*25mm,10um);mobile phase: [CCL-ACN / i-PrOH (0.1% NH3 in H2O)]; 70% B isocratic elution mode) to give N-[3-(3-chloro-4-cyano-phenoxy)- 2,2,4,4-tetramethyl-cyclobutyl]-2-[2-[[4-[(9S)-4,5,13-trimethyl-9-(oxazol-2-ylmethyl)-3-thia-1.8.11.12-tetrazatri cyclo[8.3.0.02, 6]trideca-2(6), 4, 7, 10, 12-pentaen-7-yl]phenyl]methyl]-7- azaspiro[3.5]nonan-7-yl]pyrimidine-5-carboxamide (II-4, 16 mg, 18 % yield, 99% ee) as a white solid. ‘HNMR (400 MHz, methonal-d4) δ 8.70 (s, 2 H), 7.90 (s, 1 H), 7.63 - 7.77 (m, 1 H), 7.29 (d, J= 7.70 Hz, 2 H), 7.17 - 7.23 (m, 2 H), 7.08 - 7.15 (m, 2 H), 6.98 (dd, J= 8.68, 2.32 Hz, 1 H), 4.77 (d, J= 6.72 Hz, 1 H), 4.58 (s, 1 H), 4.26 (s, 1 H), 4.09 - 4.16 (m, 1 H), 3.91 - 4.05 (m, 2 H), 3.82 - 3.87 (m, 2 H), 3.78 (dd, J= 6.30, 5.32 Hz, 2 H), 2.78 (d, J= 7.46 Hz, 2 H), 2.71 (s, 3 H), 2.60 (d, J = 7.95 Hz, 1 H), 2.45 (s, 3 H), 1.93 - 2.02 (m, 2 H), 1.49 - 1.67 (m, 9 H), 1.26 -1 .29 (m, 6 H), 1 .21 (s, 6 H). LC-MS: MS (ES+): RT = 3.03 min, m / z = 909.4 [M + H+]; LCMS method: 25.EXAMPLE 13 - Synthesis of Additional Compounds

[0330] Compounds in the following table were prepared based on procedures analogous to those described above. Physical characterization data for exemplary compounds is provided.EXAMPLE 14 - Assay for Binding Affinity to Androgen Receptor

[0331] Exemplary compounds were tested for ability to bind to the androgen receptor.Experimental procedures and results are provided below.Part I - Experimental Procedure

[0332] Fractions of cell cytosol (106 cell / point) were incubated for 24 hr at 4 °C with 1 nM [3H]methyltrienolone in the absence or presence of the test compound in a buffer containing 25 mM Hepes-Tris (pH 7.4), 1 mM EDTA, 10 mM Na2MoO4, 2 mM DTT, 5 μM triamcinolone acetonide, and 10% glycerol. Nonspecific binding was determined in the presence of 1 μM testosterone. Following incubation, the samples were filtered rapidly under vacuum through glass fiber filters (GF / B, Packard) presoaked with 0.3% PEI and rinsed several times with ice- cold 50 mM Tris-HCl using a 96-sample cell harvester (Unifilter, Packard). The filters were dried then counted for radioactivity in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard). The results are expressed as a percent inhibition of the control radioligand specific binding. The standard reference compound is testosterone, which is tested in each experiment at several concentrations to obtain a competition curve from which its IC50 is calculated.Part II - Results

[0333] Results showing ability of exemplary compounds to bind to the androgen receptor are provided in Table 3 below. The symbol “++++” indicates a Kd less than 0.05 μM. The symbol “+++” indicates an Kd in the range of 0.05 μM to 0.5 μM. The symbol “++” indicates a Kd in the range of greater than 0.5 μM to 2.5 μM. The symbol “+” indicates a Kd greater than 2.5 μM.TABLE 3.EXAMPLE 15- Assay for Binding Affinity to BRD4-BD1

[0334] Exemplary compounds were tested for ability to bind to BRD4-BD1. Experimental procedures and results are provided below.Part I - Experimental Procedure

[0335] Compounds were tested using a bromoKdELECT assay. T7 phage strains displaying bromodomains were grown in parallel in 24-well blocks in an E. coli host derived from the BL21 strain. E. coli were grown to log-phase and infected with T7 phage from a frozen stock(multiplicity of infection = 0.4) and incubated with shaking at 32 °C until lysis (90-150 minutes). The lysates were centrifuged (5,000 x g) and filtered (0.2pm) to remove cell debris. Streptavidin- coated magnetic beads were treated with biotinylated small molecule or acetylated peptide ligands for 30 minutes at room temperature to generate affinity resins for bromodomain assays. The liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce nonspecific phage binding. Binding reactions were assembled by combining bromodomains, liganded affinity beads, and test compounds in lx binding buffer (17% SeaBlock, 0.33x PBS, 0.04% Tween 20, 0.02% BSA, 0.004% Sodium azide, 7.4 mM DTT). Test compounds were prepared as 1000X stocks in 100% DMSO. Kds were determined using an 11-point 3-fold compound dilution series with one DMSO control point. All compounds for Kd measurements are distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds were then diluted directly into the assays such that the final concentration of DMSO was 0.09%. All reactions performed in polypropylene 384-well plates. Each was a final volume of 0.02 ml. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (lx PBS, 0.05% Tween 20). The beads were then resuspended in elution buffer (lx PBS, 0.05% Tween 20, 2 μM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The bromodomain concentration in the eluates was measured by qPCR.Part II - Results

[0336] Results showing ability of exemplary compounds to bind to BRD4-BD1 are provided in Table 4 below. The symbol “++++” indicates a Kd less than 0.05 μM. The symbol “+++” indicates a Kd in the range of 0.05 μM to 0.5 μM. The symbol “++” indicates a Kd in the range of greater than 0.5 μM to 2.5 μM. The symbol “+” indicates a Kd greater than 2.5 μM.TABLE 4.EXAMPLE 16- Assay for Binding Affinity to BRD4-BD2

[0337] Exemplary compounds were tested for ability to bind to BRD4-BD2. Experimental procedures and results are provided below.Part I - Experimental Procedure

[0338] Compounds were tested using a bromoKdELECT assay. T7 phage strains displaying bromodomains were grown in parallel in 24-well blocks in an E. coli host derived from the BL21 strain. E. coli were grown to log-phase and infected with T7 phage from a frozen stock (multiplicity of infection = 0.4) and incubated with shaking at 32 °C until lysis (90-150 minutes). The lysates were centrifuged (5,000 x g) and fdtered (0.2pm) to remove cell debris. Streptavidin- coated magnetic beads were treated with biotinylated small molecule or acetylated peptide ligands for 30 minutes at room temperature to generate affinity resins for bromodomain assays. The liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce nonspecific phage binding. Binding reactions were assembled by combining bromodomains, liganded affinity beads, and test compounds in lx binding buffer (17% SeaBlock, 0.33x PBS, 0.04% Tween 20, 0.02% BSA, 0.004% Sodium azide, 7.4 mM DTT). Test compounds were prepared as 1000X stocks in 100% DMSO. Kds were determined using an 11-point 3-fold compound dilution series with one DMSO control point. All compounds for Kd measurements are distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds were then diluted directly into the assays such that the final concentration of DMSO was 0.09%. All reactions performed in polypropylene 384-well plates. Each was a final volume of 0.02 ml. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (lx PBS, 0.05% Tween 20). The beads were then resuspended in elution buffer (lx PBS, 0.05% Tween 20, 2 μM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The bromodomain concentration in the eluates was measured by qPCR.Part II - Results

[0339] Results showing ability of exemplary compounds to bind to BRD4-BD2 are provided in Table 5 below. The symbol “+++-1-” indicates a Kd less than 0.05 μM. The symbol “+++”indicates a Kd in the range of 0.05 μM to 0.5 μM. The symbol “++” indicates a Kd in the range of greater than 0.5 μM to 2.5 μM. The symbol “+” indicates a Kd greater than 2.5 μM.TABLE 5.EXAMPLE 17 - Cellular Growth Inhibition Assay Using T-Rex 293 Cells

[0340] Exemplary compounds were tested for ability to inhibit the proliferation of the following types of cells: (i) a T-Rex 293 cell line having increased expression of androgen receptor protein due to exposure to doxycycline and (ii) a T-Rex 293 cell line lacking increased expression of androgen receptor protein. Experimental procedures and results are provided below.Part I - Experimental Procedure

[0341] The following types of cells were prepared for this experiment: (i) a T-Rex 293 cell line having increased expression of androgen receptor protein due to exposure to doxycycline and (ii) a T-Rex 293 cell line lacking increased expression of androgen receptor protein. Ability of the test compounds to inhibit proliferation of the foregoing cell types was evaluated according to the procedures set forth below.

[0342] The doxycycline-inducible androgen receptor protein expressing cell line was established using the following protocol: T-Rex 293 cells were purchased from Invitrogen (Cat#R71007) and transfected using Lipofectamine 2000 with the wild-type androgen receptor protein sequence cloned into the pcDNA4 / TO vector. Transfected cells were selected using 400 pg / mL Zeocin (Invitrogen Cat#R25001). Following selection, single clones were raised and maintained in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w / w Tetracycline-free fetal bovine serum (FBS) and 250 pg / mL Zeocin. Clones were analyzed for expression of androgen receptor protein in the presence and absence of 10 ng / mL doxycycline (Sigma Cat#D9891), and a single doxycycline-inducible clone (hereinafter “SC3”) was selected for use in downstream assays.

[0343] The SC3 cells were seeded on poly-D-lysine coated, black clear-bottom 384- well plates at 2500 / well, in 25 μL Phenol Red Free Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w / w charcoal-dextran treated fetal bovine serum (FBS) and 1% w / w pen-strep, with or without 10 ng / mL doxycycline. Pen-Strep is a commercially available mixture of penicillin G and streptomycin, which is used in mammalian cell culture media to prevent bacterial contamination. Phenol Red Free Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w / w charcoal-dextran treated fetal bovine serum (FBS) and 1% w / w pen-strep, with or without 10 ng / mL doxycycline is herein referred to as Treatment Medium. Following seeding of cells in the plates, the plates were spun at 300 * g for 30 seconds, then equilibrated to room temperature for 30 minutes, and then deposited in a humidified tissue culture incubator maintained at 37 °C with 5% CO2.[00344J At 24 hours after seeding of the cells, dilutions of test compound were prepared in DMSO and dissolved in Treatment Medium, to achieve a final DMSO concentration of 0.5% w / w, thereby providing the Test Compound Solution. A 25 μL aliquot of the Test Compound Solution was added to cells in the well plates. An equal volume of a solution containing DMSO and Treatment Medium was used as a negative control. Following treatment of cells with Test Compound Solution or said equal volume of a solution containing DMSO and Treatment Medium, the plates were spun at 300 x g for 30 seconds, and then left in an incubator for 72 hours.

[0345] At the end of the treatment duration, cell viability was quantified with CellTiter-Glo 2.0 reagent (Promega Cat#G9243). For this purpose, plates were equilibrated to room temperature for 30 minutes, and then 25 μL of CellTiter-Glo 2.0 reagent was added to cells in the plate wells. Plates were then agitated on a shaker for two minutes at 500 rpm and subsequently incubated at room temperature for 10 minutes. Following incubation, the plates were spun at 3000 x g for 30 seconds, then sealed with an optical adhesive cover, and luminescence readings were measured with an EnVision Plate Reader.

[0346] Data was normalized using zero luminescence for baseline. A four-parameter non- linear regression curve fit was applied to dose-response data in GraphPad Prism data analysis software to determine the half-maximal growth inhibitory concentration (GI50) for each test compound.Part II - Results

[0347] The half-maximal growth inhibitory concentration (GI50) results are provided in Tables 6 and 7 below for exemplary compounds. Table 6 provides results from the experiment analyzing ability of test compounds to inhibit proliferation of the T-Rex 293 cell line SC3 cells having increased expression of androgen receptor protein due to exposure to doxycycline. The symbol “++++” indicates a GI50 less than 0.5 μM. The symbol “+++” indicates an GI50 in the range of 0.5 μM to 1.5 μM. The symbol “++” indicates a GI50 in the range of greater than 1.5 μM to 3 μM. The symbol “+” indicates a GI50 greater than 3 μM.TABLE 6.TABLE 7.EXAM PEE 18 - Cellular Growth Inhibition Assay for VCaP Cells

[0348] Exemplary compounds were tested for ability to inhibit the proliferation of VCaP cells. VCap cells are a commercially available human prostate cancer cell line. Experimental procedures and results are provided below.Part I - Experimental Procedure

[0349] VCaP cells were purchased from American Type Cell Culture (ATCC Cat#CRL2876) and then seeded on poly-D-lysine coated, black clear-bottom 384-well plates at 5000 / well in 25 μL Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w / w Fetal bovine serum (FBS) and 1% w / w Pen-Strep. Pen-Strep is a commercially available mixture of penicillin G and streptomycin, which is used in mammalian cell culture media to prevent bacterial contamination. Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w / w fetal bovine serum (FBS) and 1% w / w Pen-Strep is herein referred to as Treatment Medium.Following seeding of cells in the plates, the plates were spun at 300 x g for 30 seconds, then equilibrated to room temperature for 30 minutes, and then deposited in a humidified tissue culture incubator maintained at 37 °C with 5% CO2.

[0350] At 24 hours after seeding of the cells, dilutions of test compound were prepared in DMSO and dissolved in Treatment Medium, to achieve a final DMSO concentration of 0.5% w / w, thereby providing the Test Compound Solution. A 25 μL aliquot of the Test Compound Solution was added to cells in the well plates. An equal volume of a solution containing DMSO and Treatment Medium was used as a negative control. Following treatment of cells with Test Compound Solution or said equal volume of a solution containing DMSO and Treatment Medium, the plates were spun at 300 x g for 30 seconds, and then left in an incubator for 72 hours.

[0351] At the end of the treatment duration, cell viability was quantified with CellTiter-Glo 2.0 reagent (Promega Cat#G9243). For this purpose, plates were equilibrated to room temperature for 30 minutes, and then 25 μL of CellTiter-Glo 2.0 reagent was added to cells in the plate wells. Plates were then agitated on a shaker for two minutes at 500 rpm and subsequently incubated at room temperature for 10 minutes. Following incubation, the plates were spun at 3000 x g for 30 seconds, then sealed with an optical adhesive cover, and luminescence readings were measured with an EnVision Plate Reader.

[0352] Data was normalized using zero luminescence for baseline. A four-parameter non- linear regression curve fit was applied to dose-response data in GraphPad Prism data analysis software to determine the half-maximal growth inhibitory concentration (GI50) for each test compound.Part II - Results

[0353] The half-maximal growth inhibitory concentration (GI50) results are provided in Table 8 below for exemplary compounds. The symbol “++++” indicates a GI50 less than 0.5 μM. The symbol “+++” indicates an GI50 in the range of 0.5 μM to 1.5 μM. The symbol “++” indicates a GI50 in the range of greater than 1.5 μM to 3 μM. The symbol “+” indicates a GI50 greater than 3 μM.TABLE 8.EXAMPLE 19 - Cellular Growth Inhibition Assay Using T-Rex 293 Cells

[0354] Using the experimental procedures described below, compounds may be tested for ability to inhibit the proliferation of the following types of cells: (i) a T-Rex 293 cell line having increased expression of progesterone receptor isoform B protein due to exposure of doxycycline and (ii) a T-Rex 293 cell line lacking increased expression of progesterone receptor isoform B protein.

[0355] The doxycycline-inducible progesterone receptor isoform B protein expressing cell line may be established using the following protocol: T-Rex 293 cells are purchased from Invitrogen (Cat#R71007) and transfected using Lipofectamine 2000 with the wild-type progesterone receptor B protein sequence cloned into the pcDNA4 / TO vector. Transfected cells are selected using 400 pg / mL Zeocin (Invitrogen Cat#R25001). Following selection, single clones are raised and maintained in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w / w Tetracycline-free fetal bovine serum (FBS) and 250 pg / mL Zeocin. Clones are analyzed for expression of progesterone receptor isoform B protein in the presence and absence of 10 ng / mL doxycycline (Sigma Cat#D9891), and a single doxycycline-inducible clone (hereinafter “SC”) is selected for use in downstream assays.

[0356] The SC cells are seeded on poly-D-lysine coated, black clear-bottom 384- well plates at 2500 / well, in 25 μL Phenol Red Free Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w / w charcoal-dextran treated fetal bovine serum (FBS) and 1% w / w pen-strep, with or without 10 ng / mL doxycycline. Pen-Strep is a commercially available mixture of penicillin G and streptomycin, which is used in mammalian cell culture media to prevent bacterial contamination. Phenol Red Free Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w / w charcoal-dextran treated fetal bovine serum (FBS) and 1% w / wpen-strep, with or without 10 ng / mL doxycycline is herein referred to as Treatment Medium. Following seeding of cells in the plates, the plates are spun at 300 * g for 30 seconds, then equilibrated to room temperature for 30 minutes, and then deposited in a humidified tissue culture incubator maintained at 37 °C with 5% CO2.

[0357] At 24 hours after seeding of the cells, dilutions of test compound are prepared in DMSO and dissolved in Treatment Medium, to achieve a final DMSO concentration of 0.5% w / w, thereby providing the Test Compound Solution. A 25 μL aliquot of the Test Compound Solution is added to cells in the well plates. An equal volume of a solution containing DMSO and Treatment Medium is used as a negative control. Following treatment of cells with Test Compound Solution or said equal volume of a solution containing DMSO and Treatment Medium, the plates are spun at 300 x g for 30 seconds, and then left in an incubator for 72 hours.

[0358] At the end of the treatment duration, cell viability is quantified with CellTiter-Glo 2.0 reagent (Promega Cat#G9243). For this purpose, plates are equilibrated to room temperature for 30 minutes, and then 25 μL of CellTiter-Glo 2.0 reagent is added to cells in the plate wells. Plates were then agitated on a shaker for two minutes at 500 rpm and subsequently incubated at room temperature for 10 minutes. Following incubation, the plates are spun at 3000 x g for 30 seconds, then sealed with an optical adhesive cover, and luminescence readings are measured with an EnVision Plate Reader (Perkin Elmer).

[0359] Data may be normalized using zero luminescence for baseline. A four-parameter non- linear regression curve fit is applied to dose-response data in GraphPad Prism data analysis software to determine the half-maximal growth inhibitory concentration (GI50) for each test compound.EXAM PEE 20 - Cellular Growth Inhibition Assay for T47D Cells

[0360] Exemplary compounds were tested for ability to inhibit the proliferation of T47D cells. T47D cells are a commercially available human breast cancer cell line. Experimental procedures and results are provided below.Part I - Experimental Procedure

[0361] T47D cells were purchased from American Type Cell Culture (ATCC Cat# E1TB- 133) and then seeded on poly-D-lysine coated, black clear-bottom 384-well plates at 3000 / wellin 25 μL Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w / w Fetal bovine serum (FBS), 0.2 units / mL recombinant human insulin (Gibco Cat# 12585014), and 1% w / w Pen-Strep. Pen-Strep is a commercially available mixture of penicillin G and streptomycin, which is used in mammalian cell culture media to prevent bacterial contamination. Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% w / w fetal bovine serum (FBS), 0.2 units / mL recombinant human insulin, and 1% w / w Pen-Strep is herein referred to as Treatment Medium. Following seeding of cells in the plates, the plates were spun at 300 x g for 30 seconds, then equilibrated to room temperature for 30 minutes, and then deposited in a humidified tissue culture incubator maintained at 37 °C with 5% CO2.

[0362] At 24 hours after seeding of the cells, dilutions of test compound were prepared in DMSO and dissolved in Treatment Medium, to achieve a final DMSO concentration of 0.5% w / w, thereby providing the Test Compound Solution. A 25 μL aliquot of the Test Compound Solution was added to cells in the well plates. An equal volume of a solution containing DMSO and Treatment Medium was used as a negative control. Following treatment of cells with Test Compound Solution or said equal volume of a solution containing DMSO and Treatment Medium, the plates were spun at 300 x g for 30 seconds, and then left in an incubator for 72 hours.

[0363] At the end of the treatment duration, cell viability was quantified with CellTiter-Glo 2.0 reagent (Promega Cat#G9243). For this purpose, plates were equilibrated to room temperature for 30 minutes, and then 25 μL of CellTiter-Glo 2.0 reagent was added to cells in the plate wells. Plates were then agitated on a shaker for two minutes at 500 rpm and subsequently incubated at room temperature for 10 minutes. Following incubation, the plates were spun at 3000 x g for 30 seconds, then sealed with an optical adhesive cover, and luminescence readings were measured with an EnVision Plate Reader (Perkin Elmer).

[0364] Data was normalized using zero luminescence for baseline. A four-parameter non- linear regression curve fit was applied to dose-response data in GraphPad Prism data analysis software to determine the half-maximal growth inhibitory concentration (GI50) for each test compound.Part II - Results

[0365] The half-maximal growth inhibitory concentration (GI50) results are provided in Table 11 below for exemplary compounds. The symbol “++++” indicates a GI50 less than 0.5 μM. The symbol “+++” indicates an GI50 in the range of 0.5 μM to 1.5 μM. The symbol “++” indicates a GI50 in the range of greater than 1.5 μM to 3 μM. The symbol “+” indicates a GI50 greater than 3 μM.TABLE 11.EXAMPLE 21 - Assay for Binding Affinity to Progesterone Receptor

[0366] Exemplary compounds were tested for ability to bind to the progesterone receptor. Experimental procedures and results are provided below.Part I - Experimental Procedure

[0367] Compounds were tested using the PR Human Progesterone NHR Binding (Agonist Radioligand) Assay, Cerep at Eurofins Discovery using a modified version of the protocol from Sarup et al. (Cancer Res 1988;48:5071-5078). Briefly, cytosolic fractions of T47D cells were incubated with 0.5 nM [3H]progesterone for 1 hour at 4°C in the absence or presence of the test compound. Nonspecific binding was determined in the presence of 1 μM promegestone.Reactions were subjected to scintillation counting. Results are expressed as a percent inhibition of the control radioligand specific binding.Part II - Results

[0368] Results showing ability of exemplary compounds to bind to the progesterone receptor are provided in Table 12 below. The symbol “++++” indicates a Kd less than 0.05 μM. The symbol “+++” indicates an Kd in the range of 0.05 μM to 0.5 μM. The symbol “++” indicates a Kd in the range of greater than 0.5 μM to 2.5 μM. The symbol “+” indicates a Kd greater than 2.5 μM.TABLE 12.EXAMPLE 22 - FP Assay for Binding Affinity to Progesterone Receptor

[0369] Compounds may be tested for ability to bind to the progesterone receptor ligand binding domain (LBD) according to the procedures provided below.

[0370] Compounds may be tested using the PolarScreen™ Progesterone Receptor Competitor Assay Kit (Life Technologies Cat# Al 5905 or al 5906), as per the manufacturer’s instructions. Briefly, GST-tagged PR LBD, Fluormone tracer, and compound are mixed and incubated for 2 hours at room temperature in the dark. Following incubation, the plates are spun at 3000 x g for 30 seconds, then sealed with an optical adhesive cover, and fluorescence polarization is measured using appropriate excitation and emission filters with an EnVision Plate Reader (Perkin Elmer). Compound concentration vs. mP value are plotted in Prism (GraphPad). A four-parameter non-linear regression curve fit is applied to dose-response data to determine the half-maximal inhibitory concentration (IC50) for each test compound.INCORPORATION BY REFERENCE

[0371] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes.EQUIVALENTS

[0372] The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

Claims:

1. A compound represented by Formula I:or a pharmaceutically acceptable salt thereof; wherein:R1is phenyl substituted by cyano, halogen, and m occurrences of R4;R2represents independently for each occurrence C1-4 alkyl;R3is hydrogen or C1-4 alkyl;R4represents independently for each occurrence C1-4 alkyl;R?represents independently for each occurrence Ci-4 alkyl or halogen;B1is (i) cyclobutylene substituted by 1, 2, 3, or 4 occurrences of R2or (ii) cyclohexylene substituted by 0, 1, or 2 occurrences of R2;A1is a pyridazinylene, pyrimidinylene, or pyrazinylene, each of which is substituted with n occurrences of R5;R1Ais Ci-4 alkyl;R2Arepresents independently for each occurrence Ci-4 alkyl;R3Ais hydrogen, halo, C1-2 alkyl, or C1-2 haloalkyl;R4Ais C1-4 alkyl or -(C1-3 alkylene)-(oxazolyl substituted by 0 or 1 occurrence of C1-2 alkyl); m and n are independently 0, 1, or 2; andL is one of the following:(i) -(piperidinylene)-(Ci-4 alkylene)-O-*** or -(piperidinylene)-O-(C2-4 alkylene)-O- ***, wherein *** is the point of attachment to A2;(ii) an 8-1 1 membered spirocyclic, saturated heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclic ring is substituted with 0, 1, or 2 occurrences of fluoro;(iii) -(8-10 membered spirocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-O-*** or -(8-10 membered spirocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(Ci-4 alkylene)-***, wherein *** is the point of attachment to A2;(iv) -(7-8 membered spirocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C2-4 alkynylene)-***, wherein *** is the point of attachment to A2;(v) a 7-9 membered fused bicyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen, wherein the heterocyclic ring is substituted by 1 or 2 occurrences of fluoro;(vi) l,2,3,5-tetrahydropyrrolo[3,4-c]pyrrolylene; or(vii) -(azetidinylene)-(Ci-4 alkylene)-(azetidinylene)-.The compound of claim 1, wherein m is 0.

3. The compound of claim 1, wherein R1is4. The compound of any one of claims 1-3, wherein R2is methyl.

5. The compound of any one of claims 1-4, wherein R3is hydrogen.

6. The compound of any one of claims 1-5, wherein the compound is a compound of Formula I.

7. The compound of any one of claims 1-3, wherein the compound is a compound of Formula la or a pharmaceutically acceptable salt thereof:

8. The compound of any one of claims 1-3, wherein the compound is a compound of Formula lb or a pharmaceutically acceptable salt thereof:

9. The compound of any one of claims 1-5, wherein the compound is a compound of Formula Ic, or a pharmaceutically acceptable salt thereof:

10. The compound of claim 1, wherein the compound is a compound of Formula Id or a pharmaceutically acceptable salt thereof:

11. The compound of claim 1, wherein the compound is a compound of Formula le or a pharmaceutically acceptable salt thereof:

12. The compound of any one of claims 1-4, wherein the compound is a compound of Formula If or a pharmaceutically acceptable salt thereof:

13. The compound of any one of claims 1-4, wherein the compound is a compound of FormulaIg, or a pharmaceutically acceptable salt thereof:

14. The compound of claim 1, wherein the compound is a compound of Formula Ih or a pharmaceutically acceptable salt thereof15. The compound of claim 1, wherein the compound is a compound of Formula li or a pharmaceutically acceptable salt thereof:

16. The compound of any one of claims 1-15, wherein A1is pyridazinylene substituted with n occurrences of R5.N-N £ _ / / \\ _ |17. The compound of any one of claims 1-15, wherein A1is \= / 18. The compound of any one of claims 1-15, wherein A1is pyrimidinylene substituted with n occurrences of R5.

19. The compound of any one of claims 1-15, wherein A1is, wherein ** is the point of attachment to L.H j-**20. The compound of any one of claims 1-15, wherein A1isN, wherein ** is the point of attachment to L.

21. The compound of any one of claims 1-15, wherein A1is pyrazinylene substituted with n occurrences of R5.

22. The compound of any one of claims 1-15, wherein A1is23. The compound of any one of claims 1-16, 18, or 21, wherein n is 0.

24. The compound of any one of claims 1-23, wherein R1Ais methyl.

25. The compound of any one of claims 1-24, wherein R2Ais methyl.

26. The compound of any one of claims 1-25, wherein R3Ais hydrogen.

27. The compound of any one of claims 1-25, wherein R3Ais halo.

28. The compound of any one of claims 1-25, wherein R3Ais fluoro.

29. The compound of any one of claims 1-25, wherein R3Ais C1-2 haloalkyl.

30. The compound of any one of claims 1-25, wherein R3Ais trifluoromethyl.

31. The compound of any one of claims 1-30, wherein R4Ais C1-4 alkyl.

32. The compound of any one of claims 1-30, wherein R4Ais methyl.

33. The compound of any one of claims 1-30, wherein R4Ais -(C1.3 alkylene)-(oxazolyl substituted by 0 or 1 occurrences of C1-2 alkyl).

34. The compound of any one of claims 1-30, wherein R4Ais -(CH2)-(oxazolyl).

35. The compound of any one of claims 1-23, wherein36. The compound of any one of claims 1-23, wherein37. The compound of any one of claims 1-23, wherein39. The compound of any one of claims 1-23, wherein40. The compound of any one of claims 1-23, wherein42. The compound of any one of claims 1-41, wherein L is -(piperidinylene)-(C1-4alkylene)-O- *** or -(piperidinylene)-O-(C2-4 alkylene)-O-***, wherein *** is the point of attachment to A2.

43. The compound of any one of claims 1-41, wherein L is an 8-11 membered spirocyclic, saturated heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclic ring is substituted with 0, 1, or 2 occurrences of fluoro.

44. The compound of any one of claims 1-41, wherein L is -(8-10 membered spirocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-O-*** or - (8-10 membered spirocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C1-4 alkylene)-***, wherein *** is the point of attachment to A2.

45. The compound of any one of claims 1-41, wherein L is -(7-8 membered spirocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C2-4 alkynylene)- ***, wherein *** is the point of attachment to A2.

46. The compound of any one of claims 1-41, wherein L is a 7-9 membered fused bicyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen, wherein the heterocyclic ring is substituted by 1 or 2 occurrences of fluoro.

47. The compound of any one of claims 1-41, wherein L is l,2,3,5-tetrahydropyrrolo[3,4- c]pyrrolylene.

48. The compound of any one of claims 1-41, wherein L is -(azetidinylene)-(Ci-4 alkylene)- (azetidinylene)-.

49. The compound of any one of claims 1-41, wherein L is one of the following, wherein *** is the point of attachment to A2:

50. The compound of any one of claims 1-41, wherein L is one of the following, wherein *** is the point of attachment to A2:51 . The compound of any one of claims 1-41, wherein L is one of the following, wherein *** is the point of attachment to A2:

52. The compound of any one of claims 1-41, wherein L is one of the following, wherein *** is the point of attachment to A2:

53. The compound of any one of claims 1-41, wherein L is one of the following, wherein *the point of attachment to A2:

54. A compound in Table 1 or 2, or a pharmaceutically acceptable salt thereof.

55. A pharmaceutical composition comprising a compound of any one of claims 1-54 and a pharmaceutically acceptable carrier.

56. A method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-54 to treat the cancer.

57. The method of claim 56, wherein the cancer is ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland carcinoma, bile duct cancer, gallbladder cancer, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma, or leukemia.

58. The method of claim 56, wherein the cancer is prostate cancer.

59. A method of causing death of a cancer cell, comprising contacting a cancer cell with an effective amount of a compound of any one of claims 1-54 to cause death of the cancer cell.

60. The method of claim 59, wherein the cancer cell is selected from an ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland carcinoma, bile duct cancer, gallbladder cancer, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, lymphoma, or leukemia cell.

61. The method of claim 59, wherein the cancer cell is a prostate cancer cell.